本文提供以結合至191P4D12蛋白質(連接素(Nectin)-4)之抗體藥物結合物(antibody drug conjugate，ADC)來治療癌症之方法。特定言之，本文提供以結合至191P4D12蛋白質之抗體藥物結合物(ADC)組合派姆單抗(pembrolizumab)治療不能接受基於順鉑(cisplatin)之化學療法的不可切除性局部晚期或轉移性尿路上皮癌之患者之方法。Provided herein are methods for treating cancer using an antibody drug conjugate (ADC) that binds to the 191P4D12 protein (Nectin-4). Specifically, provided herein are methods for treating patients with unresectable locally advanced or metastatic urothelial carcinoma who are unable to receive cisplatin-based chemotherapy using an antibody drug conjugate (ADC) that binds to the 191P4D12 protein in combination with pembrolizumab.
癌症為美國35歲至65歲人群的主要死亡原因，且其為全世界第二主要死亡原因。據估計，2019年美國存在約170萬例新癌症病例及約610000例癌症死亡(美國國家癌症研究所(National Cancer Institute). 2019. Cancer Stat Facts: Cancer of Any Site. seer.cancer.gov/statfacts/html/all.html. 2019年6月5日存取)。在全球範圍內，估計2018年存在1810萬例新癌症病例且2018年存在約960萬例歸因於癌症的死亡(世界衛生組織(World Health Organization)，2018年9月新聞稿，who.int/cancer/PRGlobocanFinal.pdf，2019年6月5日存取)。現在大多數的死亡發生於轉移性癌症之患者。實際上，在過去20年中，治療(包括手術、放射治療及輔助化學療法)之進步治癒了大部分局部癌症之患者。就總存活期(OS)而言，癌症表現為或者復發為轉移性疾病的患者僅從常規療法獲得不大的益處，且很少有治癒。Cancer is the leading cause of death among people aged 35 to 65 in the United States, and it is the second leading cause of death worldwide. It is estimated that there were approximately 1.7 million new cancer cases and approximately 610,000 cancer deaths in the United States in 2019 (National Cancer Institute. 2019. Cancer Stat Facts: Cancer of Any Site. seer.cancer.gov/statfacts/html/all.html. Accessed on June 5, 2019). Globally, there were an estimated 18.1 million new cancer cases and approximately 9.6 million deaths attributed to cancer in 2018 (World Health Organization, September 2018 press release, who.int/cancer/PRGlobocanFinal.pdf, accessed on June 5, 2019). Most deaths now occur in patients with metastatic cancer. In fact, over the past 20 years, advances in treatment (including surgery, radiation therapy, and adjuvant chemotherapy) have cured most patients with localized cancer. Patients whose cancer manifests as or recurs as metastatic disease receive only modest benefit from conventional therapies in terms of overall survival (OS), and few are cured.
針對晚期及/或轉移性癌症之新治療策略包括靶向對癌細胞存活重要之分子路徑及新穎細胞毒性化合物。此等新穎藥物之益處反映在延長了存活期；然而，大部分有遠端轉移之患者的結果仍然很差，且需要新穎療法。New therapeutic strategies for advanced and/or metastatic cancers include targeting molecular pathways important for cancer cell survival and novel cytotoxic compounds. The benefit of these novel drugs is reflected in prolonged survival; however, the outcome for the majority of patients with distant metastases remains poor and novel therapies are needed.
191P4D12 (其亦稱為連接素-4)為一種66 kDa的I型跨膜蛋白，屬於黏附分子之連接素家族。其由含有3個類免疫球蛋白(Ig)子域之胞外域(ECD)、跨膜螺旋及胞內區域構成(Takai等人, Annu Rev Cell Dev Biol (2008); 24: 309-42)。認為連接素經由黏著連接(adherens junction)處的嗜同性與嗜異性反式相互作用介導Ca2+非依賴性細胞-細胞黏附，在該等黏著連接處其可募集鈣黏蛋白(cadherin)且調節細胞骨架重排(Rikitake等人, Cell Mol Life Sci (2008); 65(2): 253-63.)。連接素-4與其他連接素家族成員的序列一致性較低，且在ECD中，該序列一致性的範圍在25%-30%之間(Reymond等人, Biol Chem (2001); 276(46): 43205-15)。191P4D12 (also known as nectin-4) is a 66 kDa type I transmembrane protein that belongs to the nectin family of adhesion molecules. It consists of an extracellular domain (ECD) containing three immunoglobulin (Ig)-like subdomains, a transmembrane helix, and an intracellular region (Takai et al., Annu Rev Cell Dev Biol (2008); 24: 309-42). Nexins are believed to mediateCa2+ -independent cell-cell adhesion via homophilic and heterophilic trans interactions at adherens junctions, where they can recruit cadherin and regulate cytoskeletal rearrangements (Rikitake et al., Cell Mol Life Sci (2008); 65(2): 253-63.). The sequence identity of nectin-4 to other nectin family members is low, and in the ECD, the sequence identity ranges from 25% to 30% (Reymond et al., Biol Chem (2001); 276(46): 43205-15).
連接素-4之ECD中的3個類Ig子域稱為V、C1及C2。C1域負責順式相互作用(均二聚)，而大部分連接素分子的V域促成反式相互作用及細胞-細胞黏附(Mandai等人, Curr Top Dev Biol (2015);112: 197-231；Takai等人, Nat Rev Mol Cell Biol (2008); 9(8): 603-15.)。The three Ig-like subdomains in the ECD of nectin-4 are called V, C1, and C2. The C1 domain is responsible for cis interactions (homodimerization), while the V domain of most nectin molecules contributes to trans interactions and cell-cell adhesion (Mandai et al., Curr Top Dev Biol (2015); 112: 197-231; Takai et al., Nat Rev Mol Cell Biol (2008); 9(8): 603-15.).
連接素-4最初係根據生物資訊學鑑別且自人類氣管中選殖(Reymond等人, J Biol Chem (2001) 276(46): 43205-15.)。藉由對尿路上皮癌試樣池使用抑制消減雜交術而鑑別出連接素-4在尿路上皮癌中明顯上調。在核糖核酸(RNA)層面上及根據免疫組織化學(IHC)對多個腫瘤試樣中之表現進行的表徵亦展現出，乳癌、胰臟癌、肺癌及其他癌症中存在較高水平的連接素-4 (Challita-Eid等人, Cancer Res (2016); 76(10): 3003-13.)。NEC-4 was originally identified bioinformatically and cloned from human trachea (Reymond et al., J Biol Chem (2001) 276(46): 43205-15.). NEC-4 was identified as being significantly upregulated in urothelial carcinoma using suppression subtractive hybridization of a pool of urothelial carcinoma samples. Characterization of expression in multiple tumor samples at the RNA level and by immunohistochemistry (IHC) also demonstrated elevated levels of NEC-4 in breast, pancreatic, lung, and other cancers (Challita-Eid et al., Cancer Res (2016); 76(10): 3003-13.).
已發現，連接素-4表現於多種癌症中，特定言之，尿路上皮癌、乳癌、肺癌、胰臟癌及卵巢癌。較高的表現量與疾病惡化及/或不良預後相關(Fabre-Lafay等人, BMC Cancer (2007); 7: 73)。It has been found that nectin-4 is expressed in a variety of cancers, specifically urothelial, breast, lung, pancreatic, and ovarian cancers. Higher expression levels are associated with disease progression and/or poor prognosis (Fabre-Lafay et al., BMC Cancer (2007); 7: 73).
PD-1PD-1
PD-1被視為免疫調節及周邊耐受性維持中的重要分子。PD-1在初始T、B及NKT細胞上中度表現且藉由淋巴球、單核球及骨髓細胞上之T/B細胞受體信號傳導而上調(Sharpe, Arlene H.等人, The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection.NatureImmunology(2007); 8:239-245)。PD-1 is considered an important molecule in immune regulation and peripheral tolerance maintenance. PD-1 is moderately expressed on naive T, B and NKT cells and is upregulated by T/B cell receptor signaling on lymphocytes, monocytes and bone marrow cells (Sharpe, Arlene H. et al., The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection.NatureImmunology (2007); 8:239-245).
PD-1之兩種已知配位體PD-L1 (B7-H1)及PD-L2 (B7-DC)在各種組織中出現的人類癌症中表現。在例如卵巢癌、腎癌、結腸直腸癌、胰臟癌、肝癌及黑色素瘤之大樣本集中，顯示PD-L1表現與不良預後相關，且與後續治療無關地縮短總存活期(Dong, Haidong等人, Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002年8月;8(8):793-800；Yang, Wanhua等人, PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro.Invest Ophthalmol Vis Sci. 2008年6月; 49(6 (2008): 49: 2518-2525；Ghebeh, Hazem等人, The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors.Neoplasia(2006) 8: 190-198；Hamanishi, Junzo等人, Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer.Proc. Natl. Acad. Sci. USA(2007): 104: 3360-3365；Thompson, R Houston及Eugene D Kwon, Significance of B7-H1 overexpression in kidney cancer. Clinical genitourinCancer(2006): 5: 206-211；Nomi, Takeo等人, Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer.Clinical Cancer Research(2007);13:2151-2157；Ohigashi, Yuichiro等人, Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand 2 expression in human esophageal cancer.Clin. Cancer Research(2005): 11: 2947-2953；Inman, Brant A等人, PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression.Cancer(2007): 109: 1499-1505；Shimauchi, Takatoshi等人, Augmented expression of programmed death-1 in both neoplasmatic and nonneoplastic CD4+ T-cells in adult T-cell Leukemia/ Lymphoma.Int. J. Cancer(2007): 121:2585-2590；Gao, Qiang等人, Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma.Clinical Cancer Research(2009) 15: 971-979；Nakanishi, Juro等人, Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers.Cancer Immunol Immunother. (2007) 56: 1173-1182；Hino等人, Tumor cell expression of programmed cell death-1 is a prognostic factor for malignant melanoma.Cancer(2010): 00: 1-9)。類似地，發現腫瘤浸潤性淋巴球上之PD-1表現標記乳癌及黑色素瘤中之功能異常T細胞(Ghebeh, Hazem等人, Foxp3+ tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: implication for immunotherapy.BMC Cancer. 2008年2月23日;8:57；Ahmadzadeh, Mojgan等人, Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired.Blood(2009) 114: 1537-1544)且與腎癌之不良預後相關(Thompson, R Houston等人, PD-1 is expressed by tumor infiltrating cells and is associated with poor outcome for patients with renal carcinoma.Clinical Cancer Research(2007) 15: 1757-1761)。因此，已提出表現PD-L1之腫瘤細胞與表現PD-1之T細胞相互作用以減弱T細胞活化且逃避免疫監視，藉此導致針對腫瘤之免疫反應減弱。Two known ligands of PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers arising in various tissues. In large sample sets of ovarian cancer, kidney cancer, colorectal cancer, pancreatic cancer, liver cancer, and melanoma, PD-L1 expression was shown to be associated with poor prognosis and shortened overall survival regardless of subsequent treatment (Dong, Haidong et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002 Aug;8(8):793-800; Yang, Wanhua et al., PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro.Invest Ophthalmol Vis Sci . 2008 Jun; 49(6 (2008): 49: 2518-2525; Ghebeh, Hazem et al., The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in 247 cells of the umbilical cord and 104% of the umbilical cord. in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors.Neoplasia (2006) 8: 190-198；Hamanishi, Junzo et al., Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer.Proc. Natl. Acad. Sci. USA (2007): 104: 3360-3365；Thompson, R Houston and Eugene D Kwon, Significance of B7-H1 overexpression in kidney cancer. Clinical genitourinCancer (2006): 5: 206-211；Nomi, Takeo et al., Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer.Clinical Cancer Research (2007);13:2151-2157；Ohigashi, Yuichiro et al., Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand 2 expression in human esophageal cancer.Clin. Cancer Research (2005): 11: 2947-2953；Inman, Brant A et al., PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression.Cancer (2007): 109: 1499-1505；Shimauchi, Takatoshi et al., Augmented expression of programmed death-1 in both neoplasmatic and nonneoplastic CD4+ T-cells in adult T-cell Leukemia/ Lymphoma.Int. J. Cancer (2007): 121:2585-2590；Gao, Qiang et al., Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma.Clinical Cancer Research (2009) 15: 971-979；Nakanishi, Juro et al., Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers.Cancer Immunol Immunother . (2007) 56: 1173-1182；Hino et al., Tumor cell expression of programmed cell death-1 is a prognostic factor for malignant melanoma.Cancer (2010): 00: 1-9）. Similarly, PD-1 expression on tumor-infiltrating lymphocytes was found to mark functionally abnormal T cells in breast cancer and melanoma (Ghebeh, Hazem et al., Foxp3+ tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: implication for immunotherapy.BMC Cancer . 2008 Feb 23;8:57; Ahmadzadeh, Mojgan et al., Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired.Blood (2009) 114: 1537-1544) and is associated with poor prognosis in renal cancer (Thompson, R Houston et al., PD-1 is expressed by tumor infiltrating cells and is associated with poor outcome for patients with renal carcinoma.Clinical Cancer Research (2007) 15: 1757-1761). Therefore, it has been proposed that tumor cells expressing PD-L1 interact with T cells expressing PD-1 to attenuate T cell activation and evade immune surveillance, thereby resulting in a weakened immune response against the tumor.
抑制PD-1與其配位體PD-L1及PD-L2中之一或兩者之間的相互作用的若干單株抗體已批准用於治療癌症。派姆單抗(KEYTRUDA®, Merck & Co., Inc., Rahway, NJ, USA)係一種強效人源化免疫球蛋白G4 (IgG4) mAb，其具有與計劃性細胞死亡1 (PD-1)受體結合之高特異性，由此抑制該受體與計劃性細胞死亡配位體1 (PD-L1)及計劃性細胞死亡配位體2 (PD-L2)的相互作用。基於臨床前活體外資料，派姆單抗對PD-1具有高親和力及強效受體阻斷活性。Keytruda® (派姆單抗)適用於治療多種適應症之患者，且適用於高度微衛星不穩定性或錯配修復缺陷(microsatellite instability-high or mismatch repair deficient，MSI-H/dMMR)的不可切除性或轉移性CRC之患者的一線治療。派姆單抗為一線MSI-H/dMMR mCRC之當前標準照護療法。Several monoclonal antibodies that inhibit the interaction between PD-1 and one or both of its ligands PD-L1 and PD-L2 have been approved for the treatment of cancer. Pembrolizumab (KEYTRUDA®, Merck & Co., Inc., Rahway, NJ, USA) is a potent humanized immunoglobulin G4 (IgG4) mAb that has high specificity for binding to the programmed cell death 1 (PD-1) receptor, thereby inhibiting the interaction of the receptor with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity for PD-1 and potent receptor blocking activity. Keytruda® (pembrolizumab) is indicated for the treatment of patients across multiple indications and is indicated as first-line treatment for patients with unresectable or metastatic CRC that is microsatellite instability-high or mismatch repair deficient (MSI-H/dMMR). Pembrolizumab is the current standard of care for first-line MSI-H/dMMR mCRC.
尿路上皮癌Urothelial carcinoma
根據國際癌症研究機構(International Agency for Research on Cancer，IARC)，每年有超過165000名患者死於尿路上皮癌，且尿路上皮癌為全世界第九大常見癌症。歐洲每年診斷出約151000例新的尿路上皮癌病例，且每年有52000例死亡。日本每年診斷出逾22000例新病例，且每年有7600例死亡(Cancer Fact Sheets: All cancers excluding Non-Melanoma Skin，國際癌症研究機構2017年，自gco.iarc.fr/today/fact-sheets- cancers?cancer=29&type=0&sex=0擷取，2017年12月19日存取)。在美國，國家癌症研究所估計2017年診斷出超過79,000例新的膀胱癌病例，且超過16,800人死於該病(國家癌症研究所2018年)。According to the International Agency for Research on Cancer (IARC), more than 165,000 patients die from urothelial cancer each year, and urothelial cancer is the ninth most common cancer in the world. Approximately 151,000 new cases of urothelial cancer are diagnosed each year in Europe, with 52,000 deaths each year. In Japan, more than 22,000 new cases are diagnosed each year, with 7,600 deaths each year (Cancer Fact Sheets: All cancers excluding Non-Melanoma Skin, International Agency for Research on Cancer, 2017, retrieved from gco.iarc.fr/today/fact-sheets-cancers?cancer=29&type=0&sex=0, accessed on December 19, 2017). In the United States, the National Cancer Institute estimates that more than 79,000 new cases of bladder cancer were diagnosed in 2017, and more than 16,800 people died from the disease (National Cancer Institute 2018).
轉移性尿路上皮癌之5年死亡率為約85% (美國癌症協會(American Cancer Society，ACS) 2016年)。The 5-year mortality rate for metastatic urothelial carcinoma is approximately 85% (American Cancer Society (ACS) 2016).
尿路上皮癌為膀胱癌的最常見類型(90%病例)，且亦可發現於腎盂(腎臟內的尿液收集於此)、輸尿管(連接腎臟與膀胱的管)及尿道襯裡的尿路上皮細胞中。Urothelial carcinoma is the most common type of bladder cancer (90% of cases) and can also be found in the urothelial cells lining the renal pelvis (where urine collects in the kidneys), ureters (the tubes that connect the kidneys to the bladder), and the urethra.
針對具有足夠腎功能之患者的轉移性尿路上皮癌之一線療法由基於順式-二胺二氯鉑(II) (順鉑)之組合，如甲胺喋呤(methotrexate)、長春鹼(vinblastine)、小紅莓(doxorubicin)及順鉑(MVAC)或吉西他濱(gemcitabine)加順鉑組成，其展現高達55%之客觀反應率(ORR)，包括約12%完全反應(CR) (von der Maase 2000)。儘管最初存在化學敏感性，但患者未被治癒，且轉移性尿路上皮癌在此等方案之後的結果不良：中值惡化時間為7個月且中值總存活期(OS)為14個月。長期存活率不良(約15%)，且對於內臟轉移之患者，預後尤其嚴峻，該等患者之五年存活率為7% (von der Maase 2005；Bellmunt 2011)。One-line therapy for metastatic urothelial carcinoma in patients with adequate renal function consists of cis-diaminedichloroplatinum(II) (cisPu)-based combinations such as methotrexate, vinblastine, doxorubicin, and cisPu (MVAC) or gemcitabine plus cisPu, which demonstrate objective response rates (ORRs) up to 55%, including approximately 12% complete responses (CR) (von der Maase 2000). Despite initial chemosensitivity, patients are not cured, and metastatic urothelial carcinoma has poor outcomes following these regimens: median time to progression is 7 months and median overall survival (OS) is 14 months. Long-term survival is poor (approximately 15%) and is particularly severe for patients with visceral metastases, for whom the five-year survival rate is 7% (von der Maase 2005; Bellmunt 2011).
幾乎一半的尿路上皮癌患者由於腎功能受損、體能狀態不佳或共生病症而不適於含有順鉑的化學療法(Dash等人, Cancer (2006);107(3): 506-13)。在此等患者中，尚未確定標準一線治療，但當前選項通常包括基於順式-二胺(環丁烷1,1二羧根基)鉑(卡鉑(carboplatin))之方案或單藥劑紫杉烷或吉西他濱(Cathomas 2015)。在此情況下，長期存活率甚至更低(De Santis等人, J Clin Oncol (2009); 27(33): 5634-9)。2017年4月，美國食品及藥物管理局(Food and Drug Administration，FDA)批准抗計劃性死亡-配位體1(PD-L1)免疫檢查點抑制劑(CPI)阿特珠單抗(atezolizumab) (TECENTRIQ®)作為不適合順鉑之局部晚期或轉移性尿路上皮癌(la/mUC)患者的一線治療。加速批准係基於開放標記單組研究，該研究展示較長的反應持續時間，表明在此難治性群體中存在活性，其中客觀反應率(ORR)為23%，此在不同的目標表現量中相似(Balar 2017)。此等患者的中值OS為15.9個月，但此研究為單組研究，且任何OS益處均需要在隨機經驗中得到證實(Balar等人, Lancet (2017); 389(10064): 67-76)。Almost half of patients with urothelial carcinoma are not suitable for cis-platinum-containing chemotherapy due to impaired renal function, poor performance status, or comorbidities (Dash et al., Cancer (2006); 107(3): 506-13). In these patients, standard first-line treatment has not been established, but current options generally include cis-diamine (cyclobutane 1,1 dicarboxylate) platinum (carboplatin)-based regimens or single-agent taxanes or gemcitabine (Cathomas 2015). In this setting, long-term survival is even lower (De Santis et al., J Clin Oncol (2009); 27(33): 5634-9). In April 2017, the U.S. Food and Drug Administration (FDA) approved the anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor (CPI) atezolizumab (TECENTRIQ®) as a first-line treatment for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who are ineligible for cisplatin. The accelerated approval was based on an open-label, single-arm study that demonstrated prolonged duration of response, indicating activity in this refractory population, with an objective response rate (ORR) of 23%, which was similar across target expression levels (Balar 2017). The median OS for these patients was 15.9 months, but this study was a single-arm study and any OS benefit needs to be confirmed in a randomized experience (Balar et al., Lancet (2017); 389(10064): 67-76).
2017年5月，派姆單抗(Keytruda®)被FDA加速批准作為不適合順鉑之la/mUC患者的一線治療。批准所基於之研究產生29%之ORR且在分析時未達到中值反應持續時間(中值隨訪時間為7.8個月) (派姆單抗處方資訊，Merck Sharp and Dohme Corp., 2017)。2018年5月，FDA發出警示，此係關於與基於鉑之化學療法相比，在一線情況下以派姆單抗或阿特珠單抗治療的具有低PD-L1表現之患者的存活率降低。隨後，此兩種CPI之處方資訊經修訂，要求適合含鉑化學療法之一線轉移性尿路上皮癌患者具有高PD-L1表現。此發展進一步限制了具有低PD-L1表現之轉移性尿路上皮癌患者的選項。In May 2017, pembrolizumab (Keytruda®) was granted accelerated approval by the FDA as a first-line treatment for patients with la/mUC who are not eligible for cisplatin. The study on which the approval was based produced an ORR of 29% and the median duration of response had not been reached at the time of analysis (median follow-up was 7.8 months) (Pembrolizumab Prescribing Information, Merck Sharp and Dohme Corp., 2017). In May 2018, the FDA issued an alert regarding decreased survival in patients with low PD-L1 expression treated with pembrolizumab or atezolizumab in the first-line setting compared with platinum-based chemotherapy. Subsequently, the prescribing information for these two CPIs was revised to require high PD-L1 expression in patients with metastatic urothelial carcinoma who are eligible for first-line platinum-containing chemotherapy. This development further limits options for patients with metastatic urothelial carcinoma with low PD-L1 expression.
不適合一線順鉑之患者的其他選項通常包括基於卡鉑之方案或單藥劑紫杉烷或吉西他濱(Cathomas等人, Hematol Oncol Clin North Am (2015); 29(2): 329-40)。Other options for patients who are not suitable for first-line cisplatin generally include carboplatin-based regimens or single-agent taxanes or gemcitabine (Cathomas et al., Hematol Oncol Clin North Am (2015); 29(2): 329-40).
可供轉移性疾病之二線治療使用的選項極少。在歐盟，小分子微管蛋白抑制劑長春氟寧(vinflunine) (Javlor®)基於其適度的活性(總反應率9%)、2個月的中度存活益處(長春氟寧+最佳支持性照護(BSC)為6.9個月，而單獨BSC為4.6個月，危險比0.88)及有利的安全概況而於2009年獲得授權(Bellmunt等人, Clin Oncol (2009); 27(27): 4454-61)。2016年5月，FDA加速批准了阿特珠單抗在美國作為la/mUC之繼鉑劑之後的第一補救療法，此療法隨後在2017年9月獲得歐盟批准。2017年2月，納武單抗(nivolumab) (Opdivo®)成為獲得FDA加速批准的第二免疫療法，此療法隨後在2017年6月獲得歐盟批准。2017年3月及5月，FDA分別授予阿維魯單抗(avelumab) (Bavencio®)及德瓦魯單抗(durvalumab) (ImfinziTM)加速批准，此兩種PD-L1阻斷抗體適用於治療局部晚期或轉移性尿路上皮癌患者，該等患者在含鉑化學療法期間或之後疾病出現惡化，或在使用含鉑化學療法的前輔助(neoadjuvant)或輔助治療的12個月內疾病出現惡化。2017年5月，派姆單抗被FDA常規批准作為二線治療(吉舒達(Keytruda)處方資訊，Merck，2017年5月)。該批准係基於首次在局部晚期或轉移性鉑後尿路上皮癌情況下針對CPI報導的隨機經驗，此係一項在542名患者中進行的3期研究，顯示出OS為10.3個月，而相比之下，紫杉烷化學療法或長春氟寧的OS為7.4個月。另外，派姆單抗的ORR為21%，而化學療法的ORR為11%。在兩個組之間，未觀測到無惡化存活期(PFS)存在統計學顯著差異(Bellmunt等人, N Engl J Med (2017);376(11): 1015-26)。針對相同適應症，2017年9月獲得歐盟批准且2018年1月獲得日本批准。其他計劃性細胞死亡蛋白1 (PD-1)及PD-L1抑制劑目前正在尿路上皮癌的臨床試驗中作為一線及二線療法接受評估(Mullane等人, Curr Opin Urol (2016);26(6): 556-63)。Few options are available for second-line treatment of metastatic disease. In the European Union, the small molecule tubulin inhibitor vinflunine (Javlor®) was licensed in 2009 based on its modest activity (overall response rate 9%), a modest survival benefit of 2 months (6.9 months for vinflunine plus best supportive care (BSC) versus 4.6 months for BSC alone, hazard ratio 0.88), and a favorable safety profile (Bellmunt et al., Clin Oncol (2009); 27(27): 4454-61). In May 2016, the FDA granted accelerated approval to atezolizumab as the first rescue therapy after platinum for la/mUC in the United States, and the therapy was subsequently approved by the EU in September 2017. In February 2017, nivolumab (Opdivo®) became the second immunotherapy to receive accelerated approval from the FDA, and the therapy was subsequently approved by the EU in June 2017. In March and May 2017, the FDA granted accelerated approval to avelumab (Bavencio®) and durvalumab (Imfinzi™ ), two PD-L1 blocking antibodies, for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant therapy with platinum-containing chemotherapy. In May 2017, pembrolizumab was routinely approved by the FDA as a second-line treatment (Keytruda Prescribing Information, Merck, May 2017). The approval was based on the first reported randomized experience with CPI in locally advanced or metastatic post-platinum urothelial carcinoma, a phase 3 study in 542 patients that showed an OS of 10.3 months compared with 7.4 months with taxane chemotherapy or vinflunine. In addition, the ORR was 21% with pembrolizumab compared with 11% with chemotherapy. No statistically significant difference in progression-free survival (PFS) was observed between the two groups (Bellmunt et al., N Engl J Med (2017);376(11):1015-26). Approval was obtained in the EU in September 2017 and in Japan in January 2018 for the same indication. Other planned cell death protein 1 (PD-1) and PD-L1 inhibitors are currently being evaluated in clinical trials for urothelial carcinoma as first- and second-line therapies (Mullane et al., Curr Opin Urol (2016);26(6):556-63).
雖然CPI為治療轉移性尿路上皮癌提供了一種新方法，但少數患者發生腫瘤反應且長期存活期僅延長幾個月。舉例而言，2017年5月，Roche宣佈二線阿特珠單抗的驗證型3期試驗未能達到其OS主要終點(Roche新聞稿「Roche provides update on phase III study of Tecentriq (atezolizumab) in people with previously treated advanced bladder cancer」，2017年5月10日)。大多數局部晚期或轉移性尿路上皮癌患者對CPI無反應且許多有反應的患者最終出現疾病惡化(Rosenberg等人, Lancet (2016); 387(10031): 1909-20)。仍然需要新穎的治療，尤其是對CPI尚無反應或在CPI療法後已惡化的患者。Although CPIs offer a new approach to treating metastatic urothelial cancer, tumor responses occur in a minority of patients and long-term survival is extended by only a few months. For example, in May 2017, Roche announced that a confirmatory phase III trial of second-line atezolizumab failed to meet its primary endpoint of OS (Roche press release “Roche provides update on phase III study of Tecentriq (atezolizumab) in people with previously treated advanced bladder cancer,” May 10, 2017). Most patients with locally advanced or metastatic urothelial cancer do not respond to CPIs and many who do respond eventually experience disease progression (Rosenberg et al., Lancet (2016); 387(10031): 1909-20). Novel treatments are still needed, especially for patients who have not responded to CPIs or have worsened after CPI therapy.
缺乏批准用於轉移性尿路上皮癌患者的一線療法，且在二線化學療法情況下觀測到的活性有限，充分證明了此群體之醫療需求仍亟待滿足。The lack of approved first-line therapies for patients with metastatic urothelial carcinoma and the limited activity observed with second-line chemotherapy underscore the high unmet medical need in this population.
膀胱癌Bladder Cancer
在美國所有新的癌症病例中，膀胱癌在男性中佔約5% (第五大常見贅瘤)且在女性中佔約3% (第八大常見贅瘤)。隨著老年人口增加，發病率正緩慢增加。美國癌症協會(cancer.org)估計每年新增81,400例病例，包括男性62,100例及女性19,300例，在所有癌症病例中佔4.5%。在美國，男性及女性按年齡調整的發病率為20/100,000。估計每年因膀胱癌死亡17,980例(男性13,050例及女性4,930例)，佔癌症相關死亡數的3%。膀胱癌發病率及死亡率隨著年齡增加而大幅度增加，且隨著人口老年化加劇將成為日益嚴重的問題。在全球範圍內，2020年約580,000人將被診斷患有膀胱癌，且膀胱癌在全世界範圍內將造成約210,000例死亡。Bladder cancer accounts for approximately 5% of all new cancer cases in the United States in men (the fifth most common tumor) and approximately 3% in women (the eighth most common tumor). The incidence is slowly increasing as the elderly population increases. The American Cancer Society (cancer.org) estimates that there are 81,400 new cases each year, including 62,100 cases in men and 19,300 cases in women, accounting for 4.5% of all cancer cases. The age-adjusted incidence rate in the United States is 20 per 100,000 men and women. An estimated 17,980 deaths from bladder cancer occur each year (13,050 in men and 4,930 in women), accounting for 3% of cancer-related deaths. Bladder cancer incidence and mortality rates increase significantly with age and will become an increasingly serious problem as the population ages. Globally, approximately 580,000 people will be diagnosed with bladder cancer in 2020, and bladder cancer will cause an estimated 210,000 deaths worldwide.
大部分膀胱癌在膀胱中復發。膀胱癌係藉由膀胱之經尿道切除(TUR)與膀胱內化學療法或免疫療法之組合來管控。膀胱癌之多病灶及復發性質指出了TUR之侷限性。單獨的TUR無法治癒大部分肌肉侵襲性癌症。根治性膀胱切除術及尿路分流術為消除癌症的最有效手段，但對泌尿及性功能產生不可否認的影響。對有益於膀胱癌患者之治療模式繼續存在相當大的需求。Most bladder cancers recur in the bladder. Bladder cancer is managed by a combination of transurethral resection (TUR) of the bladder and intravesical chemotherapy or immunotherapy. The multifocal and recurrent nature of bladder cancer points to the limitations of TUR. TUR alone cannot cure most muscle-invasive cancers. Radical cystectomy and urinary diversion are the most effective means of eliminating the cancer, but have an undeniable impact on urinary and sexual function. There continues to be a significant need for treatment modalities that benefit patients with bladder cancer.
對尿路上皮癌及膀胱癌之額外治療方法存在相當大的需求。此等包括使用抗體及抗體藥物結合物，包括組合其他藥劑作為治療模式。There is a significant need for additional treatment approaches for urothelial carcinoma and bladder cancer. These include the use of antibodies and antibody-drug conjugates, including in combination with other agents as treatment modalities.
本文提供用於治療人類個體之多種癌症之方法，包括用於以結合至191P4D12蛋白質之抗體藥物結合物(ADC)組合派姆單抗治療不能接受基於順鉑之化學療法的不可切除性局部晚期或轉移性尿路上皮癌之患者之方法。Provided herein are methods for treating a variety of cancers in human subjects, including methods for treating patients with unresectable locally advanced or metastatic urothelial carcinoma who are unable to receive cisplatin-based chemotherapy with an antibody drug conjugate (ADC) that binds to the 191P4D12 protein in combination with pembrolizumab.
在某些實施例中，經本文所提供之方法治療之人類個體不適合接受順鉑治療且先前未接受免疫檢查點抑制劑(CPI) (例如，PD-1抑制劑、PD-L1抑制劑或PD-L2抑制劑(包括(但不限於)阿特珠單抗、派姆單抗、納武單抗、德瓦魯單抗或阿維魯單抗))治療。In certain embodiments, the human subject treated with the methods provided herein is not a candidate for cisplatin therapy and has not previously been treated with an immune checkpoint inhibitor (CPI), e.g., a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor (including but not limited to atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab).
實施例1. 一種治療人類個體之癌症之方法，其包含向該個體投與： (a)有效量之包含抗191P4D12抗體或其抗原結合片段之抗體藥物結合物(ADC)，及 (b)有效量之抗PD-1抗體； 其中該抗191P4D12抗體或其抗原結合片段結合至191P4D12且與單甲基奧瑞他汀E (monomethyl auristatin E，MMAE)之一或多個單元結合； 其中該抗PD-1抗體包含：(i)輕鏈可變區，其分別包含SEQ ID NO: 24、25及26之輕鏈CDR1、CDR2及CDR3；及(ii)重鏈可變區，其分別包含SEQ ID NO: 29、30及31之重鏈CDR1、CDR2及CDR3； 其中該抗191P4D12抗體或其抗原結合片段包含：重鏈可變區，其包含含有SEQ ID NO:22中所闡述之重鏈可變區之互補決定區(CDR)之胺基酸序列的CDR；及輕鏈可變區，其包含含有SEQ ID NO:23中所闡述之輕鏈可變區之CDR之胺基酸序列的CDR； 其中該個體患有尿路上皮癌或膀胱癌； 其中該個體尚未接受免疫檢查點抑制劑(CPI)療法；且 其中該個體不適合接受順鉑治療(不符合順鉑治療資格)。Example 1. A method for treating cancer in a human subject, comprising administering to the subject:(a) an effective amount of an antibody-drug conjugate (ADC) comprising an anti-191P4D12 antibody or an antigen-binding fragment thereof, and(b) an effective amount of an anti-PD-1 antibody;wherein the anti-191P4D12 antibody or an antigen-binding fragment thereof binds to 191P4D12 and to one or more units of monomethyl auristatin E (MMAE);wherein the anti-PD-1 antibody comprises: (i) a light chain variable region comprising light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 24, 25 and 26, respectively; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 29, 30 and 31, respectively;wherein the anti-191P4D12 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising a complementation determining region (CDR) comprising the amino acid sequence of the heavy chain variable region as described in SEQ ID NO:22; and a light chain variable region comprising a CDR comprising the amino acid sequence of the CDR of the light chain variable region as described in SEQ ID NO:23;wherein the individual suffers from urothelial carcinoma or bladder cancer;wherein the individual has not received immune checkpoint inhibitor (CPI) therapy; andwherein the individual is not suitable for cisplatin treatment (is not eligible for cisplatin treatment).
實施例2. 如實施例1之方法，其中該個體具有內臟轉移。Embodiment 2. The method of embodiment 1, wherein the subject has visceral metastasis.
實施例3. 如實施例1之方法，其中該個體具有僅淋巴結轉移疾病(lymph nodes only disease)。Embodiment 3. The method of Embodiment 1, wherein the individual has lymph nodes only disease.
實施例4. 如實施例1至3中任一項之方法，其中疾病起源部位在上泌尿道。Embodiment 4. A method as in any one of embodiments 1 to 3, wherein the origin of the disease is in the upper urinary tract.
實施例5. 如實施例1至3中任一項之方法，其中疾病起源部位在下泌尿道。Embodiment 5. The method of any one of Embodiments 1 to 3, wherein the origin of the disease is in the lower urinary tract.
實施例6. 如實施例1至5中任一項之方法，其中該個體具有大於或等於10之PD-L1表現綜合陽性評分(combined positive score，CPS)。Embodiment 6. The method of any one of Embodiments 1 to 5, wherein the individual has a PD-L1 expression combined positive score (CPS) greater than or equal to 10.
實施例7. 如實施例1至5中任一項之方法，其中該個體具有小於10之PD-L1表現CPS。Embodiment 7. The method of any one of Embodiments 1 to 5, wherein the individual has a PD-L1 expression CPS of less than 10.
實施例8. 如實施例1至6中任一項之方法，其中該個體具有0與300之間的連接素-4 H評分。Embodiment 8. The method of any one of Embodiments 1 to 6, wherein the individual has a nectin-4 H score between 0 and 300.
實施例9. 如實施例1至7中任一項之方法，其中該個體具有0與200之間的連接素-4 H評分。Embodiment 9. The method of any one of Embodiments 1 to 7, wherein the individual has a nectin-4 H score between 0 and 200.
實施例10. 如實施例1至9中任一項之方法，其中該個體具有1至2分的ECOG體能狀態。Embodiment 10. The method of any one of embodiments 1 to 9, wherein the individual has an ECOG performance status of 1 to 2.
實施例11. 如實施例1至9中任一項之方法，其中該個體具有一或多個選自由以下組成之群的條件：2分的ECOG體能狀態、腎功能受損及不小於2級的聽力損失。Embodiment 11. The method of any one of embodiments 1 to 9, wherein the individual has one or more conditions selected from the group consisting of: an ECOG performance status of 2, impaired renal function, and hearing loss of not less than grade 2.
實施例12. 如實施例1至9中任一項之方法，其中該個體具有NYHA III級心臟衰竭。Embodiment 12. The method of any one of embodiments 1 to 9, wherein the subject has NYHA class III heart failure.
實施例13. 如實施例11之方法，其中該個體具有2分的ECOG體能狀態，且 其中該個體(i)血紅素≥10 g/dL；(ii) GFR≥50 mL/min；及(iii)不具有NYHA III級心臟衰竭。Example 13. The method of Example 11, wherein the individual has an ECOG performance status of 2, and wherein the individual (i) has hemoglobin ≥ 10 g/dL; (ii) has GFR ≥ 50 mL/min; and (iii) does not have NYHA class III heart failure.
實施例14. 如實施例11之方法，其中該腎功能受損係由小於60 mL/min的肌酐清除率(CrCl)確定。Embodiment 14. The method of embodiment 11, wherein the impaired renal function is determined by a creatinine clearance (CrCl) of less than 60 mL/min.
實施例15. 如實施例11之方法，其中該腎功能受損係由小於60 mL/min但不小於30 mL/min的CrCl確定。Embodiment 15. The method of embodiment 11, wherein the impaired renal function is determined by CrCl less than 60 mL/min but not less than 30 mL/min.
實施例16. 如實施例11之方法，其中該腎功能受損係由小於30 mL/min但不小於15 mL/min的CrCl確定。Embodiment 16. The method of embodiment 11, wherein the impaired renal function is determined by a CrCl of less than 30 mL/min but not less than 15 mL/min.
實施例17. 如實施例1至16中任一項之方法，其中該個體具有一或多個選自由以下組成之群的條件： (i)絕對嗜中性白血球計數不小於1500/µL； (ii)血小板計數不小於100,000/µL； (iii)血紅素不小於9 g/dL； (iv)血清膽紅素不超過1.5倍的正常值上限(ULN)或對於吉爾伯氏病(Gilbert's disease)患者不超過3倍ULN； (v) CrCl不小於30 mL/min，及 (vi)丙胺酸轉胺酶及天冬胺酸轉胺酶不超過3倍ULN。Embodiment 17. A method as in any one of embodiments 1 to 16, wherein the subject has one or more conditions selected from the group consisting of:(i) absolute neutrophil count is not less than 1500/µL;(ii) platelet count is not less than 100,000/µL;(iii) hemoglobin is not less than 9 g/dL;(iv) serum bilirubin is not more than 1.5 times the upper limit of normal (ULN) or not more than 3 times ULN for patients with Gilbert's disease;(v) CrCl is not less than 30 mL/min, and(vi) alanine transaminase and aspartate transaminase are not more than 3 times ULN.
實施例18. 如實施例17之方法，其中該個體具有實施例15之所有條件(i)至(vi)。Embodiment 18. The method of embodiment 17, wherein the subject has all of conditions (i) to (vi) of embodiment 15.
實施例19. 如實施例14至18中任一項之方法，其中該CrCl係藉由24小時尿液收集量測或藉由科克羅夫特-高爾特準則(Cockcroft-Gault criteria)估算。Embodiment 19. The method of any one of embodiments 14 to 18, wherein the CrCl is measured by 24-hour urine collection or estimated by Cockcroft-Gault criteria.
實施例20. 如實施例1至19中任一項之方法，其中該個體具有不超過2級的感覺或運動神經病變。Embodiment 20. The method of any one of embodiments 1 to 19, wherein the subject has no more than grade 2 sensory or motor neuropathy.
實施例21. 如實施例1至20中任一項之方法，其中該個體不具有活動性中樞神經系統轉移。Embodiment 21. The method of any one of embodiments 1 to 20, wherein the subject does not have active central nervous system metastasis.
實施例22. 如實施例1至21中任一項之方法，其中該個體不具有不可控的糖尿病。Embodiment 22. The method of any one of embodiments 1 to 21, wherein the individual does not have uncontrolled diabetes.
實施例23. 如實施例22之方法，其中該不可控的糖尿病係由血紅素A1c (HbA1c)不小於8%或HbA1c在7%與8%之間與不另說明的相關糖尿病症狀確定。Embodiment 23. The method of embodiment 22, wherein the uncontrolled diabetes is determined by hemoglobin A1c (HbA1c) not less than 8% or HbA1c between 7% and 8% and related diabetes symptoms not otherwise specified.
實施例24. 如實施例23之方法，其中該等相關糖尿病症狀包含以下或由以下組成：多尿症、煩渴症或多尿症及煩渴症兩者。Embodiment 24. The method of embodiment 23, wherein the relevant diabetic symptoms comprise or consist of polyuria, dysphoria, or both polyuria and dysphoria.
實施例25. 如實施例1至24中任一項之方法，其中該個體患有局部晚期或轉移性尿路上皮癌。Embodiment 25. The method of any one of embodiments 1 to 24, wherein the individual has locally advanced or metastatic urothelial carcinoma.
實施例26. 如實施例1至25中任一項之方法，其中該個體患有局部晚期或轉移性膀胱癌。Embodiment 26. The method of any one of embodiments 1 to 25, wherein the individual suffers from locally advanced or metastatic bladder cancer.
實施例27. 如實施例1至26中任一項之方法，其中該抗191P4D12抗體或其抗原結合片段包含：含有SEQ ID NO:9之胺基酸序列的CDR-H1、含有SEQ ID NO:10之胺基酸序列的CDR-H2、含有SEQ ID NO:11之胺基酸序列的CDR-H3；含有SEQ ID NO:12之胺基酸序列的CDR-L1、含有SEQ ID NO:13之胺基酸序列的CDR-L2及含有SEQ ID NO:14之胺基酸序列的CDR-L3，或 其中該抗191P4D12抗體或其抗原結合片段包含：含有SEQ ID NO:16之胺基酸序列的CDR-H1、含有SEQ ID NO:17之胺基酸序列的CDR-H2、含有SEQ ID NO:18之胺基酸序列的CDR-H3；含有SEQ ID NO:19之胺基酸序列的CDR-L1、含有SEQ ID NO:20之胺基酸序列的CDR-L2及含有SEQ ID NO:21之胺基酸序列的CDR-L3。Embodiment 27. The method of any one of Embodiments 1 to 26, wherein the anti-191P4D12 antibody or antigen-binding fragment thereof comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 9, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 10, CDR-H3 comprising the amino acid sequence of SEQ ID NO: 11; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 12, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 13, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 14, or wherein the anti-191P4D12 antibody or antigen-binding fragment thereof comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 16, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 17, CDR-H3 comprising the amino acid sequence of SEQ ID NO: 18; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 12, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 13, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 14. CDR-L1 containing the amino acid sequence of SEQ ID NO:19, CDR-L2 containing the amino acid sequence of SEQ ID NO:20, and CDR-L3 containing the amino acid sequence of SEQ ID NO:21.
實施例28. 如實施例1至26中任一項之方法，其中該抗191P4D12抗體或其抗原結合片段包含：由SEQ ID NO:9之胺基酸序列組成的CDR-H1、由SEQ ID NO:10之胺基酸序列組成的CDR-H2、由SEQ ID NO:11之胺基酸序列組成的CDR-H3；由SEQ ID NO:12之胺基酸序列組成的CDR-L1、由SEQ ID NO:13之胺基酸序列組成的CDR-L2及由SEQ ID NO:14之胺基酸序列組成的CDR-L3，或 其中該抗191P4D12抗體或其抗原結合片段包含：由SEQ ID NO:16之胺基酸序列組成的CDR-H1、由SEQ ID NO:17之胺基酸序列組成的CDR-H2、由SEQ ID NO:18之胺基酸序列組成的CDR-H3；由SEQ ID NO:19之胺基酸序列組成的CDR-L1、由SEQ ID NO:20之胺基酸序列組成的CDR-L2及由SEQ ID NO:21之胺基酸序列組成的CDR-L3。Embodiment 28. The method of any one of Embodiments 1 to 26, wherein the anti-191P4D12 antibody or antigen-binding fragment thereof comprises: CDR-H1 consisting of the amino acid sequence of SEQ ID NO: 9, CDR-H2 consisting of the amino acid sequence of SEQ ID NO: 10, CDR-H3 consisting of the amino acid sequence of SEQ ID NO: 11; CDR-L1 consisting of the amino acid sequence of SEQ ID NO: 12, CDR-L2 consisting of the amino acid sequence of SEQ ID NO: 13, and CDR-L3 consisting of the amino acid sequence of SEQ ID NO: 14, or wherein the anti-191P4D12 antibody or antigen-binding fragment thereof comprises: CDR-H1 consisting of the amino acid sequence of SEQ ID NO: 16, CDR-H2 consisting of the amino acid sequence of SEQ ID NO: 17, CDR-H3 consisting of the amino acid sequence of SEQ ID NO: 11; CDR-L1 consisting of the amino acid sequence of SEQ ID NO: 12, CDR-L2 consisting of the amino acid sequence of SEQ ID NO: 13, and CDR-L3 consisting of the amino acid sequence of SEQ ID NO: 14. CDR-H3 composed of the amino acid sequence of SEQ ID NO:18; CDR-L1 composed of the amino acid sequence of SEQ ID NO:19, CDR-L2 composed of the amino acid sequence of SEQ ID NO:20, and CDR-L3 composed of the amino acid sequence of SEQ ID NO:21.
實施例29. 如實施例1至28中任一項之方法，其中該抗191P4D12抗體或其抗原結合片段包含含有SEQ ID NO:22之胺基酸序列的重鏈可變區及含有SEQ ID NO:23之胺基酸序列的輕鏈可變區。Embodiment 29. The method of any one of embodiments 1 to 28, wherein the anti-191P4D12 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23.
實施例30. 如實施例1至29中任一項之方法，其中該抗191P4D12抗體包含：重鏈，其包含SEQ ID NO:7之第20個胺基酸(麩胺酸)至第466個胺基酸(離胺酸)範圍內的胺基酸序列；及輕鏈，其包含SEQ ID NO:8之第23個胺基酸(天冬胺酸)至第236個胺基酸(半胱胺酸)範圍內的胺基酸序列。Embodiment 30. The method of any one of Embodiments 1 to 29, wherein the anti-191P4D12 antibody comprises: a heavy chain comprising an amino acid sequence within the range of the 20th amino acid (glutamine) to the 466th amino acid (lysine) of SEQ ID NO:7; and a light chain comprising an amino acid sequence within the range of the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8.
實施例31. 如實施例1至30中任一項之方法，其中該抗191P4D12抗原結合片段為Fab、F(ab')2、Fv或scFv。Embodiment 31. The method of any one of embodiments 1 to 30, wherein the anti-191P4D12 antigen-binding fragment is Fab, F(ab')2 , Fv or scFv.
實施例32. 如實施例1至30中任一項之方法，其中該抗191P4D12抗體為完全人類抗體。Embodiment 32. The method of any one of embodiments 1 to 30, wherein the anti-191P4D12 antibody is a fully human antibody.
實施例33. 如實施例1至30及32中任一項之方法，其中該抗191P4D12抗體為IgG1且輕鏈為κ輕鏈。Embodiment 33. The method of any one of embodiments 1 to 30 and 32, wherein the anti-191P4D12 antibody is IgG1 and the light chain is a kappa light chain.
實施例34. 如實施例1至33中任一項之方法，其中該抗191P4D12抗體或其抗原結合片段係以重組方式產生。Embodiment 34. The method of any one of embodiments 1 to 33, wherein the anti-191P4D12 antibody or antigen-binding fragment thereof is produced recombinantly.
實施例35. 如實施例1至34中任一項之方法，其中該抗191P4D12抗體或抗原結合片段經由連接子與MMAE之各單元結合。Embodiment 35. The method of any one of embodiments 1 to 34, wherein the anti-191P4D12 antibody or antigen-binding fragment is conjugated to each unit of MMAE via a linker.
實施例36. 如實施例35之方法，其中該連接子為酶可裂解連接子，且其中該連接子與該抗體或其抗原結合片段之硫原子形成鍵結。Embodiment 36. The method of embodiment 35, wherein the linker is an enzyme-cleavable linker, and wherein the linker forms a bond with a sulfur atom of the antibody or antigen-binding fragment thereof.
實施例37. 如實施例35或36之方法，其中該連接子具有式：-Aa-Ww-Yy-；其中-A-為延伸子單元，a為0或1；-W-為胺基酸單元，w為0至12範圍內的整數；且-Y-為間隔子單元，y為0、1或2。Embodiment 37. A method as in Embodiment 35 or 36, wherein the linker has the formula: -Aa-Ww-Yy-; wherein -A- is a stretcher unit, a is 0 or 1; -W- is an amino acid unit, w is an integer in the range of 0 to 12; and -Y- is a spacer unit, y is 0, 1 or 2.
實施例38. 如實施例37之方法，其中該延伸子單元具有下式(1)結構；該胺基酸單元為纈胺酸-瓜胺酸；且該間隔子單元為包含下式(2)結構的PAB基團：式(1)式(2)。Embodiment 38. The method of embodiment 37, wherein the stretcher unit has a structure of formula (1); the amino acid unit is valine-citrulline; and the spacer unit is a PAB group comprising a structure of formula (2): Formula 1) Formula (2).
實施例39. 如實施例37或38之方法，其中該延伸子單元與該抗體或其抗原結合片段之硫原子形成鍵結；且其中該間隔子單元經由胺基甲酸酯基連接至MMAE。Embodiment 39. The method of embodiment 37 or 38, wherein the Stretcher unit forms a bond with a sulfur atom of the antibody or antigen-binding fragment thereof; and wherein the Spacer unit is linked to MMAE via a carbamate group.
實施例40. 如實施例1至39中任一項之方法，其中該ADC包含每個抗體或其抗原結合片段1至20個MMAE單元。Embodiment 40. The method of any one of embodiments 1 to 39, wherein the ADC comprises 1 to 20 MMAE units per antibody or antigen-binding fragment thereof.
實施例41. 如實施例1至40中任一項之方法，其中該ADC包含每個抗體或其抗原結合片段1至10個MMAE單元。Embodiment 41. The method of any one of embodiments 1 to 40, wherein the ADC comprises 1 to 10 MMAE units per antibody or antigen-binding fragment thereof.
實施例42. 如實施例1至41中任一項之方法，其中該ADC包含每個抗體或其抗原結合片段2至8個MMAE單元。Embodiment 42. The method of any one of embodiments 1 to 41, wherein the ADC comprises 2 to 8 MMAE units per antibody or antigen-binding fragment thereof.
實施例43. 如實施例1至42中任一項之方法，其中該ADC包含每個抗體或其抗原結合片段3至5個MMAE單元。Embodiment 43. The method of any one of embodiments 1 to 42, wherein the ADC comprises 3 to 5 MMAE units per antibody or antigen-binding fragment thereof.
實施例44. 如實施例1至43中任一項之方法，其中該ADC具有以下結構：其中L-表示該抗191P4D12抗體或其抗原結合片段，且p為1至10。Embodiment 44. The method of any one of embodiments 1 to 43, wherein the ADC has the following structure: wherein L- represents the anti-191P4D12 antibody or an antigen-binding fragment thereof, and p is 1 to 10.
實施例45. 如實施例44之方法，其中p為2至8。Embodiment 45. The method according to embodiment 44, wherein p is 2 to 8.
實施例46. 如實施例44或45之方法，其中p為3至5。Embodiment 46. The method of embodiment 44 or 45, wherein p is 3 to 5.
實施例47. 如實施例44至46中任一項之方法，其中p為3至4。Embodiment 47. The method of any one of embodiments 44 to 46, wherein p is 3 to 4.
實施例48. 如實施例44至47中任一項之方法，其中p為約4。Embodiment 48. The method of any one of embodiments 44 to 47, wherein p is about 4.
實施例49. 如實施例44至47中任一項之方法，其中該有效量之該等抗體藥物結合物的平均p值為約3.8。Embodiment 49. The method of any one of embodiments 44 to 47, wherein the average p-value of the effective amount of the antibody-drug conjugates is about 3.8.
實施例50. 如實施例1至49中任一項之方法，其中該ADC係以每公斤該個體體重約1至約10 mg、每公斤該個體體重約1至約5 mg、每公斤該個體體重約1至約2.5 mg或每公斤該個體體重約1至約1.25 mg之劑量向該個體投與。Embodiment 50. The method of any one of Embodiments 1 to 49, wherein the ADC is administered to the subject in an amount of about 1 to about 10 mg/kg of the subject's body weight, about 1 to about 5 mg/kg of the subject's body weight, about 1 to about 2.5 mg/kg of the subject's body weight, or about 1 to about 1.25 mg/kg of the subject's body weight.
實施例51. 如實施例1至50中任一項之方法，其中該ADC係以每公斤該個體體重約0.25 mg、約0.5 mg、約0.75 mg、約1.0 mg、約1.25 mg、約1.5 mg、約1.75 mg、約2.0 mg、約2.25 mg或約2.5 mg之劑量向該個體投與。Embodiment 51. The method of any one of embodiments 1 to 50, wherein the ADC is administered to the subject in an amount of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, or about 2.5 mg per kg of the subject's body weight.
實施例52. 如實施例1至51中任一項之方法，其中該ADC係以每公斤該個體體重約1 mg之劑量向該個體投與。Embodiment 52. The method of any one of embodiments 1 to 51, wherein the ADC is administered to the subject at a dose of about 1 mg per kg of body weight of the subject.
實施例53. 如實施例1至51中任一項之方法，其中該ADC係以每公斤該個體體重約1.25 mg之劑量向該個體投與。Embodiment 53. The method of any one of embodiments 1 to 51, wherein the ADC is administered to the subject at a dose of about 1.25 mg per kg of body weight of the subject.
實施例54. 如實施例1至53中任一項之方法，其中該ADC係藉由靜脈內(IV)注射或輸注向該個體投與。Embodiment 54. The method of any one of embodiments 1 to 53, wherein the ADC is administered to the subject by intravenous (IV) injection or infusion.
實施例55. 如實施例1至54中任一項之方法，其中該ADC係在21天治療週期之至多2天藉由IV注射或輸注向該個體投與。Embodiment 55. The method of any one of embodiments 1 to 54, wherein the ADC is administered to the subject by IV injection or infusion on up to 2 days of a 21-day treatment cycle.
實施例56. 如實施例1至55中任一項之方法，其中該ADC係在21天治療週期之第1天及第8天藉由IV注射或輸注向該個體投與。Embodiment 56. The method of any one of Embodiments 1 to 55, wherein the ADC is administered to the subject by IV injection or infusion on Day 1 and Day 8 of a 21-day treatment cycle.
實施例57. 如實施例1至56中任一項之方法，其中該ADC係在21天治療週期之至多2天藉由IV注射或輸注經約30分鐘向該個體投與。Embodiment 57. The method of any one of embodiments 1 to 56, wherein the ADC is administered to the subject by IV injection or infusion over about 30 minutes on up to 2 days of a 21-day treatment cycle.
實施例58. 如實施例1至57中任一項之方法，其中該ADC係在21天治療週期之第1天及第8天藉由IV注射或輸注經約30分鐘投與。Embodiment 58. The method of any one of embodiments 1 to 57, wherein the ADC is administered by IV injection or infusion over about 30 minutes on day 1 and day 8 of a 21-day treatment cycle.
實施例59. 如實施例1至58中任一項之方法，其中該ADC調配成包含L-組胺酸、聚山梨醇酯-20 (TWEEN-20)及二水合海藻糖的醫藥組合物。Embodiment 59. The method of any one of embodiments 1 to 58, wherein the ADC is formulated as a pharmaceutical composition comprising L-histidine, polysorbate-20 (TWEEN-20) and trehalose dihydrate.
實施例60. 如實施例1至59中任一項之方法，其中該ADC調配成包含約20 mM L-組胺酸、約0.02% (w/v) TWEEN-20、約5.5% (w/v)二水合海藻糖及鹽酸鹽的醫藥組合物，且其中該醫藥組合物在25℃下的pH為約6.0。Embodiment 60. The method of any one of embodiments 1 to 59, wherein the ADC is formulated into a pharmaceutical composition comprising about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.5% (w/v) trehalose dihydrate, and hydrochloride, and wherein the pH of the pharmaceutical composition at 25° C. is about 6.0.
實施例61. 如實施例1至59中任一項之方法，其中該ADC調配成包含約9 mM組胺酸、約11 mM單水合組胺酸鹽酸鹽、約0.02% (w/v) TWEEN-20及約5.5% (w/v)二水合海藻糖的醫藥組合物，且其中該醫藥組合物在25℃下的pH為約6.0。Embodiment 61. The method of any one of embodiments 1 to 59, wherein the ADC is formulated into a pharmaceutical composition comprising about 9 mM histidine, about 11 mM histidine hydrochloride monohydrate, about 0.02% (w/v) TWEEN-20, and about 5.5% (w/v) trehalose dihydrate, and wherein the pH of the pharmaceutical composition at 25°C is about 6.0.
實施例62. 如實施例1至61中任一項之方法，其中該ADC具有以下結構：其中L-表示該抗體或其抗原結合片段且p為約3至約4，該抗191P4D12抗體包含重鏈，該重鏈包含SEQ ID NO:7之第20個胺基酸(麩胺酸)至第466個胺基酸(離胺酸)範圍內之胺基酸序列；及輕鏈，該輕鏈包含SEQ ID NO:8之第23個胺基酸(天冬胺酸)至第236個胺基酸(半胱胺酸)範圍內之胺基酸序列，其中該ADC係以每公斤該個體體重約1.25 mg之劑量投與，且其中該劑量係在21天治療週期之第1天及第8天藉由IV注射或輸注經約30分鐘投與。Embodiment 62. The method of any one of embodiments 1 to 61, wherein the ADC has the following structure: wherein L- represents the antibody or an antigen-binding fragment thereof and p is about 3 to about 4, the anti-191P4D12 antibody comprises a heavy chain comprising an amino acid sequence ranging from the 20th amino acid (glutamine) to the 466th amino acid (lysine) of SEQ ID NO:7; and a light chain comprising an amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8, wherein the ADC is administered at a dose of about 1.25 mg per kilogram of body weight of the individual, and wherein the dose is administered by IV injection or infusion over about 30 minutes on Days 1 and 8 of a 21-day treatment cycle.
實施例63. 如實施例1至60中任一項之方法，其中該抗PD-1抗體係以約100 mg至約400 mg之劑量向該個體投與。Embodiment 63. The method of any one of Embodiments 1 to 60, wherein the anti-PD-1 antibody is administered to the subject in an amount of about 100 mg to about 400 mg.
實施例64. 如實施例1至61中任一項之方法，其中該抗PD-1抗體係以約200 mg之劑量向該個體投與。Embodiment 64. The method of any one of Embodiments 1 to 61, wherein the anti-PD-1 antibody is administered to the subject in a dose of about 200 mg.
實施例65. 如實施例62之方法，其中： (a)該抗PD-1抗體係以約200 mg之劑量向該個體投與；及 (b)在步驟(a)之後，該抗PD-1抗體每42天以約400 mg之劑量向該個體投與。Embodiment 65. The method of Embodiment 62, wherein:(a) the anti-PD-1 antibody is administered to the individual at a dose of about 200 mg; and(b) after step (a), the anti-PD-1 antibody is administered to the individual at a dose of about 400 mg every 42 days.
實施例66. 如實施例1至65中任一項之方法，其中該抗PD-1抗體係在該21天治療週期之1天藉由IV輸注向該個體投與。Embodiment 66. The method of any one of Embodiments 1 to 65, wherein the anti-PD-1 antibody is administered to the subject by IV infusion on day 1 of the 21-day treatment cycle.
實施例67. 如實施例1至66中任一項之方法，其中該抗PD-1抗體係在各21天治療週期之第1天藉由IV輸注向該個體投與。Embodiment 67. The method of any one of Embodiments 1 to 66, wherein the anti-PD-1 antibody is administered to the subject by IV infusion on Day 1 of each 21-day treatment cycle.
實施例68. 如實施例1至67中任一項之方法，其中該抗PD-1抗體係在該21天治療週期之1天藉由IV輸注經約30分鐘向該個體投與。Embodiment 68. The method of any one of Embodiments 1 to 67, wherein the anti-PD-1 antibody is administered to the subject by IV infusion over about 30 minutes on day 1 of the 21-day treatment cycle.
實施例69. 如實施例1至66中任一項之方法，其中該抗PD-1抗體係在各21天治療週期之第1天藉由IV輸注經約30分鐘向該個體投與。Embodiment 69. The method of any one of Embodiments 1 to 66, wherein the anti-PD-1 antibody is administered to the subject by IV infusion over about 30 minutes on Day 1 of each 21-day treatment cycle.
實施例70. 如實施例1至69中任一項之方法，其中該個體在治療之後具有完全反應。Embodiment 70. The method of any one of embodiments 1 to 69, wherein the subject has a complete response after treatment.
實施例71. 如實施例1至69中任一項之方法，其中該個體在治療之後具有部分反應。Embodiment 71. The method of any one of embodiments 1 to 69, wherein the subject has a partial response after treatment.
實施例72. 如實施例1至69中任一項之方法，其中該個體在治療之後具有完全反應或部分反應。Embodiment 72. The method of any one of embodiments 1 to 69, wherein the subject has a complete response or a partial response after treatment.
實施例73. 如實施例1至69中任一項之方法，其中該個體在治療之後具有穩定疾病。Embodiment 73. The method of any one of Embodiments 1 to 69, wherein the subject has stable disease after treatment.
實施例74. 如實施例1至69中任一項之方法，其中該個體在治療之後具有至少或約6個月之反應持續時間。Embodiment 74. The method of any one of embodiments 1 to 69, wherein the subject has a duration of response of at least or about 6 months after treatment.
實施例75. 如實施例1至69中任一項之方法，其中該個體在治療之後具有至少或約12個月之反應持續時間。Embodiment 75. The method of any one of embodiments 1 to 69, wherein the subject has a duration of response of at least or about 12 months after treatment.
實施例76. 如實施例1至69中任一項之方法，其中該個體在治療之後具有至少或約24個月之反應持續時間。Embodiment 76. The method of any one of embodiments 1 to 69, wherein the subject has a duration of response of at least or about 24 months after treatment.
實施例77. 如實施例1至69中任一項之方法，其中該個體在治療之後具有至少或約27個月之反應持續時間。Embodiment 77. The method of any one of embodiments 1 to 69, wherein the subject has a duration of response of at least or about 27 months after treatment.
實施例78. 如實施例1至69中任一項之方法，其中該個體在治療之後具有至少或約6個月之無惡化存活期。Embodiment 78. The method of any one of embodiments 1 to 69, wherein the subject has a progression-free survival of at least or about 6 months after treatment.
實施例79. 如實施例1至69中任一項之方法，其中該個體在治療之後具有至少或約8個月之無惡化存活期。Embodiment 79. The method of any one of embodiments 1 to 69, wherein the subject has a progression-free survival of at least or about 8 months after treatment.
實施例80. 如實施例1至69中任一項之方法，其中該個體在治療之後具有至少或約12個月之無惡化存活期。Embodiment 80. The method of any one of embodiments 1 to 69, wherein the subject has a progression-free survival of at least or about 12 months after treatment.
實施例81. 如實施例1至69中任一項之方法，其中該個體在治療之後具有至少或約20個月之無惡化存活期。Embodiment 81. The method of any one of embodiments 1 to 69, wherein the subject has a progression-free survival of at least or about 20 months after treatment.
實施例82. 如實施例1至69中任一項之方法，其中該個體在治療之後具有至少或約29個月之無惡化存活期。Embodiment 82. The method of any one of embodiments 1 to 69, wherein the subject has a progression-free survival of at least or about 29 months after treatment.
實施例83. 如實施例1至69中任一項之方法，其中該個體在治療之後具有至少或約22個月之總存活期。Embodiment 83. The method of any one of embodiments 1 to 69, wherein the subject has an overall survival of at least or about 22 months after treatment.
實施例84. 如實施例1至69中任一項之方法，其中該個體在治療之後具有至少或約27個月之總存活期。Embodiment 84. The method of any one of Embodiments 1 to 69, wherein the subject has an overall survival of at least or about 27 months after treatment.
實施例85. 如實施例1至69中任一項之方法，其中該個體在治療之後具有至少或約30個月之總存活期。Embodiment 85. The method of any one of Embodiments 1 to 69, wherein the subject has an overall survival of at least or about 30 months after treatment.
實施例86. 如實施例1至69中任一項之方法，其中該個體在治療之後具有19至25個月範圍內之總存活期。Embodiment 86. The method of any one of embodiments 1 to 69, wherein the subject has an overall survival in the range of 19 to 25 months after treatment.
實施例87. 如實施例1至69中任一項之方法，其中該個體在治療之後具有28至32個月範圍內之總存活期。Embodiment 87. The method of any one of embodiments 1 to 69, wherein the subject has an overall survival in the range of 28 to 32 months after treatment.
實施例88. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體中具有完全反應之個體的百分比為至少或約10%。Embodiment 88. The method of any one of embodiments 1 to 69, wherein a population of said individuals is treated by said methods, and wherein the percentage of individuals in the treated population having a complete response is at least or about 10%.
實施例89. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體中具有部分反應之個體的百分比為至少或約54%。Embodiment 89. The method of any one of embodiments 1 to 69, wherein a population of said individuals is treated by said methods, and wherein the percentage of individuals in the treated population having a partial response is at least or about 54%.
實施例90. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之客觀反應率為至少或約65%。Embodiment 90. The method of any one of embodiments 1 to 69, wherein a population of said individuals is treated by said methods, and wherein the objective response rate of the treated population is at least or about 65%.
實施例91. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之客觀反應率在53%至75%範圍內。Embodiment 91. The method of any one of embodiments 1 to 69, wherein a population of said individuals is treated by said methods, and wherein the objective response rate of the treated population is in the range of 53% to 75%.
實施例92. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體中具有穩定疾病之個體的百分比為至少或約22%。Embodiment 92. The method of any one of embodiments 1 to 69, wherein a population of said individuals is treated by said methods, and wherein the percentage of individuals with stable disease in the treated population is at least or about 22%.
實施例93. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之反應持續時間為至少或約6個月。Embodiment 93. The method of any one of embodiments 1 to 69, wherein a population of said individuals is treated by said methods, and wherein the duration of response of the treated population is at least or about 6 months.
實施例94. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之反應持續時間為至少或約12個月。Embodiment 94. The method of any one of embodiments 1 to 69, wherein the population of said individuals is treated by said methods, and wherein the duration of response of the treated population is at least or about 12 months.
實施例95. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之反應持續時間為至少或約24個月。Embodiment 95. The method of any one of embodiments 1 to 69, wherein the population of said individuals is treated by said methods, and wherein the duration of response of the treated population is at least or about 24 months.
實施例96. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之反應持續時間為至少或約27個月。Embodiment 96. The method of any one of embodiments 1 to 69, wherein the population of said individuals is treated by said methods, and wherein the duration of response of the treated population is at least or about 27 months.
實施例97. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之無惡化存活期為至少或約6個月。Embodiment 97. The method of any one of embodiments 1 to 69, wherein a population of said individuals is treated by said methods, and wherein the treated population has a progression-free survival of at least or about 6 months.
實施例98. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之無惡化存活期為至少或約12個月。Embodiment 98. The method of any one of embodiments 1 to 69, wherein the population of said individuals is treated by said methods, and wherein the treated population has a progression-free survival of at least or about 12 months.
實施例99. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之無惡化存活期為至少或約20個月。Embodiment 99. The method of any one of embodiments 1 to 69, wherein the population of said individuals is treated by said methods, and wherein the treated population has a progression-free survival of at least or about 20 months.
實施例100. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之無惡化存活期為至少或約29個月。Embodiment 100. The method of any one of Embodiments 1 to 69, wherein a population of said individuals is treated by said methods, and wherein the progression-free survival of the treated population is at least or about 29 months.
實施例101. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之中值總存活期為至少或約22個月。Embodiment 101. The method of any one of Embodiments 1 to 69, wherein a population of said individuals is treated by said methods, and wherein the median overall survival of the treated population is at least or about 22 months.
實施例102. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之中值總存活期為至少或約27個月。Embodiment 102. The method of any one of Embodiments 1 to 69, wherein a population of said individuals is treated by said methods, and wherein the median overall survival of the treated population is at least or about 27 months.
實施例103. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之中值總存活期為至少或約30個月。Embodiment 103. A method as in any one of Embodiments 1 to 69, wherein a population of said individuals is treated by said methods, and wherein the median overall survival of the treated population is at least or about 30 months.
實施例104. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之總存活期在19至25個月範圍內。Embodiment 104. The method of any one of Embodiments 1 to 69, wherein a group of said individuals are treated by said methods, and wherein the overall survival of the treated group is in the range of 19 to 25 months.
實施例105. 如實施例1至69中任一項之方法，其中該等個體之群體藉由該等方法治療，且其中所治療群體之總存活期在30至32個月範圍內。Embodiment 105. The method of any one of Embodiments 1 to 69, wherein a group of said individuals are treated by said methods, and wherein the overall survival of the treated group is in the range of 30 to 32 months.
實施例106. 如實施例1至70及72中任一項之方法，其中以該方法治療之個體群體的完全反應率為至少或約10%。Embodiment 106. A method as in any of Embodiments 1 to 70 and 72, wherein the complete response rate of the subject population treated by the method is at least or about 10%.
實施例107. 如實施例1至69、71及72中任一項之方法，其中以該方法治療之個體群體的部分反應率為至少或約54%。Embodiment 107. A method as in any one of Embodiments 1 to 69, 71 and 72, wherein the partial response rate of the subject population treated by the method is at least or about 54%.
實施例108. 如實施例1至72中任一項之方法，其中以該方法治療之個體群體的客觀反應率為至少或約65%。Embodiment 108. A method as in any one of Embodiments 1 to 72, wherein the objective response rate of the population of individuals treated by the method is at least or about 65%.
實施例109. 如實施例1至72中任一項之方法，其中以該方法治療之個體群體的客觀反應率為53%至75%。Embodiment 109. A method as in any one of embodiments 1 to 72, wherein the objective response rate of the subject group treated by the method is 53% to 75%.
實施例110. 如實施例1至69及73中任一項之方法，其中以該方法治療之個體群體的穩定疾病率為至少或約22%。Embodiment 110. A method as in any one of embodiments 1 to 69 and 73, wherein the stable disease rate in the population of individuals treated by the method is at least or about 22%.
實施例111. 如實施例1至69及74至77中任一項之方法，其中以該方法治療之個體群體的反應持續時間為至少或約6個月。Embodiment 111. A method as in any one of embodiments 1 to 69 and 74 to 77, wherein the duration of response in the subject population treated by the method is at least or about 6 months.
實施例112. 如實施例1至69及74至77中任一項之方法，其中以該方法治療之個體群體的反應持續時間為至少或約12個月。Embodiment 112. A method as in any one of embodiments 1 to 69 and 74 to 77, wherein the duration of response in the subject population treated by the method is at least or about 12 months.
實施例113. 如實施例1至69及74至77中任一項之方法，其中以該方法治療之個體群體的反應持續時間為至少或約24個月。Embodiment 113. A method as in any one of embodiments 1 to 69 and 74 to 77, wherein the duration of response in the subject population treated by the method is at least or about 24 months.
實施例114. 如實施例1至69及74至77中任一項之方法，其中以該方法治療之個體群體的反應持續時間為至少或約27個月。Embodiment 114. A method as in any one of embodiments 1 to 69 and 74 to 77, wherein the duration of response in the subject population treated by the method is at least or about 27 months.
實施例115. 如實施例1至69及78至82中任一項之方法，其中以該方法治療之個體群體的無惡化存活期為至少或約6個月。Embodiment 115. A method as in any one of embodiments 1 to 69 and 78 to 82, wherein the progression-free survival of the population of individuals treated by the method is at least or about 6 months.
實施例116. 如實施例1至69及78至82中任一項之方法，其中以該方法治療之個體群體的無惡化存活期為至少或約12個月。Embodiment 116. A method as in any one of embodiments 1 to 69 and 78 to 82, wherein the progression-free survival of the population of individuals treated by the method is at least or about 12 months.
實施例117. 如實施例1至69及78至82中任一項之方法，其中以該方法治療之個體群體的無惡化存活期為至少或約20個月。Embodiment 117. A method as in any one of embodiments 1 to 69 and 78 to 82, wherein the progression-free survival of the population of individuals treated by the method is at least or about 20 months.
實施例118. 如實施例1至69及78至82中任一項之方法，其中以該方法治療之個體群體的無惡化存活期為至少或約29個月。Embodiment 118. A method as in any one of embodiments 1 to 69 and 78 to 82, wherein the progression-free survival of the population of individuals treated by the method is at least or about 29 months.
實施例119. 如實施例1至69及83至87中任一項之方法，其中以該等方法治療之個體群體的中值總存活期為至少或約22個月。Embodiment 119. A method as in any one of embodiments 1 to 69 and 83 to 87, wherein the median overall survival of the population of individuals treated by such methods is at least or about 22 months.
實施例120. 如實施例1至69及83至87中任一項之方法，其中以該等方法治療之個體群體的中值總存活期為至少或約27個月。Embodiment 120. A method as in any one of embodiments 1 to 69 and 83 to 87, wherein the median overall survival of the population of individuals treated by such methods is at least or about 27 months.
實施例121. 如實施例1至69及83至87中任一項之方法，其中以該等方法治療之個體群體的中值總存活期為至少或約30個月。Embodiment 121. A method as in any one of embodiments 1 to 69 and 83 to 87, wherein the median overall survival of the population of individuals treated by such methods is at least or about 30 months.
實施例122. 如實施例1至69、79及80中任一項之方法，其中以該等方法治療之個體群體的總存活期為19至25個月。Embodiment 122. A method as in any one of embodiments 1 to 69, 79 and 80, wherein the overall survival of the subject population treated by such methods is 19 to 25 months.
實施例123. 如實施例1至69、79及80中任一項之方法，其中以該等方法治療之個體群體的總存活期為30至32個月。Embodiment 123. A method as described in any one of embodiments 1 to 69, 79 and 80, wherein the overall survival of the individual population treated by such methods is 30 to 32 months.
相關申請案之交叉參考Cross-reference to related applications
本申請案主張2022年7月25日申請之美國申請案第63/392,067號、2022年8月31日申請之美國申請案第63/402,830號及2023年5月24日申請之美國申請案第63/504,183號之權益，該等申請案各自的揭示內容以全文引用之方式併入本文中。序列表This application claims the benefit of U.S. Application No. 63/392,067 filed on July 25, 2022, U.S. Application No. 63/402,830 filed on August 31, 2022, and U.S. Application No. 63/504,183 filed on May 24, 2023, the disclosures of each of which are incorporated herein byreference in their entirety.
本申請案含有已以XML檔案格式與本申請案一起提交之電腦可讀序列表，該序列表之全部內容以全文引用之方式併入本文中。與本申請案一起提交之序列表XML檔案的名稱為「14369-295-185_SEQLISTING.xml」，創建於2023年7月18日，且大小為62,806個位元組。This application contains a computer-readable sequence listing that has been submitted with this application in XML file format, the entire contents of which are incorporated herein by reference in their entirety. The sequence listing XML file submitted with this application is named "14369-295-185_SEQLISTING.xml", was created on July 18, 2023, and is 62,806 bytes in size.
在進一步描述本發明之前，應瞭解，本發明不限於本文所闡述之特定實施例，且亦應瞭解，本文所用之術語係僅出於描述特定實施例之目的且不希望具有限制性。5.1定義Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described herein, and it should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.5.1Definitions
本文所描述或參考之技術及程序包括熟習此項技術者使用習知方法總體上充分理解及/或通常採用之技術及程序，該等習知方法諸如Sambrook等人, Molecular Cloning: A Laboratory Manual (第3版2001)；Current Protocols in Molecular Biology (Ausubel等人編, 2003)；Therapeutic Monoclonal Antibodies: From Bench to Clinic (An編2009)；Monoclonal Antibodies: Methods and Protocols (Albitar編2010)；及Antibody Engineering第1及2卷(Kontermann及Dübel編, 第2版2010)中所描述的廣泛使用之方法。The techniques and procedures described or referenced herein include those that are generally well understood and/or commonly employed by those skilled in the art using known methods, such as Sambrook et al., Molecular Cloning: A Laboratory Manual (3rd ed. 2001); Current Protocols in Molecular Biology (Ausubel et al., ed., 2003); Therapeutic Monoclonal Antibodies: From Bench to Clinic (An, ed. 2009); Monoclonal Antibodies: Methods and Protocols (Albitar, ed. 2010); and the widely used methods described in Antibody Engineering, Vols. 1 and 2 (Kontermann and Dübel, ed., 2nd ed. 2010).
除非本文中另外定義，否則本說明書中所用之技術及科學術語具有一般熟習此項技術者通常所理解之含義。出於解釋本說明書之目的，將應用以下術語說明且只要適當，則以單數形式使用之術語亦將包括複數形式且反之亦然。在所闡述之術語之任何說明與以引用之方式併入本文中之任何文獻存在衝突之情況下，以下文闡述之術語描述為準。Unless otherwise defined herein, the technical and scientific terms used in this specification have the meanings commonly understood by those skilled in the art. For the purpose of interpreting this specification, the following term descriptions will apply and, whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event of a conflict between any description of a term and any document incorporated herein by reference, the term descriptions described below shall prevail.
術語「抗體」、「免疫球蛋白」或「Ig」在本文中可互換使用，且以最廣泛意義使用且特定地涵蓋例如單株抗體(包括促效劑、拮抗劑、中和抗體、全長或完整單株抗體)、具有多抗原決定基或單抗原決定基特異性之抗體組合物、多株或單價抗體、多價抗體、由至少兩種完整抗體形成之多特異性抗體(例如雙特異性抗體，只要其展現所需生物活性即可)、單鏈抗體及其片段，如下文所描述。抗體可為人類抗體、人源化抗體、嵌合抗體及/或親和力成熟抗體，以及來自其他物種(例如小鼠及兔等)之抗體。術語「抗體」意欲包括免疫球蛋白類別之多肽內的B細胞之多肽產物，其能夠結合至特定分子抗原且由兩對相同的多肽鏈構成，其中每一對具有一條重鏈(約50-70 kDa)及一條輕鏈(約25 kDa)，各鏈之各胺基末端部分包括具有約100至約130個或更多個胺基酸之可變區，且各鏈之各羧基末端部分包括恆定區。參見例如Antibody Engineering (Borrebaeck編, 第2版，1995)；及Kuby, Immunology (第3版，1997)。在特定實施例中，特定分子抗原可以被本文所提供之抗體結合，包括多肽或抗原決定基。抗體亦包括但不限於合成抗體、以重組方式產生的抗體、駱駝化抗體、胞內抗體、抗個體基因型(抗Id)抗體，及以上中之任一者之功能片段(例如抗原結合片段)，該等功能片段係指抗體重鏈或輕鏈多肽之保留該片段所來源之抗體的一些或全部結合活性的部分。功能片段(例如抗原結合片段)之非限制性實例包括單鏈Fv (scFv) (例如包括單特異性、雙特異性等)、Fab片段、F(ab')片段、F(ab)2片段、F(ab')2片段、二硫鍵連接的Fv (dsFv)、Fd片段、Fv片段、雙功能抗體、三功能抗體、四功能抗體及微型抗體。特定言之，本文所提供之抗體包括免疫球蛋白分子及免疫球蛋白分子之免疫活性部分，例如含有結合至抗原之抗原結合位點的抗原結合域或分子(例如抗體的一或多個CDR)。此類抗體片段可見於例如Harlow及Lane, Antibodies: A Laboratory Manual (1989)；Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers編, 1995)；Huston等人, 1993, Cell Biophysics 22:189-224；Plückthun及Skerra, 1989, Meth. Enzymol. 178:497-515；及Day, Advanced Immunochemistry (第2版1990)。本文所提供之抗體可屬於免疫球蛋白分子之任何類別(例如IgG、IgE、IgM、IgD及IgA)或任何子類(例如IgG1、IgG2、IgG3、IgG4、IgA1及IgA2)。抗體可為促效抗體或拮抗抗體。The terms "antibody", "immunoglobulin" or "Ig" are used interchangeably herein and are used in the broadest sense and specifically cover, for example, monoclonal antibodies (including agonists, antagonists, neutralizing antibodies, full-length or intact monoclonal antibodies), antibody compositions with multi-epitope or single-epitope specificity, polyclonal or monovalent antibodies, multivalent antibodies, multispecific antibodies formed from at least two intact antibodies (e.g., bispecific antibodies, as long as they exhibit the desired biological activity), single-chain antibodies and fragments thereof, as described below. Antibodies can be human antibodies, humanized antibodies, chimeric antibodies and/or affinity matured antibodies, as well as antibodies from other species (e.g., mice and rabbits, etc.). The term "antibody" is intended to include polypeptide products of B cells within the immunoglobulin class of polypeptides that are capable of binding to a specific molecular antigen and are composed of two pairs of identical polypeptide chains, each pair having a heavy chain (about 50-70 kDa) and a light chain (about 25 kDa), each amino terminal portion of each chain including a variable region having about 100 to about 130 or more amino acids, and each carboxyl terminal portion of each chain including a constant region. See, for example, Antibody Engineering (Borrebaeck, ed., 2nd ed., 1995); and Kuby, Immunology (3rd ed., 1997). In specific embodiments, a specific molecular antigen can be bound by an antibody provided herein, including a polypeptide or an antigenic determinant. Antibodies also include, but are not limited to, synthetic antibodies, recombinantly produced antibodies, camelized antibodies, intracellular antibodies, anti-idiotypic (anti-Id) antibodies, and functional fragments (e.g., antigen-binding fragments) of any of the above, which are portions of antibody heavy or light chain polypeptides that retain some or all of the binding activity of the antibody from which the fragment is derived. Non-limiting examples of functional fragments (e.g., antigen-binding fragments) include single-chain Fv (scFv) (e.g., including monospecific, bispecific, etc.), Fab fragments, F(ab') fragments, F(ab)2 fragments, F(ab')2 fragments, disulfide-linked Fv (dsFv), Fd fragments, Fv fragments, bifunctional antibodies, trifunctional antibodies, tetrafunctional antibodies, and miniantibodies. Specifically, antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, such as antigen binding domains or molecules (e.g., one or more CDRs of an antibody) that contain an antigen binding site that binds to an antigen. Such antibody fragments can be found in, for example, Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers, 1995); Huston et al., 1993, Cell Biophysics 22: 189-224; Plückthun and Skerra, 1989, Meth. Enzymol. 178: 497-515; and Day, Advanced Immunochemistry (2nd ed. 1990). The antibodies provided herein may belong to any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) of immunoglobulin molecules. The antibodies may be agonist antibodies or antagonist antibodies.
術語「單株抗體」係指自實質上均質抗體之群體獲得的抗體，亦即構成該群體的個別抗體除了可能少量存在的可能天然存在之突變之外均相同。單株抗體針對單一抗原位點具有高度特異性。與可包括針對不同決定子(抗原決定基)之不同抗體的多株抗體製劑相比，各單株抗體係針對抗原上之單一決定子。The term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in small amounts. Monoclonal antibodies are highly specific for a single antigenic site. In contrast to polyclonal antibody preparations, which may include different antibodies directed against different determinants (antigenic determinants), each monoclonal antibody is directed against a single determinant on the antigen.
「抗原」為抗體可選擇性結合之結構。目標抗原可為多肽、碳水化合物、核酸、脂質、半抗原或其他天然存在的或合成的化合物。在一些實施例中，目標抗原為多肽。在某些實施例中，抗原與細胞相關，例如存在於細胞(例如癌細胞)上或中。"Antigen" is a structure to which an antibody can selectively bind. The target antigen can be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen is a polypeptide. In certain embodiments, the antigen is associated with a cell, such as present on or in a cell (e.g., a cancer cell).
「完整」抗體為包含抗原結合位點以及CL及至少重鏈恆定區CH1、CH2及CH3的抗體。恆定區可包括人類恆定區或其胺基酸序列變異體。在某些實施例中，完整抗體具有一或多種效應功能。A "complete" antibody is an antibody that includes an antigen binding site as well as CL and at least the heavy chain constant regions CH1, CH2 and CH3. The constant regions may include human constant regions or amino acid sequence variants thereof. In certain embodiments, the complete antibody has one or more effector functions.
術語「抗原結合片段」、「抗原結合域」、「抗原結合區」及類似術語係指抗體中包含與抗原相互作用之胺基酸殘基且賦予結合劑針對抗原之特異性及親和力的部分(例如CDR)。如本文所用，「抗原結合片段」包括「抗體片段」，其包含完整抗體之一部分，諸如完整抗體之抗原結合區或可變區。抗體片段之實例包括但不限於Fab、Fab'、F(ab')2及Fv片段；雙功能抗體及二-雙功能抗體(參見例如Holliger等人, 1993, Proc. Natl. Acad. Sci. 90:6444-48；Lu等人, 2005, J. Biol. Chem. 280:19665-72；Hudson等人, 2003, Nat. Med. 9:129-34；WO 93/11161；及美國專利第5,837,242號及第6,492,123號)；單鏈抗體分子(參見例如美國專利第4,946,778號；第5,260,203號；第5,482,858號；及第5,476,786號)；雙可變域抗體(參見例如美國專利第7,612,181號)；單可變域抗體(sdAb) (參見例如Woolven等人, 1999, Immunogenetics 50: 98-101；及Streltsov等人, 2004, Proc Natl Acad Sci USA. 101:12444-49)；及由抗體片段形成之多特異性抗體。The terms "antigen-binding fragment", "antigen-binding domain", "antigen-binding region" and similar terms refer to the portion of an antibody that contains the amino acid residues that interact with the antigen and imparts the specificity and affinity of the binding agent to the antigen (e.g., CDR). As used herein, "antigen-binding fragment" includes "antibody fragments" that contain a portion of an intact antibody, such as the antigen-binding region or variable region of an intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2 , and Fv fragments; bifunctional antibodies and di-bifunctional antibodies (see, e.g., Holliger et al., 1993, Proc. Natl. Acad. Sci. 90:6444-48; Lu et al., 2005, J. Biol. Chem. 280:19665-72; Hudson et al., 2003, Nat. Med. 9:129-34; WO 93/11161; and U.S. Patent Nos. 5,837,242 and 6,492,123); single chain antibody molecules (see, e.g., U.S. Patent Nos. 4,946,778; 5,260,203; 5,482,858; and 5,476,786); bivariable domain antibodies (see, e.g., U.S. Patent No. 7,612,181); single variable domain antibodies (sdAbs) (see, e.g., Woolven et al., 1999, Immunogenetics 50: 98-101; and Streltsov et al., 2004, Proc Natl Acad Sci USA. 101: 12444-49); and multispecific antibodies formed from antibody fragments.
術語「結合(binds)」或「結合(binding)」係指分子間的相互作用，包括例如形成複合物。相互作用可為例如非共價相互作用，包括氫鍵、離子鍵、疏水相互作用及/或凡得瓦爾相互作用(van der Waals interaction)。複合物亦可包括藉由共價或非共價鍵、相互作用或力保持在一起的兩個或更多個分子之結合。抗體上之單一抗原結合位點與目標分子(諸如抗原)之單一抗原決定基之間的總非共價相互作用之強度為抗體或功能片段對該抗原決定基之親和力。結合分子(例如抗體)對單價抗原之解離速率(koff)與締合速率(kon)的比率(koff/kon)為解離常數KD，該解離常數與親和力逆相關。KD值愈低，抗體親和力愈高。KD值因抗體與抗原之不同複合物而變且視kon與koff而定。本文所提供之抗體的解離常數KD可使用本文所提供之任何方法或熟習此項技術者熟知之任何其他方法測定。一個結合位點處之親和力不能始終反映抗體與抗原之間的真實相互相用強度。當含有多個重複抗原決定子之複合抗原(諸如多價抗原)與含有多個結合位點之抗體接觸時，抗體與抗原在一個位點處之相互相用將增加第二個位點處的反應機率。多價抗體與抗原之間的此類多重相互作用之強度稱為親合力。The term "binds" or "binding" refers to interactions between molecules, including, for example, the formation of a complex. The interaction may be, for example, a non-covalent interaction, including hydrogen bonds, ionic bonds, hydrophobic interactions, and/or van der Waals interactions. A complex may also include the binding of two or more molecules held together by covalent or non-covalent bonds, interactions, or forces. The strength of the total non-covalent interactions between a single antigen binding site on an antibody and a single antigenic determinant of a target molecule (such as an antigen) is the affinity of the antibody or functional fragment for the antigenic determinant. The ratio (koff /kon ) of the dissociation rate (koff ) to the association rate (kon ) of a binding molecule (such as an antibody) for a monovalent antigen is the dissociation constant KD , which is inversely related to affinity. The lower theKD value, the higher the antibody affinity.The KD value varies for different complexes of antibody and antigen and depends onkon andkoff . The dissociation constantKD of the antibodies provided herein can be determined using any of the methods provided herein or any other method known to those skilled in the art. The affinity at one binding site does not always reflect the true strength of the interaction between the antibody and the antigen. When a complex antigen containing multiple repeated antigenic determinants (such as a multivalent antigen) is contacted with an antibody containing multiple binding sites, the interaction between the antibody and the antigen at one site will increase the probability of reaction at a second site. The strength of such multiple interactions between a multivalent antibody and an antigen is called avidity.
關於本文所述之抗體或抗原結合片段，諸如「結合至」、「特異性結合至」之術語及類似術語亦可在本文中互換地使用且係指特異性結合至抗原(諸如多肽)之抗原結合域的結合分子。結合至或特異性結合至抗原之抗體或抗原結合片段可具有與相關抗原的交叉反應性。在某些實施例中，結合至或特異性結合至抗原之抗體或抗原結合片段不具有與其他抗原的交叉反應性。結合至或特異性結合至抗原的抗體或抗原結合片段可藉由例如免疫分析、Octet®、Biacore®或熟習此項技術者已知之其他技術來鑑別。在一些實施例中，如使用諸如放射免疫分析(RIA)及酶聯免疫吸附分析(ELISA)之實驗技術測定，抗體或抗原結合片段當以比針對任何交叉反應性抗原更高的親和力結合至抗原時，其結合至或特異性結合至抗原。通常，特異性或選擇性反應將為背景信號或雜訊的至少兩倍且可超過背景的10倍。關於結合特異性之論述，參見例如Fundamental Immunology 332-36 (Paul編, 第2版, 1989)。在某些實施例中，抗體或抗原結合片段對「非目標」蛋白質結合的程度小於結合分子或抗原結合域對其特定目標抗原之結合的約10%，例如藉由螢光活化細胞分選(FACS)分析或RIA所測定。諸如「特異性結合」、「特異性結合至」或「特異性針對」等術語意謂結合可量測地不同於非特異性相互作用。特異性結合可例如藉由與對照分子之結合相比測定分子之結合來量測，對照分子一般為具有不具結合活性之類似結構的分子。舉例而言，可藉由與目標(例如過量的未標記之目標)類似之對照分子之競爭來測定特異性結合。在此情況下，若經標記之目標與探針之結合受過量的未標記目標競爭性抑制，則指示特異性結合。結合至抗原之抗體或抗原結合片段包括能夠以足以使得結合分子適用作例如靶向抗原之診斷劑的親和力結合抗原的抗體或抗原結合片段。在某些實施例中，結合至抗原的抗體或抗原結合片段具有小於或等於1000 nM、800 nM、500 nM、250 nM、100 nM、50 nM、10 nM、5 nM、4 nM、3 nM、2 nM、1 nM、0.9 nM、0.8 nM、0.7 nM、0.6 nM、0.5 nM、0.4 nM、0.3 nM、0.2 nM或0.1 nM的解離常數(KD)。在某些實施例中，抗體或抗原結合片段結合至抗原之抗原決定基，該抗原決定基在來自不同物種之抗原間(例如在人類與食蟹獼猴物種之間)為保守的。With respect to the antibodies or antigen-binding fragments described herein, terms such as "bind to,""specifically bind to," and similar terms may also be used interchangeably herein and refer to binding molecules that specifically bind to the antigen-binding domain of an antigen (e.g., a polypeptide). An antibody or antigen-binding fragment that binds to or specifically binds to an antigen may have cross-reactivity with related antigens. In certain embodiments, an antibody or antigen-binding fragment that binds to or specifically binds to an antigen does not have cross-reactivity with other antigens. An antibody or antigen-binding fragment that binds to or specifically binds to an antigen may be identified by, for example, immunoassays,Octet® ,Biacore® , or other techniques known to those skilled in the art. In some embodiments, an antibody or antigen-binding fragment binds to or specifically binds to an antigen when it binds to the antigen with a higher affinity than to any cross-reactive antigen, as determined using experimental techniques such as radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA). Typically, a specific or selective reaction will be at least twice the background signal or noise and may exceed 10 times the background. For a discussion of binding specificity, see, for example, Fundamental Immunology 332-36 (Paul, ed., 2nd ed., 1989). In certain embodiments, the extent of binding of an antibody or antigen-binding fragment to a "non-target" protein is less than about 10% of the binding of the binding molecule or antigen-binding domain to its specific target antigen, as determined, for example, by fluorescence activated cell sorting (FACS) analysis or RIA. Terms such as "specific binding,""binds specifically to," or "specifically against" mean that the binding is measurably distinct from non-specific interactions. Specific binding can be measured, for example, by measuring the binding of a molecule compared to the binding of a control molecule, which is generally a molecule of similar structure that has no binding activity. For example, specific binding can be measured by competition with a control molecule similar to the target (e.g., an excess of unlabeled target). In this case, if the binding of the labeled target to the probe is competitively inhibited by the excess unlabeled target, specific binding is indicated. Antibodies or antigen-binding fragments that bind to an antigen include antibodies or antigen-binding fragments that are capable of binding to an antigen with an affinity sufficient to render the binding molecule useful, for example, as a diagnostic agent targeting the antigen. In certain embodiments, the antibody or antigen-binding fragment that binds to an antigen has a dissociation constant (KD) of less than or equal to 1000 nM, 800 nM, 500 nM, 250 nM, 100 nM, 50 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, or 0.1 nM. In certain embodiments, the antibody or antigen-binding fragment binds to an antigenic determinant of an antigen that is conserved between antigens from different species (e.g., between human and cynomolgus macaque species).
「結合親和力」一般係指分子(例如結合蛋白，諸如抗體)之單一結合位點與其結合搭配物(例如抗原)之間的非共價相互作用之總強度。除非另外指示，否則如本文所用，「結合親和力」係指反映結合對(例如，抗體與抗原)成員之間1:1相互作用之固有結合親和力。結合分子X對其結合搭配物Y之親和力通常可由解離常數(KD)表示。親和力可藉由此項技術中已知之常用方法，包括本文所描述之方法量測。低親和力抗體一般緩慢結合抗原且傾向於容易解離，而高親和力抗體一般較快結合抗原且傾向於較長時間保持結合狀態。此項技術中已知多種量測結合親和力的方法，其中任一者可用於本發明之目的。特定說明性實施例包括以下。在一個實施例中，「KD」或「KD值」可藉由此項技術中已知的分析量測，例如藉由結合分析量測。KD可用RIA量測，例如使用所關注抗體之Fab形式及其抗原進行(Chen等人, 1999, J. Mol Biol 293:865-81)。KD或KD值亦可藉由使用生物層干涉術(BLI)或表面電漿子共振(SPR)分析藉由Octet®，使用例如Octet®QK384系統，或藉由Biacore®，使用例如Biacore®TM-2000或Biacore®TM-3000來量測。「締合速率(on-rate)」或「締合之速率(rate of association)」或「締合速率(association rate)」或「kon」亦可用上文描述之相同生物層干涉術(BLI)或表面電漿子共振(SPR)技術，使用例如Octet®QK384、Biacore®TM-2000或Biacore®TM-3000系統測定。"Binding affinity" generally refers to the overall strength of non-covalent interactions between a single binding site of a molecule (e.g., a binding protein, such as an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a binding molecule X for its binding partner Y can generally be represented by a dissociation constant (KD ). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind antigen slowly and tend to dissociate easily, while high-affinity antibodies generally bind antigen faster and tend to remain bound longer. A variety of methods for measuring binding affinity are known in the art, any of which can be used for the purposes of the present invention. Specific illustrative embodiments include the following. In one embodiment, "KD " or "KD value" can be measured by an assay known in the art, such as by a binding assay.KD can be measured by RIA, such as using a Fab form of the antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81).KD orKD value can also be measured by using biolayer interferometry (BLI) or surface plasmon resonance (SPR) analysis by Octet®, using, for example, the Octet® QK384 system, or by Biacore®, using, for example, a Biacore® TM-2000 or a Biacore® TM-3000. The "on-rate" or "rate of association" or "association rate" or "kon" can also be measured using the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above, using, for example, an Octet® QK384, Biacore® TM-2000, or Biacore® TM-3000 system.
在某些實施例中，抗體或抗原結合片段可包含「嵌合」序列，其中重鏈及/或輕鏈之一部分與來源於特定物種或屬於特定抗體類別或子類別之抗體中的對應序列一致或同源，而該(等)鏈之其餘部分與來源於另一物種或屬於另一抗體類別或子類別之抗體以及此類抗體之片段中的對應序列一致或同源，只要其展現所需生物活性即可(參見美國專利第4,816,567號；及Morrison等人, 1984, Proc. Natl. Acad. Sci. USA 81:6851-55)。In certain embodiments, antibodies or antigen-binding fragments may comprise "chimeric" sequences, in which a portion of the heavy and/or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, and the remainder of the chain(s) is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see U.S. Patent No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81:6851-55).
在某些實施例中，抗體或抗原結合片段可包含非人類(例如鼠類)抗體之「人源化」形式之部分，該等非人類抗體係包括人類免疫球蛋白之嵌合抗體(例如接受者抗體)，其中原生CDR殘基經來自具有所需特異性、親和力及能力之非人類物種(諸如小鼠、大鼠、兔或非人類靈長類動物) (例如供體抗體)之相應CDR的殘基置換。在一些情況下，人類免疫球蛋白之一或多個FR區殘基由相應的非人類殘基置換。此外，人源化抗體可包含接受者抗體或供體抗體中未發現之殘基。進行此等修飾以進一步優化抗體效能。人源化抗體重鏈或輕鏈可包含實質上全部至少一或多個可變區，其中全部或實質上全部CDR對應於非人類免疫球蛋白之CDR且全部或實質上全部FR為人類免疫球蛋白序列之FR。在某些實施例中，人源化抗體將包含免疫球蛋白恆定區(Fc)之至少一部分，通常人類免疫球蛋白之至少一部分。關於其他細節，參見Jones等人, 1986, Nature 321:522-25；Riechmann等人, 1988, Nature 332:323-29；Presta, 1992, Curr. Op. Struct. Biol. 2:593-96；Carter等人, 1992, Proc. Natl. Acad. Sci. USA 89:4285-89；美國專利第6,800,738號；第6,719,971號；第6,639,055號；第6,407,213號；及第6,054,297號。In certain embodiments, the antibody or antigen-binding fragment may comprise a portion of a "humanized" form of a non-human (e.g., murine) antibody, which is a chimeric antibody comprising a human immunoglobulin (e.g., a recipient antibody) in which native CDR residues are replaced with residues from a non-human species (e.g., mouse, rat, rabbit, or non-human primate) (e.g., a donor antibody) having the desired specificity, affinity, and capacity. In some cases, one or more FR region residues of a human immunoglobulin are replaced with corresponding non-human residues. In addition, a humanized antibody may comprise residues not found in the recipient antibody or the donor antibody. Such modifications are performed to further optimize antibody performance. Humanized antibody heavy or light chain can comprise substantially all of at least one or more variable regions, wherein all or substantially all of the CDRs correspond to the CDRs of non-human immunoglobulins and all or substantially all of the FRs are FRs of human immunoglobulin sequences. In certain embodiments, humanized antibodies will comprise at least a portion of an immunoglobulin constant region (Fc), typically at least a portion of a human immunoglobulin. For additional details, see Jones et al., 1986, Nature 321:522-25; Riechmann et al., 1988, Nature 332:323-29; Presta, 1992, Curr. Op. Struct. Biol. 2:593-96; Carter et al., 1992, Proc. Natl. Acad. Sci. USA 89:4285-89; U.S. Patent Nos. 6,800,738; 6,719,971; 6,639,055; 6,407,213; and 6,054,297.
在某些實施例中，抗體或抗原結合片段可包含「完全人類抗體」或「人類抗體」之部分，其中該等術語在本文中可互換使用且係指包含人類可變區及例如人類恆定區之抗體。在特定實施例中，該等術語係指包含人類來源之可變區及恆定區之抗體。在某些實施例中，「完全人類」抗體亦可涵蓋結合多肽且由核酸序列編碼之抗體，該等核酸序列為人類生殖系免疫球蛋白核酸序列之天然存在之體細胞變異體。術語「完全人類抗體」包括含有對應於人類生殖系免疫球蛋白序列之可變區及恆定區的抗體，如Kabat等人所述(參見Kabat等人(1991) Sequences of Proteins of Immunological Interest, 第五版, 美國衛生與公眾服務部(U.S. Department of Health and Human Services), NIH出版物第91-3242號)。「人類抗體」為胺基酸序列對應於由人類產生之抗體之胺基酸序列及/或已使用任何製備人類抗體之技術製得之抗體。人類抗體之此定義特定地排除包含非人類抗原結合殘基之人源化抗體。人類抗體可以使用此項技術中已知的各種技術產生，包括噬菌體呈現庫(Hoogenboom及Winter, 1991, J. Mol. Biol. 227:381；Marks等人, 1991, J. Mol. Biol. 222:581)及酵母呈現庫(Chao等人, 2006, Nature Protocols 1: 755-68)。Cole等人, Monoclonal Antibodies and Cancer Therapy 77 (1985)；Boerner等人, 1991, J. Immunol. 147(1):86-95；及van Dijk及van de Winkel, 2001, Curr. Opin. Pharmacol. 5: 368-74中所描述之方法亦可用於製備人類單株抗體。人類抗體可藉由向已經修飾以回應於抗原刺激而產生此類抗體，但其內源性基因座已失能之轉殖基因動物(例如小鼠)投與抗原來製備(參見例如Jakobovits, 1995, Curr. Opin. Biotechnol. 6(5):561-66；Brüggemann及Taussing, 1997, Curr. Opin. Biotechnol. 8(4):455-58；及美國專利第6,075,181號及第6,150,584號，關於XENOMOUSETM技術)。關於經由人類B細胞融合瘤技術產生的人類抗體，亦參見例如Li等人, 2006, Proc. Natl. Acad. Sci. USA, 103:3557-62。In certain embodiments, the antibody or antigen-binding fragment may comprise a portion of a "fully human antibody" or a "human antibody," wherein these terms are used interchangeably herein and refer to antibodies comprising a human variable region and, for example, a human constant region. In specific embodiments, these terms refer to antibodies comprising a variable region and a constant region of human origin. In certain embodiments, a "fully human" antibody may also encompass antibodies that bind to a polypeptide and are encoded by a nucleic acid sequence that is a naturally occurring somatic variant of a human germline immunoglobulin nucleic acid sequence. The term "fully human antibody" includes antibodies containing variable and constant regions that correspond to human germline immunoglobulin sequences as described by Kabat et al. (see Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242). A "human antibody" is an antibody whose amino acid sequence corresponds to the amino acid sequence of an antibody produced by humans and/or has been made using any technique for making human antibodies. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries (Hoogenboom and Winter, 1991, J. Mol. Biol. 227:381; Marks et al., 1991, J. Mol. Biol. 222:581) and yeast display libraries (Chao et al., 2006, Nature Protocols 1: 755-68). The methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy 77 (1985); Boerner et al., 1991, J. Immunol. 147(1):86-95; and van Dijk and van de Winkel, 2001, Curr. Opin. Pharmacol. 5: 368-74 can also be used to prepare human monoclonal antibodies. Human antibodies can be prepared by administering antigen to transgenic animals (e.g., mice) that have been modified to produce such antibodies in response to antigenic stimulation, but whose endogenous loci have been disabled (see, e.g., Jakobovits, 1995, Curr. Opin. Biotechnol. 6(5):561-66; Brüggemann and Taussing, 1997, Curr. Opin. Biotechnol. 8(4):455-58; and U.S. Patent Nos. 6,075,181 and 6,150,584 for XENOMOUSE™ technology). See also, e.g., Li et al., 2006, Proc. Natl. Acad. Sci. USA, 103:3557-62 for human antibodies produced by human B cell fusion tumor technology.
在某些實施例中，抗體或抗原結合片段可包含「重組人類抗體」之部分，其中該片語包括藉由重組方式製備、表現、產生或分離的人類抗體，諸如使用轉染至宿主細胞中之重組表現載體表現的抗體；自重組組合性人類抗體庫分離的抗體；自人類免疫球蛋白基因之轉殖基因及/或轉殖染色體動物(例如小鼠或乳牛)分離的抗體(參見例如Taylor, L. D.等人(1992)Nucl.AcidsRes.20:6287-6295)，或藉由任何其他方式製備、表現、產生或分離的抗體，包括將人類免疫球蛋白基因序列剪接至其他DNA序列。此類重組人類抗體可具有來源於人類生殖系免疫球蛋白序列之可變區及恆定區(參見Kabat, E. A.等人(1991) Sequences of Proteins of Immunological Interest, 第五版，美國衛生與公眾服務部，NIH出版物第91-3242號)。然而，在某些實施例中，對此類重組人類抗體進行活體外突變誘發(或，當使用人類Ig序列轉殖基因之動物時，為活體內體細胞突變誘發)，且因此重組抗體之VH及VL區之胺基酸序列為雖然來源於人類生殖系VH及VL序列且與人類生殖系VH及VL序列相關、但可以並非天然存在於活體內人類抗體生殖系譜系內的序列。In certain embodiments, the antibody or antigen-binding fragment may comprise a portion of a "recombinant human antibody," wherein the phrase includes human antibodies prepared, expressed, generated or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell; antibodies isolated from a recombinant combinatorial human antibody library; antibodies isolated from transgenic and/or transchromosomal animals (e.g., mice or cows) containing human immunoglobulin genes (see, e.g., Taylor, LD et al. (1992)Nucl.AcidsRes. 20:6287-6295), or antibodies prepared, expressed, generated or isolated by any other means, including splicing human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies may have variable and constant regions derived from human germline immunoglobulin sequences (see Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutation induction (or, when using animals transgenic with human Ig sequences, in vivo somatic cell mutation induction), and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, although derived from and related to human germline VH and VL sequences, may not naturally exist in the human antibody germline repertoire in vivo.
在某些實施例中，抗體或抗原結合片段可包含「單株抗體」之一部分，其中如本文所用，該術語係指自實質上均質抗體之群體(例如，除可能少量存在的可能的天然存在之突變以外，組成該群體之個別抗體為一致的)獲得之抗體，且各單株抗體將通常識別抗原上之單一抗原決定基。在特定實施例中，如本文所用之「單株抗體」為由單一融合瘤或其他細胞產生之抗體。術語「單株」不限於任何用於製備抗體之特定方法。舉例而言，適用於本發明之單株抗體可藉由首次由Kohler等人, 1975, Nature 256:495所描述之融合瘤方法製備，或可在細菌或真核動物或植物細胞中使用重組DNA方法製備(參見例如美國專利第4,816,567號)。「單株抗體」亦可使用例如Clackson等人, 1991, Nature 352:624-28及Marks等人, 1991, J. Mol. Biol., 222:581-97中所描述之技術，自噬菌體抗體庫中分離。用於製備純系細胞株及由其表現之單株抗體的其他方法係此項技術中熟知的。參見例如Short Protocols in Molecular Biology (Ausubel等人編, 第5版. 2002)。In certain embodiments, an antibody or antigen-binding fragment may comprise a portion of a "monoclonal antibody," wherein as used herein, the term refers to an antibody obtained from a population of substantially homogeneous antibodies (e.g., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in small amounts), and each monoclonal antibody will typically recognize a single antigenic determinant on an antigen. In specific embodiments, a "monoclonal antibody" as used herein is an antibody produced by a single hybridoma or other cell. The term "monoclonal" is not limited to any particular method for making an antibody. For example, monoclonal antibodies suitable for use in the present invention can be prepared by the fusion tumor method first described by Kohler et al., 1975, Nature 256:495, or can be prepared using recombinant DNA methods in bacteria or eukaryotic animal or plant cells (see, for example, U.S. Patent No. 4,816,567). "Monoclonal antibodies" can also be isolated from phagosome antibody libraries using techniques described, for example, by Clackson et al., 1991, Nature 352:624-28 and Marks et al., 1991, J. Mol. Biol., 222:581-97. Other methods for preparing pure cell lines and monoclonal antibodies expressed therefrom are well known in the art. See, for example, Short Protocols in Molecular Biology (Ausubel et al., ed., 5th ed. 2002).
典型的4鏈抗體單元為雜四聚醣蛋白，其由兩條相同輕(L)鏈及兩條相同重(H)鏈構成。在IgG之情況下，4鏈單元一般為約150,000道爾頓。各L鏈經一個共價二硫鍵連接至H鏈，而兩條H鏈視H鏈同型而定經一或多個二硫鍵彼此連接。各H鏈及L鏈亦具有有規律地間隔之鏈內二硫橋鍵。各H鏈在N端具有可變域(VH)，隨後為三個恆定域(CH) (對於α及γ鏈中之各者而言)以及四個CH域(對於μ及ε同型而言)。各L鏈在N端具有可變域(VL)，繼之為在其另一端的恆定域(CL)。VL與VH對齊，且CL與重鏈之第一恆定域(CH1)對齊。咸信特定胺基酸殘基形成輕鏈與重鏈可變域之間的界面。VH與VL配對在一起以形成單一抗原結合位點。關於不同類別之抗體的結構及特性，參見例如Basic and Clinical Immunology 71 (Stites等人編, 第8版. 1994)；及Immunobiology (Janeway等人編, 第5版. 2001)。The typical 4-chain antibody unit is a heterotetraglycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. In the case of IgG, the 4-chain unit is generally about 150,000 daltons. Each L chain is linked to the H chain via one covalent disulfide bond, and the two H chains are linked to each other via one or more disulfide bonds depending on the H chain isotype. Each H chain and L chain also has regularly spaced intrachain disulfide bridges. Each H chain has a variable domain (VH) at the N-terminus, followed by three constant domains (CH) (for each of the α and γ chains) and four CH domains (for the μ and ε isotypes). Each L chain has a variable domain (VL) at the N-terminus, followed by a constant domain (CL) at its other end. The VL is aligned with the VH, and the CL is aligned with the first constant domain (CH1) of the heavy chain. It is believed that specific amino acid residues form the interface between the light chain and the heavy chain variable domain. VH and VL are paired together to form a single antigen binding site. For the structure and properties of different classes of antibodies, see, for example, Basic and Clinical Immunology 71 (Stites et al., ed., 8th edition. 1994); and Immunobiology (Janeway et al., ed., 5th edition. 2001).
術語「Fab」或「Fab區」係指結合至抗原的抗體區域。習知IgG通常包含兩個Fab區，各存在於Y形IgG結構之兩個臂之一上。各Fab區通常由重鏈及輕鏈中之各者的一個可變區及一個恆定區構成。更特定言之，Fab區中之重鏈可變區及恆定區為VH及CH1區，且Fab區中之輕鏈可變區及恆定區為VL及CL區。Fab區中之VH、CH1、VL及CL可根據本發明以不同方式排列以賦予抗原結合能力。舉例而言，VH及CH1區可位於一個多肽上，且VL及CL區可位於各別多肽上，類似於習知IgG之Fab區。或者，VH、CH1、VL及CL區皆可位於同一多肽上且以不同次序定向，如下文章節中更詳細地描述。The term "Fab" or "Fab region" refers to the region of an antibody that binds to an antigen. Conventional IgG typically comprises two Fab regions, each present on one of the two arms of the Y-shaped IgG structure. Each Fab region is typically composed of one variable region and one constant region of each of the heavy chain and light chain. More specifically, the heavy chain variable region and constant region in the Fab region are VH and CH1 regions, and the light chain variable region and constant region in the Fab region are VL and CL regions. The VH, CH1, VL and CL in the Fab region can be arranged in different ways according to the present invention to impart antigen binding ability. For example, the VH and CH1 regions can be located on one polypeptide, and the VL and CL regions can be located on separate polypeptides, similar to the Fab region of conventional IgG. Alternatively, the VH, CH1, VL and CL regions can all be located on the same polypeptide and oriented in a different order, as described in more detail in the following section.
術語「可變區」、「可變域」、「V區」或「V域」係指抗體之輕鏈或重鏈的一部分，其一般位於輕鏈或重鏈之胺基端且在重鏈中長度為約120至130個胺基酸且在輕鏈中長度為約100至110個胺基酸，且用於各特定抗體對其特定抗原之結合及特異性。重鏈之可變區可稱為「VH」。輕鏈之可變區可稱為「VL」。術語「可變」係指可變區之某些區段的序列在抗體間廣為不同之事實。V區介導抗原結合且定義特定抗體對其特定抗原之特異性。然而，可變性不均勻分佈於可變區之110個胺基酸跨度內。實情為，V區由以下組成：約15-30個胺基酸之較小可變性(例如相對恆定)片段(稱為構架區(FR))，該等片段被較短的較大可變性(例如極度可變性)區域(稱為「高變區」，各約9-12個胺基酸長)分隔。重鏈及輕鏈之可變區各自包含基本上採用β褶板組態之四個FR，該等FR由三個高變區連接，該等高變區形成連接β褶板結構之環且在一些情況下形成β褶板結構之一部分。各鏈中之高變區藉由FR與來自其他鏈之高變區緊密結合在一起，促進形成抗體之抗原結合位點(參見例如Kabat等人, Sequences of Proteins of Immunological Interest (第5版, 1991))。恆定區不直接涉及抗體對抗原之結合，但展現多種效應功能，諸如使抗體參與抗體依賴性細胞的細胞毒性(ADCC)及補體依賴性細胞毒性(CDC)。可變區的序列在不同抗體之間廣泛不同。在特定實施例中，可變區為人類可變區。The terms "variable region", "variable domain", "V region" or "V domain" refer to a portion of the light or heavy chain of an antibody that is generally located at the amino terminus of the light or heavy chain and is about 120 to 130 amino acids in length in the heavy chain and about 100 to 110 amino acids in length in the light chain, and is used for the binding and specificity of each particular antibody for its specific antigen. The variable region of the heavy chain may be referred to as "VH". The variable region of the light chain may be referred to as "VL". The term "variable" refers to the fact that the sequence of certain segments of the variable region differs widely between antibodies. The V region mediates antigen binding and defines the specificity of a particular antibody for its specific antigen. However, the variability is not evenly distributed across the 110 amino acid span of the variable region. In fact, the V region consists of relatively variable (e.g., relatively constant) stretches of about 15-30 amino acids, called framework regions (FRs), separated by shorter, more variable (e.g., extremely variable) regions, called "hypervariable regions," each about 9-12 amino acids long. The variable regions of the heavy and light chains each include four FRs, essentially adopting a β-sheet configuration, connected by three hypervariable regions, which form loops connecting the β-sheet structure and, in some cases, form part of the β-sheet structure. The hypervariable regions in each chain are tightly bound together by the FRs with the hypervariable regions from the other chains, facilitating the formation of the antigen-binding site of the antibody (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest (5th ed., 1991)). The constant region is not directly involved in the binding of the antibody to the antigen, but exhibits various effector functions, such as enabling the antibody to participate in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The sequence of the variable region varies widely between different antibodies. In a specific embodiment, the variable region is a human variable region.
術語「根據Kabat之可變區殘基編號」或「如Kabat中之胺基酸位置編號」及其變化形式係指Kabat等人, 前述中用於編譯抗體之重鏈可變區或輕鏈可變區的編號系統。使用此編號系統，實際線性胺基酸序列可含有對應於可變域之FR或CDR之縮短或向其中之插入的較少或額外胺基酸。舉例而言，重鏈可變域可包括位於殘基52之後的單一胺基酸插入(殘基52a，根據Kabat)及位於殘基82之後的三個插入殘基(例如殘基82a、82b及82c等，根據Kabat)。對於既定抗體，可藉由將抗體序列之同源區與「標準」Kabat編號序列比對來確定殘基之Kabat編號。Kabat編號系統一般在提及可變域中之殘基(大致輕鏈之殘基1-107及重鏈之殘基1-113)時使用(例如Kabat等人, 見上文)。「EU編號系統」或「EU索引」一般在提及免疫球蛋白重鏈恆定區中之殘基時使用(例如Kabat等人, 見上文中報導之EU索引)。「如Kabat中之EU索引」係指人類IgG1 EU抗體之殘基編號。已例如藉由AbM、Chothia、Contact、IMGT及AHon描述其他編號系統。The term "variable region residue numbering according to Kabat" or "amino acid position numbering as in Kabat" and variations thereof refer to the numbering system used by Kabat et al., supra, for encoding heavy chain variable regions or light chain variable regions of antibodies. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or CDR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insertion after residue 52 (residue 52a, according to Kabat) and three inserted residues after residue 82 (e.g., residues 82a, 82b, and 82c, etc., according to Kabat). For a given antibody, the Kabat numbering of residues can be determined by aligning homologous regions of the antibody sequence with the "standard" Kabat numbering sequence. The Kabat numbering system is generally used when referring to residues in the variable domains (roughly residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., supra). The "EU numbering system" or "EU index" is generally used when referring to residues in the constant region of the heavy chain of an immunoglobulin (e.g., the EU index reported in Kabat et al., supra). The "EU index as in Kabat" refers to the residue numbering of the human IgG1 EU antibody. Other numbering systems have been described, for example, by AbM, Chothia, Contact, IMGT and AHon.
當參考抗體使用時，術語「重鏈」係指約50-70 kDa之多肽鏈，其中胺基端部分包括約120至130個或更多個胺基酸之可變區，且羧基端部分包括恆定區。基於重鏈恆定區之胺基酸序列，恆定區可為五種不同類型(例如同型)之一，稱為alpha (α)、delta (δ)、epsilon (ε)、gamma (γ)及mu (μ)。不同重鏈之尺寸不同：α、δ及γ含有約450個胺基酸，而µ及ε含有約550個胺基酸。此等不同類型的重鏈當與輕鏈組合時，產生五種熟知的抗體類別(例如同型)，分別為IgA、IgD、IgE、IgG及IgM，包括IgG的四種亞類，亦即IgG1、IgG2、IgG3及IgG4。When used with reference to antibodies, the term "heavy chain" refers to a polypeptide chain of about 50-70 kDa, wherein the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids, and the carboxyl-terminal portion includes a constant region. Based on the amino acid sequence of the constant region of the heavy chain, the constant region can be one of five different types (e.g., isotypes), called alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ). The different heavy chains vary in size: α, δ, and γ contain about 450 amino acids, while µ and ε contain about 550 amino acids. These different types of heavy chains, when combined with light chains, produce five well-known antibody classes (e.g., isotypes), namely IgA, IgD, IgE, IgG, and IgM, including the four subclasses of IgG, namely IgG1, IgG2, IgG3, and IgG4.
當參考抗體使用時，術語「輕鏈」係指約25 kDa之多肽鏈，其中胺基端部分包括約100至約110個或更多個胺基酸之可變區，且羧基端部分包括恆定區。輕鏈之大致長度為211至217個胺基酸。基於恆定域之胺基酸序列，存在兩種不同類型，稱為kappa (κ)或lambda (λ)。When used with reference to an antibody, the term "light chain" refers to a polypeptide chain of about 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids, and the carboxyl-terminal portion includes a constant region. The approximate length of the light chain is 211 to 217 amino acids. There are two different types, called kappa (κ) or lambda (λ), based on the amino acid sequence of the constant domain.
如本文所用，術語「高變區」、「HVR」、「互補決定區」及「CDR」可互換使用。「CDR」係指免疫球蛋白(Ig或抗體) VH β-褶板構架之非構架區內之三個高變區(H1、H2或H3)中之一者，或抗體VL β-褶板構架之非構架區內之三個高變區(L1、L2或L3)中之一者。因此，CDR為構架區序列內穿插之可變區序列。As used herein, the terms "hypervariable region", "HVR", "complementary determining region" and "CDR" are used interchangeably. "CDR" refers to one of the three hypervariable regions (H1, H2 or H3) within the non-framework region of the VH β-pleat framework of an immunoglobulin (Ig or antibody), or one of the three hypervariable regions (L1, L2 or L3) within the non-framework region of the VL β-pleat framework of an antibody. Thus, CDRs are variable region sequences interspersed within framework region sequences.
CDR區已為熟習此項技術者熟知且已由熟知編號系統定義。舉例而言，Kabat互補決定區(CDR)係基於序列可變性且最常用(參見例如Kabat等人, 見上文)。而Chothia提及結構環之位置(參見例如Chothia及Lesk, 1987, J. Mol. Biol. 196:901-17)。在使用Kabat編號規約進行編號時，Chothia CDR-H1環之末端在H32與H34之間變化，此視環之長度而定(此係因為Kabat編號方案將插入置於H35A及H35B；若既不存在35A，亦不存在35B，則環末端位於32；若僅存在35A，則環末端位於33；若35A與35B均存在，則環末端位於34)。AbM高變區表示Kabat CDR與Chothia結構環之間的折衷，且由Oxford Molecular之AbM抗體模型化軟體使用(參見例如Antibody Engineering第2卷(Kontermann及Dübel編, 第2版, 2010))。「contact」高變區係基於對可用複雜晶體結構之分析。已開發及廣泛採用之另一通用編號系統為ImMunoGeneTics (IMGT) Information System®(Lafranc等人, 2003, Dev. Comp. Immunol. 27(1):55-77)。IMGT為專用於人類及其他脊椎動物之免疫球蛋白(IG)、T細胞受體(TCR)及主要組織相容複合體(MHC)的整合式資訊系統。本文中，依據胺基酸序列及輕鏈或重鏈內的位置提及CDR。由於免疫球蛋白可變域結構內之CDR的「位置」在物種之間為保守的且存在於稱為環的結構中，因此藉由使用根據結構特徵比對可變域序列的編號系統容易鑑別出CDR及構架殘基。此資訊可用於將來自一個物種之免疫球蛋白的CDR殘基移植及置換至通常來自人類抗體之接受體構架中。Honegger及Plückthun, 2001, J. Mol. Biol. 309: 657-70已開發出另一種編號系統(AHon)。編號系統(包括例如Kabat編號及IMGT獨特編號系統)之間的對應性已為熟習此項技術者熟知(參見例如Kabat, 見上文；Chothia及Lesk, 見上文；Martin, 見上文；Lefranc等人, 見上文)。來自此等高變區或CDR中之每一者的殘基標示於下表1中表1
既定CDR之邊界可視用於鑑別之方案而變化。因此，除非另外規定，否則術語既定抗體之「CDR」及「互補決定區」或其區域，諸如可變區，以及抗體之個別CDR (例如CDR-H1、CDR-H2)或其區域應理解為涵蓋如由上文所描述之已知方案中之任一者所定義之互補決定區。在一些情況下，指定用於鑑別一或多個特定CDR之方案，諸如藉由Kabat、Chothia或Contact方法所定義之CDR。在其他情況下，給出CDR之特定胺基酸序列。The boundaries of a given CDR may vary depending on the scheme used for identification. Therefore, unless otherwise specified, the terms "CDR" and "complementary determining region" or regions thereof, such as variable regions, and individual CDRs (e.g., CDR-H1, CDR-H2) or regions thereof of a given antibody should be understood to encompass complementary determining regions as defined by any of the known schemes described above. In some cases, schemes for identifying one or more specific CDRs are specified, such as CDRs defined by the Kabat, Chothia or Contact methods. In other cases, specific amino acid sequences of CDRs are given.
高變區可包含如下「延伸的高變區」：VL中的24-36或24-34 (L1)、46-56或50-56 (L2)及89-97或89-96 (L3)；以及VH中的26-35或26-35A (H1)、50-65或49-65 (H2)及93-102、94-102或95-102 (H3)。The hypervariable region may comprise the following "extended hypervariable regions": 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in VL; and 26-35 or 26-35A (H1), 50-65 or 49-65 (H2) and 93-102, 94-102 or 95-102 (H3) in VH.
術語「恆定區」或「恆定域」係指輕鏈及重鏈之羧基端部分，其不直接涉及抗體與抗原之結合，但展現多種效應功能，諸如與Fc受體之相互相用。該術語係指免疫球蛋白分子的一部分，該部分包含的胺基酸序列比免疫球蛋白之含有抗原結合位點的其他部分(可變區)更保守。恆定區可含有重鏈之CH1、CH2及CH3區以及輕鏈之CL區。The term "constant region" or "constant domain" refers to the carboxyl-terminal portion of the light and heavy chains that is not directly involved in antibody-antigen binding but exhibits a variety of effector functions, such as interaction with Fc receptors. The term refers to a portion of the immunoglobulin molecule that contains an amino acid sequence that is more conserved than the rest of the immunoglobulin (variable region) that contains the antigen-binding site. The constant region may contain the CH1, CH2, and CH3 regions of the heavy chain and the CL region of the light chain.
術語「構架」或「FR」係指側接CDR之彼等可變區殘基。FR殘基存在於例如嵌合、人源化、人類、域抗體、雙功能抗體、線性抗體及雙特異性抗體中。FR殘基為除高變區殘基或CDR殘基之外的彼等可變域殘基。The term "framework" or "FR" refers to those variable region residues that flank the CDRs. FR residues are found, for example, in chimeric, humanized, human, domain antibodies, bifunctional antibodies, linear antibodies, and bispecific antibodies. FR residues are those variable domain residues other than hypervariable region residues or CDR residues.
在本文中，術語「Fc區」用於定義免疫球蛋白重鏈之C端區域，包括例如原生序列Fc區、重組型Fc區及變異型Fc區。儘管免疫球蛋白重鏈之Fc區之邊界可變化，但人類IgG重鏈Fc區通常定義為自位置Cys226之胺基酸殘基或自Pro230延伸至其羧基端。可移除Fc區之C端離胺酸(殘基447，根據EU編號系統)，例如在抗體之生產或純化期間，或藉由以重組方式工程改造編碼抗體之重鏈的核酸進行。因此，完整抗體之組合物可包含所有K447殘基均被移除之抗體群、K447殘基未移除之抗體群，以及含有具有及不具有K447殘基之抗體之混合物的抗體群。「功能性Fc區」具有原生序列Fc區之「效應功能」。例示性「效應功能」包括C1q結合；CDC；Fc受體結合；ADCC；吞噬作用；細胞表面受體(例如B細胞受體)之下調等。此類效應功能一般需要Fc區與結合區或結合域(例如抗體可變區或可變域)組合且可使用熟習此項技術者已知之各種分析法評估。「變異型Fc區」包含與原生序列Fc區之差異為至少一個胺基酸修飾(例如取代、添加或缺失)的胺基酸序列。在某些實施例中，變異型Fc區相較於原生序列Fc區或相較於親本多肽之Fc區，在原生序列Fc區中或在親本多肽之Fc區中具有至少一個胺基酸取代，例如約一個至約十個胺基酸取代，或約一個至約五個胺基酸取代。本文中，變異型Fc區可與原生序列Fc區及/或親本多肽之Fc區具有至少約80%同源性，或與其具有至少約90%同源性，例如與其具有至少約95%同源性。Herein, the term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain, including, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is generally defined as extending from the amino acid residue at position Cys226 or from Pro230 to its carboxyl terminus. The C-terminal lysine (residue 447, according to the EU numbering system) of the Fc region can be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding the heavy chain of the antibody. Thus, a composition of intact antibodies may include a population of antibodies in which all K447 residues have been removed, a population of antibodies in which the K447 residue has not been removed, and a population of antibodies containing a mixture of antibodies with and without the K447 residue. A "functional Fc region" has the "effector function" of a native sequence Fc region. Exemplary "effector functions" include C1q binding; CDC; Fc receptor binding; ADCC; phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors), etc. Such effector functions generally require the Fc region to be combined with a binding region or binding domain (e.g., an antibody variable region or variable domain) and can be assessed using a variety of assays known to those skilled in the art. A "variant Fc region" comprises an amino acid sequence that differs from a native sequence Fc region by at least one amino acid modification (e.g., substitution, addition, or deletion). In certain embodiments, the variant Fc region has at least one amino acid substitution in the native sequence Fc region or in the Fc region of the parent polypeptide, such as about one to about ten amino acid substitutions, or about one to about five amino acid substitutions, compared to the native sequence Fc region or to the Fc region of the parent polypeptide. Herein, the variant Fc region may have at least about 80% homology with the native sequence Fc region and/or the Fc region of the parent polypeptide, or at least about 90% homology therewith, such as at least about 95% homology therewith.
如本文所用，「抗原決定基」為此項技術中之術語且係指結合分子(例如抗體)可特異性結合之抗原的局部區域。抗原決定基可為線性抗原決定基或可為構形、非線性或不連續之抗原決定基。舉例而言，在多肽抗原之情況下，抗原決定基可為多肽之連續胺基酸(「線性」抗原決定基)或抗原決定基可包含來自多肽之兩個或更多個非連續區域的胺基酸(「構形」、「非線性」或「不連續」抗原決定基)。熟習此項技術者應瞭解，一般而言，線性抗原決定基可或可不依賴於二級、三級或四級結構。舉例而言，在一些實施例中，結合分子結合至一組胺基酸，不論其是否摺疊成天然三維蛋白質結構。在其他實施例中，結合分子需要構成抗原決定基之胺基酸殘基展現特定構形(例如彎曲、扭轉、轉角或摺疊)以識別及結合抗原決定基。As used herein, "antigenic determinant" is a term in the art and refers to a localized region of an antigen to which a binding molecule (e.g., an antibody) can specifically bind. An antigenic determinant may be a linear antigenic determinant or may be a conformational, nonlinear, or discontinuous antigenic determinant. For example, in the case of a polypeptide antigen, an antigenic determinant may be contiguous amino acids of the polypeptide (a "linear" antigenic determinant) or an antigenic determinant may comprise amino acids from two or more noncontiguous regions of the polypeptide (a "conformational," "nonlinear," or "discontinuous" antigenic determinant). Those skilled in the art will appreciate that, in general, a linear antigenic determinant may or may not rely on secondary, tertiary, or quaternary structure. For example, in some embodiments, the binding molecule binds to a group of amino acids, whether or not it is folded into a native three-dimensional protein structure. In other embodiments, the binding molecule requires the amino acid residues that constitute the antigenic determinant to exhibit a specific conformation (e.g., bend, twist, turn or fold) in order to recognize and bind to the antigenic determinant.
術語「多肽」及「肽」及「蛋白質」在本文中可互換使用且係指任何長度之胺基酸聚合物。聚合物可為直鏈或分支鏈，其可包含經修飾之胺基酸，且其可間雜有非胺基酸。該等術語亦涵蓋已經天然修飾或藉由干預(例如二硫鍵形成、醣基化、脂質化、乙醯化、磷酸化，或任何其他操縱或修飾)修飾之胺基酸聚合物。定義內亦包括例如含有胺基酸之一或多種類似物(包括(但不限於)非天然胺基酸)以及此項技術中已知之其他修飾的多肽。應理解，由於本發明之多肽可基於免疫球蛋白超家族之抗體或其他成員，在某些實施例中，「多肽」可以單鏈形式或以兩個或更多個相關鏈形式出現。The terms "polypeptide" and "peptide" and "protein" are used interchangeably herein and refer to amino acid polymers of any length. The polymer may be a straight or branched chain, it may contain modified amino acids, and it may be interspersed with non-amino acids. The terms also encompass amino acid polymers that have been modified naturally or by intervention (e.g., disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification). Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including but not limited to non-natural amino acids) and other modifications known in the art. It should be understood that, because the polypeptides of the present invention may be based on antibodies or other members of the immunoglobulin superfamily, in certain embodiments, a "polypeptide" may appear in a single chain or in the form of two or more related chains.
如本文所用，術語「醫藥學上可接受」意謂經聯邦或州政府之管制機構批准或列於美國藥典(U.S. Pharmacopia)、歐洲藥典(European Pharmacopia)或其他公認藥典中用於動物，且更特定言之人類。As used herein, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the U.S. Pharmacopia, European Pharmacopia, or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
「賦形劑」意謂醫藥學上可接受之材料、組合物或媒劑，諸如液體或固體填充劑、稀釋劑、溶劑或囊封材料。賦形劑包括例如囊封材料或添加劑，諸如吸收加速劑、抗氧化劑、黏合劑、緩衝劑、載劑、包衣劑、著色劑、稀釋劑、崩解劑、乳化劑、增量劑、填充劑、調味劑、保濕劑、潤滑劑、香料、防腐劑、推進劑、釋放劑、滅菌劑、甜味劑、增溶劑、潤濕劑及其混合物。術語「賦形劑」亦可指稀釋劑、佐劑(例如弗氏佐劑(Freunds' adjuvant) (完全或不完全)或媒劑。"Formulating agent" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, solvent or encapsulating material. Formulating agents include, for example, encapsulating materials or additives, such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavorings, humectants, lubricants, flavors, preservatives, propellants, release agents, bactericides, sweeteners, solubilizers, wetting agents and mixtures thereof. The term "excipient" may also refer to a diluent, an adjuvant (eg, Freunds' adjuvant (complete or incomplete)), or a vehicle.
在一個實施例中，各組分在以下意義上為「醫藥學上可接受的」：與醫藥調配物之其他成分相容且適用於與人類及動物之組織或器官接觸而無過度毒性、刺激、過敏反應、免疫原性或其他問題或併發症，與合理益處/風險比相稱。參見例如Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 第6版; Rowe等人編；The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 第3版；Ash及Ash編；Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 第2版; Gibson編; CRC Press LLC: Boca Raton, FL, 2009。在一些實施例中，醫藥學上可接受之賦形劑在所用劑量及濃度下對暴露於其之細胞或哺乳動物無毒。在一些實施例中，醫藥學上可接受之賦形劑為水性pH緩衝溶液。In one embodiment, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio. See, e.g., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th edition; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd edition; Ash and Ash, eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd edition; Gibson, ed.; CRC Press LLC: Boca Raton, FL, 2009. In some embodiments, the pharmaceutically acceptable excipient is non-toxic to cells or mammals exposed thereto at the dosages and concentrations used. In some embodiments, the pharmaceutically acceptable excipient is an aqueous pH buffered solution.
縮寫「MMAE」係指單甲基奧瑞他汀E。The abbreviation "MMAE" refers to monomethylauristatin E.
除非上下文另外指示，否則連字符(-)表示與側分子之連接點。Unless the context indicates otherwise, a hyphen (-) indicates a point of attachment to a side molecule.
術語「化學治療劑」係指有效抑制腫瘤生長之所有化合物。化學治療劑之非限制性實例包括：烷基化劑，例如氮芥、伸乙亞胺化合物及磺酸烷基酯；抗代謝物，例如葉酸、嘌呤或嘧啶拮抗劑；有絲分裂抑制劑，例如抗微管蛋白劑，諸如長春花生物鹼、奧瑞他汀(auristatin)及鬼臼毒素(podophyllotoxin)之衍生物；細胞毒性抗生素；損傷或干擾DNA表現或複製之化合物，例如DNA小溝結合劑；及生長因子受體拮抗劑。另外，化學治療劑包括細胞毒性劑(如本文所定義)、抗體、生物分子及小分子。The term "chemotherapeutic agent" refers to all compounds that are effective in inhibiting tumor growth. Non-limiting examples of chemotherapeutic agents include: alkylating agents, such as nitrogen mustards, ethylenimine compounds, and alkyl sulfonates; anti-metabolites, such as folic acid, purine or pyrimidine antagonists; mitotic inhibitors, such as anti-tubulin agents, such as derivatives of vinca alkaloids, auristatins, and podophyllotoxin; cytotoxic antibiotics; compounds that damage or interfere with DNA expression or replication, such as DNA minor groove binders; and growth factor receptor antagonists. In addition, chemotherapeutic agents include cytotoxic agents (as defined herein), antibodies, biological molecules, and small molecules.
如本文所用，術語「保守取代」係指胺基酸之取代為熟習此項技術者已知的且一般可進行而不會改變所得分子之生物活性。熟習此項技術者認識到，一般而言，在多肽之非必需區域中之單胺基酸取代實質上不改變生物活性(參見例如Watson等人, MOLECULAR BIOLOGY OF THE GENE, The Benjamin/Cummings Pub. Co., 第224頁(第4版1987))。此類例示性取代較佳根據表2及表3中所闡述之彼等取代進行。舉例而言，此類變化包括異白胺酸(I)、纈胺酸(V)及白胺酸(L)中之任一個取代此等疏水性胺基酸中之任何其他胺基酸；天冬胺酸(D)取代麩胺酸(E)且反之亦然；麩醯胺酸(Q)取代天冬醯胺(N)且反之亦然；及絲胺酸(S)取代蘇胺酸(T)且反之亦然。視特定胺基酸之環境及其在蛋白質三維結構中之作用而定，其他取代亦可視為保守的。舉例而言，甘胺酸(G)與丙胺酸(A)常常為可互換的，且丙胺酸(A)與纈胺酸(V)亦可為可互換的。相對呈疏水性之甲硫胺酸(M)時常可與白胺酸及異白胺酸互換，且有時可與纈胺酸互換。離胺酸(K)與精胺酸(R)在胺基酸殘基之顯著特徵為其電荷之位置中時常為可互換的且該兩個胺基酸殘基之pK差異不顯著。在特定環境中，仍有其他變化可視為「保守的」(參見例如本文中之表3；「Biochemistry」第2版的第13-15頁, Lubert Stryer編(Stanford University)；Henikoff等人, PNAS 1992 第89卷10915-10919；Lei等人, J Biol Chem 1995年5月19日; 270(20):11882-11886)。其他取代亦可容許且可憑經驗或根據已知之保守取代確定。表2胺基酸縮寫
術語「同源性」或「同源」欲意謂兩個聚核苷酸之間或兩個多肽之間的序列相似性。相似性可藉由對出於比較目的而比對之各序列中的位置進行比較來判定。若兩種多肽序列之給定位置不一致，則該位置之相似性或保守性可藉由評估該位置之胺基酸的相似性(例如根據表3)來確定。序列之間之相似程度隨該等序列共有之匹配或同源位置的數目而變化。比對兩個序列以確定其序列相似性百分比可使用此項技術中已知之軟體程式進行，諸如Ausubel等人, Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, MD(1999)中描述之軟體程式。較佳地，使用預設參數進行比對，其實例闡述如下。可使用的此項技術中熟知之一個比對程式係設定成預設參數之BLAST。特定言之，程式為BLASTN及BLASTP，使用以下預設參數：遺傳密碼=標準；過濾器=無；股=兩條；截止值=60；期望值=10；矩陣=BLOSUM62；描述=50個序列；分選方式=HIGH SCORE；資料庫=非冗餘，GenBank + EMBL + DDBJ + PDB + GenBank CDS轉譯+ Swissprotein + SPupdate + PIR。此等程式之詳情可見於國家生物技術資訊中心(National Center for Biotechnology Information)。The term "homology" or "homologous" is intended to mean sequence similarity between two polynucleotides or between two polypeptides. Similarity can be determined by comparing positions in each sequence that is aligned for comparison purposes. If a given position of two polypeptide sequences is not identical, the similarity or conservation of that position can be determined by evaluating the similarity of the amino acids at that position (e.g., according to Table 3). The degree of similarity between sequences varies with the number of matching or homologous positions shared by the sequences. Aligning two sequences to determine their percent sequence similarity can be performed using software programs known in the art, such as the software program described in Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, MD (1999). Preferably, the alignment is performed using preset parameters, examples of which are described below. One well-known alignment program of this technique that can be used is BLAST set to default parameters. Specifically, the programs are BLASTN and BLASTP, using the following default parameters: genetic code = standard; filter = none; strands = two; cutoff = 60; expectation = 10; matrix = BLOSUM62; description = 50 sequences; sorting method = HIGH SCORE; databases = non-redundant, GenBank + EMBL + DDBJ + PDB + GenBank CDS translation + Swissprotein + SPupdate + PIR. Details of these programs can be found at the National Center for Biotechnology Information.
既定胺基酸序列或核酸序列之術語「同源物」意指「同源物」之對應序列與既定胺基酸序列或核酸序列具有實質上的一致性或同源性。The term "homolog" of a given amino acid sequence or nucleic acid sequence means that the corresponding sequence of the "homolog" has substantial identity or homology with the given amino acid sequence or nucleic acid sequence.
兩個序列(例如胺基酸序列或核酸序列)之間的一致性百分比之測定可使用數學演算法來實現。用於比較兩個序列之數學演算法的較佳非限制性實例為Karlin及Altschul, 1990, Proc. Natl. Acad. Sci. U.S.A. 87:2264 2268之演算法，如Karlin及Altschul, 1993, Proc. Natl. Acad. Sci. U.S.A. 90:5873 5877中所修改。將此類演算法併入Altschul等人, 1990, J. Mol. Biol. 215:403之NBLAST及XBLAST程式中。可利用NBLAST核苷酸程式參數集(例如對於分數=100而言，字長=12)進行BLAST核苷酸搜尋，以獲得與本文所述之核酸分子同源的核苷酸序列。可利用XBLAST程式參數集(例如對分數50而言，字長=3)進行BLAST蛋白質搜尋，以獲得與本文所述之蛋白質分子同源的胺基酸序列。為獲得間隙比對以達成比較目的，可如Altschul等人, 1997, Nucleic Acids Res. 25:3389 3402中所描述利用間隙式BLAST。替代地，PSI BLAST可用於進行迭代搜尋，其偵測分子間之遠距離關係(同上)。當利用BLAST、間隙式BLAST及PSI Blast程式時，可使用各別程式(例如XBLAST及NBLAST)之預設參數(參見例如，全球資訊網上之國家生物技術資訊中心(NCBI)，ncbi.nlm.nih.gov)。用於序列比較之數學演算法的另一個非限制實例為Myers及Miller, 1988, CABIOS 4:11 17之演算法。此類演算法併入ALIGN程式(2.0版)中，該ALIGN程式為GCG序列比對套裝軟體之一部分。當利用ALIGN程式來比較胺基酸序列時，可使用PAM120權重殘基表、間隙長度罰分12及間隙罰分4。The determination of the percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be achieved using a mathematical algorithm. A preferred non-limiting example of a mathematical algorithm for comparing two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. U.S.A. 87:2264 2268, as modified in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci. U.S.A. 90:5873 5877. Such algorithms are incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J. Mol. Biol. 215:403. BLAST nucleotide searches can be performed using the NBLAST nucleotide program parameter set (e.g., wordlength = 12 for score = 100) to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. BLAST protein searches can be performed using the XBLAST program parameter set (e.g., wordlength = 3 for score 50) to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be used as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402. Alternatively, PSI BLAST can be used to perform an iterated search, which detects distant relationships between molecules (supra). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the World Wide Web, ncbi.nlm.nih.gov). Another non-limiting example of a mathematical algorithm used for sequence comparison is the algorithm of Myers and Miller, 1988, CABIOS 4:11 17. Such an algorithm is incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment suite. When utilizing the ALIGN program to compare amino acid sequences, a PAM120 weighted residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.
兩個序列之間的一致性百分比可在允許有間隙或不允許有間隙的情況下，使用與上文所描述類似的技術來測定。在計算一致性百分比時，通常僅對精確匹配進行計數。The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating the percent identity, typically only exact matches are counted.
術語「細胞毒性劑」係指抑制或阻止細胞表現活性、細胞功能及/或引起細胞破壞之物質。該術語意欲包括放射性同位素、化學治療劑及毒素，諸如細菌、真菌、植物或動物來源之小分子毒素或酶活性毒素，包括其片段及/或變異體。細胞毒性劑之實例包括但不限於奧瑞他汀(例如奧瑞他汀E、奧瑞他汀F、MMAE及MMAF)、金黴素(auromycins)、類美登素(maytansinoids)、蓖麻毒素(ricin)、蓖麻毒素A鏈、康普瑞汀(combrestatin)、倍癌黴素(duocarmycins)、海兔毒素(dolastatins)、小紅莓(doxorubicin)、道諾黴素(daunorubicin)、紫杉醇(taxols)、順鉑、cc1065、溴化乙錠、絲裂黴素(mitomycin)、依託泊苷(etoposide)、替尼泊苷(tenoposide)、長春新鹼(vincristine)、長春鹼(vinblastine)、秋水仙鹼(colchicine)、二羥基炭疽菌素二酮、放線菌素(actinomycin)、白喉毒素(diphtheria toxin)、綠膿桿菌外毒素(PE) A、PE40、相思子毒素(abrin)、相思子毒素A鏈、莫迪素A鏈(modeccin A chain)、α-帚麴菌素(sarcin)、白樹素(gelonin)、有絲分裂素(mitogellin)、侷限麴菌素(retstrictocin)、酚黴素(phenomycin)、伊諾黴素(enomycin)、麻瘋樹逆境蛋白(curicin)、巴豆毒素(crotin)、卡奇黴素(calicheamicin)、肥皂草抑制劑(Sapaonaria officinalis inhibitor)及糖皮質激素及其他化學治療劑，以及放射性同位素，諸如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212或Bi213、P32及Lu之放射性同位素，包括Lu177。抗體亦可與能夠將前藥轉化成其活性形式的抗癌前藥活化酶結合。The term "cytotoxic agent" refers to a substance that inhibits or prevents cell activity, cell function and/or causes cell destruction. The term is intended to include radioactive isotopes, chemotherapeutic agents and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof. Examples of cytotoxic agents include, but are not limited to, auristatins (e.g., auristatin E, auristatin F, MMAE and MMAF), auromycins, maytansinoids, ricin, ricin A chain, combrestatin, duocarmycins, dolastatins, doxorubicin, daunomycin ... orubicin), paclitaxel, cisplatin, cc1065, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxyanthraquinone, actinomycin, diphtheria toxin toxin), Pseudomonas exotoxin (PE) A, PE40, abrin, abrin A chain, modeccin A chain, α-sarcin, gelonin, mitogellin, retstrictocin, phenomycin, enomycin, curicin, crotin, calicheamicin, Sapaonaria officinalis inhibitor, and glucocorticoids and other chemotherapeutic agents, as well as radioactive isotopes such as At211 , I131 , I125 , Y90 , Re186 , Re188 , Sm153 , Bi212 or Bi213 , P32 and radioactive isotopes of Lu, including Lu177 . The antibody may also be conjugated to an anticancer prodrug activating enzyme capable of converting the prodrug into its active form.
如本文所用，術語「有效量」或「治療有效量」係指足以產生所需結果的本文所提供之結合分子(例如抗體)或醫藥組合物的量。As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a binding molecule (eg, antibody) or pharmaceutical composition provided herein sufficient to produce a desired result.
術語「個體」與「患者」可互換使用。如本文所用，在某些實施例中，個體為哺乳動物，諸如非靈長類動物(例如乳牛、豬、馬、貓、犬、大鼠等)或靈長類動物(例如猴及人類)。在特定實施例中，個體為人類。在一個實施例中，個體為診斷患有病狀或病症之哺乳動物，例如人類。在另一實施例中，個體為處於發展病狀或病症之風險下的哺乳動物，例如人類。The terms "subject" and "patient" are used interchangeably. As used herein, in certain embodiments, the subject is a mammal, such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.) or a primate (e.g., monkeys and humans). In specific embodiments, the subject is a human. In one embodiment, the subject is a mammal, such as a human, diagnosed with a condition or disorder. In another embodiment, the subject is a mammal, such as a human, at risk of developing a condition or disorder.
「投與(administer/administration)」係指將存在於體外的物質注射或另外物理遞送至患者體內之操作，諸如藉由經黏膜、皮內、靜脈內、肌肉內遞送，及/或本文所描述或此項技術中已知之任何其他物理遞送方法。"Administer" or "administration" refers to the act of injecting or otherwise physically delivering a substance present outside the body into a patient's body, such as by transmucosal, intradermal, intravenous, intramuscular, and/or any other physical delivery method described herein or known in the art.
如本文所用，術語「治療(treat/treatment/treating)」係指疾病或病狀之惡化、嚴重度及/或持續時間因投與一或多種療法而減少或改善。治療可如下確定：評估與潛在病症相關之一或多種症狀是否已減少、緩解及/或緩和，從而觀測到患者之改善，儘管患者可能仍罹患該潛在病症。術語「治療」包括管控及改善疾病兩者。術語「管控(manage/managing/management)」係指個體自療法獲得之有益作用，其未必引起疾病治癒。As used herein, the term "treat/treatment/treating" refers to a reduction or improvement in the worsening, severity, and/or duration of a disease or condition as a result of the administration of one or more therapies. Treatment can be determined by assessing whether one or more symptoms associated with the underlying condition have been reduced, alleviated, and/or relieved, thereby observing improvement in the patient, although the patient may still be suffering from the underlying condition. The term "treat" includes both management and improvement of the disease. The term "manage/managing/management" refers to the beneficial effects obtained by an individual's self-treatment, which may not necessarily result in a cure for the disease.
術語「預防(prevent/preventing/prevention)」係指降低疾病、病症、病狀或相關症狀(例如癌症)發作(或復發)之可能性。The terms "prevent" (preventing) or "prevention" refer to reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or related symptoms (e.g., cancer).
術語「癌症」或「癌細胞」在本文中用於指代發現於贅瘤中之組織或細胞，其擁有將其與正常組織或組織細胞區分開的特徵。此類特徵包括(但不限於)：退行發育程度、形狀之不規則性、細胞輪廓不清晰、細胞核尺寸、細胞核或細胞質結構的變化、其他表型變化、指示癌性或癌前狀態之細胞蛋白質的存在、有絲分裂數目增加，及能夠轉移。關於「癌症」之詞包括癌瘤、肉瘤、腫瘤、上皮瘤、白血病、淋巴瘤、息肉及硬癌、轉形、贅瘤及其類似者。The term "cancer" or "cancer cells" is used herein to refer to tissues or cells found in tumors that possess characteristics that distinguish them from normal tissues or tissue cells. Such characteristics include, but are not limited to, degree of anaplasia, irregularity of shape, lack of clear cell outlines, nuclear size, changes in nuclear or cytoplasmic structure, other phenotypic changes, the presence of cellular proteins indicative of a cancerous or precancerous state, increased number of mitoses, and the ability to metastasize. The term "cancer" includes carcinomas, sarcomas, tumors, epithelioma, leukemias, lymphomas, polyps and scirrhosis, transformations, tumors, and the like.
如本文所用，「局部晚期」癌症係指已自其開始處擴散至附近組織或淋巴結的癌症。As used herein, "locally advanced" cancer refers to cancer that has spread from where it started to nearby tissues or lymph nodes.
如本文所用，「轉移性」癌症係指已自其開始處擴散至身體之不同部分的癌症。As used herein, "metastatic" cancer refers to cancer that has spread to different parts of the body from where it started.
術語「約」及「大致」意謂在既定值或範圍的20%以內、15%以內、10%以內、9%以內、8%以內、7%以內、6%以內、5%以內、4%以內、3%以內、2%以內、1%以內或更小。The terms "about" and "substantially" mean within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1% or less of a stated value or range.
除非上下文另有明確規定，否則如本發明及申請專利範圍中所用，單數形式「一(a)」、「一(an)」及「該(the)」包括複數形式。As used in the present invention and claims, the singular forms "a", "an" and "the" include plural forms unless the context clearly dictates otherwise.
應理解，每當在本文中用術語「包含」描述實施例時，亦提供用術語「由……組成」及/或「基本上由……組成」描述之另外類似的實施例。亦應理解，每當在本文中用片語「基本上由……組成」描述實施例時，亦提供用術語「由……組成」描述之另外類似的實施例。It should be understood that whenever an embodiment is described herein using the term "comprising", additional similar embodiments described using the term "consisting of" and/or "consisting essentially of" are also provided. It should also be understood that whenever an embodiment is described herein using the phrase "consisting essentially of", additional similar embodiments described using the term "consisting of" are also provided.
如諸如「A及/或B」之片語中所使用的術語「及/或」在本文中意欲包括A及B兩者；A或B；A (單獨)；及B (單獨)。同樣，如諸如「A、B及/或C」之片語中所使用的術語「及/或」意欲涵蓋以下實施例中之各者：A、B及C；A、B或C；A或C；A或B；B或C；A及C；A及B；B及C；A (單獨)；B (單獨)；及C (單獨)。The term "and/or" as used in phrases such as "A and/or B" is intended herein to include both A and B; A or B; A (alone); and B (alone). Similarly, the term "and/or" as used in phrases such as "A, B, and/or C" is intended to cover each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
術語「變異體」係指與所述類型或規範展現不同的分子，諸如在具體描述蛋白質(例如圖1A中所示之191P4D12蛋白質)之對應位置中具有一或多個不同胺基酸殘基的蛋白質。類似物為變異蛋白之一個實例。剪接同功異型物及單一核苷酸多態現象(SNP)係變異體之其他實例。The term "variant" refers to a molecule that exhibits differences from the described type or specification, such as a protein having one or more different amino acid residues in corresponding positions of a specific described protein (e.g., the 191P4D12 protein shown inFigure1A ). Analogs are one example of a variant protein. Splice isoforms and single nucleotide polymorphisms (SNPs) are other examples of variants.
本發明之「191P4D12蛋白質」及/或「191P4D12相關蛋白質」包括本文中具體鑑別之彼等蛋白質(參見圖1A)，以及遵循本文中概述或此項技術中容易獲得的方法、無需過度實驗便可分離/產生及表徵的對偶基因變異體、保守取代變異體、類似物及同源物。將不同191P4D12蛋白質或其片段之各部分組合的融合蛋白以及191P4D12蛋白質與異源多肽之融合蛋白亦包括在內。此類191P4D12蛋白質統稱為191P4D12相關蛋白質、本發明之蛋白質或191P4D12。術語「191P4D12相關蛋白質」係指4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25個或超過25個胺基酸；或至少30、35、40、45、50、55、60、65、70、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195、200、225、250、275、300、325、330、335、339個或更多個胺基酸的多肽片段或191P4D12蛋白質序列。術語「191P4D12」可與連接素-4互換使用。5.2治療癌症之方法The "191P4D12 protein" and/or "191P4D12-related protein" of the present invention include those proteins specifically identified herein (seeFigure1A ), as well as allele variants, conservative substitution variants, analogs and homologs that can be isolated/produced and characterized without undue experimentation following the methods outlined herein or readily available in the art. Fusion proteins combining parts of different 191P4D12 proteins or fragments thereof and fusion proteins of 191P4D12 proteins and heterologous polypeptides are also included. Such 191P4D12 proteins are collectively referred to as 191P4D12-related proteins, proteins of the present invention or 191P4D12. The term "191P4D12-related protein" refers to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more amino acids; or at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95, 100, 10 5. A polypeptide fragment of 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 330, 335, 339 or more amino acids or a 191P4D12 protein sequence. The term "191P4D12" may be used interchangeably with nectin-4.5.2Methods of treating cancer
不適合順鉑之患者的尿路上皮癌及膀胱癌(包括局部晚期尿路上皮癌、轉移性尿路上皮癌、局部晚期膀胱癌及轉移性膀胱癌)為特別難以治療的疾病。通常，此等患者體虛，罹患除尿路上皮癌/膀胱癌之外的多種共生病症，且不能夠耐受其他治療，導致許多患者完全中止療法。因此，此等患者具有不良預後及極少治療選項。本發明部分地基於第一臨床試驗之結果以證明客觀反應，其中恩諾單抗維多汀與派姆單抗之組合作為一線治療向不能接受基於順鉑之化學療法的不可切除性局部晚期或轉移性尿路上皮癌(la/mUC)之患者投與。本發明因此提供經證明有效治療尿路上皮癌及/或膀胱癌(包括局部晚期尿路上皮癌、轉移性尿路上皮癌、局部晚期膀胱癌及轉移性膀胱癌)患者的方法，該等患者但在此情況下由於腎功能不充分或如本文所提供之其他條件而不能接收基於順鉑之化學療法。在本文所述之結果之前，考慮到歷史上已證明此患者群體如此難以治療，因此本文提供的方法是否會有效存在相當大的不確定性。如下文進一步描述，所得功效水平特別顯著且驚人。5.2.1治療一般患者及所選患者之癌症的方法Urothelial carcinoma and bladder cancer (including locally advanced urothelial carcinoma, metastatic urothelial carcinoma, locally advanced bladder cancer, and metastatic bladder cancer) in patients who are not suitable for cisplatin are particularly difficult to treat diseases. Typically, these patients are weak, suffer from multiple comorbidities in addition to urothelial carcinoma/bladder cancer, and cannot tolerate other treatments, causing many patients to discontinue treatment completely. Therefore, these patients have a poor prognosis and very few treatment options. The present invention is based in part on the results of the first clinical trial to demonstrate objective response, in which the combination of enrofloxacin and pembrolizumab was administered as a first-line treatment to patients with unresectable locally advanced or metastatic urothelial carcinoma (la/mUC) who cannot accept cisplatin-based chemotherapy. The present invention therefore provides methods that have been shown to be effective in treating patients with urothelial carcinoma and/or bladder cancer (including locally advanced urothelial carcinoma, metastatic urothelial carcinoma, locally advanced bladder cancer, and metastatic bladder cancer), who in this case are unable to receive cisplatin-based chemotherapy due to insufficient renal function or other conditions as provided herein. Prior to the results described herein, there was considerable uncertainty as to whether the methods provided herein would be effective, given that this patient population has historically proven to be so difficult to treat. As further described below, the levels of efficacy achieved are particularly remarkable and surprising.5.2.1Methods for Treating Cancer in General Patients and Selected Patients
本文提供使用結合191P4D12之抗體藥物結合物(ADC)組合抗PD-1抗體(例如派姆單抗)對個體(包括不能接受基於順鉑之化學療法的不可切除性局部晚期或轉移性尿路上皮癌(la/mUC)之個體)之多種癌症進行一線及二線治療的方法。Provided herein are methods of using an antibody-drug conjugate (ADC) that binds 191P4D12 in combination with an anti-PD-1 antibody (e.g., pembrolizumab) for first-line and second-line treatment of a variety of cancers in individuals, including individuals with unresectable locally advanced or metastatic urothelial carcinoma (la/mUC) who are unable to receive cisplatin-based chemotherapy.
在一個態樣中，本文提供使用結合191P4D12之ADC及抗PD-1抗體(例如派姆單抗)治療個體之癌症的方法。在一些實施例中，經本文所提供之方法治療的人類個體先前未接受過除結合191P4D12之ADC之外的癌症治療。在某些實施例中，經本文所提供之方法治療的人類個體先前未接受包括免疫檢查點抑制劑(CPI)或由免疫檢查點抑制劑(CPI)組成之治療。在一些實施例中，CPI為抗PD-1抗體(例如派姆單抗)。在一些實施例中，CPI為PD-1抑制劑、PD-L1抑制劑或PD-L2抑制劑(包括(但不限於)阿特珠單抗、派姆單抗、納武單抗、德瓦魯單抗或阿維魯單抗)。在特定實施例中，CPI為阿特珠單抗、派姆單抗、納武單抗、德瓦魯單抗或阿維魯單抗。在某些實施例中，經本文所提供之方法治療的人類個體尚未接受針對另一刺激性或共抑制性T細胞受體之藥劑(包括(但不限於) CD137促效劑、CTLA 4抑制劑或OX-40促效劑)。在特定實施例中，針對另一刺激性或共抑制性T細胞受體之藥劑為CD137促效劑、CTLA 4抑制劑或OX-40促效劑。在一些實施例中，經本文所提供之方法治療的人類個體不適合接受順鉑療法。在其他實施例中，經本文所提供之方法治療的人類個體不適合接受順鉑療法且先前未接受過包括CPI或由CPI組成的療法。在某些實施例中，經本文所提供之方法治療的人類個體不適合接受順鉑治療，先前未接受過包括CPI或由CPI組成之治療，且在隨機分組之前12個月內未接受過輔助/前輔助基於鉑之療法。在另外其他實施例中，經本文所提供之方法治療的人類個體不適合接受順鉑治療，先前未接受過包括CPI或由CPI組成之治療，在隨機分組之前12個月內未接受過輔助/前輔助基於鉑之療法，且先前未接受過針對局部晚期或轉移性疾病之全身治療。在一些實施例中，癌症為尿路上皮癌。在某些實施例中，癌症為膀胱癌。在某些實施例中，癌症為腎盂癌。在某些實施例中，癌症為輸尿管癌。在某些實施例中，癌症為尿道癌。在一個實施例中，癌症為局部晚期癌。在另一實施例中，癌症為轉移性癌症。在另一實施例中，癌症為局部晚期尿路上皮癌。在另一實施例中，癌症為不可切除性局部晚期尿路上皮癌。在又一實施例中，癌症為轉移性尿路上皮癌。在一個實施例中，癌症為局部晚期膀胱癌。在另一實施例中，癌症為轉移性膀胱癌。5.2.1.1不適合順鉑的患者In one aspect, provided herein is a method for treating cancer in an individual using an ADC that binds 191P4D12 and an anti-PD-1 antibody (e.g., pembrolizumab). In some embodiments, the human individual treated by the method provided herein has not previously received cancer treatment other than an ADC that binds 191P4D12. In certain embodiments, the human individual treated by the method provided herein has not previously received treatment including or consisting of an immune checkpoint inhibitor (CPI). In some embodiments, the CPI is an anti-PD-1 antibody (e.g., pembrolizumab). In some embodiments, the CPI is a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). In certain embodiments, the CPI is atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab. In certain embodiments, the human subject treated by the methods provided herein has not received an agent directed to another stimulatory or co-inhibitory T cell receptor (including but not limited to a CD137 agonist, a CTLA 4 inhibitor, or an OX-40 agonist). In certain embodiments, the agent directed to another stimulatory or co-inhibitory T cell receptor is a CD137 agonist, a CTLA 4 inhibitor, or an OX-40 agonist. In some embodiments, the human subject treated by the methods provided herein is not suitable for cisplatin therapy. In other embodiments, the human subject treated with the methods provided herein is not suitable for cisplatin therapy and has not previously received a therapy comprising or consisting of a CPI. In certain embodiments, the human subject treated with the methods provided herein is not suitable for cisplatin therapy, has not previously received a therapy comprising or consisting of a CPI, and has not received adjuvant/pre-adjuvant platinum-based therapy within 12 months prior to randomization. In yet other embodiments, the human subject treated by the methods provided herein is not suitable for cisplatin therapy, has not previously received therapy comprising or consisting of a CPI, has not received adjuvant/pre-adjuvant platinum-based therapy within 12 months prior to randomization, and has not previously received systemic therapy for locally advanced or metastatic disease. In some embodiments, the cancer is urothelial carcinoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is renal pelvic cancer. In some embodiments, the cancer is ureteral cancer. In some embodiments, the cancer is urethral cancer. In one embodiment, the cancer is locally advanced cancer. In another embodiment, the cancer is metastatic cancer. In another embodiment, the cancer is locally advanced urothelial carcinoma. In another embodiment, the cancer is unresectable locally advanced urothelial carcinoma. In yet another embodiment, the cancer is metastatic urothelial carcinoma. In one embodiment, the cancer is locally advanced bladder cancer. In another embodiment, the cancer is metastatic bladder cancer.5.2.1.1Patients Not Suitable for Cisplatin
對於本文所提供之方法，包括(但不限於)前述段落中的方法，可利用不同條件確定人類個體之順鉑不適合性。在一個實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由腎功能受損(例如腎小球濾過率(GFR)或肌酐清除率＜60 mL/min但≥30 mL/min (藉由科克羅夫特-高爾特公式、腎病膳食改良[modification of diet in renal disease，MDRD]或24小時尿液估算))組成。在某些實施例中，用於確定順鉑不適合性的條件包含不小於2級的聽力損失(例如CI CTCAE 4.03版≥2級聽力損失)或由其組成。在某些實施例中，用於確定順鉑不適合性的條件包含或由NYHA III級心臟衰竭組成。在一個實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態及腎功能受損組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態及不小於2級的聽力損失組成。在某些實施例中，用於確定順鉑不適合性的條件包含或由腎功能受損及不小於2級的聽力損失組成。在其他實施例中，用於確定順鉑不適合性的條件包含或由腎功能受損及NYHA III級心臟衰竭組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、腎功能受損及不小於2級的聽力損失組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由腎功能受損、不小於2級的聽力損失及NYHA III級心臟衰竭組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、腎功能受損及不小於2級的聽力損失中的任一者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由腎功能受損、不小於2級的聽力損失及NYHA III級心臟衰竭中的任一者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、腎功能受損及不小於2級的聽力損失中之任兩者的任何組合或排列組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由腎功能受損、不小於2級的聽力損失及NYHA III級心臟衰竭中之任兩者的任何組合或排列組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、腎功能受損及不小於2級的聽力損失中的所有三者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由腎功能受損、不小於2級的聽力損失及NYHA III級心臟衰竭中的所有三者組成。在本文所提供之方法的一些實施例中，個體先前未接受過針對局部晚期或轉移性疾病之全身治療。在本文所提供之方法的一些實施例中，個體在隨機分組之前12個月內未接受輔助/前輔助基於鉑之療法。在本文所提供之方法的一些實施例中，其中個體具有2分的ECOG體能狀態，個體(i)血紅素≥10 g/dL；(ii) GFR≥50 mL/min；及(iii)不具有NYHA III級心臟衰竭。For the methods provided herein, including but not limited to the methods in the preceding paragraphs, different conditions can be used to determine cisplatin incompatibility in a human subject. In one embodiment, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of impaired renal function (e.g., glomerular filtration rate (GFR) or creatinine clearance <60 mL/min but ≥30 mL/min (estimated by Cockcroft-Gault formula, modification of diet in renal disease, MDRD, or 24-hour urine)). In certain embodiments, the conditions for determining cisplatin incompatibility include or consist of hearing loss of not less than 2 grades (e.g., CI CTCAE version 4.03 ≥ 2 grades of hearing loss). In certain embodiments, the conditions for determining cisplatin incompatibility include or consist of NYHA class III heart failure. In one embodiment, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2 points and impaired renal function. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2 points and hearing loss of not less than 2 grades. In certain embodiments, the conditions for determining cisplatin incompetence include or consist of impaired renal function and hearing loss of not less than grade 2. In other embodiments, the conditions for determining cisplatin incompetence include or consist of impaired renal function and NYHA class III heart failure. In yet other embodiments, the conditions for determining cisplatin incompetence include or consist of an ECOG performance status of 2, impaired renal function, and hearing loss of not less than grade 2. In some embodiments, the conditions for determining cisplatin incompetence include or consist of impaired renal function, hearing loss of not less than grade 2, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompetence include or consist of any one of an ECOG performance status of 2, impaired renal function, and hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompetence include or consist of any one of impaired renal function, hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompetence include or consist of any combination or permutation of any two of an ECOG performance status of 2, impaired renal function, and hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompetence include or consist of any combination or permutation of any two of impaired renal function, hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompetence include or consist of all three of an ECOG performance status of 2, impaired renal function, and hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompetence include or consist of all three of impaired renal function, hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments of the methods provided herein, the individual has not previously received systemic therapy for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject has not received adjuvant/pre-adjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, wherein the subject has an ECOG performance status of 2, the subject (i) has hemoglobin ≥ 10 g/dL; (ii) has a GFR ≥ 50 mL/min; and (iii) does not have NYHA class III heart failure.
可利用此項技術中已知及可獲得的不同方式確定腎功能受損。對於本文所提供之方法，包括(但不限於)前述段落中的方法，本文提供了各種實施例來確定人類個體的腎功能受損。在一個實施例中，根據小於60 mL/min的腎小球濾過率(GFR)來確定腎功能受損。在一些實施例中，根據小於60 mL/min、但不小於30 mL/min的GFR來確定腎功能受損。在某些實施例中，根據小於30 mL/min、但不小於15 mL/min的GFR來確定腎功能受損。在本段落所提供之方法的一些實施例中，藉由24小時尿液收集來量測GFR。在本段落所提供之方法的其他實施例中，藉由科克羅夫特-高爾特準則來估算GFR。在本段落所提供之方法的其他實施例中，藉由腎病膳食改良[MDRD]來量測GFR。Impaired renal function may be determined using various methods known and available in the art. For the methods provided herein, including but not limited to the methods in the preceding paragraphs, various embodiments are provided herein to determine impaired renal function in a human individual. In one embodiment, impaired renal function is determined based on a glomerular filtration rate (GFR) of less than 60 mL/min. In some embodiments, impaired renal function is determined based on a GFR of less than 60 mL/min but not less than 30 mL/min. In certain embodiments, impaired renal function is determined based on a GFR of less than 30 mL/min but not less than 15 mL/min. In some embodiments of the methods provided in this paragraph, GFR is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, GFR is estimated by the Cockcroft-Gault criterion. In other embodiments of the methods provided in this paragraph, GFR is measured by the Modification of Diet in Renal Disease [MDRD].
在另一實施例中，根據小於60 mL/min的肌酐清除率(CrCl)來確定腎功能受損。在一些實施例中，根據小於60 mL/min、但不小於30 mL/min的CrCl來確定腎功能受損。在某些實施例中，根據小於30 mL/min、但不小於15 mL/min的CrCl來確定腎功能受損。在本段落所提供之方法的一些實施例中，藉由24小時尿液收集來量測CrCl。在本段落所提供之方法的其他實施例中，藉由科克羅夫特-高爾特準則來估算CrCl。In another embodiment, impaired renal function is determined based on a creatinine clearance (CrCl) of less than 60 mL/min. In some embodiments, impaired renal function is determined based on a CrCl of less than 60 mL/min, but not less than 30 mL/min. In certain embodiments, impaired renal function is determined based on a CrCl of less than 30 mL/min, but not less than 15 mL/min. In some embodiments of the methods provided in this paragraph, CrCl is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, CrCl is estimated by the Cockcroft-Gault criterion.
因此，對於本文所提供之方法，包括(但不限於)前述段落中的方法，可利用基於GFR或肌酐清除率的一些特定條件來確定人類個體的順鉑不適合性。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的GFR組成。在一個實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態及小於60 mL/min的CrCl組成。在其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的GFR及不小於2級的聽力損失組成。在其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的GFR及NYHA III級心臟衰竭組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min的GFR及不小於2級的聽力損失組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的GFR及不小於2級的聽力損失以及NYHA III級心臟衰竭組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min的GFR及不小於2級的聽力損失中的任一者組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的GFR及不小於2級的聽力損失以及NYHA III級心臟衰竭中的任一者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min的GFR及不小於2級的聽力損失中之任兩者的任何組合或排列組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的GFR及不小於2級的聽力損失以及NYHA III級心臟衰竭中之任兩者的任何組合或排列組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min的GFR及不小於2級的聽力損失中的所有三者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的GFR及不小於2級的聽力損失以及NYHA III級心臟衰竭中的所有三者組成。在本段落所提供之方法的一些實施例中，藉由24小時尿液收集來量測GFR。在本段落所提供之方法的其他實施例中，藉由科克羅夫特-高爾特準則來估算GFR。在本段落所提供之方法的其他實施例中，藉由腎病膳食改良[MDRD]來量測GFR。在本文所提供之方法的一些實施例中，個體先前未接受過針對局部晚期或轉移性疾病之全身治療。在本文所提供之方法的一些實施例中，個體在隨機分組之前12個月內未接受輔助/前輔助基於鉑之療法。在本文所提供之方法的一些實施例中，其中個體具有2分的ECOG體能狀態，個體(i)血紅素≥10 g/dL；(ii) GFR≥50 mL/min；及(iii)不具有NYHA III級心臟衰竭。Thus, for the methods provided herein, including but not limited to the methods in the preceding paragraphs, certain specific conditions based on GFR or creatinine clearance can be used to determine cisplatin incompatibility in a human individual. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of a GFR of less than 60 mL/min. In one embodiment, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2 and a CrCl of less than 60 mL/min. In other embodiments, the conditions for determining cisplatin incompatibility include or consist of a GFR of less than 60 mL/min and a hearing loss of not less than grade 2. In other embodiments, the conditions for determining cisplatin incompatibility include or consist of a GFR of less than 60 mL/min and NYHA class III heart failure. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2, a GFR of less than 60 mL/min, and a hearing loss of not less than 2 grades. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of a GFR of less than 60 mL/min, a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any one of an ECOG performance status of 2, a GFR of less than 60 mL/min, and a hearing loss of not less than 2 grades. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of any one of a GFR of less than 60 mL/min and a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any combination or permutation of any two of an ECOG performance status of 2, a GFR of less than 60 mL/min, and a hearing loss of not less than 2 grades. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of any combination or permutation of any two of a GFR of less than 60 mL/min and a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompetence include or consist of all three of an ECOG performance status of 2, a GFR of less than 60 mL/min, and a hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompetence include or consist of all three of a GFR of less than 60 mL/min, a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments of the methods provided in this paragraph, GFR is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, GFR is measured by the Modification of Diet in Renal Disease [MDRD]. In some embodiments of the methods provided herein, the subject has not previously received systemic therapy for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject has not received adjuvant/pre-adjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, wherein the subject has an ECOG performance status of 2, the subject (i) has hemoglobin ≥ 10 g/dL; (ii) has a GFR ≥ 50 mL/min; and (iii) does not have NYHA Class III heart failure.
在其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的CrCl組成。在一個實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態及小於60 mL/min的CrCl組成。在其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的CrCl及不小於2級的聽力損失組成。在其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的CrCl及NYHA III級心臟衰竭組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min的CrCl及不小於2級的聽力損失組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的CrCl及不小於2級的聽力損失以及NYHA III級心臟衰竭組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min的CrCl及不小於2級的聽力損失中的任一者組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的CrCl及不小於2級的聽力損失以及NYHA III級心臟衰竭中的任一者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min的CrCl及不小於2級的聽力損失中之任兩者的任何組合或排列組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的CrCl及不小於2級的聽力損失以及NYHA III級心臟衰竭中之任兩者的任何組合或排列組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min的CrCl及不小於2級的聽力損失中的所有三者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min的CrCl及不小於2級的聽力損失以及NYHA III級心臟衰竭中的所有三者組成。在本段落所提供之方法的一些實施例中，藉由24小時尿液收集來量測CrCl。在本段落所提供之方法的其他實施例中，藉由科克羅夫特-高爾特準則來估算CrCl。在本文所提供之方法的一些實施例中，個體先前未接受過針對局部晚期或轉移性疾病之全身治療。在本文所提供之方法的一些實施例中，個體在隨機分組之前12個月內未接受輔助/前輔助基於鉑之療法。在本文所提供之方法的一些實施例中，其中個體具有2分的ECOG體能狀態，個體(i)血紅素≥10 g/dL；(ii) GFR≥50 mL/min；及(iii)不具有NYHA III級心臟衰竭。In other embodiments, the conditions for determining cisplatin incompetence include or consist of a CrCl of less than 60 mL/min. In one embodiment, the conditions for determining cisplatin incompetence include or consist of an ECOG performance status of 2 and a CrCl of less than 60 mL/min. In other embodiments, the conditions for determining cisplatin incompetence include or consist of a CrCl of less than 60 mL/min and hearing loss of not less than grade 2. In other embodiments, the conditions for determining cisplatin incompetence include or consist of a CrCl of less than 60 mL/min and NYHA class III heart failure. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2, a CrCl of less than 60 mL/min, and a hearing loss of not less than 2 grades. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of a CrCl of less than 60 mL/min, a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any one of an ECOG performance status of 2, a CrCl of less than 60 mL/min, and a hearing loss of not less than 2 grades. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of any one of CrCl less than 60 mL/min and hearing loss of not less than grade 2 and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any combination or permutation of any two of an ECOG performance status of 2, a CrCl less than 60 mL/min and hearing loss of not less than grade 2. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of any combination or permutation of any two of a CrCl less than 60 mL/min and hearing loss of not less than grade 2 and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2, a CrCl of less than 60 mL/min, and a hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of a CrCl of less than 60 mL/min, a hearing loss of not less than 2 grades, and all three of NYHA class III heart failure. In some embodiments of the methods provided in this paragraph, CrCl is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, CrCl is estimated by the Cockcroft-Gault criterion. In some embodiments of the methods provided herein, the individual has not previously received systemic therapy for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject has not received adjuvant/pre-adjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, wherein the subject has an ECOG performance status of 2, the subject (i) has hemoglobin ≥ 10 g/dL; (ii) has a GFR ≥ 50 mL/min; and (iii) does not have NYHA class III heart failure.
或者，對於本文所提供之方法，包括(但不限於)前述段落中的方法，可利用基於GFR或肌酐清除率的其他特定條件來確定人類個體的順鉑不適合性。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的GFR組成。在一個實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態及小於60 mL/min、但不小於30 mL/min的GFR組成。在其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的GFR及不小於2級的聽力損失組成。在其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的GFR及NYHA III級心臟衰竭組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min、但不小於30 mL/min的GFR及不小於2級的聽力損失組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的GFR、不小於2級的聽力損失及NYHA III級心臟衰竭組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min、但不小於30 mL/min的GFR及不小於2級的聽力損失中的任一者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的GFR、不小於2級的聽力損失及NYHA III級心臟衰竭中的任一者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min、但不小於30 mL/min的GFR及不小於2級的聽力損失中之任兩者的任何組合或排列組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的GFR、不小於2級的聽力損失及NYHA III級心臟衰竭中之任兩者的任何組合或排列組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min、但不小於30 mL/min的GFR及不小於2級的聽力損失中的所有三者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的GFR、不小於2級的聽力損失及NYHA III級心臟衰竭中的所有三者組成。在本段落所提供之方法的一些實施例中，藉由24小時尿液收集來量測GFR。在本段落所提供之方法的其他實施例中，藉由科克羅夫特-高爾特準則來估算GFR。在本段落所提供之方法的其他實施例中，藉由腎病膳食改良[MDRD]來量測GFR。在本文所提供之方法的一些實施例中，個體先前未接受過針對局部晚期或轉移性疾病之全身治療。在本文所提供之方法的一些實施例中，個體在隨機分組之前12個月內未接受輔助/前輔助基於鉑之療法。在本文所提供之方法的一些實施例中，其中個體具有2分的ECOG體能狀態，個體(i)血紅素≥10 g/dL；(ii) GFR≥50 mL/min；及(iii)不具有NYHA III級心臟衰竭。Alternatively, for the methods provided herein, including but not limited to the methods in the preceding paragraphs, other specific conditions based on GFR or creatinine clearance can be used to determine cisplatin incompatibility in a human individual. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of a GFR of less than 60 mL/min, but not less than 30 mL/min. In one embodiment, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2 and a GFR of less than 60 mL/min, but not less than 30 mL/min. In other embodiments, the conditions for determining cisplatin incompatibility include or consist of a GFR of less than 60 mL/min, but not less than 30 mL/min, and a hearing loss of not less than grade 2. In other embodiments, the conditions for determining cisplatin incompatibility include or consist of a GFR of less than 60 mL/min but not less than 30 mL/min and NYHA class III heart failure. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2, a GFR of less than 60 mL/min but not less than 30 mL/min, and a hearing loss of not less than grade 2. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of a GFR of less than 60 mL/min but not less than 30 mL/min, a hearing loss of not less than grade 2, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any one of an ECOG performance status of 2 points, a GFR of less than 60 mL/min but not less than 30 mL/min, and a hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any one of a GFR of less than 60 mL/min but not less than 30 mL/min, a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any combination or permutation of any two of an ECOG performance status of 2 points, a GFR of less than 60 mL/min but not less than 30 mL/min, and a hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any combination or permutation of any two of a GFR of less than 60 mL/min but not less than 30 mL/min, a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of all three of an ECOG performance status of 2, a GFR of less than 60 mL/min but not less than 30 mL/min, and a hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of all three of a GFR of less than 60 mL/min but not less than 30 mL/min, a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments of the methods provided in this paragraph, GFR is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, GFR is measured by the Modification of Diet in Kidney Disease [MDRD]. In some embodiments of the methods provided herein, the individual has not previously received systemic therapy for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the individual has not received adjuvant/pre-adjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, wherein the individual has an ECOG performance status of 2, the individual (i) hemoglobin ≥ 10 g/dL; (ii) GFR ≥ 50 mL/min; and (iii) does not have NYHA Class III heart failure.
在其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的CrCl組成。在一個實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態及小於60 mL/min、但不小於30 mL/min的CrCl組成。在其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的CrCl及不小於2級的聽力損失組成。在其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的CrCl及NYHA III級心臟衰竭組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min、但不小於30 mL/min的CrCl及不小於2級的聽力損失組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的CrCl、不小於2級的聽力損失及NYHA III級心臟衰竭組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min、但不小於30 mL/min的CrCl及不小於2級的聽力損失中的任一者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的CrCl、不小於2級的聽力損失及NYHA III級心臟衰竭中的任一者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min、但不小於30 mL/min的CrCl及不小於2級的聽力損失中之任兩者的任何組合或排列組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的CrCl、不小於2級的聽力損失及NYHA III級心臟衰竭中之任兩者的任何組合或排列組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於60 mL/min、但不小於30 mL/min的CrCl及不小於2級的聽力損失中的所有三者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於60 mL/min、但不小於30 mL/min的CrCl、不小於2級的聽力損失及NYHA III級心臟衰竭中的所有三者組成。在本段落所提供之方法的一些實施例中，藉由24小時尿液收集來量測CrCl。在本段落所提供之方法的其他實施例中，藉由科克羅夫特-高爾特準則來估算CrCl。在本文所提供之方法的一些實施例中，個體先前未接受過針對局部晚期或轉移性疾病之全身治療。在本文所提供之方法的一些實施例中，個體在隨機分組之前12個月內未接受輔助/前輔助基於鉑之療法。在本文所提供之方法的一些實施例中，其中個體具有2分的ECOG體能狀態，個體(i)血紅素≥10 g/dL；(ii) GFR≥50 mL/min；及(iii)不具有NYHA III級心臟衰竭。In other embodiments, the conditions for determining cisplatin incompatibility include or consist of a CrCl of less than 60 mL/min, but not less than 30 mL/min. In one embodiment, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2 and a CrCl of less than 60 mL/min, but not less than 30 mL/min. In other embodiments, the conditions for determining cisplatin incompatibility include or consist of a CrCl of less than 60 mL/min, but not less than 30 mL/min, and hearing loss of not less than grade 2. In other embodiments, the conditions for determining cisplatin incompatibility include or consist of a CrCl of less than 60 mL/min, but not less than 30 mL/min, and NYHA class III heart failure. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2, a CrCl of less than 60 mL/min but not less than 30 mL/min, and a hearing loss of not less than grade 2. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of a CrCl of less than 60 mL/min but not less than 30 mL/min, a hearing loss of not less than grade 2, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any one of an ECOG performance status of 2, a CrCl of less than 60 mL/min but not less than 30 mL/min, and a hearing loss of not less than grade 2. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any one of CrCl less than 60 mL/min but not less than 30 mL/min, hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any combination or permutation of any two of ECOG performance status of 2 points, CrCl less than 60 mL/min but not less than 30 mL/min, and hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any combination or permutation of any two of CrCl less than 60 mL/min but not less than 30 mL/min, hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2, a CrCl of less than 60 mL/min but not less than 30 mL/min, and a hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of a CrCl of less than 60 mL/min but not less than 30 mL/min, a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments of the methods provided in this paragraph, CrCl is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, CrCl is estimated by the Cockcroft-Gault criterion. In some embodiments of the methods provided herein, the individual has not previously received systemic therapy for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject has not received adjuvant/pre-adjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, wherein the subject has an ECOG performance status of 2, the subject (i) has hemoglobin ≥ 10 g/dL; (ii) has a GFR ≥ 50 mL/min; and (iii) does not have NYHA class III heart failure.
類似地，對於本文所提供之方法，包括(但不限於)前述段落中的方法，可利用基於GFR或肌酐清除率的其他特定條件來確定人類個體的順鉑不適合性。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的GFR組成。在一個實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態及小於30 mL/min、但不小於15 mL/min的GFR組成。在其他實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的GFR及不小於2級的聽力損失組成。在其他實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的GFR及NYHA III級心臟衰竭組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於30 mL/min、但不小於15 mL/min的GFR及不小於2級的聽力損失組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的GFR、不小於2級的聽力損失及NYHA III級心臟衰竭組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於30 mL/min、但不小於15 mL/min的GFR及不小於2級的聽力損失中的任一者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的GFR、不小於2級的聽力損失及NYHA III級心臟衰竭中的任一者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於30 mL/min、但不小於15 mL/min的GFR及不小於2級的聽力損失中之任兩者的任何組合或排列組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的GFR、不小於2級的聽力損失及NYHA III級心臟衰竭中之任兩者的任何組合或排列組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於30 mL/min、但不小於15 mL/min的GFR及不小於2級的聽力損失中的所有三者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的GFR、不小於2級的聽力損失及NYHA III級心臟衰竭中的所有三者組成。在本段落所提供之方法的一些實施例中，藉由24小時尿液收集來量測GFR。在本段落所提供之方法的其他實施例中，藉由科克羅夫特-高爾特準則來估算GFR。在本段落所提供之方法的其他實施例中，藉由腎病膳食改良[MDRD]來量測GFR。在本文所提供之方法的一些實施例中，個體先前未接受過針對局部晚期或轉移性疾病之全身治療。在本文所提供之方法的一些實施例中，個體在隨機分組之前12個月內未接受輔助/前輔助基於鉑之療法。在本文所提供之方法的一些實施例中，其中個體具有2分的ECOG體能狀態，個體(i)血紅素≥10 g/dL；(ii) GFR≥50 mL/min；及(iii)不具有NYHA III級心臟衰竭。Similarly, for the methods provided herein, including but not limited to the methods in the preceding paragraphs, other specific conditions based on GFR or creatinine clearance can be used to determine cisplatin incompatibility in a human individual. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of a GFR of less than 30 mL/min, but not less than 15 mL/min. In one embodiment, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2 and a GFR of less than 30 mL/min, but not less than 15 mL/min. In other embodiments, the conditions for determining cisplatin incompatibility include or consist of a GFR of less than 30 mL/min, but not less than 15 mL/min, and a hearing loss of not less than grade 2. In other embodiments, the conditions for determining cisplatin incompatibility include or consist of a GFR of less than 30 mL/min but not less than 15 mL/min and NYHA class III heart failure. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2, a GFR of less than 30 mL/min but not less than 15 mL/min, and a hearing loss of not less than grade 2. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of a GFR of less than 30 mL/min but not less than 15 mL/min, a hearing loss of not less than grade 2, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any one of an ECOG performance status of 2 points, a GFR of less than 30 mL/min but not less than 15 mL/min, and a hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any one of a GFR of less than 30 mL/min but not less than 15 mL/min, a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any combination or permutation of any two of an ECOG performance status of 2 points, a GFR of less than 30 mL/min but not less than 15 mL/min, and a hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any combination or permutation of any two of a GFR of less than 30 mL/min but not less than 15 mL/min, a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of all three of an ECOG performance status of 2, a GFR of less than 30 mL/min but not less than 15 mL/min, and a hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of all three of a GFR of less than 30 mL/min but not less than 15 mL/min, a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments of the methods provided in this paragraph, GFR is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, GFR is measured by the Modification of Diet in Kidney Disease [MDRD]. In some embodiments of the methods provided herein, the individual has not previously received systemic therapy for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the individual has not received adjuvant/pre-adjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, wherein the individual has an ECOG performance status of 2, the individual (i) hemoglobin ≥ 10 g/dL; (ii) GFR ≥ 50 mL/min; and (iii) does not have NYHA Class III heart failure.
在一些實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的CrCl組成。在一個實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態及小於30 mL/min、但不小於15 mL/min的CrCl組成。在其他實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的CrCl及不小於2級的聽力損失組成。在其他實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的CrCl及NYHA III級心臟衰竭組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於30 mL/min、但不小於15 mL/min的CrCl及不小於2級的聽力損失組成。在又其他實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的CrCl、不小於2級的聽力損失及NYHA III級心臟衰竭組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於30 mL/min、但不小於15 mL/min的CrCl及不小於2級的聽力損失中的任一者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的CrCl、不小於2級的聽力損失及NYHA III級心臟衰竭中的任一者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於30 mL/min、但不小於15 mL/min的CrCl及不小於2級的聽力損失中之任兩者的任何組合或排列組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的CrCl、不小於2級的聽力損失及NYHA III級心臟衰竭中之任兩者的任何組合或排列組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由2分的ECOG體能狀態、小於30 mL/min、但不小於15 mL/min的CrCl及不小於2級的聽力損失中的所有三者組成。在一些實施例中，用於確定順鉑不適合性的條件包含或由小於30 mL/min、但不小於15 mL/min的CrCl、不小於2級的聽力損失及NYHA III級心臟衰竭中的所有三者組成。在本段落所提供之方法的一些實施例中，藉由24小時尿液收集來量測CrCl。在本段落所提供之方法的其他實施例中，藉由科克羅夫特-高爾特準則來估算CrCl。在本文所提供之方法的一些實施例中，個體先前未接受過針對局部晚期或轉移性疾病之全身治療。在本文所提供之方法的一些實施例中，個體在隨機分組之前12個月內未接受輔助/前輔助基於鉑之療法。在本文所提供之方法的一些實施例中，其中個體具有2分的ECOG體能狀態，個體(i)血紅素≥10 g/dL；(ii) GFR≥50 mL/min；及(iii)不具有NYHA III級心臟衰竭。5.2.1.2其他患者人口統計資料In some embodiments, the conditions for determining cisplatin incompatibility include or consist of a CrCl of less than 30 mL/min, but not less than 15 mL/min. In one embodiment, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2 and a CrCl of less than 30 mL/min, but not less than 15 mL/min. In other embodiments, the conditions for determining cisplatin incompatibility include or consist of a CrCl of less than 30 mL/min, but not less than 15 mL/min, and hearing loss of not less than grade 2. In other embodiments, the conditions for determining cisplatin incompatibility include or consist of a CrCl of less than 30 mL/min, but not less than 15 mL/min, and NYHA class III heart failure. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of an ECOG performance status of 2, a CrCl of less than 30 mL/min but not less than 15 mL/min, and a hearing loss of not less than 2 grades. In yet other embodiments, the conditions for determining cisplatin incompatibility include or consist of a CrCl of less than 30 mL/min but not less than 15 mL/min, a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any one of an ECOG performance status of 2, a CrCl of less than 30 mL/min but not less than 15 mL/min, and a hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any one of CrCl less than 30 mL/min but not less than 15 mL/min, hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any combination or permutation of any two of ECOG performance status of 2 points, CrCl less than 30 mL/min but not less than 15 mL/min, and hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompatibility include or consist of any combination or permutation of any two of CrCl less than 30 mL/min but not less than 15 mL/min, hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments, the conditions for determining cisplatin incompetence include or consist of an ECOG performance status of 2, a CrCl of less than 30 mL/min but not less than 15 mL/min, and a hearing loss of not less than 2 grades. In some embodiments, the conditions for determining cisplatin incompetence include or consist of a CrCl of less than 30 mL/min but not less than 15 mL/min, a hearing loss of not less than 2 grades, and NYHA class III heart failure. In some embodiments of the methods provided in this paragraph, CrCl is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, CrCl is estimated by the Cockcroft-Gault criterion. In some embodiments of the methods provided herein, the individual has not previously received systemic therapy for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject has not received adjuvant/pre-adjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, wherein the subject has an ECOG performance status of 2, the subject (i) has hemoglobin ≥ 10 g/dL; (ii) has a GFR ≥ 50 mL/min; and (iii) does not have NYHA Class III heart failure.5.2.1.2Other Patient Demographics
另外，可使用本文所提供之方法的人類個體為具有多種其他條件的人類個體。在一個實施例中，本文所提供之方法的人類個體可患有組織學記錄的局部晚期或轉移性尿路上皮(先前稱為移行細胞)癌(例如膀胱癌、腎盂癌、輸尿管癌或尿道癌)。在一些實施例中，本文所提供之方法的人類個體可能適合CPI療法。在某些實施例中，本文所提供之方法的人類個體可根據RECIST 1.1版量測疾病。在其他實施例中，本文所提供之方法的人類個體可能在先前照射區域中具有已惡化至視為可量測的病灶。在又其他實施例中，本文所提供之方法的人類個體可具有0分的ECOG體能狀態。在又其他實施例中，本文所提供之方法的人類個體可具有1分的ECOG體能狀態。在又其他實施例中，本文所提供之方法的人類個體可具有2分的ECOG體能狀態。在又其他實施例中，本文所提供之方法的人類個體可具有1至2分的ECOG體能狀態。在又其他實施例中，本文所提供之方法的人類個體可具有1或2分的ECOG體能狀態。在又其他實施例中，本文所提供之方法的人類個體可具有0至1分的ECOG體能狀態。在又其他實施例中，本文所提供之方法的人類個體可具有0或1分的ECOG體能狀態。在又其他實施例中，本文所提供之方法的人類個體可具有0至2分的ECOG體能狀態。在又其他實施例中，本文所提供之方法的人類個體可具有0或2分的ECOG體能狀態。在又其他實施例中，本文所提供之方法的人類個體可具有0、1或2分的ECOG體能狀態。在一個實施例中，本文所提供之方法的人類個體可具有≥3個月之預期壽命。本段落所提供之方法的一些實施例可具有前述實施例中之任一者的任何組合或排列。In addition, the human individual of the method provided herein can be used for the human individual with a variety of other conditions. In one embodiment, the human individual of the method provided herein may suffer from locally advanced or metastatic urothelial (formerly referred to as transitional cell) cancer (such as bladder cancer, renal pelvic cancer, ureteral cancer or urethral cancer) recorded by histology. In some embodiments, the human individual of the method provided herein may be suitable for CPI therapy. In certain embodiments, the human individual of the method provided herein can measure the disease according to RECIST 1.1 version. In other embodiments, the human individual of the method provided herein may have a lesion that has deteriorated to be considered as measurable in the previous irradiation area. In other embodiments, the human individual of the method provided herein may have an ECOG physical status of 0 points. In other embodiments, the human individual of the method provided herein may have an ECOG physical status of 1 point. In yet other embodiments, the human subject of the method provided herein may have an ECOG performance status of 2 points. In yet other embodiments, the human subject of the method provided herein may have an ECOG performance status of 1 to 2 points. In yet other embodiments, the human subject of the method provided herein may have an ECOG performance status of 1 or 2 points. In yet other embodiments, the human subject of the method provided herein may have an ECOG performance status of 0 to 1 point. In yet other embodiments, the human subject of the method provided herein may have an ECOG performance status of 0 or 1 point. In yet other embodiments, the human subject of the method provided herein may have an ECOG performance status of 0 to 2 points. In yet other embodiments, the human subject of the method provided herein may have an ECOG performance status of 0 or 2 points. In yet other embodiments, the human subject of the methods provided herein may have an ECOG performance status of 0, 1, or 2. In one embodiment, the human subject of the methods provided herein may have a life expectancy of ≥ 3 months. Some embodiments of the methods provided in this paragraph may have any combination or arrangement of any of the foregoing embodiments.
在本文所提供之方法的其他實施例中，包括前述段落中的方法，可使用本文所提供之方法的人類個體為具有多種其他條件的人類個體。在一個實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數(ANC)不小於1500/µL的條件。在一些實施例中，可使用本文所提供之方法的人類個體亦具有血小板計數不小於100,000/µL的條件。在某些實施例中，可使用本文所提供之方法的人類個體亦具有血紅素不小於9 g/dL的條件。在某些實施例中，可使用本文所提供之方法的人類個體亦具有血紅素不小於9 g/dL的條件，其中個體不具有紅血球生成素依賴性且其中個體在治療之前2週內未投與紅血球濃厚液(pRBC)輸注。在某些實施例中，可使用本文所提供之方法的人類個體亦具有血紅素不小於5.6 mmol/L的條件。在某些實施例中，可使用本文所提供之方法的人類個體亦具有血紅素不小於5.6 mmol/L的條件，其中個體不具有紅血球生成素依賴性且其中個體在治療之前2週內未投與紅血球濃厚液(pRBC)輸注。在某些實施例中，可使用本文所提供之方法的人類個體亦具有血紅素不小於9 g/dL或5.6 mmol/L的條件。在其他實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血清膽紅素不超過1.5倍正常值上限(ULN)；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN。在又其他實施例中，可使用本文所提供之方法的人類個體亦具有CrCl不小於30 mL/min的條件。在又其他實施例中，可使用本文所提供之方法的人類個體亦具有GFR不小於30 mL/min的條件。在又其他實施例中，可使用本文所提供之方法的人類個體亦具有CrCl或GFR不小於30 mL/min的條件。在又其他實施例中，可使用本文所提供之方法的人類個體亦具有CrCl不小於30 mL/min的條件，其中個體之肌酐含量＞1.5×機構ULN及/或≤1.5 ULN。在又其他實施例中，可使用本文所提供之方法的人類個體亦具有GFR不小於30 mL/min的條件，其中個體之肌酐含量＞1.5×機構ULN及/或≤1.5 ULN。在另一實施例中，可使用本文所提供之方法的人類個體亦具有丙胺酸轉胺酶(ALT)及天冬胺酸轉胺酶(AST)不超過3倍ULN的條件。在一個實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL及血小板計數不小於100,000/µL的條件。在一些實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL及血紅素不小於9 g/dL或5.6 mmol/L的條件。在某些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL及血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN。在其他實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL及CrCl或GFR不小於30 mL/min的條件。在其他實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL及CrCl不小於30 mL/min的條件，其中個體之肌酐含量＞1.5×機構ULN及/或≤1.5 ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL且ALT及AST不超過3倍ULN的條件。在其他實施例中，可使用本文所提供之方法的人類個體亦具有血小板計數不小於100,000/µL及血紅素不小於9 g/dL或5.6 mmol/L的條件。在一個實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血小板計數不小於100,000/µL及血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有血小板計數不小於100,000/µL及CrCl或GFR不小於30 mL/min的條件。在某些實施例中，可使用本文所提供之方法的人類個體亦具有血小板計數不小於100,000/µL且ALT及AST不超過3倍ULN的條件。在其他實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血紅素不小於9 g/dL或5.6 mmol/L及血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN。在又其他實施例中，可使用本文所提供之方法的人類個體亦具有血紅素不小於9 g/dL或5.6 mmol/L及CrCl或GFR不小於30 mL/min的條件。在一些實施例中，可使用本文所提供之方法的人類個體亦具有血紅素不小於9 g/dL或5.6 mmol/L且ALT及AST不超過3倍ULN的條件。在一個實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，及CrCl不小於30 mL/min。在另一實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，以及ALT及AST不超過3倍ULN。在另一實施例中，可使用本文所提供之方法的人類個體亦具有CrCl或GFR不小於30 mL/min且ALT及AST不超過3倍ULN的條件。在其他實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL、血小板計數不小於100,000/µL及血紅素不小於9 g/dL或5.6 mmol/L的條件。在又其他實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL，血小板計數不小於100,000/µL，及血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN。在其他實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL、血小板計數不小於100,000/µL及CrCl或GFR不小於30 mL/min的條件。在一些實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL、血小板計數不小於100,000/µL且ALT及AST不超過3倍ULN的條件。在一些實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL、血紅素不小於9 g/dL或5.6 mmol/L及血清膽紅素不超過1.5倍ULN或對於吉爾伯氏病患者不超過3倍ULN的條件。在某些實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL、血紅素不小於9 g/dL或5.6 mmol/L及CrCl或GFR不小於30 mL/min的條件。在一些實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL、血紅素不小於9 g/dL或5.6 mmol/L且ALT及AST不超過3倍ULN的條件。在又其他實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，及CrCl或GFR不小於30 mL/min。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，以及ALT及AST不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL、CrCl或GFR不小於30 mL/min且ALT及AST不超過3倍ULN的條件。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血小板計數不小於100,000/µL、血紅素不小於9 g/dL或5.6 mmol/L及血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN。在某些實施例中，可使用本文所提供之方法的人類個體亦具有血小板計數不小於100,000/µL、血紅素不小於9 g/dL或5.6 mmol/L及CrCl或GFR不小於30 mL/min的條件。在一些實施例中，可使用本文所提供之方法的人類個體亦具有血小板計數不小於100,000/µL、血紅素不小於9 g/dL或5.6 mmol/L且ALT及AST不超過3倍ULN的條件。在其他實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血小板計數不小於100,000/µL，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，及CrCl或GFR不小於30 mL/min。在又其他實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血小板計數不小於100,000/µL，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，以及ALT及AST不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有血小板計數不小於100,000/µL、CrCl或GFR不小於30 mL/min且ALT及AST不超過3倍ULN的條件。在又其他實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，及CrCl或GFR不小於30 mL/min。在其他實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，以及ALT及AST不超過3倍ULN。在某些實施例中，可使用本文所提供之方法的人類個體亦具有血紅素不小於9 g/dL或5.6 mmol/L、CrCl或GFR不小於30 mL/min且ALT及AST不超過3倍ULN的條件。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。在其他實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL、血小板計數不小於100,000/µL、血紅素不小於9 g/dL或5.6 mmol/L及血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN。在其他實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL、血小板計數不小於100,000/µL、血紅素不小於9 g/dL或5.6 mmol/L及CrCl或GFR不小於30 mL/min的條件。在一些實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL、血小板計數不小於100,000/µL、血紅素不小於9 g/dL或5.6 mmol/L且ALT及AST不超過3倍ULN的條件。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL，血小板計數不小於100,000/µL，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，及CrCl或GFR不小於30 mL/min。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL，血小板計數不小於100,000/µL，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，以及ALT及AST不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL、血小板計數不小於100,000/µL、CrCl或GFR不小於30 mL/min且ALT及AST不超過3倍ULN的條件。在某些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，及CrCl或GFR不小於30 mL/min。在某些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，以及ALT及AST不超過3倍ULN。在某些實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL、血紅素不小於9 g/dL或5.6 mmol/L、CrCl或GFR不小於30 mL/min且ALT及AST不超過3倍ULN的條件。在又其他實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。在其他實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血小板計數不小於100,000/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，及CrCl或GFR不小於30 mL/min。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血小板計數不小於100,000/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，以及ALT及AST不超過3倍ULN。在其他實施例中，可使用本文所提供之方法的人類個體亦具有血小板計數不小於100,000/µL、血紅素不小於9 g/dL或5.6 mmol/L、CrCl或GFR不小於30 mL/min且ALT及AST不超過3倍ULN的條件。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血小板計數不小於100,000/µL，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。在某些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL，血小板計數不小於100,000/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，及CrCl或GFR不小於30 mL/min。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL，血小板計數不小於100,000/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，以及ALT及AST不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有絕對嗜中性白血球計數不小於1500/µL、血小板計數不小於100,000/µL、血紅素不小於9 g/dL或5.6 mmol/L、CrCl或GFR不小於30 mL/min且ALT及AST不超過3倍ULN的條件。在某些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL，血小板計數不小於100,000/µL，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。在某些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：血小板計數不小於100,000/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下條件：絕對嗜中性白血球計數不小於1500/µL，血小板計數不小於100,000/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下中之任一者的條件：絕對嗜中性白血球計數不小於1500/µL，血小板計數不小於100,000/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下中之任兩者之任何組合或排列的條件：絕對嗜中性白血球計數不小於1500/µL，血小板計數不小於100,000/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下中之任三者之任何組合或排列的條件：絕對嗜中性白血球計數不小於1500/µL、血小板計數不小於100,000/µL、血紅素不小於9 g/dL或5.6 mmol/L、血清膽紅素不超過1.5倍ULN或對於吉爾伯氏病患者不超過3倍ULN、CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下中之任四者之任何組合或排列的條件：絕對嗜中性白血球計數不小於1500/µL，血小板計數不小於100,000/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下中之任五者之任何組合或排列的條件：絕對嗜中性白血球計數不小於1500/µL，血小板計數不小於100,000/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。在一些實施例中，可使用本文所提供之方法的人類個體亦具有以下中之全部六者的條件：絕對嗜中性白血球計數不小於1500/µL，血小板計數不小於100,000/µL，血紅素不小於9 g/dL或5.6 mmol/L，血清膽紅素不超過1.5倍ULN；直接膽紅素≤ULN，其中人類個體具有總膽紅素含量＞1.5×ULN的條件；或對於吉爾伯氏病患者血清膽紅素不超過3倍ULN，CrCl或GFR不小於30 mL/min，以及ALT及AST不超過3倍ULN。 In other embodiments of the methods provided herein, including the methods in the preceding paragraphs, the human subjects in which the methods provided herein can be used are human subjects with a variety of other conditions. In one embodiment, the human subjects in which the methods provided herein can be used also have an absolute neutrophil count (ANC) of not less than 1500/µL. In some embodiments, the human subjects in which the methods provided herein can be used also have a platelet count of not less than 100,000/µL. In certain embodiments, the human subjects in which the methods provided herein can be used also have a hemoglobin of not less than 9 g/dL. In certain embodiments, the human subjects in which the methods provided herein can be used also have a hemoglobin of not less than 9 g/dL, wherein the subject is not erythropoietin dependent and wherein the subject has not been administered a transfusion of a red blood cell concentrate (pRBC) within 2 weeks prior to treatment. In certain embodiments, the human subject for which the methods provided herein can be used also has a hemoglobin of no less than 5.6 mmol/L. In certain embodiments, the human subject for which the methods provided herein can be used also has a hemoglobin of no less than 5.6 mmol/L, wherein the subject is not erythropoietin dependent and wherein the subject has not been administered a pRBC transfusion within 2 weeks prior to treatment. In certain embodiments, the human subject for which the methods provided herein can be used also has a hemoglobin of no less than 9 g/dL or 5.6 mmol/L. In other embodiments, the human subjects in whom the methods provided herein can be used also have the following conditions: serum bilirubin does not exceed 1.5 times the upper limit of normal (ULN); direct bilirubin ≤ ULN, wherein the human subject has a total bilirubin content > 1.5 × ULN; or for patients with Gilber's disease, serum bilirubin does not exceed 3 times ULN. In yet other embodiments, the human subjects in whom the methods provided herein can be used also have a CrCl of not less than 30 mL/min. In yet other embodiments, the human subjects in whom the methods provided herein can be used also have a GFR of not less than 30 mL/min. In yet other embodiments, the human subjects in whom the methods provided herein can be used also have a CrCl or GFR of not less than 30 mL/min. In yet other embodiments, human subjects in whom the methods provided herein may be used also have a CrCl of not less than 30 mL/min, wherein the subject's creatinine level is >1.5× institutional ULN and/or ≤1.5 ULN. In yet other embodiments, human subjects in whom the methods provided herein may be used also have a GFR of not less than 30 mL/min, wherein the subject's creatinine level is >1.5× institutional ULN and/or ≤1.5 ULN. In another embodiment, human subjects in whom the methods provided herein may be used also have a condition of alanine transaminase (ALT) and aspartate transaminase (AST) not exceeding 3 times ULN. In one embodiment, human subjects in whom the methods provided herein may be used also have an absolute neutrophil count of not less than 1500/µL and a platelet count of not less than 100,000/µL. In some embodiments, the human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of not less than 1500/µL and a hemoglobin of not less than 9 g/dL or 5.6 mmol/L. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: an absolute neutrophil count of not less than 1500/µL and a serum bilirubin of not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has a total bilirubin content of > 1.5×ULN; or for Gilber's disease patients, serum bilirubin of not more than 3 times ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of not less than 1500/µL and a CrCl or GFR of not less than 30 mL/min. In other embodiments, the human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of no less than 1500/µL and a CrCl of no less than 30 mL/min, wherein the subject's creatinine level is >1.5× institutional ULN and/or ≤1.5 ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of no less than 1500/µL and ALT and AST no more than 3 times ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have a platelet count of no less than 100,000/µL and a hemoglobin of no less than 9 g/dL or 5.6 mmol/L. In one embodiment, the human subject for whom the methods provided herein can be used also has the following conditions: platelet count is not less than 100,000/µL and serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content> 1.5×ULN; or for patients with Gilber's disease, serum bilirubin is not more than 3 times ULN. In some embodiments, the human subject for whom the methods provided herein can be used also has the conditions of platelet count is not less than 100,000/µL and CrCl or GFR is not less than 30 mL/min. In certain embodiments, the human subject for whom the methods provided herein can be used also has the conditions of platelet count is not less than 100,000/µL and ALT and AST are not more than 3 times ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: hemoglobin is not less than 9 g/dL or 5.6 mmol/L and serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content> 1.5×ULN; or for patients with Gilber's disease, serum bilirubin is not more than 3 times ULN. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin is not less than 9 g/dL or 5.6 mmol/L and CrCl or GFR is not less than 30 mL/min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin is not less than 9 g/dL or 5.6 mmol/L and ALT and AST are not more than 3 times ULN. In one embodiment, the human subject for which the methods provided herein can be used also has the following conditions: serum bilirubin does not exceed 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has a total bilirubin content> 1.5 x ULN; or for patients with Gilbert's disease, serum bilirubin does not exceed 3 times ULN, and CrCl is not less than 30 mL/min. In another embodiment, the human subject for which the methods provided herein can be used also has the following conditions: serum bilirubin does not exceed 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has a total bilirubin content> 1.5 x ULN; or for patients with Gilbert's disease, serum bilirubin does not exceed 3 times ULN, and ALT and AST do not exceed 3 times ULN. In another embodiment, the human subject for whom the methods provided herein can be used also has a CrCl or GFR of not less than 30 mL/min and ALT and AST of not more than 3 times ULN. In other embodiments, the human subject for whom the methods provided herein can be used also has an absolute neutrophil count of not less than 1500/µL, a platelet count of not less than 100,000/µL, and a hemoglobin of not less than 9 g/dL or 5.6 mmol/L. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count is not less than 1500/µL, platelet count is not less than 100,000/µL, and serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content > 1.5×ULN; or for patients with Gilber's disease, serum bilirubin is not more than 3 times ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count is not less than 1500/µL, platelet count is not less than 100,000/µL, and CrCl or GFR is not less than 30 mL/min. In some embodiments, the human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of no less than 1500/µL, a platelet count of no less than 100,000/µL, and ALT and AST no more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of no less than 1500/µL, a hemoglobin of no less than 9 g/dL or 5.6 mmol/L, and a serum bilirubin no more than 1.5 times ULN or no more than 3 times ULN for Gilber's disease patients. In certain embodiments, the human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of no less than 1500/µL, hemoglobin of no less than 9 g/dL or 5.6 mmol/L, and CrCl or GFR of no less than 30 mL/min. In certain embodiments, the human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of no less than 1500/µL, hemoglobin of no less than 9 g/dL or 5.6 mmol/L, and ALT and AST of no more than 3 times ULN. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count is not less than 1500/µL, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content > 1.5×ULN; or for Gilbert's disease patients, serum bilirubin is not more than 3 times ULN, and CrCl or GFR is not less than 30 mL/min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count is not less than 1500/µL, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, where the human subject has the condition of total bilirubin content > 1.5×ULN; or for patients with Gilber's disease, serum bilirubin is not more than 3 times ULN, and ALT and AST are not more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count is not less than 1500/µL, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: platelet count is not less than 100,000/µL, hemoglobin is not less than 9 g/dL or 5.6 mmol/L, and serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, where the human subject has the condition of total bilirubin content> 1.5×ULN; or serum bilirubin is not more than 3 times ULN for patients with Gilber's disease. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count is not less than 100,000/µL, hemoglobin is not less than 9 g/dL or 5.6 mmol/L, and CrCl or GFR is not less than 30 mL/min. In some embodiments, the human subjects for whom the methods provided herein can be used also have a platelet count of not less than 100,000/µL, hemoglobin of not less than 9 g/dL or 5.6 mmol/L, and ALT and AST of not more than 3 times ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: platelet count of not less than 100,000/µL, serum bilirubin of not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has a total bilirubin content of > 1.5×ULN; or for patients with Gilbert's disease, serum bilirubin of not more than 3 times ULN, and CrCl or GFR of not less than 30 mL/min. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: platelet count is not less than 100,000/µL, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content> 1.5×ULN; or for patients with Gilber's disease, serum bilirubin is not more than 3 times ULN, and ALT and AST are not more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count is not less than 100,000/µL, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: hemoglobin is not less than 9 g/dL or 5.6 mmol/L, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content > 1.5×ULN; or for Gilbert's disease patients, serum bilirubin is not more than 3 times ULN, and CrCl or GFR is not less than 30 mL/min. In other embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: hemoglobin is not less than 9 g/dL or 5.6 mmol/L, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content> 1.5×ULN; or for patients with Gilber's disease, serum bilirubin is not more than 3 times ULN, and ALT and AST are not more than 3 times ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin is not less than 9 g/dL or 5.6 mmol/L, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: serum bilirubin no more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content > 1.5×ULN; or for Gilbert's disease patients, serum bilirubin no more than 3 times ULN, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 times ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count not less than 1500/µL, platelet count not less than 100,000/µL, hemoglobin not less than 9 g/dL or 5.6 mmol/L, and serum bilirubin not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has a total bilirubin content> 1.5 x ULN; or for patients with Gilber's disease, serum bilirubin does not exceed 3 times ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of not less than 1500/µL, a platelet count of not less than 100,000/µL, a hemoglobin of not less than 9 g/dL or 5.6 mmol/L, and a CrCl or GFR of not less than 30 mL/min. In some embodiments, the human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of not less than 1500/µL, a platelet count of not less than 100,000/µL, a hemoglobin of not less than 9 g/dL or 5.6 mmol/L, and ALT and AST of not more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count no less than 1500/µL, platelet count no less than 100,000/µL, serum bilirubin no more than 1.5 times ULN; direct bilirubin ≤ ULN, where the human subject has a total bilirubin content > 1.5×ULN; or for Gilbert's disease patients, serum bilirubin no more than 3 times ULN, and CrCl or GFR no less than 30 mL/min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count is not less than 1500/µL, platelet count is not less than 100,000/µL, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, where the human subject has the condition of total bilirubin content > 1.5×ULN; or for patients with Gilber's disease, serum bilirubin is not more than 3 times ULN, and ALT and AST are not more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count is not less than 1500/µL, platelet count is not less than 100,000/µL, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count no less than 1500/µL, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than 1.5 times ULN; direct bilirubin ≤ ULN, where the human subject has a total bilirubin content > 1.5×ULN; or for Gilbert's disease patients, serum bilirubin no more than 3 times ULN, and CrCl or GFR no less than 30 mL/min. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count is not less than 1500/µL, hemoglobin is not less than 9 g/dL or 5.6 mmol/L, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content> 1.5×ULN; or for patients with Gilber's disease, serum bilirubin is not more than 3 times ULN, and ALT and AST are not more than 3 times ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count is not less than 1500/µL, hemoglobin is not less than 9 g/dL or 5.6 mmol/L, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count is not less than 1500/µL, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content > 1.5×ULN; or for Gilbert's disease patients, serum bilirubin is not more than 3 times ULN, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: platelet count not less than 100,000/µL, hemoglobin not less than 9 g/dL or 5.6 mmol/L, serum bilirubin not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content > 1.5×ULN; or for patients with Gilbert's disease, serum bilirubin not more than 3 times ULN, and CrCl or GFR not less than 30 mL/min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: platelet count is not less than 100,000/µL, hemoglobin is not less than 9 g/dL or 5.6 mmol/L, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content> 1.5×ULN; or for patients with Gilber's disease, serum bilirubin is not more than 3 times ULN, and ALT and AST are not more than 3 times ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count is not less than 100,000/µL, hemoglobin is not less than 9 g/dL or 5.6 mmol/L, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: platelet count is not less than 100,000/µL, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content > 1.5×ULN; or for Gilbert's disease patients, serum bilirubin is not more than 3 times ULN, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: hemoglobin is not less than 9 g/dL or 5.6 mmol/L, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content > 1.5×ULN; or for patients with Gilbert's disease, serum bilirubin is not more than 3 times ULN, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count no less than 1500/µL, platelet count no less than 100,000/µL, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than 1.5 times ULN; direct bilirubin ≤ ULN, where the human subject has a total bilirubin content > 1.5×ULN; or for Gilbert's disease patients, serum bilirubin no more than 3 times ULN, and CrCl or GFR no less than 30 mL/min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count no less than 1500/µL, platelet count no less than 100,000/µL, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than 1.5 times ULN; direct bilirubin ≤ ULN, where the human subject has a total bilirubin content > 1.5×ULN; or for Gilbert's disease patients, serum bilirubin no more than 3 times ULN, and ALT and AST no more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of not less than 1500/µL, a platelet count of not less than 100,000/µL, a hemoglobin of not less than 9 g/dL or 5.6 mmol/L, a CrCl or GFR of not less than 30 mL/min, and ALT and AST of not more than 3 times ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count is not less than 1500/µL, platelet count is not less than 100,000/µL, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content > 1.5×ULN; or for patients with Gilber's disease, serum bilirubin is not more than 3 times ULN, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count not less than 1500/µL, hemoglobin not less than 9 g/dL or 5.6 mmol/L, serum bilirubin not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content > 1.5×ULN; or for patients with Gilbert's disease, serum bilirubin not more than 3 times ULN, CrCl or GFR not less than 30 mL/min, and ALT and AST not more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: platelet count is not less than 100,000/µL, hemoglobin is not less than 9 g/dL or 5.6 mmol/L, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has the condition of total bilirubin content > 1.5×ULN; or for patients with Gilbert's disease, serum bilirubin is not more than 3 times ULN, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the following conditions: absolute neutrophil count no less than 1500/µL, platelet count no less than 100,000/µL, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than 1.5 times ULN; direct bilirubin ≤ ULN, where the human subject has a total bilirubin content > 1.5×ULN; or for Gilbert's disease patients, serum bilirubin no more than 3 times ULN, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have any of the following conditions: absolute neutrophil count is not less than 1500/µL, platelet count is not less than 100,000/µL, hemoglobin is not less than 9 g/dL or 5.6 mmol/L, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has a total bilirubin content> 1.5 x ULN; or for Gilbert's disease patients, serum bilirubin is not more than 3 times ULN, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have any combination or arrangement of any two of the following conditions: absolute neutrophil count is not less than 1500/µL, platelet count is not less than 100,000/µL, hemoglobin is not less than 9 g/dL or 5.6 mmol/L, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has a total bilirubin content> 1.5 x ULN; or for Gilbert's disease patients, serum bilirubin is not more than 3 times ULN, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have any combination or arrangement of any three of the following conditions: absolute neutrophil count no less than 1500/µL, platelet count no less than 100,000/µL, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than 1.5 times ULN or no more than 3 times ULN for Gilbert's disease patients, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have any combination or arrangement of any four of the following conditions: absolute neutrophil count is not less than 1500/µL, platelet count is not less than 100,000/µL, hemoglobin is not less than 9 g/dL or 5.6 mmol/L, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has a total bilirubin content> 1.5 x ULN; or for Gilber's disease patients, serum bilirubin is not more than 3 times ULN, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have any combination or arrangement of any five of the following conditions: absolute neutrophil count is not less than 1500/µL, platelet count is not less than 100,000/µL, hemoglobin is not less than 9 g/dL or 5.6 mmol/L, serum bilirubin is not more than 1.5 times ULN; direct bilirubin ≤ ULN, wherein the human subject has a total bilirubin content> 1.5 x ULN; or for Gilber's disease patients, serum bilirubin is not more than 3 times ULN, CrCl or GFR is not less than 30 mL/min, and ALT and AST are not more than 3 times ULN. In some embodiments, the human subject for whom the methods provided herein can be used also has all six of the following conditions: absolute neutrophil count no less than 1500/µL, platelet count no less than 100,000/µL, hemoglobin no less than 9 g/dL or 5.6 mmol/L, serum bilirubin no more than 1.5 times ULN; direct bilirubin ≤ ULN, where the human subject has a total bilirubin content > 1.5×ULN; or for Gilbert's disease patients, serum bilirubin no more than 3 times ULN, CrCl or GFR no less than 30 mL/min, and ALT and AST no more than 3 times ULN.
在某些實施例中，本文所提供之方法人類個體在用本文所提供之方法中的任一者治療之前至少1年可能先前已以手術方式或放射療法治療，其中個體無前列腺癌，且其中(i)若個體已經歷或接受根除性前列腺切除術，則個體在用本文所提供之方法中的任一者治療之前必須具有不可偵測的PSA＞1年，(ii)若個體曾接受放射，則個體之PSA倍增時間＞1年(基於至少3個相隔＞1個月確定的值)且總PSA值不滿足生物化學復發之菲尼克斯準則(Phoenix criteria) (例如高於最低點＜2.0 ng/mL)。在某些實施例中，本文所提供之方法的人類個體可具有未經治療的低風險前列腺癌，其中個體接受主動監測具有格里森評分(Gleason score)≤6，PSA倍增時間＞1年(基於至少3個相隔＞1個月確定的值)。In certain embodiments, the methods provided herein include human subjects who may have been previously treated surgically or with radiation therapy at least 1 year prior to treatment with any of the methods provided herein, wherein the subject does not have prostate cancer, and wherein (i) if the subject has undergone or received radical prostatectomy, the subject must have an undetectable PSA for >1 year prior to treatment with any of the methods provided herein, (ii) if the subject has received radiation, the subject's PSA doubling time is >1 year (based on at least 3 values determined >1 month apart) and the total PSA value does not meet the Phoenix criteria for biochemical recurrence (e.g., <2.0 ng/mL above nadir). In certain embodiments, the human subjects of the methods provided herein can have untreated low-risk prostate cancer, wherein the subject undergoes active surveillance with a Gleason score ≤ 6 and a PSA doubling time > 1 year (based on at least 3 values determined > 1 month apart).
在本文所提供之方法的其他實施例中，包括前述段落中的方法，可使用本文所提供之方法的人類個體為不具有某些條件的人類個體。在一個實施例中，本文所提供之方法的人類個體先前未接受過任何CPI治療。CPI定義為PD-1抑制劑、PD-L1抑制劑或PD-L2抑制劑(包括(但不限於)阿特珠單抗、派姆單抗、納武單抗、德瓦魯單抗或阿維魯單抗)。在一些實施例中，本文所提供之方法的人類個體未接受過PD-1抑制劑、PD-L1抑制劑或PD-L2抑制劑。在某些實施例中，本文所提供之方法的人類個體未接受過阿特珠單抗、派姆單抗、納武單抗、德瓦魯單抗或阿維魯單抗。在某些實施例中，本文所提供之方法的人類個體先前未接受過任何針對另一刺激性或共抑制性T細胞受體之藥劑(包括(但不限於) CD137促效劑、CTLA 4抑制劑或OX-40促效劑)治療。在某些實施例中，本文所提供之方法的人類個體先前未接受過任何CD137促效劑、CTLA 4抑制劑或OX-40促效劑治療。在一個實施例中，本文所提供之方法的人類個體可具有不超過2級的感覺或運動神經病變。在一個實施例中，本文所提供之方法的人類個體可不具有活動性中樞神經系統轉移。在一個實施例中，本文所提供之方法的人類個體可不具有不可控的糖尿病。在一個實施例中，本文所提供之方法的人類個體可具有不超過2級的感覺或運動神經病變且無活動性中樞神經系統轉移。在一些實施例中，本文所提供之方法的人類個體可具有不超過2級的感覺或運動神經病變且無不可控的糖尿病。在又其他實施例中，本文所提供之方法的人類個體可具有不超過2級的感覺或運動神經病變，無活動性中樞神經系統轉移且無不可控的糖尿病。在一些實施例中，本文所提供之方法的人類個體可具有以下中之任一者：不超過2級的感覺或運動神經病變、無活動性中樞神經系統轉移，及無不可控的糖尿病。在一些實施例中，本文所提供之方法的人類個體可具有以下中之任兩者的任何組合或排列：不超過2級的感覺或運動神經病變、無活動性中樞神經系統轉移，及無不可控的糖尿病。在一些實施例中，本文所提供之方法的人類個體可具有以下中之所有三者：不超過2級的感覺或運動神經病變、無活動性中樞神經系統轉移，及無不可控的糖尿病。在本段落所提供之方法的一個實施例中，不可控的糖尿病係根據血紅素A1c (HbA1c)不小於8%來確定。在本段落所提供之方法的一些實施例中，不可控的糖尿病係根據7%與8%之間的HbA1c與不另說明的相關糖尿病症狀來確定。在本段落所提供之方法的其他實施例中，相關糖尿病症狀包含多尿症或由多尿症組成。在本段落所提供之方法的一些其他實施例中，相關糖尿病症狀包含煩渴症或由煩渴症組成。在本段落所提供之方法的又其他實施例中，相關糖尿病症狀包含多尿症與煩渴症或由多尿症與煩渴症組成。In other embodiments of the methods provided herein, including the methods in the preceding paragraphs, the human subjects in which the methods provided herein can be used are human subjects that do not have certain conditions. In one embodiment, the human subjects in the methods provided herein have not previously received any CPI treatment. CPIs are defined as PD-1 inhibitors, PD-L1 inhibitors, or PD-L2 inhibitors (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). In some embodiments, the human subjects in the methods provided herein have not received PD-1 inhibitors, PD-L1 inhibitors, or PD-L2 inhibitors. In certain embodiments, the human subjects in the methods provided herein have not received atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab. In certain embodiments, the human subject of the methods provided herein has not previously been treated with any agent directed to another stimulatory or co-inhibitory T cell receptor (including, but not limited to, CD137 agonists, CTLA 4 inhibitors, or OX-40 agonists). In certain embodiments, the human subject of the methods provided herein has not previously been treated with any CD137 agonists, CTLA 4 inhibitors, or OX-40 agonists. In one embodiment, the human subject of the methods provided herein may have no more than grade 2 sensory or motor neuropathy. In one embodiment, the human subject of the methods provided herein may not have active central nervous system metastasis. In one embodiment, the human subject of the methods provided herein may not have uncontrolled diabetes. In one embodiment, the human subject of the methods provided herein may have no more than 2 grades of sensory or motor neuropathy and no active central nervous system metastasis. In some embodiments, the human subject of the methods provided herein may have no more than 2 grades of sensory or motor neuropathy and no uncontrolled diabetes. In yet other embodiments, the human subject of the methods provided herein may have no more than 2 grades of sensory or motor neuropathy, no active central nervous system metastasis and no uncontrolled diabetes. In some embodiments, the human subject of the methods provided herein may have any of the following: no more than 2 grades of sensory or motor neuropathy, no active central nervous system metastasis, and no uncontrolled diabetes. In some embodiments, the human subject of the methods provided herein may have any combination or permutation of any two of the following: no more than grade 2 sensory or motor neuropathy, no active central nervous system metastasis, and no uncontrolled diabetes. In some embodiments, the human subject of the methods provided herein may have all three of the following: no more than grade 2 sensory or motor neuropathy, no active central nervous system metastasis, and no uncontrolled diabetes. In one embodiment of the methods provided in this paragraph, uncontrolled diabetes is determined based on a hemoglobin A1c (HbA1c) of not less than 8%. In some embodiments of the methods provided in this paragraph, uncontrolled diabetes is determined based on an HbA1c between 7% and 8% and related diabetic symptoms not otherwise specified. In other embodiments of the methods provided in this paragraph, the associated diabetes symptoms include or consist of polyuria. In some other embodiments of the methods provided in this paragraph, the associated diabetes symptoms include or consist of thirst. In still other embodiments of the methods provided in this paragraph, the associated diabetes symptoms include or consist of polyuria and thirst.
在某些實施例中，本文所提供之方法的人類個體可能不具有正在發生的與先前治療相關的臨床顯著毒性(2級或更高)。在某些實施例中，本文所提供之方法的人類個體可能不具有正在發生的與先前治療相關的臨床顯著毒性(2級或更高)，其中先前治療為放射治療或手術。在一個實施例中，本文所提供之方法的人類個體可能不具有需要高劑量類固醇(例如＞10 mg/天普賴松(prednisone)或等效物)或其他免疫抑制性藥品的病狀。在一個實施例中，本文所提供之方法的人類個體可能不具有需要高劑量類固醇或其他免疫抑制性藥品的病狀，其中類固醇或其他免疫抑制性藥品不為吸入或局部類固醇。在某些實施例中，本文所提供之方法的人類個體可能先前未經恩諾單抗維多汀或其他基於MMAE之ADC治療尿路上皮癌。在某些實施例中，本文所提供之方法的人類個體在用本文所提供之方法治療前3年內可能不具有另一侵襲性惡性腫瘤病史。在某些實施例中，本文所提供之方法的人類個體可能不具有來自先前診斷之惡性腫瘤的殘留疾病的證據。在某些實施例中，本文所提供之方法的人類個體在第一次給與恩諾單抗維多汀時可不接受針對活動性感染之全身抗微生物治療，其中感染為病毒、細菌或真菌感染。在第一次給與恩諾單抗維多汀時，針對活動性感染(病毒、細菌或真菌)進行全身抗微生物治療。在某些實施例中，本文所提供之方法的人類個體可能不具有陽性B型肝炎表面抗原及/或抗B型肝炎核心抗體。在某些實施例中，本文所提供之方法的人類個體可能不具有活動性C型肝炎感染或已知人類免疫缺乏病毒(HIV)感染。在某些實施例中，本文所提供之方法的人類個體可能不具有活動性肺結核。在某些實施例中，本文所提供之方法的人類個體在第一次給與恩諾單抗維多汀之前6個月內，不具有腦血管事件(中風或短暫局部缺血發作)、不穩定型心絞痛、心肌梗塞或符合NYHA IV級之心臟症狀(包括充血性心臟衰竭)的病史記錄。在某些實施例中，本文所提供之方法的人類個體在用本文所提供之方法治療之前2週可能不進行放射治療或大手術。在某些實施例中，本文所提供之方法的人類個體在用本文所提供之方法治療之前4週可能不具有未完成的化學療法、生物製劑或研究性藥劑治療。在某些實施例中，本文所提供之方法的人類個體可能不具有針對恩諾單抗維多汀或針對恩諾單抗維多汀藥物調配物中所含之任何賦形劑(包括組胺酸、二水合海藻糖及聚山梨醇酯20)的已知重度(≥3級)超敏反應。在某些實施例中，本文所提供之方法的人類個體可能不具有針對派姆單抗或針對派姆單抗藥物調配物中所含之任何賦形劑的已知重度(≥3級)超敏反應。在某些實施例中，本文所提供之方法的人類個體可能不具有活動性角膜炎或角膜潰瘍。在某些實施例中，本文所提供之方法的人類個體可能不具有在過去2年內需要全身治療的活動性自體免疫性疾病(例如使用疾病調節劑、皮質類固醇或免疫抑制性藥物)。在某些實施例中，本文所提供之方法的人類個體可能不具有在過去2年內需要全身治療的活動性自體免疫性疾病，其中全身治療包含疾病調節劑、皮質類固醇或免疫抑制性藥物。在一些實施例中，全身治療不為替代療法(例如針對腎上腺或垂體機能不全之甲狀腺素、胰島素或生理皮質類固醇替代療法)。在一些實施例中，全身治療不為針對腎上腺或垂體機能不全之甲狀腺素、胰島素或生理皮質類固醇替代療法。在某些實施例中，本文所提供之方法的人類個體可能不具有特發性肺纖維化病史；機化性肺炎、藥物誘導之肺炎、特發性肺炎或篩檢胸部CT掃描時活動性肺炎之證據。在某些實施例中，本文所提供之方法的人類個體可能先前未接受同種異體幹細胞或實體器官移植。在某些實施例中，本文所提供之方法的人類個體可能在用本文所提供之方法治療之前30天內未接受減毒活疫苗。在特定實施例中，活疫苗為麻疹、流行性腮腺炎、風疹、水痘/帶狀疱疹(雞痘)、黃熱病、狂犬病、BCG或傷寒疫苗。在特定實施例中，減毒活疫苗為鼻內流感痘苗。在某些實施例中，本文所提供之方法的人類個體可能不具有損害個體接受或耐受本文所提供之方法之能力的潛在醫學病狀。In certain embodiments, the human subject of the methods provided herein may not have ongoing clinically significant toxicity (grade 2 or higher) associated with a prior treatment. In certain embodiments, the human subject of the methods provided herein may not have ongoing clinically significant toxicity (grade 2 or higher) associated with a prior treatment, wherein the prior treatment is radiation therapy or surgery. In one embodiment, the human subject of the methods provided herein may not have a condition requiring high doses of steroids (e.g., >10 mg/day prednisone or equivalent) or other immunosuppressive drugs. In one embodiment, the human subject of the methods provided herein may not have a condition requiring high doses of steroids or other immunosuppressive drugs, wherein the steroid or other immunosuppressive drug is not an inhaled or topical steroid. In certain embodiments, the human subject of the methods provided herein may not have previously been treated for urothelial carcinoma with Enromax or other MMAE-based ADCs. In certain embodiments, the human subject of the methods provided herein may not have a history of another aggressive malignant tumor within 3 years prior to treatment with the methods provided herein. In certain embodiments, the human subject of the methods provided herein may not have evidence of residual disease from a previously diagnosed malignant tumor. In certain embodiments, the human subject of the methods provided herein may not receive systemic antimicrobial therapy for active infection when Enromax is first administered, wherein the infection is a viral, bacterial, or fungal infection. Systemic antimicrobial therapy is performed for active infection (viral, bacterial, or fungal) when Enromax is first administered. In certain embodiments, the human subject of the methods provided herein may not have positive hepatitis B surface antigen and/or anti-hepatitis B core antibody. In certain embodiments, the human subject of the methods provided herein may not have active hepatitis C infection or known human immunodeficiency virus (HIV) infection. In certain embodiments, the human subject of the methods provided herein may not have active tuberculosis. In certain embodiments, the human subject of the methods provided herein does not have a history of cerebrovascular events (stroke or transient ischemic attack), unstable angina, myocardial infarction, or heart symptoms (including congestive heart failure) in accordance with NYHA IV class within 6 months before the first administration of Ennomaxab Vedotin. In certain embodiments, the human subject of the methods provided herein may not have undergone radiation therapy or major surgery 2 weeks prior to treatment with the methods provided herein. In certain embodiments, the human subject of the methods provided herein may not have unfinished chemotherapy, biologics, or investigational drug treatment 4 weeks prior to treatment with the methods provided herein. In certain embodiments, the human subject of the methods provided herein may not have a known severe (≥ Grade 3) hypersensitivity reaction to enrofloxacin or to any excipient contained in the enrofloxacin drug formulation (including histidine, trehalose dihydrate, and polysorbate 20). In certain embodiments, the human subject of the methods provided herein may not have a known severe (≥ Grade 3) hypersensitivity reaction to pembrolizumab or to any excipient contained in a pembrolizumab drug formulation. In certain embodiments, the human subject of the methods provided herein may not have active keratitis or corneal ulcers. In certain embodiments, the human subject of the methods provided herein may not have an active autoimmune disease requiring systemic treatment within the past 2 years (e.g., use of disease modifiers, corticosteroids, or immunosuppressive drugs). In certain embodiments, the human subject of the methods provided herein may not have an active autoimmune disease requiring systemic treatment within the past 2 years, wherein the systemic treatment comprises a disease modifier, a corticosteroid, or an immunosuppressive drug. In some embodiments, the systemic therapy is not a replacement therapy (e.g., thyroid hormone, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency). In some embodiments, the systemic therapy is not thyroid hormone, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency. In some embodiments, the human subject of the methods provided herein may not have a history of idiopathic pulmonary fibrosis; evidence of organizing pneumonia, drug-induced pneumonia, idiopathic pneumonia, or active pneumonia on screening chest CT scan. In some embodiments, the human subject of the methods provided herein may not have previously received an allogeneic stem cell or solid organ transplant. In certain embodiments, the human subject of the methods provided herein may not have received a live attenuated vaccine within 30 days prior to treatment with the methods provided herein. In certain embodiments, the live vaccine is measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, or typhoid vaccine. In certain embodiments, the live attenuated vaccine is intranasal influenza vaccine. In certain embodiments, the human subject of the methods provided herein may not have a potential medical condition that impairs the ability of the subject to receive or tolerate the methods provided herein.
在本文所提供之方法的一些實施例中，藉由24小時尿液收集來量測CrCl。在本文所提供之方法的其他實施例中，藉由科克羅夫特-高爾特準則來估算CrCl。In some embodiments of the methods provided herein, CrCl is measured by 24-hour urine collection. In other embodiments of the methods provided herein, CrCl is estimated by the Cockcroft-Gault criterion.
在本文所提供之方法的一些實施例中，藉由24小時尿液收集來量測GFR。在本文所提供之方法的其他實施例中，藉由科克羅夫特-高爾特準則來估算GFR。在本段落所提供之方法的其他實施例中，藉由腎病膳食改良[MDRD]來量測GFR。In some embodiments of the methods provided herein, GFR is measured by 24-hour urine collection. In other embodiments of the methods provided herein, GFR is estimated by the Cockcroft-Gault criterion. In other embodiments of the methods provided in this paragraph, GFR is measured by Modification of Diet in Renal Disease [MDRD].
在本文所提供之方法的一些實施例中，個體已以一或多種其他癌症治療來治療。在本文所提供之方法的某些實施例中，尿路上皮癌(包括局部晚期或轉移性尿路上皮癌)已以一或多種其他癌症治療來治療。In some embodiments of the methods provided herein, the subject has been treated with one or more other cancer therapies. In certain embodiments of the methods provided herein, urothelial carcinoma (including locally advanced or metastatic urothelial carcinoma) has been treated with one or more other cancer therapies.
在一些實施例中，本文所描述之CPI可包含此章節(章節5.2.1)中所描述之任何CPI或由其組成。In some embodiments, the CPIs described herein may include or consist of any CPIs described in this section (Section 5.2.1).
在本文所提供之所有方法及前述段落具體描述的彼等方法中：章節3、5.2、5.3、5.4、5.5及6中描述了可使用的ADC，本文中且本章節(章節5.2)及章節3及6中舉例說明了選擇用於治療的患者，本章節(章節5.2)、下述章節5.4、5.6、5.7及6中描述了投與治療劑的給藥方案及醫藥組合物，本文中描述了且本章節(章節5.2，包括5.2.1及5.2.2)及章節6中舉例說明了可用於鑑別治療劑、選擇患者、測定此等方法之結果及/或以任何方式充當此等方法之準則的生物標記物，生物標記物可如章節5.8中所描述或如此項技術中所知來測定，本章節(章節5.2，包括章節5.2.1.4)及章節3及6中描述了本文所提供之方法的治療結果，本文所提供之方法的其他治療結果可為本文所描述之生物標記物的改良，例如本章節(章節5.2，包括5.2.2)及章節3及6中所描述且舉例說明的彼等生物標記物，且本章節(章節5.2)及章節5.5中描述了包括ADC及其他治療劑的組合療法。因此，熟習此項技術者應瞭解，本文所提供之方法包括如上文及下文所描述之患者、治療劑、給藥方案、生物標記物及治療結果的所有排列及組合。In all methods provided herein and those methods specifically described in the preceding paragraphs: ADCs that can be used are described in Sections 3, 5.2, 5.3, 5.4, 5.5 and 6, patients selected for treatment are exemplified herein and in this section (Section 5.2) and Sections 3 and 6, dosing regimens and pharmaceutical compositions for administering therapeutic agents are described in this section (Section 5.2), the following Sections 5.4, 5.6, 5.7 and 6, and methods that can be used to identify therapeutic agents, select patients, determine the results of these methods and/or are exemplified herein and in this section (Section 5.2, including 5.2.1 and 5.2.2) and Section 6. or biomarkers that in any way serve as criteria for such methods, biomarkers can be determined as described in Section 5.8 or as known in the art, treatment outcomes of the methods provided herein are described in this section (Section 5.2, including Section 5.2.1.4) and Sections 3 and 6, other treatment outcomes of the methods provided herein can be improvements of the biomarkers described herein, such as those described and exemplified in this section (Section 5.2, including Section 5.2.2) and Sections 3 and 6, and combination therapies including ADCs and other therapeutic agents are described in this section (Section 5.2) and Section 5.5. Therefore, those skilled in the art will understand that the methods provided herein include all permutations and combinations of patients, therapeutic agents, dosing regimens, biomarkers, and treatment outcomes as described above and below.
在某些實施例中，本文所提供之方法用於治療患有尿路上皮癌之個體，該等尿路上皮癌表現191P4D12 RNA、表現191P4D12蛋白質，或表現191P4D12 RNA與191P4D12蛋白質。在一個實施例中，本文所提供之方法用於治療患有尿路上皮癌之個體，該等尿路上皮癌表現191P4D12 RNA、表現191P4D12蛋白質，或表現191P4D12 RNA與191P4D12蛋白質。In certain embodiments, the methods provided herein are used to treat individuals with urothelial carcinoma that express 191P4D12 RNA, express 191P4D12 protein, or express 191P4D12 RNA and 191P4D12 protein. In one embodiment, the methods provided herein are used to treat individuals with urothelial carcinoma that express 191P4D12 RNA, express 191P4D12 protein, or express 191P4D12 RNA and 191P4D12 protein.
在某些實施例中，本文所提供之方法用於患有局部晚期尿路上皮癌之個體，該等局部晚期尿路上皮癌表現191P4D12 RNA、表現191P4D12蛋白質，或表現191P4D12 RNA與191P4D12蛋白質。在一個實施例中，本文所提供之方法用於治療患有局部晚期尿路上皮癌且先前已以CPI治療之個體，該等尿路上皮癌表現191P4D12 RNA、表現191P4D12蛋白質，或表現191P4D12 RNA與191P4D12蛋白質。In certain embodiments, the methods provided herein are used for individuals with locally advanced urothelial carcinoma that express 191P4D12 RNA, express 191P4D12 protein, or express 191P4D12 RNA and 191P4D12 protein. In one embodiment, the methods provided herein are used to treat individuals with locally advanced urothelial carcinoma that have been previously treated with a CPI that expresses 191P4D12 RNA, expresses 191P4D12 protein, or expresses 191P4D12 RNA and 191P4D12 protein.
在某些實施例中，本文所提供之方法用於治療患有轉移性癌症的個體，該等轉移性癌症表現191P4D12 RNA、表現191P4D12蛋白質，或表現191P4D12 RNA與191P4D12蛋白質。在一個實施例中，本文所提供之方法用於治療患有轉移性尿路上皮癌之個體，該等轉移性尿路上皮癌表現191P4D12 RNA、表現191P4D12蛋白質，或表現191P4D12 RNA與191P4D12蛋白質。In certain embodiments, the methods provided herein are used to treat individuals with metastatic cancers that express 191P4D12 RNA, express 191P4D12 protein, or express 191P4D12 RNA and 191P4D12 protein. In one embodiment, the methods provided herein are used to treat individuals with metastatic urothelial carcinomas that express 191P4D12 RNA, express 191P4D12 protein, or express 191P4D12 RNA and 191P4D12 protein.
在一些實施例中，癌症中之191P4D12 RNA表現係藉由聚核苷酸雜交、定序(評估序列之相對豐度)及/或PCR (包括RT-PCR)來確定。在一些實施例中，癌症中之191P4D12蛋白質表現係藉由IHC、螢光活化細胞分選(FACS)分析及/或西方墨點法確定。在一些實施例中，藉由超過一種方法來確定癌症中之191P4D12蛋白質表現。在一些實施例中，藉由兩種IHC方法來確定癌症中之191P4D12蛋白質表現。In some embodiments, 191P4D12 RNA expression in cancer is determined by polynucleotide hybridization, sequencing (assessing the relative abundance of sequences) and/or PCR (including RT-PCR). In some embodiments, 191P4D12 protein expression in cancer is determined by IHC, fluorescence activated cell sorting (FACS) analysis and/or Western blot. In some embodiments, 191P4D12 protein expression in cancer is determined by more than one method. In some embodiments, 191P4D12 protein expression in cancer is determined by two IHC methods.
在一些實施例中，局部晚期或轉移性尿路上皮癌在組織學上、細胞學上、或組織學上與細胞學上得到確認。在一些實施例中，局部晚期或轉移性膀胱癌在組織學上、細胞學上、或組織學上與細胞學上得到確認。In some embodiments, locally advanced or metastatic urothelial carcinoma is confirmed histologically, cytologically, or both histologically and cytologically. In some embodiments, locally advanced or metastatic bladder cancer is confirmed histologically, cytologically, or both histologically and cytologically.
在一些實施例中，個體具有內臟轉移。在一些實施例中，個體具有僅淋巴結轉移疾病。在一些實施例中，疾病起源部位在上泌尿道。在一些實施例中，疾病起源部位在下泌尿道。In some embodiments, the subject has visceral metastases. In some embodiments, the subject has lymph node-only metastatic disease. In some embodiments, the site of disease origin is in the upper urinary tract. In some embodiments, the site of disease origin is in the lower urinary tract.
在一些實施例中，個體具有大於或等於10之PD-L1表現綜合陽性評分(CPS)。PD-L1蛋白質表現藉由使用綜合陽性評分(CPS)來確定，其為PD-L1陽性細胞(亦即，腫瘤細胞、淋巴球及巨噬細胞)之數目除以活腫瘤細胞之總數目，且隨後乘以100。在一些實施例中，個體具有小於10之PD-L1表現CPS。基於以下計算，連接素H評分在0-300範圍內：H評分=[(0×陰性細胞%) + (1×弱陽性細胞%) + (2×中等陽性細胞%) + (3×強陽性細胞%)]。尿路上皮癌一般具有260-270之中值H評分。在一些實施例中，個體具有0與300之間的連接素-4 H評分。在一些實施例中，個體具有0與250之間、0與200之間、0與150之間、0與100之間或0與50之間的連接素-4 H評分。在一些實施例中，個體具有0與200之間的連接素-4 H評分。5.2.1.3檢查點抑制劑及與派姆單抗之組合療法檢查點抑制劑In some embodiments, the subject has a PD-L1 expression combined positive score (CPS) greater than or equal to 10. PD-L1 protein expression is determined by using a combined positive score (CPS), which is the number of PD-L1 positive cells (i.e., tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells, and then multiplied by 100. In some embodiments, the subject has a PD-L1 expression CPS less than 10. The nectin H score ranges from 0-300 based on the following calculation: H score = [(0×negative cells%) + (1×weakly positive cells%) + (2×moderately positive cells%) + (3×strongly positive cells%)]. Urothelial carcinoma generally has a median H score of 260-270. In some embodiments, the subject has a nectin-4 H score between 0 and 300. In some embodiments, the subject has a nectin-4 H score between 0 and 250, between 0 and 200, between 0 and 150, between 0 and 100, or between 0 and 50. In some embodiments, the subject has a nectin-4 H score between 0 and 200.5.2.1.3Checkpoint Inhibitors and Combination Therapy with PembrolizumabCheckpoint Inhibitors
在一些實施例中，可以本文所提供之方法治療的個體具有某些表型或基因型特徵。在一些實施例中，個體具有本文所描述之表型或基因型特徵的任何排列及組合。In some embodiments, the individual that can be treated by the methods provided herein has certain phenotypic or genotypic characteristics. In some embodiments, the individual has any arrangement and combination of the phenotypic or genotypic characteristics described herein.
在一些實施例中，組織學、細胞學上或組織學及細胞學上兩者判定表型或基因型特徵。在本文所提供之方法的一些實施例中，表型及/或基因型特徵之組織學及/或細胞學確認係如美國臨床腫瘤學會/美國病理學家協會(ASCO/CAP)指導原則中所描述，基於最近分析之組織執行，其係以全文引用的方式併入本文中。在一些實施例中，藉由包括下一代定序(例如Illumina, Inc之NGS)在內之定序、DNA雜交及/或RNA雜交來測定表型或基因型特徵。In some embodiments, the phenotypic or genotypic characteristics are determined histologically, cytologically, or both histologically and cytologically. In some embodiments of the methods provided herein, the histological and/or cytological confirmation of the phenotypic and/or genotypic characteristics is performed as described in the American Society of Clinical Oncology/American Association of Pathologists (ASCO/CAP) guidelines, based on recently analyzed tissues, which are incorporated herein by reference in their entirety. In some embodiments, the phenotypic or genotypic characteristics are determined by sequencing, DNA hybridization, and/or RNA hybridization, including next generation sequencing (e.g., NGS by Illumina, Inc).
在本文所提供之方法(包括此章節(章節5.2)中所提供的方法，諸如此段落及前述段落中所提供的方法)的各種態樣或實施例中，本文所提供之方法的人類個體先前未接受過任何CPI治療。CPI定義為PD-1抑制劑、PD-L1抑制劑或PD-L2抑制劑(包括(但不限於)阿特珠單抗、派姆單抗、納武單抗、德瓦魯單抗或阿維魯單抗)。在一些實施例中，本文所提供之方法的人類個體未接受過PD-1抑制劑、PD-L1抑制劑或PD-L2抑制劑治療。在某些實施例中，本文所提供之方法的人類個體先前未接受過阿特珠單抗、派姆單抗、納武單抗、德瓦魯單抗或阿維魯單抗治療。如本文所用，術語「免疫檢查點抑制劑」或「檢查點抑制劑」(CPI)係指完全或部分地減少、抑制、干擾或調節一或多種檢查點蛋白質之分子。已知多種檢查點蛋白質，諸如CTLA-4及其配位體CD80及CD86；以及PD-1與其配位體PD-Ll及PD-L2 (Pardoll,NatureReviewsCancer,2012,12, 252-264)。其他例示性檢查點蛋白質包括LAG-3、B7、TIM3 (HAVCR2)、OX40 (CD134)、GITR、CD137、CD40、VTCN1、IDO1、CD276、PVRIG、TIGIT、CD25 (IL2RA)、IFNAR2、IFNAR1、CSF1R、VSIR (VISTA)或HLA。此等蛋白質似乎擔負著T細胞反應的共刺激或抑制性相互作用。免疫檢查點蛋白質似乎調節及維持自身耐受及生理免疫反應之持續時間及幅度。免疫檢查點抑制劑包括抗體或衍生自抗體。In various aspects or embodiments of the methods provided herein (including the methods provided in this section (Section 5.2), such as the methods provided in this paragraph and the preceding paragraphs), the human subject of the methods provided herein has not previously received any CPI treatment. CPI is defined as a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor (including but not limited to atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). In some embodiments, the human subject of the methods provided herein has not previously received PD-1 inhibitors, PD-L1 inhibitors, or PD-L2 inhibitors. In certain embodiments, the human subject of the methods provided herein has not previously received atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab treatment. As used herein, the term "immune checkpoint inhibitor" or "checkpoint inhibitor" (CPI) refers to a molecule that completely or partially reduces, inhibits, interferes with, or modulates one or more checkpoint proteins. A variety of checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 and its ligands PD-L1 and PD-L2 (Pardoll,NatureReviewsCancer ,2012 ,12 , 252-264). Other exemplary checkpoint proteins include LAG-3, B7, TIM3 (HAVCR2), OX40 (CD134), GITR, CD137, CD40, VTCN1, IDO1, CD276, PVRIG, TIGIT, CD25 (IL2RA), IFNAR2, IFNAR1, CSF1R, VSIR (VISTA) or HLA. These proteins appear to be responsible for either co-stimulatory or inhibitory interactions of T cell responses. Immune checkpoint proteins appear to regulate and maintain self-tolerance and the duration and magnitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies.
在某些實施例中，本文所提供之方法用的檢查點抑制劑可為針對癌症中上調之檢查點蛋白質的抑制劑或活化劑。在一些特定實施例中，本文所提供之方法用的檢查點抑制劑可為針對檢查點蛋白質的抑制劑或活化劑，該檢查點蛋白質包括LAG-3、B7、TIM3 (HAVCR2)、OX40 (CD134)、GITR、CD137、CD40、VTCN1、IDO1、CD276、PVRIG、TIGIT、CD25 (IL2RA)、IFNAR2、IFNAR1、CSF1R、VSIR (VISTA)或HLA。在一些實施例中，本文所提供之方法用的檢查點抑制劑可為選自由以下組成之群的抑制劑或活化劑：PD-1抑制劑、PD-L1抑制劑、PD-L2抑制劑、CTLA-4抑制劑、LAG-3抑制劑、B7抑制劑、TIM3 (HAVCR2)抑制劑、OX40 (CD134)抑制劑、GITR促效劑、CD137促效劑、或CD40促效劑、VTCN1抑制劑、IDO1抑制劑、CD276抑制劑、PVRIG抑制劑、TIGIT抑制劑、CD25 (IL2RA)抑制劑、IFNAR2抑制劑、IFNAR1抑制劑、CSF1R抑制劑、VSIR (VISTA)抑制劑或靶向HLA之治療劑。此類抑制劑、活化劑或治療劑進一步提供於下文中。In certain embodiments, the checkpoint inhibitors used in the methods provided herein can be inhibitors or activators of checkpoint proteins that are upregulated in cancer. In some specific embodiments, the checkpoint inhibitors used in the methods provided herein can be inhibitors or activators of checkpoint proteins, including LAG-3, B7, TIM3 (HAVCR2), OX40 (CD134), GITR, CD137, CD40, VTCN1, IDO1, CD276, PVRIG, TIGIT, CD25 (IL2RA), IFNAR2, IFNAR1, CSF1R, VSIR (VISTA), or HLA. In some embodiments, the checkpoint inhibitor used in the methods provided herein can be an inhibitor or activator selected from the group consisting of: PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, B7 inhibitor, TIM3 (HAVCR2) inhibitor, OX40 (CD134) inhibitor, GITR agonist, CD137 agonist, or CD40 agonist, VTCN1 inhibitor, IDO1 inhibitor, CD276 inhibitor, PVRIG inhibitor, TIGIT inhibitor, CD25 (IL2RA) inhibitor, IFNAR2 inhibitor, IFNAR1 inhibitor, CSF1R inhibitor, VSIR (VISTA) inhibitor or HLA-targeted therapeutic. Such inhibitors, activators or therapeutic agents are provided further below.
在一些實施例中，檢查點抑制劑為CTLA-4抑制劑。在一個實施例中，CTLA-4抑制劑為抗CTLA-4抗體。抗CTLA-4抗體之實例包括(但不限於)美國專利第5,811,097號、第5,811,097號、第5,855,887號、第6,051,227號、第6,207,157號、第6,682,736號、第6,984,720號及第7,605,238號中所述之彼等抗體，該等專利皆以全文引用之方式併入本文中。在一個實施例中，抗CTLA-4抗體為曲美木單抗(tremelimumab) (亦稱為替西木單抗(ticilimumab)或CP-675,206)。在另一實施例中，抗CTLA-4抗體為伊派利單抗(ipilimumab) (亦稱為MDX-010或MDX-101)。伊派利單抗為結合至CTLA-4之全人類單株IgG抗體。伊派利單抗以商標名Yervoy™出售。In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor. In one embodiment, the CTLA-4 inhibitor is an anti-CTLA-4 antibody. Examples of anti-CTLA-4 antibodies include, but are not limited to, those described in U.S. Patent Nos. 5,811,097, 5,811,097, 5,855,887, 6,051,227, 6,207,157, 6,682,736, 6,984,720, and 7,605,238, all of which are incorporated herein by reference in their entirety. In one embodiment, the anti-CTLA-4 antibody is tremelimumab (also known as ticilimumab or CP-675,206). In another embodiment, the anti-CTLA-4 antibody is ipilimumab (also known as MDX-010 or MDX-101). Ipilimumab is a fully human monoclonal IgG antibody that binds to CTLA-4. Ipilimumab is sold under the trade name Yervoy™.
在某些實施例中，檢查點抑制劑為PD-1/PD-L1抑制劑。PD-l/PD-L1抑制劑之實例包括(但不限於)美國專利第7,488,802號、第7,943,743號、第8,008,449號、第8,168,757號、第8,217,149號，以及PCT專利申請公開案第WO2003042402號、第WO2008156712號、第WO2010089411號、第WO2010036959號、第WO2011066342號、第WO2011159877號、第WO2011082400號及第WO2011161699中所述之彼等抑制劑，該等文獻皆以全文引用之方式併入本文中。In certain embodiments, the checkpoint inhibitor is a PD-1/PD-L1 inhibitor. Examples of PD-1/PD-L1 inhibitors include, but are not limited to, those described in U.S. Patent Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, and PCT Patent Application Publication Nos. WO2003042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, and WO2011161699, all of which are incorporated herein by reference in their entirety.
「PD-1拮抗劑」意謂阻斷癌細胞上表現之PD-L1與免疫細胞(T細胞、B細胞或自然殺手T細胞)上表現之PD-1結合且在特定實施例中亦阻斷癌細胞上表現之PD-L2與免疫細胞表現之PD-1結合的任何化合物或生物分子。PD-1及其配位體之替代名稱或同義詞包括：PDCD1、PD1、CD279及SLEB2用於PD-1；PDCD1L1、PDL1、B7H1、B7-4、CD274及B7-H用於PD-L1；及PDCD1L2、PDL2、B7-DC、Btdc及CD273用於PD-L2。在其中人類個體正進行治療之任何本發明之治療方法、藥劑及用途中，PD-1拮抗劑阻斷人類PD-L1與人類PD-1之結合，且在特定實施例中阻斷人類PD-L1及PD-L2與人類PD-1之結合。人類PD-1胺基酸序列可見於NCBI基因座編號：NP_005009中。人類PD-L1及PD-L2胺基酸序列分別可見於NCBI基因座編號：NP_054862及NP_079515中。"PD-1 antagonist" means any compound or biological molecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells, or natural killer T cells), and in certain embodiments, also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed on immune cells. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279, and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc, and CD273 for PD-L2. In any of the treatment methods, medicaments, and uses of the invention in which a human subject is being treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and in specific embodiments blocks the binding of human PD-L1 and PD-L2 to human PD-1. The human PD-1 amino acid sequence can be found in NCBI Locus No.: NP_005009. The human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.
在一些實施例中，檢查點抑制劑為PD-1抑制劑或拮抗劑。在一個實施例中，PD-1抑制劑或拮抗劑為抗PD-1抗體。在一個實施例中，抗PD-1抗體為BGB-A317、納武單抗(亦稱為ONO-4538、BMS-936558或MDX1106)或派姆單抗(亦稱為MK-3475、SCH 900475，或藍布洛利珠單抗(lambrolizumab))。在一個實施例中，抗PD-1抗體為納武單抗。納武單抗為人類IgG4抗PD-1單株抗體，且以商標名Opdivo™出售。在另一實施例中，抗PD-1抗體為派姆單抗。派姆單抗為人源化單株IgG4抗體，且以商標名Keytruda™出售。在又另一實施例中，抗PD-1抗體為人源化抗體CT-011。單獨投與CT-011在治療復發的急性骨髓白血病(AML)時未顯示反應。在又另一實施例中，抗PD-1抗體為融合蛋白AMP-224。在另一實施例中，PD-1抗體為BGB-A317。BGB-A317為一種單株抗體，其中特異性地工程改造出結合Fc γ受體I之能力，且其具有以高親和力及優良目標特異性與PD-1獨特結合之特徵。在一個實施例中，PD-1抗體為西米普利單抗(cemiplimab)。在另一實施例中，PD-1抗體為卡瑞利珠單抗(camrelizumab)。在另一實施例中，PD-1抗體為斯迪利單抗(sintilimab)。在一些實施例中，PD-1抗體為替雷利珠單抗(tislelizumab)。在某些實施例中，PD-1抗體為TSR-042。在又另一實施例中，PD-1抗體為PDR001。在又另一實施例中，PD-1抗體為特瑞普利單抗(toripalimab)。In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist. In one embodiment, the PD-1 inhibitor or antagonist is an anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody is BGB-A317, nivolumab (also known as ONO-4538, BMS-936558, or MDX1106), or pembrolizumab (also known as MK-3475, SCH 900475, or lambrolizumab). In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody and is sold under the trade name Opdivo™. In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 antibody and is sold under the trade name Keytruda™. In yet another embodiment, the anti-PD-1 antibody is the humanized antibody CT-011. CT-011 alone has not shown a response in the treatment of relapsed acute myeloid leukemia (AML). In yet another embodiment, the anti-PD-1 antibody is the fusion protein AMP-224. In another embodiment, the PD-1 antibody is BGB-A317. BGB-A317 is a monoclonal antibody in which the ability to bind to Fc gamma receptor I is specifically engineered, and it has the characteristics of uniquely binding to PD-1 with high affinity and excellent target specificity. In one embodiment, the PD-1 antibody is cemiplimab. In another embodiment, the PD-1 antibody is camrelizumab. In another embodiment, the PD-1 antibody is sintilimab. In some embodiments, the PD-1 antibody is tislelizumab. In certain embodiments, the PD-1 antibody is TSR-042. In yet another embodiment, the PD-1 antibody is PDR001. In yet another embodiment, the PD-1 antibody is toripalimab.
在某些實施例中，檢查點抑制劑為PD-L1抑制劑。在一個實施例中，PD-L1抑制劑為抗PD-L1抗體。在一個實施例中，抗PD-L1抗體為MEDI4736 (德瓦魯單抗)。在另一實施例中，抗PD-L1抗體為BMS-936559 (亦稱為MDX-1105-01)。在又另一實施例中，PD-L1抑制劑為阿特珠單抗(亦稱為MPDL3280A及Tecentriq®)。在另一實施例中，PD-L1抑制劑為阿維魯單抗。In certain embodiments, the checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody. In one embodiment, the anti-PD-L1 antibody is MEDI4736 (durvalumab). In another embodiment, the anti-PD-L1 antibody is BMS-936559 (also known as MDX-1105-01). In yet another embodiment, the PD-L1 inhibitor is atezolizumab (also known as MPDL3280A and Tecentriq®). In another embodiment, the PD-L1 inhibitor is avelumab.
在一個實施例中，檢查點抑制劑為PD-L2抑制劑。在一個實施例中，PD-L2抑制劑抗PD-L2抗體。在一個實施例中，抗PD-L2抗體為rHIgM12B7A。In one embodiment, the checkpoint inhibitor is a PD-L2 inhibitor. In one embodiment, the PD-L2 inhibitor is an anti-PD-L2 antibody. In one embodiment, the anti-PD-L2 antibody is rHIgM12B7A.
在一個實施例中，檢查點抑制劑為淋巴球活化基因-3 (LAG-3)抑制劑。在一個實施例中，LAG-3抑制劑為可溶Ig融合蛋白IMP321 (Brignone等人,J.Immunol.,2007,179, 4202-4211)。在另一實施例中，LAG-3抑制劑為BMS-986016。In one embodiment, the checkpoint inhibitor is a lymphocyte activation gene-3 (LAG-3) inhibitor. In one embodiment, the LAG-3 inhibitor is a soluble Ig fusion protein IMP321 (Brignone et al.,J.Immunol. ,2007 ,179 , 4202-4211). In another embodiment, the LAG-3 inhibitor is BMS-986016.
在一個實施例中，檢查點抑制劑為B7抑制劑。在一個實施例中，B7抑制劑為B7-H3抑制劑或B7-H4抑制劑。在一個實施例中，B7-H3抑制劑為抗B7-H3抗體MGA271 (Loo等人,Clin.CancerRes.,2012, 3834)。In one embodiment, the checkpoint inhibitor is a B7 inhibitor. In one embodiment, the B7 inhibitor is a B7-H3 inhibitor or a B7-H4 inhibitor. In one embodiment, the B7-H3 inhibitor is the anti-B7-H3 antibody MGA271 (Loo et al.,Clin.CancerRes. ,2012 , 3834).
在一個實施例中，檢查點抑制劑為TIM3 (T細胞免疫球蛋白域及黏蛋白域3)抑制劑(Fourcade等人,J. Exp. Med.,2010,207, 2175-86；Sakuishi等人,J. Exp. Med.,2010,207, 2187-94)。In one embodiment, the checkpoint inhibitor is a TIM3 (T cell immunoglobulin domain and mucin domain 3) inhibitor (Fourcade et al.,J. Exp. Med. ,2010 ,207 , 2175-86; Sakuishi et al.,J. Exp. Med. ,2010 ,207 , 2187-94).
在一個實施例中，檢查點抑制劑為OX40 (CD134)促效劑。在一個實施例中，檢查點抑制劑為抗OX40抗體。在一個實施例中，抗OX40抗體為抗OX-40。在另一實施例中，抗OX40抗體為MEDI6469。In one embodiment, the checkpoint inhibitor is an OX40 (CD134) agonist. In one embodiment, the checkpoint inhibitor is an anti-OX40 antibody. In one embodiment, the anti-OX40 antibody is anti-OX-40. In another embodiment, the anti-OX40 antibody is MEDI6469.
在一個實施例中，檢查點抑制劑為GITR促效劑。在一個實施例中，檢查點抑制劑為抗GITR抗體。在一個實施例中，抗GITR抗體為TRX518。In one embodiment, the checkpoint inhibitor is a GITR agonist. In one embodiment, the checkpoint inhibitor is an anti-GITR antibody. In one embodiment, the anti-GITR antibody is TRX518.
在一個實施例中，檢查點抑制劑為CD137促效劑。在一個實施例中，檢查點抑制劑為抗CD137抗體。在一個實施例中，抗CD137抗體為烏瑞蘆單抗(urelumab)。在另一實施例中，抗CD137抗體為PF-05082566。In one embodiment, the checkpoint inhibitor is a CD137 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD137 antibody. In one embodiment, the anti-CD137 antibody is urelumab. In another embodiment, the anti-CD137 antibody is PF-05082566.
在一個實施例中，檢查點抑制劑為CD40促效劑。在一個實施例中，檢查點抑制劑為抗CD40抗體。在一個實施例中，抗CD40抗體為CF-870,893。In one embodiment, the checkpoint inhibitor is a CD40 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD40 antibody. In one embodiment, the anti-CD40 antibody is CF-870,893.
在一個實施例中，檢查點抑制劑為重組人類介白素-15 (rhIL-15)。In one embodiment, the checkpoint inhibitor is recombinant human interleukin-15 (rhIL-15).
在一個實施例中，檢查點抑制劑為VTCN抑制劑。在一個實施例中，VTCN抑制劑為FPA150。In one embodiment, the checkpoint inhibitor is a VTCN inhibitor. In one embodiment, the VTCN inhibitor is FPA150.
在一個實施例中，檢查點抑制劑為IDO抑制劑。在一個實施例中，IDO抑制劑為INCB024360。在另一實施例中，IDO抑制劑為因多莫得(indoximod)。在一個實施例中，IDO抑制劑為艾卡哚司他(epacadostat)。在另一實施例中，IDO抑制劑為BMS986205。在又另一實施例中，IDO抑制劑為那沃莫德(Navoximod)。在一個實施例中，IDO抑制劑為PF-06840003。在另一實施例中，IDO抑制劑為KHK2455。在又另一實施例中，IDO抑制劑為RG70099。在一個實施例中，IDO抑制劑為IOM-E。在另一實施例中，IDO抑制劑為IOM-D。In one embodiment, the checkpoint inhibitor is an IDO inhibitor. In one embodiment, the IDO inhibitor is INCB024360. In another embodiment, the IDO inhibitor is indoximod. In one embodiment, the IDO inhibitor is epacadostat. In another embodiment, the IDO inhibitor is BMS986205. In yet another embodiment, the IDO inhibitor is Navoximod. In one embodiment, the IDO inhibitor is PF-06840003. In another embodiment, the IDO inhibitor is KHK2455. In yet another embodiment, the IDO inhibitor is RG70099. In one embodiment, the IDO inhibitor is IOM-E. In another embodiment, the IDO inhibitor is IOM-D.
在一些實施例中，檢查點抑制劑為TIGIT抑制劑。在某些實施例中，TIGIT抑制劑為抗TIGIT抗體。在一個實施例中，TIGIT抑制劑為MTIG7192A。在另一實施例中，TIGIT抑制劑為BMS-986207。在又另一實施例中，TIGIT抑制劑為OMP-313M32。在一個實施例中，TIGIT抑制劑為MK-7684。在另一實施例中，TIGIT抑制劑為AB154。在又另一實施例中，TIGIT抑制劑為CGEN-15137。在一個實施例中，TIGIT抑制劑為SEA-TIGIT。在另一實施例中，TIGIT抑制劑為ASP8374。在又另一實施例中，TIGIT抑制劑為AJUD008。In some embodiments, the checkpoint inhibitor is a TIGIT inhibitor. In certain embodiments, the TIGIT inhibitor is an anti-TIGIT antibody. In one embodiment, the TIGIT inhibitor is MTIG7192A. In another embodiment, the TIGIT inhibitor is BMS-986207. In yet another embodiment, the TIGIT inhibitor is OMP-313M32. In one embodiment, the TIGIT inhibitor is MK-7684. In another embodiment, the TIGIT inhibitor is AB154. In yet another embodiment, the TIGIT inhibitor is CGEN-15137. In one embodiment, the TIGIT inhibitor is SEA-TIGIT. In another embodiment, the TIGIT inhibitor is ASP8374. In yet another embodiment, the TIGIT inhibitor is AJUD008.
在一些實施例中，檢查點抑制劑為VSIR抑制劑。在某些實施例中，VSIR抑制劑為抗VSIR抗體。在一個實施例中，VSIR抑制劑為MTIG7192A。在另一實施例中，VSIR抑制劑為CA-170。在又另一實施例中，VSIR抑制劑為JNJ 61610588。在一個實施例中，VSIR抑制劑為HMBD-002。In some embodiments, the checkpoint inhibitor is a VSIR inhibitor. In certain embodiments, the VSIR inhibitor is an anti-VSIR antibody. In one embodiment, the VSIR inhibitor is MTIG7192A. In another embodiment, the VSIR inhibitor is CA-170. In yet another embodiment, the VSIR inhibitor is JNJ 61610588. In one embodiment, the VSIR inhibitor is HMBD-002.
在一些實施例中，檢查點抑制劑為TIM3抑制劑。在某些實施例中，TIM3抑制劑為抗TIM3抗體。在一個實施例中，TIM3抑制劑為AJUD009。In some embodiments, the checkpoint inhibitor is a TIM3 inhibitor. In certain embodiments, the TIM3 inhibitor is an anti-TIM3 antibody. In one embodiment, the TIM3 inhibitor is AJUD009.
在一些實施例中，檢查點抑制劑為CD25 (IL2RA)抑制劑。在某些實施例中，CD25 (IL2RA)抑制劑為抗CD25 (IL2RA)抗體。在一個實施例中，CD25 (IL2RA)抑制劑為達利珠單抗(daclizumab)。在另一實施例中，CD25 (IL2RA)抑制劑為巴利昔單抗(basiliximab)。In some embodiments, the checkpoint inhibitor is a CD25 (IL2RA) inhibitor. In certain embodiments, the CD25 (IL2RA) inhibitor is an anti-CD25 (IL2RA) antibody. In one embodiment, the CD25 (IL2RA) inhibitor is daclizumab. In another embodiment, the CD25 (IL2RA) inhibitor is basiliximab.
在一些實施例中，檢查點抑制劑為IFNAR1抑制劑。在某些實施例中，IFNAR1抑制劑為抗IFNAR1抗體。在一個實施例中，IFNAR1抑制劑為阿尼富路單抗(anifrolumab)。在另一實施例中，IFNAR1抑制劑為絲法力單抗(sifalimumab)。In some embodiments, the checkpoint inhibitor is an IFNAR1 inhibitor. In certain embodiments, the IFNAR1 inhibitor is an anti-IFNAR1 antibody. In one embodiment, the IFNAR1 inhibitor is anifrolumab. In another embodiment, the IFNAR1 inhibitor is sifalimumab.
在一些實施例中，檢查點抑制劑為CSF1R抑制劑。在某些實施例中，CSF1R抑制劑為抗CSF1R抗體。在一個實施例中，CSF1R抑制劑為吡昔替尼(pexidartinib)。在另一實施例中，CSF1R抑制劑為依麻特珠單抗(emactuzumab)。在又另一實施例中，CSF1R抑制劑為卡比拉單抗(cabiralizumab)。在一個實施例中，CSF1R抑制劑為ARRY-382。在另一實施例中，CSF1R抑制劑為BLZ945。在又另一實施例中，CSF1R抑制劑為AJUD010。在一個實施例中，CSF1R抑制劑為AMG820。在另一實施例中，CSF1R抑制劑為IMC-CS4。在又另一實施例中，CSF1R抑制劑為JNJ-40346527。在一個實施例中，CSF1R抑制劑為PLX5622。在另一實施例中，CSF1R抑制劑為FPA008。In some embodiments, the checkpoint inhibitor is a CSF1R inhibitor. In certain embodiments, the CSF1R inhibitor is an anti-CSF1R antibody. In one embodiment, the CSF1R inhibitor is pexidartinib. In another embodiment, the CSF1R inhibitor is emactuzumab. In yet another embodiment, the CSF1R inhibitor is cabiralizumab. In one embodiment, the CSF1R inhibitor is ARRY-382. In another embodiment, the CSF1R inhibitor is BLZ945. In yet another embodiment, the CSF1R inhibitor is AJUD010. In one embodiment, the CSF1R inhibitor is AMG820. In another embodiment, the CSF1R inhibitor is IMC-CS4. In yet another embodiment, the CSF1R inhibitor is JNJ-40346527. In one embodiment, the CSF1R inhibitor is PLX5622. In another embodiment, the CSF1R inhibitor is FPA008.
在一些實施例中，檢查點抑制劑為靶向HLA之治療劑。在某些實施例中，靶向HLA之治療劑為抗HLA抗體。在一個實施例中，靶向HLA之治療劑為GSK01。在另一實施例中，靶向HLA之治療劑為IMC-C103C。在又另一實施例中，靶向HLA之治療劑為IMC-F106C。在一個實施例中，靶向HLA之治療劑為IMC-G107C。在另一實施例中，靶向HLA之治療劑為ABBV-184。In some embodiments, the checkpoint inhibitor is an HLA-targeted therapeutic. In certain embodiments, the HLA-targeted therapeutic is an anti-HLA antibody. In one embodiment, the HLA-targeted therapeutic is GSK01. In another embodiment, the HLA-targeted therapeutic is IMC-C103C. In yet another embodiment, the HLA-targeted therapeutic is IMC-F106C. In one embodiment, the HLA-targeted therapeutic is IMC-G107C. In another embodiment, the HLA-targeted therapeutic is ABBV-184.
本文所描述之方法可在適當時與一或多種如本文所描述之第二活性劑組合使用，以治療本文所描述且此項技術中理解之疾病。PD-1拮抗劑及派姆單抗The methods described herein can be used, as appropriate, in combination with one or more second active agents as described herein to treat diseases described herein and understood in the art.PD-1Antagonists and Pembrolizumab
本文提供使用結合191P4D12之抗體藥物結合物(ADC)組合派姆單抗治療個體之多種癌症之方法，該等個體包括不能接受基於順鉑之化學療法的不可切除性局部晚期或轉移性尿路上皮癌(la/mUC)之個體。在某些實施例中，治療為一線治療。在其他實施例中，治療為二線治療。Provided herein are methods for treating a variety of cancers in individuals using an antibody-drug conjugate (ADC) that binds to 191P4D12 in combination with pembrolizumab, including individuals with unresectable locally advanced or metastatic urothelial carcinoma (la/mUC) that cannot receive cisplatin-based chemotherapy. In certain embodiments, the treatment is first-line therapy. In other embodiments, the treatment is second-line therapy.
「派姆單抗」(以前稱為MK-3475、SCH 900475及藍布洛利珠單抗)，或在本文中稱為「派姆」，為具有WHO Drug Information, 第27卷, 第2期, 第161-162頁(2013)中所描述之結構的人源化IgG4 mAb，且其包含表4中所描述之重鏈及輕鏈胺基酸序列及CDR。派姆單抗已由美國FDA批准，如KEYTRUDA™之處方資訊(Merck & Co., Inc., Rahway, NJ, USA；2014年美國最初批准，2021年3月更新)中所描述。"Pembrolizumab" (formerly known as MK-3475, SCH 900475, and lamblolizumab), or "pembrolizumab" herein, is a humanized IgG4 mAb having the structure described in WHO Drug Information, Vol. 27, No. 2, pp. 161-162 (2013), and comprising the heavy and light chain amino acid sequences and CDRs described in Table 4. Pembrolizumab has been approved by the U.S. FDA as described in the prescribing information for KEYTRUDA™ (Merck & Co., Inc., Rahway, NJ, USA; initially approved in the U.S. in 2014, updated in March 2021).
如本文所用，關於派姆單抗序列之「派姆單抗變異體」或「其變異體」意謂包含與派姆單抗中之重鏈及輕鏈序列實質上一致的重鏈及輕鏈序列的單株抗體，不同之處在於具有位於輕鏈CDR外部之位置的三個、兩個或一個保守胺基酸取代及位於重鏈CDR外部的六個、五個、四個、三個、兩個或一個保守胺基酸取代，例如變異體位置位於FR區或恆定區，且視情況具有重鏈C端離胺酸殘基之缺失。換言之，派姆單抗及派姆單抗變異體包含一致的CDR序列，但由於分別在其全長輕鏈及重鏈序列中之不超過三個或六個其他位置處具有保守胺基酸取代而彼此不同。就以下特性而言，派姆單抗變異體與派姆單抗實質上相同：對PD-1之結合親和力及阻斷PD-L1及PD-L2中之每一者與PD-1之結合的能力。As used herein, "pembrolizumab variants" or "variants thereof" with respect to the pembrolizumab sequence means monoclonal antibodies comprising heavy and light chain sequences substantially identical to those in pembrolizumab, except that they have three, two or one conservative amino acid substitutions at positions outside the light chain CDRs and six, five, four, three, two or one conservative amino acid substitutions outside the heavy chain CDRs, such as variant positions located in the FR region or the constant region, and optionally have a deletion of the heavy chain C-terminal lysine residue. In other words, pembrolizumab and pembrolizumab variants comprise identical CDR sequences, but differ from each other by having conservative amino acid substitutions at no more than three or six other positions in their full-length light chain and heavy chain sequences, respectively. The pembrolizumab variants are substantially identical to pembrolizumab with respect to the following properties: binding affinity to PD-1 and the ability to block the binding of each of PD-L1 and PD-L2 to PD-1.
在一個實施例中，適用於本發明之治療、藥劑及用途之PD-1拮抗劑包括單株抗體(mAb)或其抗原結合片段，其特異性結合至PD-1或PD-L1，且較佳特異性結合至人類PD-1或人類PD-L1。mAb可為人類抗體、人源化抗體或嵌合抗體，且可包括人類恆定區。在一些實施例中，人類恆定區選自由IgG1、IgG2、IgG3及IgG4恆定區組成之群，且在一些實施例中，人類恆定區為IgG1或IgG4恆定區。在一些實施例中，抗原結合片段選自由以下組成之群：Fab、Fab'-SH、F(ab')2、scFv及Fv片段。In one embodiment, the PD-1 antagonist suitable for the treatment, medicament and use of the present invention includes a monoclonal antibody (mAb) or an antigen-binding fragment thereof, which specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in some embodiments, the human constant region is IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of: Fab, Fab'-SH, F(ab')2 , scFv and Fv fragments.
結合至人類PD-1且適用於本發明之治療方法、藥劑及用途之mAb之實例描述於美國專利第US7488802號、第US7521051號、第US8008449號、第US8354509號及第US8168757號，以及國際申請公開案第WO2004/004771號、第WO2004/072286號、第WO2004/056875號、第US2011/0271358號及第WO 2008/156712號中。適用作本發明之治療方法、藥劑及用途中之PD-1拮抗劑的特定抗人類PD-1 mAb包括：派姆單抗(亦稱為MK-3475)，一種人源化IgG4 mAb，具有WHO Drug Information, 第27卷, 第2期, 第161-162頁(2013)中所描述之結構，且包含表2中所示的重鏈及輕鏈胺基酸序列；納武單抗(BMS-936558)，一種人類IgG4 mAb，具有WHO Drug Information, 第27卷, 第1期, 第68-69頁(2013)中所描述之結構，且包含表2中所示的重鏈及輕鏈胺基酸序列；人源化抗體h409A11、h409A16及h409A17，其描述於WO2008/156712中，以及AMP-514，其由MedImmune開發；西米普利單抗；卡瑞利珠單抗；斯迪利單抗；替雷利珠單抗；及特瑞普利單抗。經考慮用於本文中之額外抗PD-1抗體包括MEDI0680 (美國專利第8609089號)、BGB-A317 (美國專利公開案第2015/0079109號)、INCSHR1210 (SHR-1210) (PCT國際申請公開案第WO2015/085847號)、REGN-2810 (PCT國際申請公開案第WO2015/112800號)、PDR001 (PCT國際申請公開案第WO2015/112900號)、TSR-042 (ANB011) (PCT國際申請公開案第WO2014/179664號)及STI-1110 (PCT國際申請公開案第WO2014/194302號)。Examples of mAbs that bind to human PD-1 and are suitable for the treatment methods, medicaments, and uses of the present invention are described in U.S. Patent Nos. US7488802, US7521051, US8008449, US8354509, and US8168757, and International Application Publication Nos. WO2004/004771, WO2004/072286, WO2004/056875, US2011/0271358, and WO 2008/156712. Specific anti-human PD-1 mAbs suitable for use as PD-1 antagonists in the treatment methods, medicaments, and uses of the present invention include: pembrolizumab (also known as MK-3475), a humanized IgG4 mAb having a structure described in WHO Drug Information, Vol. 27, No. 2, pp. 161-162 (2013), and comprising the heavy chain and light chain amino acid sequences shown in Table 2; nivolumab (BMS-936558), a human IgG4 mAb having a structure described in WHO Drug Information, Vol. 27, No. 1, pp. 161-162 (2013); 68-69 (2013), and comprising the heavy and light chain amino acid sequences shown in Table 2; humanized antibodies h409A11, h409A16 and h409A17, which are described in WO2008/156712, and AMP-514, which is developed by MedImmune; cemiprilizumab; carrelizumab; sidirizumab; tislelizumab; and toripalimab. Additional anti-PD-1 antibodies contemplated for use herein include MEDI0680 (U.S. Patent No. 8609089), BGB-A317 (U.S. Patent Publication No. 2015/0079109), INCSHR1210 (SHR-1210) (PCT International Application Publication No. WO2015/085847), REGN-2810 (PCT International Application Publication No. WO2015/112800), PDR001 (PCT International Application Publication No. WO2015/112900), TSR-042 (ANB011) (PCT International Application Publication No. WO2014/179664), and STI-1110. (PCT International Application Publication No. WO2014/194302).
結合至人類PD-L1且適用於本發明之治療方法、藥劑及用途之mAb之實例描述於US8383796中。適用作本發明之治療方法、藥劑及用途中之PD-1拮抗劑的特定抗人類PD-L1 mAb包括BMS-936559、MEDI4736及MSB0010718C。Examples of mAbs that bind to human PD-L1 and are suitable for use in the methods, medicaments, and uses of the invention are described in US8383796. Specific anti-human PD-L1 mAbs that are suitable for use as PD-1 antagonists in the methods, medicaments, and uses of the invention include BMS-936559, MEDI4736, and MSB0010718C.
在一些實施例中，PD-1拮抗劑為派姆單抗(KEYTRUDA™, Merck & Co., Inc., Rahway, NJ, USA)、納武單抗(OPDIVO™, Bristol-Myers Squibb Company, Princeton, NJ, USA)、阿特珠單抗(TECENTRIQ™, Genentech, San Francisco, CA, USA)、德瓦魯單抗(IMFINZI™, AstraZeneca Pharmaceuticals LP, Wilmington, DE)、西米普利單抗(LIBTAYO™, Regeneron Pharmaceuticals, Tarrytown, NY, USA)、阿維魯單抗(BAVENCIO™, Merck KGaA, Darmstadt, Germany)或多塔利單抗(dostarlimab) (JEMPERLI™, GlaxoSmithKline LLC, Philadelphia, PA)。在其他實施例中，PD-1拮抗劑為匹地利珠單抗(pidilizumab) (美國專利第7,332,582號)、AMP-514 (MedImmune LLC, Gaithersburg, MD, USA)、PDR001 (美國專利第9,683,048號)、BGB-A317 (美國專利第8,735,553號)或MGA012 (MacroGenics, Rockville, MD)。In some embodiments, the PD-1 antagonist is pembrolizumab (KEYTRUDA™, Merck & Co., Inc., Rahway, NJ, USA), nivolumab (OPDIVO™, Bristol-Myers Squibb Company, Princeton, NJ, USA), atezolizumab (TECENTRIQ™, Genentech, San Francisco, CA, USA), durvalumab (IMFINZI™, AstraZeneca Pharmaceuticals LP, Wilmington, DE), cemiplimab (LIBTAYO™, Regeneron Pharmaceuticals, Tarrytown, NY, USA), avelumab (BAVENCIO™, Merck KGaA, Darmstadt, Germany), or dostarlimab (JEMPERLI™, GlaxoSmithKline LLC, Philadelphia, PA). In other embodiments, the PD-1 antagonist is pidilizumab (U.S. Patent No. 7,332,582), AMP-514 (MedImmune LLC, Gaithersburg, MD, USA), PDR001 (U.S. Patent No. 9,683,048), BGB-A317 (U.S. Patent No. 8,735,553), or MGA012 (MacroGenics, Rockville, MD).
在一個實施例中，適用於本發明之方法之PD-1拮抗劑為阻斷PD-1與PD-L1及PD-L2結合的抗PD-1抗體。在本發明之治療方法、藥劑及用途之一些實施例中，PD-1拮抗劑為單株抗體或其抗原結合片段，其包含：(a)輕鏈可變區，其分別包含SEQ ID NO: 24、25及26之輕鏈CDR1、CDR2及CDR3；及(b)重鏈可變區，其分別包含SEQ ID NO: 29、30及31之重鏈CDR1、CDR2及CDR3。In one embodiment, the PD-1 antagonist used in the method of the present invention is an anti-PD-1 antibody that blocks the binding of PD-1 to PD-L1 and PD-L2. In some embodiments of the treatment methods, medicaments and uses of the present invention, the PD-1 antagonist is a monoclonal antibody or an antigen-binding fragment thereof, which comprises: (a) a light chain variable region comprising light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 24, 25 and 26, respectively; and (b) a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 29, 30 and 31, respectively.
在本發明之治療方法、藥劑及用途之其他實施例中，PD-1拮抗劑為單株抗體或其抗原結合片段，其特異性結合至人類PD-1且包含(a)包含SEQ ID NO:32或其變異體之重鏈可變區，及(b)包含SEQ ID NO:37或其變異體之輕鏈可變區。重鏈可變區序列之變異體與參考序列一致，不同之處在於在構架區中(亦即，CDR外部)具有至多六個保守胺基酸取代。輕鏈可變區序列之變異體與參考序列一致，不同之處在於在構架區中(亦即，CDR外部)具有至多三個保守胺基酸取代。In other embodiments of the treatment methods, medicaments and uses of the present invention, the PD-1 antagonist is a monoclonal antibody or an antigen-binding fragment thereof that specifically binds to human PD-1 and comprises (a) a heavy chain variable region comprising SEQ ID NO: 32 or a variant thereof, and (b) a light chain variable region comprising SEQ ID NO: 37 or a variant thereof. The variants of the heavy chain variable region sequence are identical to the reference sequence, except that they have up to six conservative amino acid substitutions in the framework region (i.e., outside the CDR). The variants of the light chain variable region sequence are identical to the reference sequence, except that they have up to three conservative amino acid substitutions in the framework region (i.e., outside the CDR).
在本發明之治療方法、藥劑及用途之另一實施例中，PD-1拮抗劑為單株抗體，其特異性結合至人類PD-1且包含(a)包含SEQ ID NO: 33之重鏈及(b)包含SEQ ID NO:28之輕鏈。在一個實施例中，PD-1拮抗劑為包含兩條重鏈及兩條輕鏈之抗PD-1抗體，且其中重鏈及輕鏈分別包含SEQ ID NO:33及SEQ ID NO:28中之胺基酸序列。In another embodiment of the treatment method, medicament and use of the present invention, the PD-1 antagonist is a monoclonal antibody that specifically binds to human PD-1 and comprises (a) a heavy chain comprising SEQ ID NO: 33 and (b) a light chain comprising SEQ ID NO: 28. In one embodiment, the PD-1 antagonist is an anti-PD-1 antibody comprising two heavy chains and two light chains, wherein the heavy chain and the light chain comprise the amino acid sequences in SEQ ID NO: 33 and SEQ ID NO: 28, respectively.
在所有以上治療方法、藥劑及用途中，PD-1拮抗劑抑制PD-L1與PD-1之結合，且在特定實施例中亦抑制PD-L2與PD-1之結合。在以上治療方法、藥劑及用途之一些實施例中，PD-1拮抗劑為單株抗體或其抗原結合片段，其特異性結合至PD-1或PD-L1且阻斷PD-L1與PD-1之結合。In all of the above treatment methods, agents, and uses, the PD-1 antagonist inhibits the binding of PD-L1 to PD-1, and in certain embodiments also inhibits the binding of PD-L2 to PD-1. In some embodiments of the above treatment methods, agents, and uses, the PD-1 antagonist is a monoclonal antibody or an antigen-binding fragment thereof that specifically binds to PD-1 or PD-L1 and blocks the binding of PD-L1 to PD-1.
下表4提供用於本發明之治療方法、藥劑及用途中之例示性抗PD-1 mAb之胺基酸序列之清單。 表4例示性PD-1抗體序列
在一個實施例中，抗PD-1抗體或其抗原結合片段包含重鏈恆定區，例如人類恆定區，諸如g1、g2、g3或g4人類重鏈恆定區或其變異體。在另一實施例中，抗PD-1抗體或抗原結合片段包含輕鏈恆定區，例如人類輕鏈恆定區，諸如λ或κ人類輕鏈區或其變異體。舉例而言而非限制，人類重鏈恆定區可為g4且人類輕鏈恆定區可為κ。在一替代性實施例中，抗體之Fc區為具有Ser228Pro突變之g4(Schuurman, J等人,Mol. Immunol. 38: 1-8, 2001)。在一些實施例中，不同恆定域可附接至衍生自本文提供之CDR之人源化VL及VH區。舉例而言，若本發明之抗體(或片段)特定預期用途為需要改變效應功能，則可使用除人類IgG1以外之重鏈恆定域，或可利用雜交IgG1/IgG4。雖然人類IgG1抗體提供長半衰期及效應功能，諸如補體活化抗體依賴性細胞毒性，但此類活性可能並非抗體所有用途所需。在此等情況下，可使用例如人類IgG4恆定域。本發明包括包含IgG4恆定域之抗PD-1抗體或其抗原結合片段之用途。在一個實施例中，IgG4恆定域可在對應於EU系統中之位置228及KABAT系統中之位置241的位置不同於天然人類IgG4恆定域(Swiss-Prot登錄號P01861.1)，其中天然Ser108經Pro置換，以防止Cys106與Cys109之間可干擾適當鏈內雙硫鍵形成之潛在鏈間雙硫鍵形成(對應於EU系統中之位置Cys 226及Cys 229及KABAT系統中之位置Cys 239及Cys 242)。參見Angal等人(1993)Mol. Imunol. 30:105。在其他情況下，可使用經修飾以增加半衰期或降低效應功能之經修飾之IgG1恆定域。In one embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain constant region, such as a human constant region, such as a g1, g2, g3 or g4 human heavy chain constant region or a variant thereof. In another embodiment, the anti-PD-1 antibody or antigen-binding fragment comprises a light chain constant region, such as a human light chain constant region, such as a λ or κ human light chain region or a variant thereof. By way of example and not limitation, the human heavy chain constant region may be g4 and the human light chain constant region may be κ. In an alternative embodiment, the Fc region of the antibody is g4 with a Ser228Pro mutation (Schuurman, J et al.,Mol. Immunol . 38: 1-8, 2001). In some embodiments, different constant domains may be attached to humanized VL and VH regions derived from the CDRs provided herein. For example, if the specific intended use of the antibody (or fragment) of the present invention requires a change in effector function, a heavy chain constant domain other than human IgG1 may be used, or a hybrid IgG1/IgG4 may be utilized. Although human IgG1 antibodies provide a long half-life and effector functions, such as complement-activated antibody-dependent cellular cytotoxicity, such activities may not be required for all uses of the antibody. In such cases, for example, a human IgG4 constant domain may be used. The present invention includes the use of anti-PD-1 antibodies or antigen-binding fragments thereof comprising an IgG4 constant domain. In one embodiment, the IgG4 constant domain may differ from the native human IgG4 constant domain (Swiss-Prot accession number P01861.1) at a position corresponding to position 228 in the EU system and position 241 in the KABAT system, wherein the native Ser108 is replaced by Pro to prevent potential interchain disulfide bond formation between Cys106 and Cys109 that could interfere with proper intrachain disulfide bond formation (corresponding to positions Cys 226 and Cys 229 in the EU system and positions Cys 239 and Cys 242 in the KABAT system). See Angal et al. (1993)Mol. Imunol . 30:105. In other cases, a modified IgG1 constant domain modified to increase half-life or reduce effector function may be used.
在另一實施例中，PD-1拮抗劑為具有與上文所描述之可變輕鏈域或可變重鏈域中之一者具有至少95%、90%、85%、80%、75%或50%序列一致性之可變輕鏈域及/或可變重鏈域且展現與PD-1之特異性結合的抗體或抗原結合蛋白。在本發明之治療方法之另一實施例中，PD-1拮抗劑為包含具有至多1、2、3、4或5個或更多個胺基酸取代之可變輕鏈及可變重鏈域且展現與PD-1之特異性結合的抗體或抗原結合蛋白。In another embodiment, the PD-1 antagonist is an antibody or antigen-binding protein having a variable light chain domain and/or a variable heavy chain domain having at least 95%, 90%, 85%, 80%, 75% or 50% sequence identity with one of the variable light chain domain or variable heavy chain domain described above and exhibiting specific binding to PD-1. In another embodiment of the treatment method of the present invention, the PD-1 antagonist is an antibody or antigen-binding protein comprising a variable light chain and a variable heavy chain domain having at most 1, 2, 3, 4 or 5 or more amino acid substitutions and exhibiting specific binding to PD-1.
在一些實施例中，在投與本文所提供之ADC之後，投與檢查點抑制劑。在其他實施例中，與本文所提供之ADC同時(例如在相同給藥期中)投與檢查點抑制劑。在又其他實施例中，在投與本文所提供之ADC之後，投與檢查點抑制劑。In some embodiments, a checkpoint inhibitor is administered after administration of an ADC provided herein. In other embodiments, a checkpoint inhibitor is administered simultaneously with an ADC provided herein (e.g., in the same dosing period). In yet other embodiments, a checkpoint inhibitor is administered after administration of an ADC provided herein.
在一些實施例中，本文所提供之各種方法中使用之檢查點抑制劑的量可藉由標準臨床技術確定。在某些實施例中，各種方法之PD-1拮抗劑(例如派姆單抗)之量提供於章節5.6中。In some embodiments, the amount of checkpoint inhibitor used in the various methods provided herein can be determined by standard clinical techniques. In certain embodiments, the amount of PD-1 antagonist (e.g., pembrolizumab) in the various methods is provided in Section 5.6.
在一些實施例中，可以本文所提供之方法治療的個體為哺乳動物。在一些實施例中，可以本文所提供之方法治療的個體為人類。5.2.1.4本文所提供之方法的治療結果In some embodiments, the subject that can be treated by the methods provided herein is a mammal. In some embodiments, the subject that can be treated by the methods provided herein is a human.5.2.1.4Treatment results of the methods provided herein
儘管如上文所描述虛弱、除尿路上皮癌/膀胱癌之外亦罹患多種共生病症的不適合順鉑的人類個體的預後不良，但本文所提供之方法，包括在此章節(章節5.2)以及章節3及6中所描述之方法中，可為此等不適合順鉑的人類個體提供有益治療結果。在一個實施例中，人類個體在藉由本文提供之方法治療之後具有完全反應。在另一實施例中，人類個體在藉由本文提供之方法治療之後具有部分反應。在另一實施例中，人類個體在藉由本文提供之方法治療之後具有完全反應或部分反應。Despite the poor prognosis of cisplatin-incompatible human subjects who are debilitated and suffer from multiple comorbidities in addition to urothelial carcinoma/bladder cancer as described above, the methods provided herein, including those described in this section (Section 5.2) and Sections 3 and 6, can provide beneficial treatment results for these cisplatin-incompatible human subjects. In one embodiment, the human subject has a complete response after treatment by the methods provided herein. In another embodiment, the human subject has a partial response after treatment by the methods provided herein. In another embodiment, the human subject has a complete response or a partial response after treatment by the methods provided herein.
在一些實施例中，藉由評估腫瘤或癌症部位(病灶)來確定反應(完全或部分反應)。用於確定完全反應(CR)、部分反應(PR)、進行性疾病(PD)及穩定疾病(SD)的準則描述於表10中。In some embodiments, the response (complete or partial response) is determined by assessing the tumor or cancer site (lesion). The criteria used to determine complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) are described in Table 10.
在一些實施例中，人類個體與患者可互換使用。因此，熟習此項技術者應瞭解，在本文所提供之任一種方法中，人類個體與患者可互換。In some embodiments, human subjects and patients can be used interchangeably. Therefore, those skilled in the art should understand that in any method provided herein, human subjects and patients can be used interchangeably.
因此，本文所提供之方法的治療結果可基於上述反應準則中之任一者或多者加以評估。Therefore, the treatment outcomes of the methods provided herein can be evaluated based on any one or more of the above response criteria.
在一個實施例中，人類個體在藉由本文提供之方法治療之後具有部分反應。在另一實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶之直徑總和減小至少或約30%。在另一實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶之直徑總和減小至少或約35%。在另一實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶之直徑總和減小至少或約40%。在又另一實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶的直徑總和減小至少或約45%。在一個實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶的直徑總和減小至少或約50%。在另一實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶之直徑總和減小至少或約55%。在另一實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶之直徑總和減小至少或約60%。在又另一實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶的直徑總和減小至少或約65%。在一個實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶的直徑總和減小至少或約70%。在另一實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶之直徑總和減小至少或約75%。在另一實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶之直徑總和減小至少或約80%。在又另一實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶的直徑總和減小至少或約85%。在一個實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶的直徑總和減小至少或約90%。在另一實施例中，人類個體在藉由本文所提供之方法治療之後具有部分反應，其中該部分反應定義為以基線直徑總和作為參照，目標病灶的直徑總和減小至少或約95%。在一些實施例中，直徑係根據病灶之最長直徑測定。在某些實施例中，直徑係根據量測平面中病灶之最長直徑測定。在一些實施例中，直徑係根據量測平面中病灶之最長直徑測定，其中藉由CT掃描，最小尺寸為10 mm。在某些實施例中，直徑係根據量測平面中病灶之最長直徑測定，其中藉由CT掃描，最小尺寸為10 mm，且CT片層厚度不超過5 mm。In one embodiment, a human subject has a partial response after treatment by the methods provided herein. In another embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction of at least or about 30% in the sum of diameters of the target lesions as compared to the baseline sum of diameters. In another embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction of at least or about 35% in the sum of diameters of the target lesions as compared to the baseline sum of diameters. In another embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction of at least or about 40% in the sum of diameters of the target lesions as compared to the baseline sum of diameters. In yet another embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction in the sum of diameters of the target lesions by at least or about 45% relative to the baseline sum of diameters. In one embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction in the sum of diameters of the target lesions by at least or about 50% relative to the baseline sum of diameters. In another embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction in the sum of diameters of the target lesions by at least or about 55% relative to the baseline sum of diameters. In another embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction in the sum of diameters of the target lesions by at least or about 60% relative to the baseline sum of diameters. In yet another embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction in the sum of diameters of the target lesions by at least or about 65% relative to the baseline sum of diameters. In one embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction in the sum of diameters of the target lesions by at least or about 70% relative to the baseline sum of diameters. In another embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction in the sum of diameters of the target lesions by at least or about 75% relative to the baseline sum of diameters. In another embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction in the sum of diameters of the target lesions by at least or about 80% relative to the baseline sum of diameters. In yet another embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction in the sum of diameters of the target lesions by at least or about 85% relative to the baseline sum of diameters. In one embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction of at least or about 90% in the sum of diameters of the target lesions as compared to the sum of baseline diameters. In another embodiment, a human subject has a partial response after treatment by the methods provided herein, wherein the partial response is defined as a reduction of at least or about 95% in the sum of diameters of the target lesions as compared to the sum of baseline diameters. In some embodiments, the diameter is measured according to the longest diameter of the lesions in the measurement plane. In some embodiments, the diameter is measured according to the longest diameter of the lesions in the measurement plane, wherein the minimum dimension is 10 mm by CT scanning. In certain embodiments, the diameter is measured based on the longest diameter of the lesion in a measurement plane, where the smallest dimension is 10 mm by CT scanning and the CT slice thickness does not exceed 5 mm.
本文所提供之方法的治療結果亦可基於疾病在治療之後是否穩定來評估。在一個實施例中，人類個體在藉由本文提供之方法治療之後具有穩定疾病。在另一實施例中，人類個體在藉由本文提供之方法治療之後無進行性疾病。The treatment outcome of the methods provided herein can also be assessed based on whether the disease is stable after treatment. In one embodiment, the human subject has stable disease after treatment by the methods provided herein. In another embodiment, the human subject has no progressive disease after treatment by the methods provided herein.
或者，可針對經本文所提供之方法治療的人類個體群體，藉由評估所治療群體中出現完全反應、部分反應或穩定疾病之個體的百分比，基於完全反應、部分反應或穩定疾病來評估治療結果。因此，在一些實施例中，治療結果或功效量度適用於藉由實際上治療個體群體而達成之結果。在其他實施例中，治療結果或功效量度係指若人類個體群體經如本文中所揭示之方法治療則能夠達成的結果或功效。儘管以下章節論述實際人類個體群體之治療，但應理解，本文中亦涵蓋能夠在患者群體中達成結果或功效量度之相應方法。簡言之，上述兩種情形均適用於以下章節；為了簡單且避免冗餘，下文僅描述一種情形。Alternatively, the treatment outcome can be evaluated based on complete response, partial response, or stable disease for a population of human individuals treated by the methods provided herein, by evaluating the percentage of individuals in the treated population who have a complete response, a partial response, or stable disease. Therefore, in some embodiments, the treatment outcome or efficacy measure is applicable to the results achieved by actually treating a population of individuals. In other embodiments, the treatment outcome or efficacy measure refers to the results or efficacy that can be achieved if a population of human individuals is treated by the methods disclosed herein. Although the following sections discuss the treatment of actual populations of human individuals, it should be understood that corresponding methods that can achieve results or efficacy measures in patient populations are also covered herein. In short, both of the above situations apply to the following sections; for simplicity and to avoid redundancy, only one situation is described below.
在本文(包括但不限於章節3、5.3、5.8及6及此章節(章節5.2)中)所提供之方法之一些實施例中，ADC為恩諾單抗維多汀。在本文(包括但不限於章節3、5.3、5.8及6及此章節(章節5.2))所提供之方法的某些實施例中，ADC為恩諾單抗維多汀之生物類似物。在本文(包括但不限於章節3、5.2.1.3、5.8及6及此章節(章節5.2))所提供之方法之一些實施例中，PD-1拮抗劑或抗PD-1抗體為派姆單抗。In some embodiments of the methods provided herein (including but not limited to Sections 3, 5.3, 5.8 and 6 and this Section (Section 5.2)), the ADC is enroku vedotin. In some embodiments of the methods provided herein (including but not limited to Sections 3, 5.3, 5.8 and 6 and this Section (Section 5.2)), the ADC is a biosimilar of enroku vedotin. In some embodiments of the methods provided herein (including but not limited to Sections 3, 5.2.1.3, 5.8 and 6 and this Section (Section 5.2)), the PD-1 antagonist or anti-PD-1 antibody is pembrolizumab.
在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有完全反應之個體的百分比為至少或約2%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有完全反應之個體的百分比為至少或約5%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有完全反應之個體的百分比為至少或約10%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有完全反應之個體的百分比為至少或約10.5%。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有完全反應之個體的百分比為至少或約15%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有完全反應之個體的百分比為至少或約20%。In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a complete response is at least or about 2%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a complete response is at least or about 5%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a complete response is at least or about 10%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a complete response is at least or about 10.5%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a complete response is at least or about 15%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a complete response is at least or about 20%.
在一個實施例中，以該方法治療之個體群體的完全反應率為至少或約10%。在另一實施例中，以該方法治療之個體群體的完全反應率為至少或約2%。在另一實施例中，以該方法治療之個體群體的完全反應率為至少或約5%。在另一實施例中，以該方法治療之個體群體的完全反應率為至少或約10%。在另一實施例中，以該方法治療之個體群體的完全反應率為至少或約10.5%。在另一實施例中，以該方法治療之個體群體的完全反應率為至少或約15%。在另一實施例中，以該方法治療之個體群體的完全反應率為至少或約20%。In one embodiment, the complete response rate of a population of individuals treated with the method is at least or about 10%. In another embodiment, the complete response rate of a population of individuals treated with the method is at least or about 2%. In another embodiment, the complete response rate of a population of individuals treated with the method is at least or about 5%. In another embodiment, the complete response rate of a population of individuals treated with the method is at least or about 10%. In another embodiment, the complete response rate of a population of individuals treated with the method is at least or about 10.5%. In another embodiment, the complete response rate of a population of individuals treated with the method is at least or about 15%. In another embodiment, the complete response rate of a population of individuals treated with the method is at least or about 20%.
類似地，利用部分反應的百分比作為準則，在一個實施例中人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有部分反應之個體的百分比為至少或約25%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有部分反應之個體的百分比為至少或約30%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有部分反應之個體的百分比為至少或約35%。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有部分反應之個體的百分比為至少或約40%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有部分反應之個體的百分比為至少或約45%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有部分反應之個體的百分比為至少或約50%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有部分反應之個體的百分比為至少或約53.9%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有部分反應之個體的百分比為至少或約54%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有部分反應之個體的百分比為至少或約55%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有部分反應之個體的百分比為至少或約60%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有部分反應之個體的百分比為至少或約65%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有部分反應之個體的百分比為至少或約70%。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有部分反應之個體的百分比為至少或約75%。Similarly, using the percentage of partial responses as a guideline, in one embodiment a population of human subjects is treated by the methods provided herein, wherein the percentage of individuals in the treated population with partial responses is at least or about 25%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of individuals in the treated population with partial responses is at least or about 30%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of individuals in the treated population with partial responses is at least or about 35%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of individuals in the treated population with partial responses is at least or about 40%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a partial response is at least or about 45%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a partial response is at least or about 50%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a partial response is at least or about 53.9%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a partial response is at least or about 54%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a partial response is at least or about 55%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a partial response is at least or about 60%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a partial response is at least or about 65%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with a partial response is at least or about 70%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population having a partial response is at least or about 75%.
在一個實施例中，以該方法治療之個體群體的部分反應率為至少或約25%。在另一實施例中，以該方法治療之個體群體的部分反應率為至少或約30%。在另一實施例中，以該方法治療之個體群體的部分反應率為至少或約35%。在另一實施例中，以該方法治療之個體群體的部分反應率為至少或約40%。在另一實施例中，以該方法治療之個體群體的部分反應率為至少或約45%。在另一實施例中，以該方法治療之個體群體的部分反應率為至少或約50%。在另一實施例中，以該方法治療之個體群體的部分反應率為至少或約53.9%。在另一實施例中，以該方法治療之個體群體的部分反應率為至少或約54%。在另一實施例中，以該方法治療之個體群體的部分反應率為至少或約55%。在另一實施例中，以該方法治療之個體群體的部分反應率為至少或約60%。在另一實施例中，以該方法治療之個體群體的部分反應率為至少或約65%。在另一實施例中，以該方法治療之個體群體的部分反應率為至少或約70%。在另一實施例中，以該方法治療之個體群體的部分反應率為至少或約75%。In one embodiment, the partial response rate of the population of individuals treated with the method is at least or about 25%. In another embodiment, the partial response rate of the population of individuals treated with the method is at least or about 30%. In another embodiment, the partial response rate of the population of individuals treated with the method is at least or about 35%. In another embodiment, the partial response rate of the population of individuals treated with the method is at least or about 40%. In another embodiment, the partial response rate of the population of individuals treated with the method is at least or about 45%. In another embodiment, the partial response rate of the population of individuals treated with the method is at least or about 50%. In another embodiment, the partial response rate of the population of individuals treated with the method is at least or about 53.9%. In another embodiment, the partial response rate of the population of individuals treated with the method is at least or about 54%. In another embodiment, the partial response rate of the subject population treated by the method is at least or about 55%. In another embodiment, the partial response rate of the subject population treated by the method is at least or about 60%. In another embodiment, the partial response rate of the subject population treated by the method is at least or about 65%. In another embodiment, the partial response rate of the subject population treated by the method is at least or about 70%. In another embodiment, the partial response rate of the subject population treated by the method is at least or about 75%.
此外，具有穩定疾病之個體的百分比可用作本文所提供之方法治療人類個體之治療結果的評估準則。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有穩定疾病之個體的百分比為至少或約10%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有穩定疾病之個體的百分比為至少或約15%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有穩定疾病之個體的百分比為至少或約20%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有穩定疾病之個體的百分比為至少或約22%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有穩定疾病之個體的百分比為至少或約22.4%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有穩定疾病之個體的百分比為至少或約25%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有穩定疾病之個體的百分比為至少或約30%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有穩定疾病之個體的百分比為至少或約35%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有穩定疾病之個體的百分比為至少或約40%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有穩定疾病之個體的百分比為至少或約45%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體中具有穩定疾病之個體的百分比為至少或約50%。In addition, the percentage of individuals with stable disease can be used as an evaluation criterion for the treatment outcome of human individuals treated by the methods provided herein. In one embodiment, a population of human individuals is treated by the methods provided herein, wherein the percentage of individuals with stable disease in the treated population is at least or about 10%. In one embodiment, a population of human individuals is treated by the methods provided herein, wherein the percentage of individuals with stable disease in the treated population is at least or about 15%. In one embodiment, a population of human individuals is treated by the methods provided herein, wherein the percentage of individuals with stable disease in the treated population is at least or about 20%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with stable disease is at least or about 22%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with stable disease is at least or about 22.4%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with stable disease is at least or about 25%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with stable disease is at least or about 30%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with stable disease is at least or about 35%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with stable disease is at least or about 40%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with stable disease is at least or about 45%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the percentage of subjects in the treated population with stable disease is at least or about 50%.
在一個實施例中，以該方法治療之個體群體的穩定疾病率為至少或約10%。在一個實施例中，以該方法治療之個體群體的穩定疾病率為至少或約15%。在一個實施例中，以該方法治療之個體群體的穩定疾病率為至少或約20%。在一個實施例中，以該方法治療之個體群體的穩定疾病率為至少或約22%。在一個實施例中，以該方法治療之個體群體的穩定疾病率為至少或約22.4%。在一個實施例中，以該方法治療之個體群體的穩定疾病率為至少或約25%。在一個實施例中，以該方法治療之個體群體的穩定疾病率為至少或約30%。在一個實施例中，以該方法治療之個體群體的穩定疾病率為至少或約35%。在一個實施例中，以該方法治療之個體群體的穩定疾病率為至少或約40%。在一個實施例中，以該方法治療之個體群體的穩定疾病率為至少或約45%。在一個實施例中，以該方法治療之個體群體的穩定疾病率為至少或約50%。In one embodiment, the stable disease rate of a population of individuals treated with the method is at least or about 10%. In one embodiment, the stable disease rate of a population of individuals treated with the method is at least or about 15%. In one embodiment, the stable disease rate of a population of individuals treated with the method is at least or about 20%. In one embodiment, the stable disease rate of a population of individuals treated with the method is at least or about 22%. In one embodiment, the stable disease rate of a population of individuals treated with the method is at least or about 22.4%. In one embodiment, the stable disease rate of a population of individuals treated with the method is at least or about 25%. In one embodiment, the stable disease rate of a population of individuals treated with the method is at least or about 30%. In one embodiment, the stable disease rate of a population of individuals treated with the method is at least or about 35%. In one embodiment, the stable disease rate of a population of individuals treated with the method is at least or about 40%. In one embodiment, the stable disease rate of a population of individuals treated with the method is at least or about 45%. In one embodiment, the stable disease rate of a population of individuals treated with the method is at least or about 50%.
同樣，作為具有完全反應之個體與具有部分反應之個體之百分比總和的客觀反應率可用作藉由本文所提供之方法治療的人類個體之治療結果的評估準則。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約30%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約35%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約40%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約45%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約50%。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約52.7%。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約53%。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約55%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約60%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約64.5%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約65%。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約70%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約75%。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約75.1%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約80%。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約85%。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率為至少或約90%。Similarly, the objective response rate as the sum of the percentage of individuals with complete responses and individuals with partial responses can be used as an evaluation criterion for the treatment results of human individuals treated by the methods provided herein. In another embodiment, a human individual population is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 30%. In one embodiment, a human individual population is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 35%. In another embodiment, a human individual population is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 40%. In one embodiment, a human individual population is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 45%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 50%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 52.7%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 53%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 55%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 60%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 64.5%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 65%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 70%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 75%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 75.1%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 80%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 85%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is at least or about 90%.
在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在40%至80%範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在40%至75%範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在40%至70%範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在45%至80%範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在45%至75%範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在45%至70%範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在50%至80%範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在50%至75%範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在52.7%至75.1%範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在55%至80%範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在55%至75%範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在55%至70%範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在55%至65%範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在60%至80%範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在60%至75%範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在60%至70%範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的客觀反應率在60%至65%範圍內。In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 40% to 80%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 40% to 75%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 40% to 70%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 45% to 80%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 45% to 75%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 45% to 70%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 50% to 80%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 50% to 75%. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 52.7% to 75.1%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 55% to 80%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 55% to 75%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 55% to 70%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 55% to 65%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 60% to 80%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 60% to 75%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 60% to 70%. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the objective response rate of the treated population is in the range of 60% to 65%.
在一個實施例中，以該方法治療之個體群體的客觀反應率為至少或約30%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約30%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約35%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約40%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約45%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約50%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約55%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約60%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約64.5%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約65%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約70%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約75%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約80%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約85%。在另一實施例中，以該方法治療之個體群體的客觀反應率為至少或約90%。In one embodiment, the objective response rate of the individual population treated with the method is at least or about 30%. In another embodiment, the objective response rate of the individual population treated with the method is at least or about 30%. In another embodiment, the objective response rate of the individual population treated with the method is at least or about 35%. In another embodiment, the objective response rate of the individual population treated with the method is at least or about 40%. In another embodiment, the objective response rate of the individual population treated with the method is at least or about 45%. In another embodiment, the objective response rate of the individual population treated with the method is at least or about 50%. In another embodiment, the objective response rate of the individual population treated with the method is at least or about 55%. In another embodiment, the objective response rate of the individual population treated with the method is at least or about 60%. In another embodiment, the objective response rate of the individual population treated with the method is at least or about 64.5%. In another embodiment, the objective response rate of the individual population treated with the method is at least or about 65%. In another embodiment, the objective response rate of the individual population treated with the method is at least or about 70%. In another embodiment, the objective response rate of the individual population treated with the method is at least or about 75%. In another embodiment, the objective response rate of the individual population treated with the method is at least or about 80%. In another embodiment, the objective response rate of the individual population treated with the method is at least or about 85%. In another embodiment, the objective response rate in a population of individuals treated with the method is at least or about 90%.
在一個實施例中，以該方法治療之個體群體的客觀反應率為40%至80%。在另一實施例中，以該方法治療之個體群體的客觀反應率為40%至75%。在另一實施例中，以該方法治療之個體群體的客觀反應率為40%至70%。在另一實施例中，以該方法治療之個體群體的客觀反應率為45%至80%。在另一實施例中，以該方法治療之個體群體的客觀反應率為45%至75%。在另一實施例中，以該方法治療之個體群體的客觀反應率為45%至70%。在另一實施例中，以該方法治療之個體群體的客觀反應率為50%至80%。在另一實施例中，以該方法治療之個體群體的客觀反應率為50%至75%。在另一實施例中，以該方法治療之個體群體的客觀反應率為52.7%至75.1%。在另一實施例中，以該方法治療之個體群體的客觀反應率為53%至75%。在另一實施例中，以該方法治療之個體群體的客觀反應率為55%至80%。在另一實施例中，以該方法治療之個體群體的客觀反應率為55%至75%。在另一實施例中，以該方法治療之個體群體的客觀反應率為55%至70%。在另一實施例中，以該方法治療之個體群體的客觀反應率為55%至65%。在另一實施例中，以該方法治療之個體群體的客觀反應率為60%至80%。在另一實施例中，以該方法治療之個體群體的客觀反應率為60%至75%。在另一實施例中，以該方法治療之個體群體的客觀反應率為60%至70%。在另一實施例中，以該方法治療之個體群體的客觀反應率為60%至65%。In one embodiment, the objective response rate of the group of individuals treated with the method is 40% to 80%. In another embodiment, the objective response rate of the group of individuals treated with the method is 40% to 75%. In another embodiment, the objective response rate of the group of individuals treated with the method is 40% to 70%. In another embodiment, the objective response rate of the group of individuals treated with the method is 45% to 80%. In another embodiment, the objective response rate of the group of individuals treated with the method is 45% to 75%. In another embodiment, the objective response rate of the group of individuals treated with the method is 45% to 70%. In another embodiment, the objective response rate of the group of individuals treated with the method is 50% to 80%. In another embodiment, the objective response rate of the group of individuals treated by the method is 50% to 75%. In another embodiment, the objective response rate of the group of individuals treated by the method is 52.7% to 75.1%. In another embodiment, the objective response rate of the group of individuals treated by the method is 53% to 75%. In another embodiment, the objective response rate of the group of individuals treated by the method is 55% to 80%. In another embodiment, the objective response rate of the group of individuals treated by the method is 55% to 75%. In another embodiment, the objective response rate of the group of individuals treated by the method is 55% to 70%. In another embodiment, the objective response rate of the group of individuals treated by the method is 55% to 65%. In another embodiment, the objective response rate of the subject population treated by the method is 60% to 80%. In another embodiment, the objective response rate of the subject population treated by the method is 60% to 75%. In another embodiment, the objective response rate of the subject population treated by the method is 60% to 70%. In another embodiment, the objective response rate of the subject population treated by the method is 60% to 65%.
此外，本文所提供之方法的治療結果可基於如章節6.1.8.2(ii)中所闡述之反應持續時間來評估。在一個實施例中，人類個體在治療之後的反應持續時間為至少或約5個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約6個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約7個月。在又另一實施例中，人類個體在治療之後的反應持續時間為至少或約8個月。在一個實施例中，人類個體在治療之後的反應持續時間為至少或約9個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約10個月。在又另一實施例中，人類個體在治療之後的反應持續時間為至少或約11個月。在一個實施例中，人類個體在治療之後的反應持續時間為至少或約12個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約13個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約14個月。在又另一實施例中，人類個體在治療之後的反應持續時間為至少或約15個月。在一個實施例中，人類個體在治療之後的反應持續時間為至少或約16個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約17個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約18個月。在又另一實施例中，人類個體在治療之後的反應持續時間為至少或約19個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約20個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約21個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約22個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約23個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約24個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約25個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約26個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約27個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約28個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約29個月。在另一實施例中，人類個體在治療之後的反應持續時間為至少或約30個月。In addition, the treatment results of the methods provided herein can be evaluated based on the duration of response as described in Section 6.1.8.2 (ii). In one embodiment, the duration of response of the human subject after treatment is at least or about 5 months. In another embodiment, the duration of response of the human subject after treatment is at least or about 6 months. In another embodiment, the duration of response of the human subject after treatment is at least or about 7 months. In yet another embodiment, the duration of response of the human subject after treatment is at least or about 8 months. In one embodiment, the duration of response of the human subject after treatment is at least or about 9 months. In another embodiment, the duration of response in a human subject after treatment is at least or about 10 months. In yet another embodiment, the duration of response in a human subject after treatment is at least or about 11 months. In one embodiment, the duration of response in a human subject after treatment is at least or about 12 months. In another embodiment, the duration of response in a human subject after treatment is at least or about 13 months. In another embodiment, the duration of response in a human subject after treatment is at least or about 14 months. In yet another embodiment, the duration of response in a human subject after treatment is at least or about 15 months. In one embodiment, the duration of response in a human subject after treatment is at least or about 16 months. In another embodiment, the duration of response in a human subject after treatment is at least or about 17 months. In another embodiment, the duration of response in a human subject after treatment is at least or about 18 months. In yet another embodiment, the duration of response in a human subject after treatment is at least or about 19 months. In another embodiment, the duration of response in a human subject after treatment is at least or about 20 months. In another embodiment, the duration of response in a human subject after treatment is at least or about 21 months. In another embodiment, the duration of response in a human subject after treatment is at least or about 22 months. In another embodiment, the duration of response in a human subject after treatment is at least or about 23 months. In another embodiment, the duration of response in a human subject after treatment is at least or about 24 months. In another embodiment, the duration of response in a human subject after treatment is at least or about 25 months. In another embodiment, the duration of response in a human subject after treatment is at least or about 26 months. In another embodiment, the duration of response in a human subject after treatment is at least or about 27 months. In another embodiment, the duration of response in the human subject after treatment is at least or about 28 months. In another embodiment, the duration of response in the human subject after treatment is at least or about 29 months. In another embodiment, the duration of response in the human subject after treatment is at least or about 30 months.
在另一實施例中，人類個體在治療之後的反應持續時間在5至30個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在5至29個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在5至28個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在5至27個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在5至26個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在5至25個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在5至24個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在5至23個月範圍內。在一些實施例中，人類個體在治療之後的反應持續時間在5至22個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在5至21個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在5至20個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在5至19個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在5至18個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在5至17個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在5至16個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在5至15個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在5至14個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在5至13個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在5至12個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至30個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至29個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至28個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至27個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至26個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至25個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至24個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至23個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在6至22個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至21個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至20個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在6至19個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在6至18個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至17個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至16個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在6至15個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在6至14個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至13個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至12個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在7至22個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在7至21個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在7至20個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在7至19個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在7至18個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在7至17個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在7至16個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在7至15個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在7至14個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在7至13個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在7至12個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在8至30個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在9至30個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在10至30個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在11至30個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在12至30個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在13至30個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在14至30個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在15至30個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在16至30個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在17至30個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在18至30個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在8至27個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在9至27個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在10至27個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在11至27個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在12至27個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在13至27個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在14至27個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在15至27個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在16至27個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在17至27個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在18至27個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在8至22個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在9至22個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在10至22個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在11至22個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在12至22個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在13至22個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在14至22個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在15至22個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在16至22個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在17至22個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在18至22個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在6至21個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在7至20個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在8至19個月範圍內。在一個實施例中，人類個體在治療之後的反應持續時間在9至18個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在10至17個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在11至16個月範圍內。在又另一實施例中，人類個體在治療之後的反應持續時間在12至15個月範圍內。在另一實施例中，人類個體在治療之後的反應持續時間在13至14個月範圍內。In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 30 months. In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 29 months. In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 28 months. In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 27 months. In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 26 months. In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 25 months. In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 24 months. In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 23 months. In some embodiments, the duration of response in a human subject after treatment ranges from 5 to 22 months. In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 21 months. In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 20 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 5 to 19 months. In one embodiment, the duration of response in a human subject after treatment ranges from 5 to 18 months. In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 17 months. In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 16 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 5 to 15 months. In one embodiment, the duration of response in a human subject after treatment ranges from 5 to 14 months. In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 13 months. In another embodiment, the duration of response in a human subject after treatment ranges from 5 to 12 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 30 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 29 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 28 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 27 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 26 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 25 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 24 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 23 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 6 to 22 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 21 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 20 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 6 to 19 months. In one embodiment, the duration of response in a human subject after treatment ranges from 6 to 18 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 17 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 16 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 6 to 15 months. In one embodiment, the duration of response in a human subject after treatment ranges from 6 to 14 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 13 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 12 months. In one embodiment, the duration of response in a human subject after treatment ranges from 7 to 22 months. In another embodiment, the duration of response in a human subject after treatment ranges from 7 to 21 months. In another embodiment, the duration of response in a human subject after treatment ranges from 7 to 20 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 7 to 19 months. In one embodiment, the duration of response in a human subject after treatment ranges from 7 to 18 months. In another embodiment, the duration of response in a human subject after treatment ranges from 7 to 17 months. In another embodiment, the duration of response in a human subject after treatment ranges from 7 to 16 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 7 to 15 months. In one embodiment, the duration of response in a human subject after treatment ranges from 7 to 14 months. In another embodiment, the duration of response in a human subject after treatment ranges from 7 to 13 months. In another embodiment, the duration of response in a human subject after treatment ranges from 7 to 12 months. In another embodiment, the duration of response in a human subject after treatment ranges from 8 to 30 months. In another embodiment, the duration of response in a human subject after treatment ranges from 9 to 30 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 10 to 30 months. In another embodiment, the duration of response in a human subject after treatment ranges from 11 to 30 months. In one embodiment, the duration of response in a human subject after treatment ranges from 12 to 30 months. In another embodiment, the duration of response in a human subject after treatment ranges from 13 to 30 months. In another embodiment, the duration of response in a human subject after treatment ranges from 14 to 30 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 15 to 30 months. In another embodiment, the duration of response in a human subject after treatment ranges from 16 to 30 months. In one embodiment, the duration of response in a human subject after treatment ranges from 17 to 30 months. In another embodiment, the duration of response in a human subject after treatment ranges from 18 to 30 months. In another embodiment, the duration of response in a human subject after treatment ranges from 8 to 27 months. In another embodiment, the duration of response in a human subject after treatment ranges from 9 to 27 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 10 to 27 months. In another embodiment, the duration of response in a human subject after treatment ranges from 11 to 27 months. In one embodiment, the duration of response in a human subject after treatment ranges from 12 to 27 months. In another embodiment, the duration of response in a human subject after treatment ranges from 13 to 27 months. In another embodiment, the duration of response in a human subject after treatment ranges from 14 to 27 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 15 to 27 months. In another embodiment, the duration of response in a human subject after treatment ranges from 16 to 27 months. In one embodiment, the duration of response in a human subject after treatment ranges from 17 to 27 months. In another embodiment, the duration of response in a human subject after treatment ranges from 18 to 27 months. In another embodiment, the duration of response in a human subject after treatment ranges from 8 to 22 months. In another embodiment, the duration of response in a human subject after treatment ranges from 9 to 22 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 10 to 22 months. In another embodiment, the duration of response in a human subject after treatment ranges from 11 to 22 months. In one embodiment, the duration of response in a human subject after treatment ranges from 12 to 22 months. In another embodiment, the duration of response in a human subject after treatment ranges from 13 to 22 months. In another embodiment, the duration of response in a human subject after treatment ranges from 14 to 22 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 15 to 22 months. In another embodiment, the duration of response in a human subject after treatment ranges from 16 to 22 months. In one embodiment, the duration of response in a human subject after treatment ranges from 17 to 22 months. In another embodiment, the duration of response in a human subject after treatment ranges from 18 to 22 months. In another embodiment, the duration of response in a human subject after treatment ranges from 6 to 21 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 7 to 20 months. In another embodiment, the duration of response in a human subject after treatment ranges from 8 to 19 months. In one embodiment, the duration of response in a human subject after treatment ranges from 9 to 18 months. In another embodiment, the duration of response in a human subject after treatment ranges from 10 to 17 months. In another embodiment, the duration of response in a human subject after treatment ranges from 11 to 16 months. In yet another embodiment, the duration of response in a human subject after treatment ranges from 12 to 15 months. In another embodiment, the duration of response in a human subject after treatment ranges from 13 to 14 months.
在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約5個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約6個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約7個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約8個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約9個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約10個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約11個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約12個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約13個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約14個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約15個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約16個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約17個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約18個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約19個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約20個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約21個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約22個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約23個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約24個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約25個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約26個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約27個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約28個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約29個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的反應持續時間為至少或約30個月。In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 5 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 6 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 7 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 8 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 9 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 10 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 11 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 12 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 13 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 14 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 15 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 16 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 17 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 18 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 19 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 20 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 21 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 22 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 23 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 24 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 25 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 26 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 27 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 28 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 29 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population after treatment is at least or about 30 months.
在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至30個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至29個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至28個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至27個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至26個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至25個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至24個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至23個月範圍內。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至22個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至21個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至20個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至19個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至18個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至17個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至16個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至15個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至14個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至13個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在5至12個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至30個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至29個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至28個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至27個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至26個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至25個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至24個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至23個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至22個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至21個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至20個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至19個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至18個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至17個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至16個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至15個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至14個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至13個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至12個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至30個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至29個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至28個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至27個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至26個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至25個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至24個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至23個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至22個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至21個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至20個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至19個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至18個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至17個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至16個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至15個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至14個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至13個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至12個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6.41至22個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在8至22個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在9至22個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在10至22個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在11至22個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在12至22個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在13至22個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在14至22個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在15至22個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在16至22個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在17至22個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在18至22個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至27個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在8至27個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在9至27個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在10至27個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在11至27個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在12至27個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在13至27個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在14至27個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在15至27個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在16至27個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在17至27個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在18至27個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在19至27個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在20至27個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在21至27個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在22至27個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在23至27個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在24至27個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至30個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在8至30個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在9至30個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在10至30個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在11至30個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在12至30個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在13至30個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在14至30個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在15至30個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在16至30個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在17至30個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在18至30個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在19至30個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在20至30個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在21至30個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在22至30個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在23至30個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在24至30個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在25至30個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在26至30個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在27至30個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在6至21個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在7至20個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在8至19個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在9至18個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在10至17個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在11至16個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在12至15個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的反應持續時間在13至24個月範圍內。 In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 30 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 29 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 28 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 27 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 26 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 25 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 24 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 23 months. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 22 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 21 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 20 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 19 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 18 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 17 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 16 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 15 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 14 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 13 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 5 to 12 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 30 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 29 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 28 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 27 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 26 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 25 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 24 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 23 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 22 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 21 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 20 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 19 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 18 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 17 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 16 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 15 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 14 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 13 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 12 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 30 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 29 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 28 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 27 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 26 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 25 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 24 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 23 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 22 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 21 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 20 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 19 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 18 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 17 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 16 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 15 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 14 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 13 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 12 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6.41 to 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 8 to 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 9 to 22 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 10 to 22 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 11 to 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 12 to 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 13 to 22 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 14 to 22 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 15 to 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 16 to 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 17 to 22 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 18 to 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 27 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 8 to 27 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 9 to 27 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 10 to 27 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 11 to 27 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 12 to 27 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 13 to 27 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 14 to 27 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 15 to 27 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 16 to 27 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 17 to 27 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 18 to 27 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 19 to 27 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 20 to 27 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 21 to 27 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 22 to 27 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 23 to 27 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 24 to 27 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 30 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 8 to 30 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 9 to 30 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 10 to 30 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 11 to 30 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 12 to 30 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 13 to 30 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 14 to 30 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 15 to 30 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 16 to 30 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 17 to 30 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 18 to 30 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 19 to 30 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 20 to 30 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 21 to 30 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 22 to 30 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 23 to 30 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 24 to 30 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 25 to 30 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 26 to 30 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 27 to 30 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 6 to 21 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 7 to 20 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 8 to 19 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 9 to 18 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 10 to 17 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 11 to 16 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response of the treated population is in the range of 12 to 15 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the duration of response in the treated population is in the range of 13 to 24 months.
在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約5個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約6個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約7個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約8個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約9個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約10個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約11個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約12個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約13個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約14個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約15個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約16個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約17個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約18個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約19個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約20個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約21個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約22個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約23個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約24個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約25個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約26個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約27個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約28個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約29個月。在某些實施例中，以該方法治療之個體群體的反應持續時間為至少或約30個月。In some embodiments, the duration of response of the individual population treated with the method is at least or about 5 months. In some embodiments, the duration of response of the individual population treated with the method is at least or about 6 months. In some embodiments, the duration of response of the individual population treated with the method is at least or about 7 months. In some embodiments, the duration of response of the individual population treated with the method is at least or about 8 months. In some embodiments, the duration of response of the individual population treated with the method is at least or about 9 months. In some embodiments, the duration of response of the individual population treated with the method is at least or about 10 months. In some embodiments, the duration of response in a population of individuals treated with the method is at least or about 11 months. In some embodiments, the duration of response in a population of individuals treated with the method is at least or about 12 months. In some embodiments, the duration of response in a population of individuals treated with the method is at least or about 13 months. In some embodiments, the duration of response in a population of individuals treated with the method is at least or about 14 months. In some embodiments, the duration of response in a population of individuals treated with the method is at least or about 15 months. In some embodiments, the duration of response in a population of individuals treated with the method is at least or about 16 months. In some embodiments, the duration of response in a population of individuals treated with the method is at least or about 17 months. In some embodiments, the duration of response in a population of individuals treated with the method is at least or about 18 months. In some embodiments, the duration of response in a population of individuals treated with the method is at least or about 19 months. In some embodiments, the duration of response in a population of individuals treated with the method is at least or about 20 months. In some embodiments, the duration of response in a population of individuals treated with the method is at least or about 21 months. In some embodiments, the duration of response in a population of individuals treated with the method is at least or about 22 months. In certain embodiments, the duration of response in a population of individuals treated with the method is at least or about 23 months. In certain embodiments, the duration of response in a population of individuals treated with the method is at least or about 24 months. In certain embodiments, the duration of response in a population of individuals treated with the method is at least or about 25 months. In certain embodiments, the duration of response in a population of individuals treated with the method is at least or about 26 months. In certain embodiments, the duration of response in a population of individuals treated with the method is at least or about 27 months. In certain embodiments, the duration of response in a population of individuals treated with the method is at least or about 28 months. In certain embodiments, the duration of response in a population of individuals treated with the method is at least or about 29 months. In certain embodiments, the duration of response in a population of individuals treated with the method is at least or about 30 months.
或者，本文所提供之方法的治療結果可基於如章節6.1.8.2(iv)中所闡述之無惡化存活期來評估。在一個實施例中，人類個體在治療之後具有至少或約5個月的無惡化存活期。在另一實施例中，人類個體在治療之後具有至少或約6個月的無惡化存活期。在另一實施例中，人類個體在治療之後具有至少或約7個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約8個月的無惡化存活期。在一個實施例中，人類個體在治療之後具有至少或約9個月的無惡化存活期。在另一實施例中，人類個體在治療之後具有至少或約10個月的無惡化存活期。在另一實施例中，人類個體在治療之後具有至少或約11個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約12個月的無惡化存活期。在一個實施例中，人類個體在治療之後具有至少或約13個月的無惡化存活期。在另一實施例中，人類個體在治療之後具有至少或約14個月的無惡化存活期。在另一實施例中，人類個體在治療之後具有至少或約15個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約16個月的無惡化存活期。在一個實施例中，人類個體在治療之後具有至少或約17個月的無惡化存活期。在另一實施例中，人類個體在治療之後具有至少或約18個月的無惡化存活期。在另一實施例中，人類個體在治療之後具有至少或約19個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約20個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約21個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約22個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約23個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約24個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約25個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約26個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約27個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約28個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約29個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約30個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約31個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約32個月的無惡化存活期。在又另一實施例中，人類個體在治療之後具有至少或約33個月的無惡化存活期。Alternatively, the treatment outcome of the methods provided herein can be assessed based on the progression-free survival as described in Section 6.1.8.2 (iv). In one embodiment, the human subject has a progression-free survival of at least or about 5 months after treatment. In another embodiment, the human subject has a progression-free survival of at least or about 6 months after treatment. In another embodiment, the human subject has a progression-free survival of at least or about 7 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 8 months after treatment. In one embodiment, the human subject has a progression-free survival of at least or about 9 months after treatment. In another embodiment, the human subject has a progression-free survival of at least or about 10 months after treatment. In another embodiment, the human subject has a progression-free survival of at least or about 11 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 12 months after treatment. In one embodiment, the human subject has a progression-free survival of at least or about 13 months after treatment. In another embodiment, the human subject has a progression-free survival of at least or about 14 months after treatment. In another embodiment, the human subject has a progression-free survival of at least or about 15 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 16 months after treatment. In one embodiment, the human subject has a progression-free survival of at least or about 17 months after treatment. In another embodiment, the human subject has a progression-free survival of at least or about 18 months after treatment. In another embodiment, the human subject has a progression-free survival of at least or about 19 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 20 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 21 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 22 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 23 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 24 months following treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 25 months following treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 26 months following treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 27 months following treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 28 months following treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 29 months following treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 30 months following treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 31 months following treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 32 months following treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 33 months following treatment.
在另一實施例中，人類個體在治療之後具有5至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至32個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至31個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至30個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至28個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至27個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至26個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至25個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至24個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至23個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有5至22個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至21個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至20個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有5至19個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有5至18個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至17個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至16個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有5至15個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有5至14個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至13個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有5至12個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至33個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至32個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至31個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至30個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至29個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至28個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至27個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至26個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至25個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至22個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至24個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至23個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至22個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有6至21個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有6至20個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至19個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有6至18個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有6至17個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有6至16個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有6至15個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有6至14個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有6至13個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有6至12個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至32個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至31個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至30個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至28個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至27個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至26個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至25個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至24個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至23個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有7至22個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至21個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至20個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有7至19個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有7至18個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至17個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至16個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有7至15個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有7至14個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至13個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有7至12個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有8至22個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有9至22個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有10至22個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有11至22個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有12至22個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有13至22個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有14至22個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有15至22個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有16至22個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有17至22個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有18至22個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有8至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有9至33個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有10至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有11至33個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有12至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有13至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有14至33個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有15至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有16至33個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有17至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有18至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有19至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有20至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有21至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有22至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有23至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有24至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有25至33個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有8至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有9至29個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有10至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有11至29個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有12至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有13至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有14至29個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有15至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有16至29個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有17至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有18至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有19至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有20至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有21至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有22至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有23至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有24至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有25至29個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有6至21個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有7至20個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有8至19個月範圍內的無惡化存活期。在一個實施例中，人類個體在治療之後具有9至18個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有10至17個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有11至16個月範圍內的無惡化存活期。在又另一實施例中，人類個體在治療之後具有12至15個月範圍內的無惡化存活期。在另一實施例中，人類個體在治療之後具有13至14個月範圍內的無惡化存活期。In another embodiment, the human subject has a progression-free survival in the range of 5 to 33 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 32 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 31 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 30 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 29 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 28 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 27 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 26 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 25 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 24 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 23 months following treatment. In one embodiment, the human subject has a progression-free survival in the range of 5 to 22 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 21 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 20 months after treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 5 to 19 months after treatment. In one embodiment, the human subject has a progression-free survival in the range of 5 to 18 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 17 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 16 months after treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 5 to 15 months following treatment. In one embodiment, the human subject has a progression-free survival in the range of 5 to 14 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 13 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 5 to 12 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 33 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 32 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 31 months after treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 30 months after treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 29 months after treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 28 months after treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 27 months after treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 26 months after treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 25 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 22 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 24 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 23 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 22 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 6 to 21 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 6 to 20 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 19 months following treatment. In one embodiment, the human subject has a progression-free survival in the range of 6 to 18 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 6 to 17 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 6 to 16 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 6 to 15 months following treatment. In one embodiment, the human subject has a progression-free survival in the range of 6 to 14 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 6 to 13 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 6 to 12 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 33 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 32 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 31 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 30 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 28 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 27 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 26 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 25 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 24 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 23 months following treatment. In one embodiment, the human subject has a progression-free survival in the range of 7 to 22 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 21 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 20 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 7 to 19 months following treatment. In one embodiment, the human subject has a progression-free survival in the range of 7 to 18 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 17 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 16 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 7 to 15 months following treatment. In one embodiment, the human subject has a progression-free survival in the range of 7 to 14 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 13 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 7 to 12 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 8 to 22 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 9 to 22 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 10 to 22 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 11 to 22 months following treatment. In one embodiment, the human subject has a progression-free survival in the range of 12 to 22 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 13 to 22 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 14 to 22 months after treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 15 to 22 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 16 to 22 months after treatment. In one embodiment, the human subject has a progression-free survival in the range of 17 to 22 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 18 to 22 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 8 to 33 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 9 to 33 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 10 to 33 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 11 to 33 months following treatment. In one embodiment, the human subject has a progression-free survival in the range of 12 to 33 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 13 to 33 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 14 to 33 months after treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 15 to 33 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 16 to 33 months after treatment. In one embodiment, the human subject has a progression-free survival in the range of 17 to 33 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 18 to 33 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 19 to 33 months after treatment. In another embodiment, the human subject has a progression-free survival in the range of 20 to 33 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 21 to 33 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 22 to 33 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 23 to 33 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 24 to 33 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 25 to 33 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 8 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 9 to 29 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 10 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 11 to 29 months following treatment. In one embodiment, the human subject has a progression-free survival in the range of 12 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 13 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 14 to 29 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 15 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 16 to 29 months following treatment. In one embodiment, the human subject has a progression-free survival in the range of 17 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 18 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 19 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 20 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 21 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 22 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 23 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 24 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 25 to 29 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 6 to 21 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 7 to 20 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 8 to 19 months following treatment. In one embodiment, the human subject has a progression-free survival in the range of 9 to 18 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 10 to 17 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 11 to 16 months following treatment. In yet another embodiment, the human subject has a progression-free survival in the range of 12 to 15 months following treatment. In another embodiment, the human subject has a progression-free survival in the range of 13 to 14 months following treatment.
在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約5個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約6個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約7個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約8個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約9個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約10個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約11個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約5個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約12個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約13個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約14個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約15個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約16個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約17個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約18個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約19個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約20個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約21個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約22個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約23個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約24個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約25個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約26個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約27個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約28個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約29個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約30個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約31個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約32個月。在某些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體在治療之後的無惡化存活期為至少或約33個月。In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 5 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 6 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 7 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 8 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 9 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 10 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 11 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 5 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 12 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 13 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 14 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 15 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 16 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 17 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 18 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 19 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 20 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 21 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 22 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 23 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 24 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 25 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 26 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 27 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 28 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 29 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 30 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 31 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 32 months after treatment. In certain embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of at least or about 33 months after treatment.
在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至33個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至32個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至31個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至30個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至29個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至28個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至27個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至26個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至25個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至24個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至23個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至22個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至21個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至20個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至19個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至18個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至17個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至16個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至15個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至14個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至13個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在5至12個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至33個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至32個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至31個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至30個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至29個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至28個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至27個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至26個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至25個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至24個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至23個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至22個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至21個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至20個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至19個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至18個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至17個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至16個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至15個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至14個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至13個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至12個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至33個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至32個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至31個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至30個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至29個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至28個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至27個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至26個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至25個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至24個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至23個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至22個月範圍內。在一些實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至21個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至20個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至19個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至18個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至17個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至16個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至15個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至14個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至13個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至12個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6.41至22個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在8至33個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在9至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在10至33個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在11至33個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在12至33個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在13至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在14至33個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在15至33個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在16至33個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在17至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在18至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在19至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在20至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在21至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在22至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在23至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在24至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在25至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在26至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在27至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在28至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在29至33個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在8至29個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在9至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在10至29個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在11至29個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在12至29個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在13至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在14至29個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在15至29個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在16至29個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在17至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在18至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在19至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在20至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在21至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在22至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在23至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在24至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在25至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在26至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在27至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在28至29個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在8至22個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在9至22個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在10至22個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在11至22個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在12至22個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在13至22個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在14至22個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在15至22個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在16至22個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在17至22個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在18至22個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在6至21個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在7至20個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在8至19個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在9至18個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在10至17個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在11至16個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在12至15個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的無惡化存活期在13至24個月範圍內。 In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 33 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 32 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 31 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 30 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 29 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 28 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 27 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 26 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 25 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 24 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 23 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 22 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 21 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 20 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 19 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 18 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 17 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 16 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 15 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 5 to 14 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the progression-free survival of the treated population is in the range of 5 to 13 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the progression-free survival of the treated population is in the range of 5 to 12 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the progression-free survival of the treated population is in the range of 6 to 33 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the progression-free survival of the treated population is in the range of 6 to 32 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 31 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 30 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 29 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 28 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 27 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 26 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 25 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 24 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 23 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 22 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 21 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 20 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 19 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 18 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 17 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 16 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 15 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 14 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 13 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 12 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 33 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 32 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 31 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 30 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 29 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 28 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 27 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 26 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 25 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 24 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 23 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 22 months. In some embodiments, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 21 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 20 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 19 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 18 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 17 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 16 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 15 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 14 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the progression-free survival of the treated population is in the range of 7 to 13 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the progression-free survival of the treated population is in the range of 7 to 12 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the progression-free survival of the treated population is in the range of 6.41 to 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the progression-free survival of the treated population is in the range of 8 to 33 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 9 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 10 to 33 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 11 to 33 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 12 to 33 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 13 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 14 to 33 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 15 to 33 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 16 to 33 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 17 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 18 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 19 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 20 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 21 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 22 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 23 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 24 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 25 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 26 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 27 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 28 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 29 to 33 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 8 to 29 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 9 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 10 to 29 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 11 to 29 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 12 to 29 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 13 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 14 to 29 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 15 to 29 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 16 to 29 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 17 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 18 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has an progression-free survival period of 19 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has an progression-free survival period of 20 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has an progression-free survival period of 21 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has an progression-free survival period of 22 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has an progression-free survival period of 23 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has an progression-free survival period of 24 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has an progression-free survival period of 25 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 26 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 27 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 28 to 29 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period in the range of 8 to 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 9 to 22 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 10 to 22 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 11 to 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 12 to 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 13 to 22 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 14 to 22 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 15 to 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 16 to 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 17 to 22 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 18 to 22 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 6 to 21 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 7 to 20 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 8 to 19 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 9 to 18 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 10 to 17 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the treated population has a progression-free survival period of 11 to 16 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the progression-free survival of the treated population is in the range of 12 to 15 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the progression-free survival of the treated population is in the range of 13 to 24 months.
在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約6個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約5個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約6個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約7個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約8個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約9個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約10個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約11個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約12個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約13個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約14個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約15個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約16個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約17個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約18個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約19個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約20個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約21個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約22個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約23個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約24個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約25個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約26個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約27個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約28個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約29個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約30個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約31個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約32個月。在一些實施例中，以該方法治療之個體群體的無惡化存活期為至少或約33個月。In some embodiments, the progression-free survival of the individual population treated with the method is at least or about 6 months. In some embodiments, the progression-free survival of the individual population treated with the method is at least or about 5 months. In some embodiments, the progression-free survival of the individual population treated with the method is at least or about 6 months. In some embodiments, the progression-free survival of the individual population treated with the method is at least or about 7 months. In some embodiments, the progression-free survival of the individual population treated with the method is at least or about 8 months. In some embodiments, the progression-free survival of the individual population treated with the method is at least or about 9 months. In some embodiments, the progression-free survival of the individual population treated with the method is at least or about 10 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 11 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 12 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 13 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 14 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 15 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 16 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 17 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 18 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 19 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 20 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 21 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 22 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 23 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 24 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 25 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 26 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 27 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 28 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 29 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 30 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 31 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 32 months. In some embodiments, the progression-free survival of a population of individuals treated with the method is at least or about 33 months.
或者，本文所提供之方法的治療結果可基於如章節6.1.8.2(v)中所闡述之總存活期來評估。在一個實施例中，人類個體在治療之後的總存活期為至少或約5個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約6個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約7個月。在又另一實施例中，人類個體在治療之後的總存活期為至少或約8個月。在一個實施例中，人類個體在治療之後的總存活期為至少或約9個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約10個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約11個月。在又另一實施例中，人類個體在治療之後的總存活期為至少或約12個月。在一個實施例中，人類個體在治療之後的總存活期為至少或約13個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約14個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約14.7個月。在又另一實施例中，人類個體在治療之後的總存活期為至少或約15個月。在一個實施例中，人類個體在治療之後的總存活期為至少或約16個月。在一個實施例中，人類個體在治療之後的總存活期為至少或約16.1個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約17個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約18個月。在又另一實施例中，人類個體在治療之後的總存活期為至少或約19個月。在一個實施例中，人類個體在治療之後的總存活期為至少或約20個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約21個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約22個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約22.3個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約23個月。在又另一實施例中，人類個體在治療之後的總存活期為至少或約24個月。在一個實施例中，人類個體在治療之後的總存活期為至少或約25個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約26個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約27個月。在一個實施例中，人類個體在治療之後的總存活期為至少或約28個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約29個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約30個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約31個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約32個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約33個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約34個月。在另一實施例中，人類個體在治療之後的總存活期為至少或約35個月。Alternatively, the treatment outcome of the methods provided herein can be assessed based on the overall survival as described in Section 6.1.8.2 (v). In one embodiment, the overall survival of the human subject after treatment is at least or about 5 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 6 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 7 months. In yet another embodiment, the overall survival of the human subject after treatment is at least or about 8 months. In one embodiment, the overall survival of the human subject after treatment is at least or about 9 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 10 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 11 months. In yet another embodiment, the overall survival of the human subject after treatment is at least or about 12 months. In one embodiment, the overall survival of the human subject after treatment is at least or about 13 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 14 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 14.7 months. In yet another embodiment, the overall survival of the human subject after treatment is at least or about 15 months. In one embodiment, the overall survival of the human subject after treatment is at least or about 16 months. In one embodiment, the overall survival of a human subject after treatment is at least or about 16.1 months. In another embodiment, the overall survival of a human subject after treatment is at least or about 17 months. In another embodiment, the overall survival of a human subject after treatment is at least or about 18 months. In yet another embodiment, the overall survival of a human subject after treatment is at least or about 19 months. In one embodiment, the overall survival of a human subject after treatment is at least or about 20 months. In another embodiment, the overall survival of a human subject after treatment is at least or about 21 months. In another embodiment, the overall survival of a human subject after treatment is at least or about 22 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 22.3 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 23 months. In yet another embodiment, the overall survival of the human subject after treatment is at least or about 24 months. In one embodiment, the overall survival of the human subject after treatment is at least or about 25 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 26 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 27 months. In one embodiment, the overall survival of the human subject after treatment is at least or about 28 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 29 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 30 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 31 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 32 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 33 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 34 months. In another embodiment, the overall survival of the human subject after treatment is at least or about 35 months.
在一個實施例中，人類個體在治療之後具有10至35個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有10至34個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有10至33個月範圍內的總存活期。在又另一實施例中，人類個體在治療之後具有10至32個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有10至31個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有10至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有10至29個月範圍內的總存活期。在又另一實施例中，人類個體在治療之後具有10至28個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有10至27個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有10至26個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有10至25個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有11至35個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有12至35個月範圍內的總存活期。在又另一實施例中，人類個體在治療之後具有13至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有14至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有14至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有15至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有16至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有17至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有18至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有19至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有20至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有21至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有22至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有23至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有24至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有25至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有26至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有27至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有28至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有29至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有30至35個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有31至35個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有15至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有16至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有17至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有18至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有19至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有20至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有21至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有22至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有23至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有24至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有25至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有26至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有27至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有28至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有29至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有30至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有31至32個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有15至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有16至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有17至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有18至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有19至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有20至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有21至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有22至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有23至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有24至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有25至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有26至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有27至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有28至30個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有29至30個月範圍內的總存活期。在又另一實施例中，人類個體在治療之後具有16至29個月範圍內的總存活期。在又另一實施例中，人類個體在治療之後具有17至29個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有17至28個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有18至28個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有18至27個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有17至27個月範圍內的總存活期。在又另一實施例中，人類個體在治療之後具有17至26個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有18至26個月範圍內的總存活期。在另一實施例中，人類個體在治療之後具有18至25個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有19至25個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有19至24個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有20至24個月範圍內的總存活期。在一個實施例中，人類個體在治療之後具有20至23個月範圍內的總存活期。In one embodiment, the human individual has an overall survival in the range of 10 to 35 months after treatment. In another embodiment, the human individual has an overall survival in the range of 10 to 34 months after treatment. In another embodiment, the human individual has an overall survival in the range of 10 to 33 months after treatment. In yet another embodiment, the human individual has an overall survival in the range of 10 to 32 months after treatment. In one embodiment, the human individual has an overall survival in the range of 10 to 31 months after treatment. In another embodiment, the human individual has an overall survival in the range of 10 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 10 to 29 months after treatment. In yet another embodiment, the human individual has an overall survival in the range of 10 to 28 months after treatment. In one embodiment, the human individual has an overall survival in the range of 10 to 27 months after treatment. In one embodiment, the human individual has an overall survival in the range of 10 to 26 months after treatment. In one embodiment, the human individual has an overall survival in the range of 10 to 25 months after treatment. In another embodiment, the human individual has an overall survival in the range of 11 to 35 months after treatment. In another embodiment, the human individual has an overall survival in the range of 12 to 35 months after treatment. In yet another embodiment, the human individual has an overall survival in the range of 13 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 14 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 14 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 15 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 16 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 17 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 18 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 19 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 20 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 21 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 22 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 23 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 24 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 25 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 26 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 27 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 28 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 29 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 30 to 35 months after treatment. In one embodiment, the human individual has an overall survival in the range of 31 to 35 months after treatment. In another embodiment, the human individual has an overall survival in the range of 15 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 16 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 17 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 18 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 19 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 20 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 21 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 22 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 23 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 24 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 25 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 26 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 27 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 28 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 29 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 30 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 31 to 32 months after treatment. In another embodiment, the human individual has an overall survival in the range of 15 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 16 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 17 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 18 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 19 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 20 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 21 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 22 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 23 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 24 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 25 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 26 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 27 to 30 months after treatment. In another embodiment, the human individual has an overall survival in the range of 28 to 30 months following treatment. In another embodiment, the human individual has an overall survival in the range of 29 to 30 months following treatment. In yet another embodiment, the human individual has an overall survival in the range of 16 to 29 months following treatment. In yet another embodiment, the human individual has an overall survival in the range of 17 to 29 months following treatment. In one embodiment, the human individual has an overall survival in the range of 17 to 28 months following treatment. In another embodiment, the human individual has an overall survival in the range of 18 to 28 months following treatment. In another embodiment, the human individual has an overall survival in the range of 18 to 27 months following treatment. In another embodiment, the human individual has an overall survival in the range of 17 to 27 months after treatment. In yet another embodiment, the human individual has an overall survival in the range of 17 to 26 months after treatment. In one embodiment, the human individual has an overall survival in the range of 18 to 26 months after treatment. In another embodiment, the human individual has an overall survival in the range of 18 to 25 months after treatment. In one embodiment, the human individual has an overall survival in the range of 19 to 25 months after treatment. In one embodiment, the human individual has an overall survival in the range of 19 to 24 months after treatment. In one embodiment, the human individual has an overall survival in the range of 20 to 24 months after treatment. In one embodiment, the human subject has an overall survival following treatment in the range of 20 to 23 months.
另外，在一些實施例中，藉由評估所治療群體的中值或平均總存活期來評估經本文所提供之方法治療之人類個體群體的總存活期。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約5個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約6個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約7個月。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約8個月。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約9個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約10個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約10.51個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約11個月。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約12個月。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約13個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約14個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約14.7個月。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約15個月。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約16個月。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約16.1個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約17個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約18個月。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約19個月。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約20個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約21個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約22個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約22.3個月。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約23個月。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約24個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約25個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約26個月。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約27個月。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約28個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約29個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約30個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約31個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約32個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約33個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約34個月。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的中值或平均總存活期為至少或約35個月。In addition, in some embodiments, the total survival of a human subject population treated by the methods provided herein is assessed by assessing the median or average total survival of the treated population. In one embodiment, a human subject population is treated by the methods provided herein, wherein the median or average total survival of the treated population is at least or about 5 months. In another embodiment, a human subject population is treated by the methods provided herein, wherein the median or average total survival of the treated population is at least or about 6 months. In another embodiment, a human subject population is treated by the methods provided herein, wherein the median or average total survival of the treated population is at least or about 7 months. In yet another embodiment, a human subject population is treated by the methods provided herein, wherein the median or average total survival of the treated population is at least or about 8 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 9 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 10 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 10.51 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 11 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 12 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 13 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 14 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 14.7 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 15 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 16 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 16.1 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 17 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 18 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 19 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 20 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 21 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 22 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 22.3 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 23 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 24 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 25 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 26 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 27 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 28 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 29 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 30 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 31 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 32 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 33 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 34 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the median or average overall survival of the treated population is at least or about 35 months.
在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在10至35個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在10至34個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在10至33個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在10至32個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在10至31個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在10至30個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在10至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在10至28個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在10至27個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在10至26個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在10至25個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在11至35個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在12至35個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在13至35個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在14至35個月範圍內。在一個實施例中，14至35個月。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在15至35個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在16至35個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在17至35個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在18至35個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在19至35個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在15至30個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在16至30個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在16至29個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在17至29個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在17至28個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在18至28個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在18至27個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在17至27個月範圍內。在又另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在17至26個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在18至26個月範圍內。在另一實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在18至25個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在19至25個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在19至24個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在20至24個月範圍內。在一個實施例中，人類個體群體藉由本文所提供之方法治療，其中所治療群體的總存活期在20至23個月範圍內。In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 10 to 35 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 10 to 34 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 10 to 33 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 10 to 32 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 10 to 31 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 10 to 30 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 10 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 10 to 28 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 10 to 27 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 10 to 26 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 10 to 25 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 11 to 35 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 12 to 35 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 13 to 35 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 14 to 35 months. In one embodiment, 14 to 35 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 15 to 35 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 16 to 35 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 17 to 35 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 18 to 35 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 19 to 35 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 15 to 30 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 16 to 30 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 16 to 29 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 17 to 29 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 17 to 28 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 18 to 28 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 18 to 27 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 17 to 27 months. In yet another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 17 to 26 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 18 to 26 months. In another embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 18 to 25 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 19 to 25 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 19 to 24 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 20 to 24 months. In one embodiment, a population of human subjects is treated by the methods provided herein, wherein the overall survival of the treated population is in the range of 20 to 23 months.
在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約5個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約6個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約7個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約8個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約9個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約10個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約11個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約12個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約13個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約14個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約15個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約16個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約17個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約18個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約19個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約20個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約21個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約22個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約22.3個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約23個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約24個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約25個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約26個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約27個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約28個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約29個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約30個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約31個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約32個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約33個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約34個月。在一個實施例中，以該方法治療之個體群體的中值總存活期為至少或約35個月。In one embodiment, the median total survival of the individual population treated with the method is at least or about 5 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 6 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 7 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 8 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 9 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 10 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 11 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 12 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 13 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 14 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 15 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 16 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 17 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 18 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 19 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 20 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 21 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 22 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 22.3 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 23 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 24 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 25 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 26 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 27 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 28 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 29 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 30 months. In one embodiment, the median total survival of the individual population treated with the method is at least or about 31 months. In one embodiment, the median overall survival of a population of individuals treated with the method is at least or about 32 months. In one embodiment, the median overall survival of a population of individuals treated with the method is at least or about 33 months. In one embodiment, the median overall survival of a population of individuals treated with the method is at least or about 34 months. In one embodiment, the median overall survival of a population of individuals treated with the method is at least or about 35 months.
在一個實施例中，以該方法治療之個體群體的總存活期為10至35個月。在一個實施例中，以該方法治療之個體群體的總存活期為10至34個月。在一個實施例中，以該方法治療之個體群體的總存活期為10至33個月。在一個實施例中，以該方法治療之個體群體的總存活期為10至32個月。在一個實施例中，以該方法治療之個體群體的總存活期為10至31個月。在一個實施例中，以該方法治療之個體群體的總存活期為10至30個月。在一個實施例中，以該方法治療之個體群體的總存活期為10至29個月。在一個實施例中，以該方法治療之個體群體的總存活期為10至28個月。在一個實施例中，以該方法治療之個體群體的總存活期為10至27個月。在一個實施例中，以該方法治療之個體群體的總存活期為10至26個月。在一個實施例中，以該方法治療之個體群體的總存活期為10至25個月。在一個實施例中，以該方法治療之個體群體的總存活期為11至35個月。在一個實施例中，以該方法治療之個體群體的總存活期為12至35個月。在一個實施例中，以該方法治療之個體群體的總存活期為13至35個月。在一個實施例中，以該方法治療之個體群體的總存活期為14至35個月。在一個實施例中，以該方法治療之個體群體的總存活期為15至35個月。在一個實施例中，以該方法治療之個體群體的總存活期為16至35個月。在一個實施例中，以該方法治療之個體群體的總存活期為17至35個月。在一個實施例中，以該方法治療之個體群體的總存活期為18至35個月。在一個實施例中，以該方法治療之個體群體的總存活期為19至35個月。在一個實施例中，以該方法治療之個體群體的總存活期為15至30個月。在一個實施例中，以該方法治療之個體群體的總存活期為16至30個月。在一個實施例中，以該方法治療之個體群體的總存活期為16至29個月。在一個實施例中，以該方法治療之個體群體的總存活期為17至29個月。在一個實施例中，以該方法治療之個體群體的總存活期為17至28個月。在一個實施例中，以該方法治療之個體群體的總存活期為18至28個月。在一個實施例中，以該方法治療之個體群體的總存活期為18至27個月。在一個實施例中，以該方法治療之個體群體的總存活期為17至27個月。在一個實施例中，以該方法治療之個體群體的總存活期為17至26個月。在一個實施例中，以該方法治療之個體群體的總存活期為18至26個月。在一個實施例中，以該方法治療之個體群體的總存活期為18至25個月。在一個實施例中，以該方法治療之個體群體的總存活期為19至25個月。在一個實施例中，以該方法治療之個體群體的總存活期為19至24個月。在一個實施例中，以該方法治療之個體群體的總存活期為20至24個月。在一個實施例中，以該方法治療之個體群體的總存活期為20至23個月。In one embodiment, the overall survival of the population of individuals treated with the method is 10 to 35 months. In one embodiment, the overall survival of the population of individuals treated with the method is 10 to 34 months. In one embodiment, the overall survival of the population of individuals treated with the method is 10 to 33 months. In one embodiment, the overall survival of the population of individuals treated with the method is 10 to 32 months. In one embodiment, the overall survival of the population of individuals treated with the method is 10 to 31 months. In one embodiment, the overall survival of the population of individuals treated with the method is 10 to 30 months. In one embodiment, the overall survival of the population of individuals treated with the method is 10 to 29 months. In one embodiment, the overall survival of the population of individuals treated with the method is 10 to 28 months. In one embodiment, the overall survival of the population of individuals treated with the method is 10 to 27 months. In one embodiment, the overall survival of the population of individuals treated with the method is 10 to 26 months. In one embodiment, the overall survival of the population of individuals treated with the method is 10 to 25 months. In one embodiment, the overall survival of the population of individuals treated with the method is 11 to 35 months. In one embodiment, the overall survival of the population of individuals treated with the method is 12 to 35 months. In one embodiment, the overall survival of the population of individuals treated with the method is 13 to 35 months. In one embodiment, the overall survival of the population of individuals treated with the method is 14 to 35 months. In one embodiment, the overall survival of the population of individuals treated with the method is 15 to 35 months. In one embodiment, the overall survival of the population of individuals treated with the method is 16 to 35 months. In one embodiment, the overall survival of the population of individuals treated with the method is 17 to 35 months. In one embodiment, the overall survival of the population of individuals treated with the method is 18 to 35 months. In one embodiment, the overall survival of the population of individuals treated with the method is 19 to 35 months. In one embodiment, the overall survival of the population of individuals treated with the method is 15 to 30 months. In one embodiment, the overall survival of the population of individuals treated with the method is 16 to 30 months. In one embodiment, the overall survival of the population of individuals treated with the method is 16 to 29 months. In one embodiment, the overall survival of the population of individuals treated with the method is 17 to 29 months. In one embodiment, the overall survival of the population of individuals treated with the method is 17 to 28 months. In one embodiment, the overall survival of the population of individuals treated with the method is 18 to 28 months. In one embodiment, the overall survival of the population of individuals treated with the method is 18 to 27 months. In one embodiment, the overall survival of the population of individuals treated with the method is 17 to 27 months. In one embodiment, the overall survival of the population of individuals treated with the method is 17 to 26 months. In one embodiment, the overall survival of the population of individuals treated with the method is 18 to 26 months. In one embodiment, the overall survival of the population of individuals treated with the method is 18 to 25 months. In one embodiment, the overall survival of the population of individuals treated with the method is 19 to 25 months. In one embodiment, the overall survival of the population of individuals treated with the method is 19 to 24 months. In one embodiment, the overall survival of the population of individuals treated with the method is 20 to 24 months. In one embodiment, the overall survival of the population of individuals treated with the method is 20 to 23 months.
在一個實施例中，以該方法治療之個體群體的總存活期為25至30個月。在一個實施例中，以該方法治療之個體群體的總存活期為26至30個月。在一個實施例中，以該方法治療之個體群體的總存活期為27至30個月。在一個實施例中，以該方法治療之個體群體的總存活期為28至30個月。在一個實施例中，以該方法治療之個體群體的總存活期為26至31個月。在一個實施例中，以該方法治療之個體群體的總存活期為27至31個月。在一個實施例中，以該方法治療之個體群體的總存活期為28至31個月。在一個實施例中，以該方法治療之個體群體的總存活期為29至31個月。在一個實施例中，以該方法治療之個體群體的總存活期為27至32個月。在一個實施例中，以該方法治療之個體群體的總存活期為28至32個月。在一個實施例中，以該方法治療之個體群體的總存活期為29至32個月。在一個實施例中，以該方法治療之個體群體的總存活期為30至32個月。在一個實施例中，以該方法治療之個體群體的總存活期為28至33個月。在一個實施例中，以該方法治療之個體群體的總存活期為29至33個月。在一個實施例中，以該方法治療之個體群體的總存活期為30至33個月。在一個實施例中，以該方法治療之個體群體的總存活期為31至33個月。在一個實施例中，以該方法治療之個體群體的總存活期為29至34個月。在一個實施例中，以該方法治療之個體群體的總存活期為30至34個月。在一個實施例中，以該方法治療之個體群體的總存活期為31至34個月。在一個實施例中，以該方法治療之個體群體的總存活期為32至34個月。在一個實施例中，以該方法治療之個體群體的總存活期為30至35個月。在一個實施例中，以該方法治療之個體群體的總存活期為31至35個月。在一個實施例中，以該方法治療之個體群體的總存活期為32至35個月。在一個實施例中，以該方法治療之個體群體的總存活期為33至35個月。5.2.2基於其他選擇準則治療患者群體之癌症的方法In one embodiment, the overall survival of the population of individuals treated with the method is 25 to 30 months. In one embodiment, the overall survival of the population of individuals treated with the method is 26 to 30 months. In one embodiment, the overall survival of the population of individuals treated with the method is 27 to 30 months. In one embodiment, the overall survival of the population of individuals treated with the method is 28 to 30 months. In one embodiment, the overall survival of the population of individuals treated with the method is 26 to 31 months. In one embodiment, the overall survival of the population of individuals treated with the method is 27 to 31 months. In one embodiment, the overall survival of the population of individuals treated with the method is 28 to 31 months. In one embodiment, the overall survival of the population of individuals treated with the method is 29 to 31 months. In one embodiment, the overall survival of the population of individuals treated with the method is 27 to 32 months. In one embodiment, the overall survival of the population of individuals treated with the method is 28 to 32 months. In one embodiment, the overall survival of the population of individuals treated with the method is 29 to 32 months. In one embodiment, the overall survival of the population of individuals treated with the method is 30 to 32 months. In one embodiment, the overall survival of the population of individuals treated with the method is 28 to 33 months. In one embodiment, the overall survival of the population of individuals treated with the method is 29 to 33 months. In one embodiment, the overall survival of the population of individuals treated with the method is 30 to 33 months. In one embodiment, the overall survival of the population of individuals treated with the method is 31 to 33 months. In one embodiment, the overall survival of the population of individuals treated with the method is 29 to 34 months. In one embodiment, the overall survival of the population of individuals treated with the method is 30 to 34 months. In one embodiment, the overall survival of the population of individuals treated with the method is 31 to 34 months. In one embodiment, the overall survival of the population of individuals treated with the method is 32 to 34 months. In one embodiment, the overall survival of the population of individuals treated with the method is 30 to 35 months. In one embodiment, the overall survival of the population of individuals treated with the method is 31 to 35 months. In one embodiment, the overall survival of the population of individuals treated with the method is 32 to 35 months. In one embodiment, the overall survival of the population of individuals treated with the method is 33 to 35 months.5.2.2Methods of treating cancer in a patient population based on other selection criteria
本文提供用於治療個體之多種癌症的方法，其中該等癌症具有如章節6中所提供的任一種適合標記物及/或特徵。本文亦提供用於治療個體之多種癌症的方法，其中該等個體具有如章節6中所提供的任一種適合特徵。Provided herein are methods for treating a variety of cancers in an individual, wherein the cancers have any suitable marker and/or characteristic as provided in Section 6. Also provided herein are methods for treating a variety of cancers in an individual, wherein the individual has any suitable characteristic as provided in Section 6.
在一個態樣中，本文提供一種預防或治療個體之癌症的方法，包含向該個體投與有效量的抗體藥物結合物，其中該抗體藥物結合物包含結合至191P4D12之抗體或其抗原結合片段與單甲基奧瑞他汀E (MMAE)之一或多個單元的結合物，其中該抗體或其抗原結合片段包含：重鏈可變區，該重鏈可變區包含含有SEQ ID NO:22中所闡述之重鏈可變區CDR胺基酸序列的互補決定區(CDR)；及輕鏈可變區，該輕鏈可變區包含含有SEQ ID NO:23中所闡述之輕鏈可變區CDR胺基酸序列的CDR；且其中該個體具有如章節6所提供之任一種適合特徵。In one aspect, provided herein is a method for preventing or treating cancer in an individual, comprising administering to the individual an effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises a conjugate of an antibody or an antigen-binding fragment thereof that binds to 191P4D12 and one or more units of monomethyl auristatin E (MMAE), wherein the antibody or antigen-binding fragment thereof comprises: a heavy chain variable region, the heavy chain variable region comprising a complementary determining region (CDR) comprising the heavy chain variable region CDR amino acid sequence set forth in SEQ ID NO:22; and a light chain variable region, the light chain variable region comprising a CDR comprising the light chain variable region CDR amino acid sequence set forth in SEQ ID NO:23; and wherein the individual has any one of the suitable characteristics provided in Section 6.
在一些態樣中，本文提供一種預防或治療個體之癌症的方法，包含向該個體投與有效量的抗體藥物結合物，其中該抗體藥物結合物包含結合至191P4D12之抗體或其抗原結合片段與單甲基奧瑞他汀E (MMAE)之一或多個單元的結合物，其中該抗體或其抗原結合片段包含：重鏈可變區，該重鏈可變區包含含有SEQ ID NO:22中所闡述之重鏈可變區CDR胺基酸序列的互補決定區(CDR)；及輕鏈可變區，該輕鏈可變區包含含有SEQ ID NO:23中所抗體藥物結合物之輕鏈可變區CDR胺基酸序列的CDR；且其中該癌症具有如章節6所提供之任一種適合標記物及/或特徵。In some aspects, provided herein is a method for preventing or treating cancer in an individual, comprising administering to the individual an effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises a conjugate of an antibody or an antigen-binding fragment thereof that binds to 191P4D12 and one or more units of monomethyl auristatin E (MMAE), wherein the antibody or antigen-binding fragment thereof comprises: a heavy chain variable region, the heavy chain variable region comprising a complementary determining region (CDR) comprising the heavy chain variable region CDR amino acid sequence described in SEQ ID NO: 22; and a light chain variable region, the light chain variable region comprising a CDR comprising the light chain variable region CDR amino acid sequence of the antibody-drug conjugate in SEQ ID NO: 23; and wherein the cancer has any one of the suitable markers and/or characteristics provided in Section 6.
在另一態樣中，本文提供一種預防或治療個體之癌症的方法，包含向該個體投與有效量的抗體藥物結合物，其中該抗體藥物結合物包含結合至191P4D12之抗體或其抗原結合片段與單甲基奧瑞他汀E (MMAE)之一或多個單元的結合物，且其中該個體具有如章節6所提供之任一種適合特徵。在另一態樣中，本文提供一種預防或治療個體之癌症的方法，包含向該個體投與有效量的抗體藥物結合物，其中該抗體藥物結合物包含結合至191P4D12之抗體或其抗原結合片段與單甲基奧瑞他汀E (MMAE)之一或多個單元的結合物，且其中該癌症具有如章節6所提供之任一種適合標記物及/或特徵。In another aspect, provided herein is a method for preventing or treating cancer in an individual, comprising administering to the individual an effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises a conjugate of an antibody or an antigen-binding fragment thereof that binds to 191P4D12 and one or more units of monomethyl auristatin E (MMAE), and wherein the individual has any one of the suitable characteristics provided in Section 6. In another aspect, provided herein is a method for preventing or treating cancer in an individual, comprising administering to the individual an effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises a conjugate of an antibody or an antigen-binding fragment thereof that binds to 191P4D12 and one or more units of monomethyl auristatin E (MMAE), and wherein the cancer has any one of the suitable markers and/or characteristics provided in Section 6.
在本文(包括章節5.2，包括章節5.2.1及5.2.2及章節3及6)所提供之方法的一些實施例中，個體為人類個體。In some embodiments of the methods provided herein (including Section 5.2, including Sections 5.2.1 and 5.2.2 and Sections 3 and 6), the subject is a human subject.
在本文所提供的所有方法及章節5.2.1及5.2.2具體描述的方法中，章節3、5.2、5.3、5.4、5.5及6中描述了可使用的治療劑(包括ADC)，本文中描述了且章節5.2 (包括章節5.2.1及5.2.2)及章節3及6中舉例說明了選擇用於治療的患者，下述章節5.4、5.6、5.7及章節6中描述了用於投與治療劑的給藥方案及醫藥組合物，本文中描述了且章節5.2 (包括章節5.2.1及5.2.2)及章節3及6中舉例說明了可用於鑑別治療劑、選擇患者、測定此等方法之結果及/或以任何方式充當此等方法之準則的生物標記物，該等生物標記物可如章節5.8中所述或如此項技術中所知來測定，本章節(章節5.2，包括章節5.2.1.4)及章節3及6中描述了本文所提供之方法的治療結果，本文所提供之方法的其他治療結果可為本文所述之生物標記物的改良，例如章節5.2 (包括章節5.2.1及5.2.2)及章節3及6中所述及舉例說明的彼等生物標記物，且本章節(章節5.2)及章節5.5中描述了包括ADC與其他治療劑的組合療法。因此，熟習此項技術者應瞭解，本文所提供之方法包括如上文及下文所描述之患者、治療劑、給藥方案、生物標記物及治療結果的所有排列及組合。5.3用於該等方法之抗體藥物結合物In all methods provided herein and in the methods specifically described in Sections 5.2.1 and 5.2.2, therapeutic agents (including ADCs) that can be used are described in Sections 3, 5.2, 5.3, 5.4, 5.5, and 6, patients selected for treatment are described herein and exemplified in Section 5.2 (including Sections 5.2.1 and 5.2.2) and Sections 3 and 6, dosing regimens and pharmaceutical compositions for administering therapeutic agents are described in the following Sections 5.4, 5.6, 5.7, and 6, and therapeutic agents are described herein and in Section 5.2. Biomarkers that can be used to identify therapeutic agents, select patients, determine the results of such methods and/or serve as criteria for such methods in any way are exemplified in Sections 5.2.1 and 5.2.2, including Sections 3 and 6, which can be determined as described in Section 5.8 or as known in the art, and the treatment outcomes of the methods provided herein are described in this section (Section 5.2, including Section 5.2.1.4) and Sections 3 and 6. Other treatment outcomes of the methods provided herein may be improvements of the biomarkers described herein, such as those described and exemplified in Section 5.2 (including Sections 5.2.1 and 5.2.2) and Sections 3 and 6, and combination therapies comprising ADCs and other therapeutic agents are described in this section (Section 5.2) and Section 5.5. Therefore, those skilled in the art will appreciate that the methods provided herein include all permutations and combinations of patients, therapeutic agents, dosing regimens, biomarkers, and treatment outcomes as described above and below.5.3Antibody Drug Conjugates for Use in Such Methods
在本文所提供之方法(包括章節5.2中所提供之方法)的各種實施例中，該等方法中所用的ADC包含或為本文及/或美國專利第8,637,642號所描述之抗191P4D12 ADC，該專利以全文引用的方式併入本文中。在一些實施例中，本文向該等方法提供的抗191P4D12抗體藥物結合物包含如本文(包括章節3、5.3.1，及6)所提供之結合至191P4D12的抗體或其抗原結合片段與如本文(包括章節3及6，及本章節(章節5.3))所提供之細胞毒性劑之一或多個單元(藥物單元，或D)的結合物，其進一步揭示於章節5.3.2及5.3.4中。在某些實施例中，細胞毒性劑(藥物單元，或D)可直接或經由如本文(包括章節3及6，及本章節(章節5.3))所提供的連接子單元(LU)共價連接，其進一步揭示於章節5.3.3中。In various embodiments of the methods provided herein (including the methods provided in Section 5.2), the ADC used in the methods comprises or is an anti-191P4D12 ADC described herein and/or U.S. Patent No. 8,637,642, which is incorporated herein by reference in its entirety. In some embodiments, the anti-191P4D12 antibody-drug conjugate provided herein for the methods comprises an antibody or antigen-binding fragment thereof that binds to 191P4D12 as provided herein (including Sections 3, 5.3.1, and 6) and a conjugate of one or more units (drug units, or D) of a cytotoxic agent as provided herein (including Sections 3 and 6, and this section (Section 5.3)), which is further disclosed in Sections 5.3.2 and 5.3.4. In certain embodiments, a cytotoxic agent (Drug Unit, or D) can be covalently linked directly or via a Linker Unit (LU) as provided herein (including Sections 3 and 6, and this section (Section 5.3)), which is further disclosed in Section 5.3.3.
在一些實施例中，抗體藥物結合物化合物具有下式： L - (LU-D)p(I)或其醫藥學上可接受之鹽或溶劑合物；其中： L為抗體單元，例如抗連接素-4抗體或其抗原結合片段，例如章節3、5.3.1及6中所提供，且 (LU-D)為連接子單元-藥物單元部分，其中： LU-為連接子單元，例如章節3及6及本章節(章節5.3)中所提供，其進一步揭示於章節5.3.3中，且 D為具有針對目標細胞之細胞抑制或細胞毒性活性的藥物單元，例如章節3及6及本章節(章節5.3)中所提供，其進一步揭示於章節5.3.2及5.3.4中；且 p為整數1至20，其他實例提供於章節3及6及本章節(章節5.3)中。In some embodiments, the antibody-drug conjugate compound has the formula: L-(LU-D)p(I) or a pharmaceutically acceptable salt or solvent thereof; wherein: L is an antibody unit, such as an anti-Nectin-4 antibody or an antigen-binding fragment thereof, such as provided in Sections 3, 5.3.1 and 6, and (LU-D) is a Linker unit-Drug unit portion, wherein: LU- is a linker unit, such as provided in Chapters 3 and 6 and this chapter (Chapter 5.3), which is further disclosed in Chapter 5.3.3, and D is a drug unit having cell inhibition or cytotoxic activity against target cells, such as provided in Chapters 3 and 6 and this chapter (Chapter 5.3), which is further disclosed in Chapters 5.3.2 and 5.3.4; and p is an integer from 1 to 20, other examples are provided in Chapters 3 and 6 and this chapter (Chapter 5.3).
在一些實施例中，p的範圍為1至20、1至19、1至18、1至17、1至16、1至15、1至14、1至13、1至12、1至11、1至10、1至9、1至8、1至7、1至6、1至5、1至4、1至3或1至2。在一些實施例中，p的範圍為2至20、2至19、2至18、2至17、2至16、2至15、2至14、2至13、2至12、2至11、2至10、2至9、2至8、2至7、2至6、2至5、2至4或2至3。在一些實施例中，p的範圍為3至20、3至19、3至18、3至17、3至16、3至15、3至14、3至13、3至12、3至11、3至10、3至9、3至8、3至7、3至6、3至5或3至4。在一些實施例中，p為約1。在一些實施例中，p為約2。在一些實施例中，p為約3。在一些實施例中，p為約4。在一些實施例中，p為約3.8。在一些實施例中，p為約5。在一些實施例中，p為約6。在一些實施例中，p為約7。在一些實施例中，p為約8。在一些實施例中，p為約9。在一些實施例中，p為約10。在一些實施例中，p為約11。在一些實施例中，p為約12。在一些實施例中，p為約13。在一些實施例中，p為約14。在一些實施例中，p為約15。在一些實施例中，p為約16。在一些實施例中，p為約17。在一些實施例中，p為約18。在一些實施例中，p為約19。在一些實施例中，p為約20。In some embodiments, p ranges from 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, p ranges from 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, 2 to 13, 2 to 12, 2 to 11, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3. In some embodiments, p ranges from 3 to 20, 3 to 19, 3 to 18, 3 to 17, 3 to 16, 3 to 15, 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 3 to 4. In some embodiments, p is about 1. In some embodiments, p is about 2. In some embodiments, p is about 3. In some embodiments, p is about 4. In some embodiments, p is about 3.8. In some embodiments, p is about 5. In some embodiments, p is about 6. In some embodiments, p is about 7. In some embodiments, p is about 8. In some embodiments, p is about 9. In some embodiments, p is about 10. In some embodiments, p is about 11. In some embodiments, p is about 12. In some embodiments, p is about 13. In some embodiments, p is about 14. In some embodiments, p is about 15. In some embodiments, p is about 16. In some embodiments, p is about 17. In some embodiments, p is about 18. In some embodiments, p is about 19. In some embodiments, p is about 20.
在一些實施例中，抗體藥物結合物化合物具有下式： L - (Aa-Ww-Yy-D)p(II)或其醫藥學上可接受之鹽或溶劑合物，其中： L為抗體單元，例如抗連接素-4抗體或其抗原結合片段，例如章節3、5.3.1及6中所提供；且 -Aa-Ww-Yy-為連接子單元(LU)，其中： -A-為延伸子單元， a為0或1， 各-W-獨立地為胺基酸單元， w為0至12範圍內之整數， -Y-為自我分解型間隔子單元， y為0、1或2； 各例如章節3及6及本章節(章節5.3)中所提供，其進一步揭示於章節5.3.3中； D為具有針對目標細胞之細胞抑制或細胞毒性活性的藥物單元，例如章節3及6及本章節(章節5.3)中所提供，其進一步揭示於章節5.3.2及5.3.4中；且 p為整數1至20，其他實例提供於章節3及6及本章節(章節5.3)中。In some embodiments, the antibody-drug conjugate compound has the formula: L-(Aa -Ww -Yy -D)p(II) or a pharmaceutically acceptable salt or solvent thereof, wherein: L is an antibody unit, such as an anti-nectin-4 antibody or an antigen-binding fragment thereof, such as provided in Sections 3, 5.3.1 and 6; and -Aa-Ww-Yy- is a Linker unit (LU), wherein: -A- is a Stretcher unit, a is 0 or 1, each -W- is independently an amino acid unit, w is an integer in the range of 0 to 12, -Y- is a self-immolative Spacer unit, y is 0, 1 or 2; each example is provided in Sections 3 and 6 and this section (Section 5.3), which is further disclosed in Section 5.3.3; D is a drug unit having cytostatic or cytotoxic activity against target cells, such as provided in Chapters 3 and 6 and this chapter (Chapter 5.3), which are further disclosed in Chapters 5.3.2 and 5.3.4; and p is an integer from 1 to 20, other examples are provided in Chapters 3 and 6 and this chapter (Chapter 5.3).
在一些實施例中，a為0或1，w為0或1，且y為0、1或2。在一些實施例中，a為0或1，w為0或1，且y為0或1。在一些實施例中，p的範圍為1至20、1至19、1至18、1至17、1至16、1至15、1至14、1至13、1至12、1至11、1至10、1至9、1至8、1至7、1至6、1至5、1至4、1至3或1至2。在一些實施例中，p的範圍為2至20、2至19、2至18、2至17、2至16、2至15、2至14、2至13、2至12、2至11、2至10、2至9、2至8、2至7、2至6、2至5、2至4或2至3。在一些實施例中，p的範圍為3至20、3至19、3至18、3至17、3至16、3至15、3至14、3至13、3至12、3至11、3至10、3至9、3至8、3至7、3至6、3至5或3至4。在一些實施例中，p為約1。在一些實施例中，p為約2。在一些實施例中，p為約3。在一些實施例中，p為約4。在一些實施例中，p為約3.8。在一些實施例中，p為約5。在一些實施例中，p為約6。在一些實施例中，p為約7。在一些實施例中，p為約8。在一些實施例中，p為約9。在一些實施例中，p為約10。在一些實施例中，p為約11。在一些實施例中，p為約12。在一些實施例中，p為約13。在一些實施例中，p為約14。在一些實施例中，p為約15。在一些實施例中，p為約16。在一些實施例中，p為約17。在一些實施例中，p為約18。在一些實施例中，p為約19。在一些實施例中，p為約20。在一些實施例中，當w不為零時，y為1或2。在一些實施例中，當w為1至12時，y為1或2。在一些實施例中，w為2至12且y為1或2。在一些實施例中，a為1且w及y為0。In some embodiments, a is 0 or 1, w is 0 or 1, and y is 0, 1 or 2. In some embodiments, a is 0 or 1, w is 0 or 1, and y is 0 or 1. In some embodiments, p ranges from 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, p ranges from 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, 2 to 13, 2 to 12, 2 to 11, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3. In some embodiments, p ranges from 3 to 20, 3 to 19, 3 to 18, 3 to 17, 3 to 16, 3 to 15, 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 3 to 4. In some embodiments, p is about 1. In some embodiments, p is about 2. In some embodiments, p is about 3. In some embodiments, p is about 4. In some embodiments, p is about 3.8. In some embodiments, p is about 5. In some embodiments, p is about 6. In some embodiments, p is about 7. In some embodiments, p is about 8. In some embodiments, p is about 9. In some embodiments, p is about 10. In some embodiments, p is about 11. In some embodiments, p is about 12. In some embodiments, p is about 13. In some embodiments, p is about 14. In some embodiments, p is about 15. In some embodiments, p is about 16. In some embodiments, p is about 17. In some embodiments, p is about 18. In some embodiments, p is about 19. In some embodiments, p is about 20. In some embodiments, when w is non-zero, y is 1 or 2. In some embodiments, when w is 1 to 12, y is 1 or 2. In some embodiments, w is 2 to 12 and y is 1 or 2. In some embodiments, a is 1 and w and y are 0.
在本文所提供之方法(包括章節5.2中所提供的方法)的一些特定實施例中，作為本文向該等方法提供之任一種ADC之一部分的細胞毒性劑包含MMAE、由MMAE組成或為MMAE。In some specific embodiments of the methods provided herein, including the methods provided in Section 5.2, the cytotoxic agent that is part of any ADC provided herein for the methods comprises, consists of, or is MMAE.
對於包含複數種抗體或其抗原結合片段之組合物而言，藥物負載由p (藥物分子之平均數目/抗體單元)表示。藥物負載可在1至20個藥物(D)/抗體之範圍內。製備結合反應物時之每個抗體的平均藥物數目可藉由諸如質譜法、ELISA分析及HPLC之習知方式來表徵。亦可根據p來測定抗體藥物結合物之定量分佈。在一些情況下，均質抗體藥物結合物(其中p為具有其他藥物負載之抗體藥物結合物的特定值)的分離、純化及表徵可藉由諸如逆相HPLC或電泳之方式來達成。在某些例示性實施例中，p為2至8。For compositions comprising a plurality of antibodies or antigen-binding fragments thereof, drug loading is represented by p (the average number of drug molecules per antibody unit). Drug loading may range from 1 to 20 drugs (D) per antibody. The average number of drugs per antibody in the preparation of binding reactants may be characterized by known methods such as mass spectrometry, ELISA analysis, and HPLC. The quantitative distribution of antibody-drug conjugates may also be determined based on p. In some cases, separation, purification, and characterization of homogeneous antibody-drug conjugates (where p is a specific value for antibody-drug conjugates with other drug loadings) may be achieved by methods such as reverse phase HPLC or electrophoresis. In certain exemplary embodiments, p is 2 to 8.
用於本文所提供之方法之ADC的其他實施例已描述於美國專利第8,637,642號及國際申請案第PCT/US2019/056214號(公開案第WO2020/117373號)，該兩者以其全文引用之方式併入本文中。Other embodiments of ADCs for use in the methods provided herein are described in U.S. Patent No. 8,637,642 and International Application No. PCT/US2019/056214 (Publication No. WO2020/117373), both of which are incorporated herein by reference in their entirety.
在本文(包括章節3、5.2及6及本章節(章節5.3))所提供之方法的一些實施例中，ADC為恩諾單抗維多汀。在本文(包括章節3、5.2及6及本章節(章節5.3))所提供之方法的某些實施例中，ADC為恩諾單抗維多汀之生物類似物。5.3.1抗191P4D12抗體或抗原結合片段In some embodiments of the methods provided herein (including Sections 3, 5.2 and 6 and this Section (Section 5.3)), the ADC is enroku vedotin. In some embodiments of the methods provided herein (including Sections 3, 5.2 and 6 and this Section (Section 5.3)), the ADC is a biosimilar of enroku vedotin.5.3.1Anti-191P4D12Antibodies or Antigen-Binding Fragments
在一個實施例中，結合連接素-4相關蛋白之抗體或其抗原結合片段為特異性結合包含SEQ ID NO:2之胺基酸序列之連接素-4蛋白的抗體或抗原結合片段(參見圖1A)。編碼191P4D12蛋白質之對應cDNA具有SEQ ID NO:1之序列(參見圖1A)。In one embodiment, the antibody or antigen-binding fragment thereof that binds to a nexin-4-related protein is an antibody or antigen-binding fragment that specifically binds to a nexin-4 protein comprising an amino acid sequence of SEQ ID NO: 2 (seeFIG.1A ). The corresponding cDNA encoding the 191P4D12 protein has a sequence of SEQ ID NO: 1 (seeFIG.1A ).
特異性結合包含SEQ ID NO:2之胺基酸序列之連接素-4蛋白的抗體包括可結合其他連接素-4相關蛋白的抗體。舉例而言，結合包含胺基酸序列SEQ ID NO:2之連接素-4蛋白的抗體可結合連接素-4相關蛋白，諸如連接素-4變異體以及其同源物或類似物。Antibodies that specifically bind to a nexin-4 protein comprising the amino acid sequence of SEQ ID NO: 2 include antibodies that can bind to other nexin-4-related proteins. For example, antibodies that bind to a nexin-4 protein comprising the amino acid sequence of SEQ ID NO: 2 can bind to nexin-4-related proteins, such as nexin-4 variants and homologs or analogs thereof.
在一些實施例中，本文所提供之抗連接素-4抗體為單株抗體。In some embodiments, the anti-Nectin-4 antibodies provided herein are monoclonal antibodies.
在一些實施例中，抗體包含胺基酸序列為SEQ ID NO:4 (cDNA序列為SEQ ID NO:3)的重鏈及/或胺基酸序列為SEQ ID NO:6 (cDNA序列為SEQ ID NO:5)的輕鏈，如圖1B及圖1C中所示。In some embodiments, the antibody comprises a heavy chain having an amino acid sequence of SEQ ID NO:4 (cDNA sequence of SEQ ID NO:3) and/or a light chain having an amino acid sequence of SEQ ID NO:6 (cDNA sequence of SEQ ID NO:5),as shown in FIG. 1B andFIG.1C .
在一些實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含含SEQ ID NO:22 (其為SEQ ID NO:7之第20個胺基酸(麩胺酸)至第136個胺基酸(絲胺酸)範圍內的胺基酸序列)中所闡述之重鏈可變區之CDR之胺基酸序列的互補決定區(CDR)；及輕鏈可變區，其包含含SEQ ID NO:23 (其為SEQ ID NO:8之第23個胺基酸(天冬胺酸)至第130個胺基酸(精胺酸)範圍內的胺基酸序列)中所闡述之輕鏈可變區之CDR之胺基酸序列的CDR。在某些實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含含SEQ ID NO:22 (其為SEQ ID NO:7之第20個胺基酸(麩胺酸)至第136個胺基酸(絲胺酸)範圍內的胺基酸序列)中所闡述之重鏈可變區序列中之對應CDR-H1、CDR-H2及CDR-H3之胺基酸序列的互補決定區1 (CDR-H1)、CDR-H2及CDR-H3；及輕鏈可變區，其包含含SEQ ID NO:23 (其為SEQ ID NO:8之第23個胺基酸(天冬胺酸)至第130個胺基酸(精胺酸)範圍內的胺基酸序列)中所闡述之輕鏈可變區序列之對應CDR-L1、CDR-L2及CDR-L3之胺基酸序列的CDR-L1、CDR-L2及CDR-L3。在一些實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含由SEQ ID NO:22 (其為SEQ ID NO:7之第20個胺基酸(麩胺酸)至第136個胺基酸(絲胺酸)範圍內的胺基酸序列)中所闡述之重鏈可變區之CDR之胺基酸序列組成的互補決定區(CDR)；及輕鏈可變區，其包含由SEQ ID NO:23 (其為SEQ ID NO:8之第23個胺基酸(天冬胺酸)至第130個胺基酸(精胺酸)範圍內的胺基酸序列)中所闡述之輕鏈可變區之CDR之胺基酸序列組成的CDR。在某些實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含由SEQ ID NO:22 (其為SEQ ID NO:7之第20個胺基酸(麩胺酸)至第136個胺基酸(絲胺酸)範圍內的胺基酸序列)中所闡述之重鏈可變區序列中之對應CDR-H1、CDR-H2及CDR-H3之胺基酸序列組成的互補決定區1 (CDR-H1)、CDR-H2及CDR-H3；及輕鏈可變區，其包含由SEQ ID NO:23 (其為SEQ ID NO:8之第23個胺基酸(天冬胺酸)至第130個胺基酸(精胺酸)範圍內的胺基酸序列)中所闡述之輕鏈可變區序列之對應CDR-L1、CDR-L2及CDR-L3之胺基酸序列組成的CDR-L1、CDR-L2及CDR-L3。SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:7及SEQ ID NO:8如圖1D及圖1E中所示且列舉如下：SEQ ID NO:22SEQ ID NO:23SEQ ID NO:7SEQ ID NO:8In some embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising a complementation determining region (CDR) comprising the amino acid sequence of the CDR of the heavy chain variable region described in SEQ ID NO:22 (which is an amino acid sequence ranging from the 20th amino acid (glutamine) to the 136th amino acid (serine) of SEQ ID NO:7); and a light chain variable region comprising a CDR comprising the amino acid sequence of the CDR of the light chain variable region described in SEQ ID NO:23 (which is an amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 130th amino acid (arginine) of SEQ ID NO:8). In certain embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising complementary determining region 1 (CDR-H1), CDR-H2 and CDR-H3 comprising the amino acid sequence corresponding to CDR-H1, CDR-H2 and CDR-H3 in the heavy chain variable region sequence described in SEQ ID NO: 22 (which is an amino acid sequence within the range of the 20th amino acid (glutamine) to the 136th amino acid (serine) of SEQ ID NO: 7); and a light chain variable region comprising SEQ ID NO: 23 (which is an amino acid sequence within the range of SEQ ID CDR-L1, CDR-L2 and CDR-L3 of the amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 corresponding to the light chain variable region sequence described in NO:8 (an amino acid sequence within the range of the 23rd amino acid (aspartic acid) to the 130th amino acid (arginine)). In some embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising a complementation determining region (CDR) consisting of the amino acid sequence of the CDR of the heavy chain variable region described in SEQ ID NO:22 (which is an amino acid sequence ranging from the 20th amino acid (glutamine) to the 136th amino acid (serine) of SEQ ID NO:7); and a light chain variable region comprising a CDR consisting of the amino acid sequence of the CDR of the light chain variable region described in SEQ ID NO:23 (which is an amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 130th amino acid (arginine) of SEQ ID NO:8). In certain embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising complementary determining region 1 (CDR-H1), CDR-H2 and CDR-H3 consisting of the amino acid sequences corresponding to CDR-H1, CDR-H2 and CDR-H3 in the heavy chain variable region sequence described in SEQ ID NO: 22 (which is an amino acid sequence ranging from the 20th amino acid (glutamine) to the 136th amino acid (serine) of SEQ ID NO: 7); and a light chain variable region comprising SEQ ID NO: 23 (which is an amino acid sequence ranging from the 20th amino acid (glutamine) to the 136th amino acid (serine) of SEQ ID NO: 7). 1D and 1E and are listedbelow :SEQ IDNO:22SEQ ID NO:23SEQ ID NO:7SEQ ID NO:8
CDR序列可根據熟知編號系統確定。如上文所描述，CDR區已為熟習此項技術者熟知且已由熟知編號系統定義。舉例而言，Kabat互補決定區(CDR)係基於序列可變性且最常用(參見例如Kabat等人, 見上文)。而Chothia提及結構環之位置(參見例如Chothia及Lesk, 1987, J. Mol. Biol. 196:901-17)。在使用Kabat編號規約進行編號時，Chothia CDR-H1環之末端在H32與H34之間變化，此視環之長度而定(此係因為Kabat編號方案將插入置於H35A及H35B；若既不存在35A，亦不存在35B，則環末端位於32；若僅存在35A，則環末端位於33；若35A與35B均存在，則環末端位於34)。AbM高變區表示Kabat CDR與Chothia結構環之間的折衷，且由Oxford Molecular之AbM抗體模型化軟體使用(參見例如Antibody Engineering第2卷(Kontermann及Dübel編, 第2版, 2010))。「contact」高變區係基於對可用複雜晶體結構之分析。已開發及廣泛採用之另一通用編號系統為ImMunoGeneTics (IMGT) Information System®(Lafranc等人, 2003, Dev. Comp. Immunol. 27(1):55-77)。IMGT為專用於人類及其他脊椎動物之免疫球蛋白(IG)、T細胞受體(TCR)及主要組織相容複合體(MHC)的整合式資訊系統。本文中，依據胺基酸序列及輕鏈或重鏈內的位置提及CDR。由於免疫球蛋白可變域結構內之CDR的「位置」在物種之間為保守的且存在於稱為環的結構中，因此藉由使用根據結構特徵比對可變域序列的編號系統容易鑑別出CDR及構架殘基。此資訊可用於將來自一個物種之免疫球蛋白的CDR殘基移植及置換至通常來自人類抗體之接受體構架中。Honegger及Plückthun, 2001, J. Mol. Biol. 309: 657-70已開發出另一種編號系統(AHon)。編號系統(包括例如Kabat編號及IMGT獨特編號系統)之間的對應性已為熟習此項技術者熟知(參見例如Kabat, 見上文；Chothia及Lesk, 見上文；Martin, 見上文；Lefranc等人, 見上文)。來自此等高變區或CDR中之每一者的殘基標示於上表1中。CDR sequences can be identified according to a well-known numbering system. As described above, CDR regions are well known to those skilled in the art and are defined by a well-known numbering system. For example, Kabat complementarity determining regions (CDRs) are based on sequence variability and are most commonly used (see, e.g., Kabat et al., supra). Chothia refers to the position of structural loops (see, e.g., Chothia and Lesk, 1987, J. Mol. Biol. 196:901-17). When numbering using the Kabat numbering convention, the terminus of the Chothia CDR-H1 loop varies between H32 and H34, depending on the length of the loop (this is because the Kabat numbering scheme places the insertion at H35A and H35B; if neither 35A nor 35B is present, the loop terminus is at 32; if only 35A is present, the loop terminus is at 33; if both 35A and 35B are present, the loop terminus is at 34). The AbM hypervariable regions represent a compromise between the Kabat CDR and Chothia structure loops and are used by Oxford Molecular's AbM antibody modeling software (see, e.g., Antibody Engineering, Vol. 2 (Kontermann and Dübel, eds., 2nd ed., 2010)). The "contact" hypervariable regions are based on analysis of available complex crystal structures. Another universal numbering system that has been developed and widely adopted is the ImMunoGeneTics (IMGT) Information System® (Lafranc et al., 2003, Dev. Comp. Immunol. 27(1):55-77). IMGT is an integrated information system for immunoglobulins (IG), T cell receptors (TCRs), and major histocompatibility complexes (MHC) in humans and other vertebrates. Herein, CDRs are referred to by amino acid sequence and position within the light or heavy chain. Since the "position" of CDRs within the immunoglobulin variable domain structure is conserved between species and is present in structures called loops, CDRs and framework residues are easily identified by using a numbering system that aligns variable domain sequences based on structural features. This information can be used to graft and replace CDR residues from immunoglobulins of one species into acceptor frameworks, usually from human antibodies. Another numbering system (AHon) has been developed by Honegger and Plückthun, 2001, J. Mol. Biol. 309: 657-70. The correspondence between numbering systems (including, for example, Kabat numbering and the IMGT unique numbering system) is well known to those skilled in the art (see, for example, Kabat, supra; Chothia and Lesk, supra; Martin, supra; Lefranc et al., supra). The residues from each of these hypervariable regions or CDRs are indicated in Table 1 above.
在一些實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含含根據Kabat編號之SEQ ID NO:22中所闡述之重鏈可變區之CDR之胺基酸序列的CDR (CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3)；及輕鏈可變區，其包含含根據Kabat編號之SEQ ID NO:23中所闡述之輕鏈可變區之CDR之胺基酸序列的CDR。In some embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3) comprising the amino acid sequence of the CDR of the heavy chain variable region set forth in SEQ ID NO:22 according to Kabat numbering; and a light chain variable region comprising CDRs comprising the amino acid sequence of the CDR of the light chain variable region set forth in SEQ ID NO:23 according to Kabat numbering.
在一些實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含含根據AbM編號之SEQ ID NO:22中所闡述之重鏈可變區之CDR之胺基酸序列的CDR (CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3)；及輕鏈可變區，其包含含根據AbM編號之SEQ ID NO:23中所闡述之輕鏈可變區之CDR之胺基酸序列的CDR。In some embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) comprising the amino acid sequence of the CDR of the heavy chain variable region set forth in SEQ ID NO:22 according to AbM numbering; and a light chain variable region comprising CDRs comprising the amino acid sequence of the CDR of the light chain variable region set forth in SEQ ID NO:23 according to AbM numbering.
在其他實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含含根據Chothia編號之SEQ ID NO:22中所闡述之重鏈可變區之CDR之胺基酸序列的CDR (CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3)；及輕鏈可變區，其包含含根據Chothia編號之SEQ ID NO:23中所闡述之輕鏈可變區之CDR之胺基酸序列的CDR。In other embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3) comprising the amino acid sequence of the CDR of the heavy chain variable region set forth in SEQ ID NO:22 according to Chothia numbering; and a light chain variable region comprising CDRs comprising the amino acid sequence of the CDR of the light chain variable region set forth in SEQ ID NO:23 according to Chothia numbering.
在其他實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含含根據Contact編號之SEQ ID NO:22中所闡述之重鏈可變區之CDR之胺基酸序列的CDR (CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3)；及輕鏈可變區，其包含含根據Contact編號之SEQ ID NO:23中所闡述之輕鏈可變區之CDR之胺基酸序列的CDR。In other embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3) comprising the amino acid sequence of the CDR of the heavy chain variable region as set forth in SEQ ID NO:22 according to Contact number; and a light chain variable region comprising CDRs comprising the amino acid sequence of the CDR of the light chain variable region as set forth in SEQ ID NO:23 according to Contact number.
在又其他實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含含根據IMGT編號之SEQ ID NO:22中所闡述之重鏈可變區之CDR之胺基酸序列的CDR (CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3)；及輕鏈可變區，其包含含根據IMGT編號之SEQ ID NO:23中所闡述之輕鏈可變區之CDR之胺基酸序列的CDR。In yet other embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3) comprising the amino acid sequence of the CDR of the heavy chain variable region set forth in SEQ ID NO:22 according to IMGT numbering; and a light chain variable region comprising CDRs comprising the amino acid sequence of the CDR of the light chain variable region set forth in SEQ ID NO:23 according to IMGT numbering.
在一些實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含由根據Kabat編號之SEQ ID NO:22中所闡述之重鏈可變區之CDR之胺基酸序列組成的CDR (CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3)；及輕鏈可變區，其包含由根據Kabat編號之SEQ ID NO:23中所闡述之輕鏈可變區之CDR之胺基酸序列組成的CDR。In some embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3) consisting of the amino acid sequence of the CDR of the heavy chain variable region set forth in SEQ ID NO:22 according to Kabat numbering; and a light chain variable region comprising CDRs consisting of the amino acid sequence of the CDR of the light chain variable region set forth in SEQ ID NO:23 according to Kabat numbering.
在一些實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含由根據AbM編號之SEQ ID NO:22中所闡述之重鏈可變區之CDR之胺基酸序列組成的CDR (CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3)；及輕鏈可變區，其包含由根據AbM編號之SEQ ID NO:23中所闡述之輕鏈可變區之CDR之胺基酸序列組成的CDR。In some embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3) consisting of the amino acid sequence of the CDR of the heavy chain variable region set forth in SEQ ID NO:22 according to AbM numbering; and a light chain variable region comprising CDRs consisting of the amino acid sequence of the CDR of the light chain variable region set forth in SEQ ID NO:23 according to AbM numbering.
在其他實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含由根據Chothia編號之SEQ ID NO:22中所闡述之重鏈可變區之CDR之胺基酸序列組成的CDR (CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3)；及輕鏈可變區，其包含由根據Chothia編號之SEQ ID NO:23中所闡述之輕鏈可變區之CDR之胺基酸序列組成的CDR。In other embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3) consisting of the amino acid sequence of the CDR of the heavy chain variable region set forth in SEQ ID NO:22 according to Chothia numbering; and a light chain variable region comprising CDRs consisting of the amino acid sequence of the CDR of the light chain variable region set forth in SEQ ID NO:23 according to Chothia numbering.
在其他實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含由根據Contact編號之SEQ ID NO:22中所闡述之重鏈可變區之CDR之胺基酸序列組成的CDR (CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3)；及輕鏈可變區，其包含由根據Contact編號之SEQ ID NO:23中所闡述之輕鏈可變區之CDR之胺基酸序列組成的CDR。In other embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3) consisting of the amino acid sequence of the CDR of the heavy chain variable region as set forth in SEQ ID NO:22 according to Contact number; and a light chain variable region comprising CDRs consisting of the amino acid sequence of the CDR of the light chain variable region as set forth in SEQ ID NO:23 according to Contact number.
在又其他實施例中，抗連接素-4抗體或其抗原結合片段包含：重鏈可變區，其包含由根據IMGT編號之SEQ ID NO:22中所闡述之重鏈可變區之CDR之胺基酸序列組成的CDR (CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3)；及輕鏈可變區，其包含由根據IMGT編號之SEQ ID NO:23中所闡述之輕鏈可變區之CDR之胺基酸序列組成的CDR。In yet other embodiments, the anti-nectin-4 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising CDRs (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3) consisting of the amino acid sequence of the CDR of the heavy chain variable region as set forth in SEQ ID NO:22 according to IMGT numbering; and a light chain variable region comprising CDRs consisting of the amino acid sequence of the CDR of the light chain variable region as set forth in SEQ ID NO:23 according to IMGT numbering.
如上文所描述，根據不同編號系統之CDR序列可容易地進行測定，例如使用線上工具，諸如由抗原受體編號及受體分類(Antigen receptor Numbering And Receptor ClassificatIon ；ANARCI)提供之工具。舉例而言，藉由ANARCI所確定，根據Kabat編號的SEQ ID NO:22內之重鏈CDR序列及SEQ ID NO:23內之輕鏈CDR序列列於下表6中。表6
作為另一實例，藉由ANARCI所確定，根據IMGT編號的SEQ ID NO:22內之重鏈CDR序列及SEQ ID NO:23內之輕鏈CDR序列列於下表7中。表7
在一些實施例中，抗體或其抗原結合片段包含：CDR-H1，其包含SEQ ID NO:9之胺基酸序列；CDR-H2，其包含SEQ ID NO:10之胺基酸序列；CDR-H3，其包含SEQ ID NO:11之胺基酸序列；CDR-L1，其包含SEQ ID NO:12之胺基酸序列；CDR-L2，其包含SEQ ID NO:13之胺基酸序列；及CDR-L3，其包含SEQ ID NO:14之胺基酸序列。In some embodiments, the antibody or its antigen-binding fragment comprises: CDR-H1, which comprises the amino acid sequence of SEQ ID NO:9; CDR-H2, which comprises the amino acid sequence of SEQ ID NO:10; CDR-H3, which comprises the amino acid sequence of SEQ ID NO:11; CDR-L1, which comprises the amino acid sequence of SEQ ID NO:12; CDR-L2, which comprises the amino acid sequence of SEQ ID NO:13; and CDR-L3, which comprises the amino acid sequence of SEQ ID NO:14.
在一些實施例中，抗體或其抗原結合片段包含：CDR-H1，其包含SEQ ID NO:16之胺基酸序列；CDR-H2，其包含SEQ ID NO:17之胺基酸序列；CDR-H3，其包含SEQ ID NO:18之胺基酸序列；CDR-L1，其包含SEQ ID NO:19之胺基酸序列；CDR-L2，其包含SEQ ID NO:20之胺基酸序列；及CDR-L3，其包含SEQ ID NO:21之胺基酸序列。In some embodiments, the antibody or its antigen-binding fragment comprises: CDR-H1, which comprises the amino acid sequence of SEQ ID NO: 16; CDR-H2, which comprises the amino acid sequence of SEQ ID NO: 17; CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 18; CDR-L1, which comprises the amino acid sequence of SEQ ID NO: 19; CDR-L2, which comprises the amino acid sequence of SEQ ID NO: 20; and CDR-L3, which comprises the amino acid sequence of SEQ ID NO: 21.
在一些實施例中，抗體或其抗原結合片段包含：CDR-H1，其由SEQ ID NO:9之胺基酸序列組成；CDR-H2，其由SEQ ID NO:10之胺基酸序列組成；CDR-H3，其由SEQ ID NO:11之胺基酸序列組成；CDR-L1，其由SEQ ID NO:12之胺基酸序列組成；CDR-L2，其由SEQ ID NO:13之胺基酸序列組成；及CDR-L3，其由SEQ ID NO:14之胺基酸序列組成。In some embodiments, the antibody or its antigen-binding fragment comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO:9; CDR-H2, which consists of the amino acid sequence of SEQ ID NO:10; CDR-H3, which consists of the amino acid sequence of SEQ ID NO:11; CDR-L1, which consists of the amino acid sequence of SEQ ID NO:12; CDR-L2, which consists of the amino acid sequence of SEQ ID NO:13; and CDR-L3, which consists of the amino acid sequence of SEQ ID NO:14.
在一些實施例中，抗體或其抗原結合片段包含：CDR-H1，其由SEQ ID NO:16之胺基酸序列組成；CDR-H2，其由SEQ ID NO:17之胺基酸序列組成；CDR-H3，其由SEQ ID NO:18之胺基酸序列組成；CDR-L1，其由SEQ ID NO:19之胺基酸序列組成；CDR-L2，其由SEQ ID NO:20之胺基酸序列組成；及CDR-L3，其由SEQ ID NO:21之胺基酸序列組成。In some embodiments, the antibody or its antigen-binding fragment comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 16; CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 17; CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 18; CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 19; CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 20; and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 21.
在一些實施例中，抗體或其抗原結合片段包含含SEQ ID NO:22之胺基酸序列的重鏈可變區及含SEQ ID NO:23之胺基酸序列的輕鏈可變區。In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23.
在一些實施例中，抗體或其抗原結合片段包含由SEQ ID NO:22之胺基酸序列組成的重鏈可變區及由SEQ ID NO:23之胺基酸序列組成的輕鏈可變區。In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO:22 and a light chain variable region consisting of the amino acid sequence of SEQ ID NO:23.
在一些實施例中，抗體包含：重鏈，其包含在SEQ ID NO:7之第20個胺基酸(麩胺酸)至第466個胺基酸(離胺酸)範圍內的胺基酸序列；及輕鏈，其包含在SEQ ID NO:8之第23個胺基酸(天冬胺酸)至第236個胺基酸(半胱胺酸)範圍內的胺基酸序列。In some embodiments, the antibody comprises: a heavy chain comprising an amino acid sequence ranging from the 20th amino acid (glutamine) to the 466th amino acid (lysine) of SEQ ID NO:7; and a light chain comprising an amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8.
在一些實施例中，抗體包含：重鏈，其由在SEQ ID NO:7之第20個胺基酸(麩胺酸)至第466個胺基酸(離胺酸)範圍內之胺基酸序列組成；及輕鏈，其由在SEQ ID NO:8之第23個胺基酸(天冬胺酸)至第236個胺基酸(半胱胺酸)範圍內之胺基酸序列組成。In some embodiments, the antibody comprises: a heavy chain consisting of an amino acid sequence ranging from the 20th amino acid (glutamine) to the 466th amino acid (lysine) of SEQ ID NO:7; and a light chain consisting of an amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8.
在一些實施例中，考慮本文所述抗體之胺基酸序列修飾。舉例而言，可能需要最佳化抗體之結合親和力及/或其他生物特性，包括(但不限於)特異性、熱穩定性、表現量、效應功能、醣基化、降低之免疫原性或溶解性。因此，除本文所述之抗體之外，亦考慮可以製備抗體變異體。舉例而言，抗體變異體可以藉由在編碼DNA中引入適當核苷酸變化及/或藉由合成所需抗體或多肽來製備。熟習此項技術者瞭解，胺基酸變化可改變抗體之轉譯後過程，諸如改變醣基化位點之數目或位置或改變膜錨定特徵。In some embodiments, amino acid sequence modifications of the antibodies described herein are contemplated. For example, it may be desirable to optimize the binding affinity and/or other biological properties of the antibody, including, but not limited to, specificity, thermal stability, expression, effector function, glycosylation, reduced immunogenicity, or solubility. Therefore, in addition to the antibodies described herein, it is also contemplated that antibody variants may be prepared. For example, antibody variants may be prepared by introducing appropriate nucleotide changes in the coding DNA and/or by synthesizing the desired antibody or polypeptide. Those skilled in the art understand that amino acid changes may alter post-translational processes of the antibody, such as altering the number or location of glycosylation sites or altering membrane anchoring characteristics.
在一些實施例中，本文所提供之抗體經化學修飾，例如藉由使任何類型的分子共價連接至抗體。抗體衍生物可包括已經化學修飾之抗體，例如藉由醣基化、乙醯化、聚乙二醇化、磷酸化、醯胺化、藉由已知保護基團/封端基團衍生化、蛋白水解裂解、連接至細胞配位體或其他蛋白質等而經化學修飾之抗體。多種化學修飾中之任一者可藉由已知技術進行，包括(但不限於)特異性化學裂解、乙醯化、甲醯化、衣黴素之代謝合成等。另外，抗體可含有一或多個非經典胺基酸。In some embodiments, the antibodies provided herein are chemically modified, for example, by covalently linking any type of molecule to the antibody. Antibody derivatives may include chemically modified antibodies, for example, by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting groups/capping groups, proteolytic cleavage, linking to cellular ligands or other proteins, etc. Any of a variety of chemical modifications may be performed by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. In addition, the antibody may contain one or more non-classical amino acids.
變異可為與初始抗體或多肽相比，導致胺基酸序列改變的編碼單域抗體或多肽之一或多個密碼子之取代、缺失或插入。胺基酸取代可為一個胺基酸經包含類似結構及/或化學特性之另一胺基酸置換的結果，諸如白胺酸經絲胺酸置換，例如保守胺基酸置換。熟習此項技術者已知的標準技術可用於將突變引入編碼本文提供之分子的核苷酸序列中，包括例如引起胺基酸取代的定點突變誘發及PCR介導突變誘發。插入或缺失視情況可在約1至5個胺基酸範圍內。在某些實施例中，相對於初始分子，取代、缺失或插入包括少於25個胺基酸取代、少於20個胺基酸取代、少於15個胺基酸取代、少於10個胺基酸取代、少於5個胺基酸取代、少於4個胺基酸取代、少於3個胺基酸取代或少於2個胺基酸取代。在一個特定實施例中，取代為在一或多個所預測之非必需胺基酸殘基處產生的保守胺基酸取代。允許發生的變異可如下測定：在序列中系統地產生胺基酸插入、缺失或取代且測試所得變異體是否具有親本抗體所展現的活性。The variation may be a substitution, deletion or insertion of one or more codons encoding a single domain antibody or polypeptide that results in an altered amino acid sequence compared to the original antibody or polypeptide. Amino acid substitution may be the result of replacing one amino acid with another amino acid comprising similar structure and/or chemical properties, such as leucine with serine, for example, conservative amino acid substitution. Standard techniques known to those skilled in the art can be used to introduce mutations into the nucleotide sequence encoding the molecules provided herein, including, for example, site-directed mutagenesis induction and PCR-mediated mutagenesis induction that cause amino acid substitutions. Insertions or deletions may be within the range of about 1 to 5 amino acids, as appropriate. In certain embodiments, substitutions, deletions or insertions include less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions or less than 2 amino acid substitutions relative to the initial molecule. In a specific embodiment, substitutions are conservative amino acid substitutions generated at one or more predicted non-essential amino acid residues. Allowed variations can be determined as follows: amino acid insertions, deletions or substitutions are systematically generated in the sequence and the resulting variants are tested for activity exhibited by the parent antibody.
胺基酸序列插入包括長度在一個殘基至含有多個殘基之多肽範圍內的胺基端及/或羧基端融合，以及單個或多個胺基酸殘基之序列內插入。末端插入之實例包括具有N端甲硫胺醯基殘基之抗體。Amino acid sequence insertions include amino-terminal and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing multiple residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue.
本發明包括藉由保守胺基酸取代產生之抗體。在保守胺基酸取代中，胺基酸殘基經包含具有類似電荷之側鏈的胺基酸殘基置換。如上文所描述，包含具有類似電荷之側鏈之胺基酸殘基之家族已經在此項技術定義。此等家族包括具有鹼性側鏈(例如離胺酸、精胺酸、組胺酸)、酸性側鏈(例如天冬胺酸、麩胺酸)、不帶電極性側鏈(例如甘胺酸、天冬醯胺、麩醯胺酸、絲胺酸、蘇胺酸、酪胺酸、半胱胺酸)、非極性側鏈(例如丙胺酸、纈胺酸、白胺酸、異白胺酸、脯胺酸、苯丙胺酸、甲硫胺酸、色胺酸)、β分支鏈側鏈(例如蘇胺酸、纈胺酸、異白胺酸)及芳族側鏈(例如酪胺酸、苯丙胺酸、色胺酸、組胺酸)之胺基酸。或者，突變可沿著編碼序列之全部或一部分隨機引入，諸如藉由飽和突變誘發，且可根據生物活性篩選所得突變體以鑑別保持活性的突變體。在突變誘發之後，可表現所編碼蛋白質，且可測定蛋白質之活性，可進行保守性(例如在具有類似特性及/或側鏈之胺基酸群組內)取代，以便維持或不顯著地改變特性。The present invention includes antibodies generated by conservative amino acid substitutions. In conservative amino acid substitutions, an amino acid residue is replaced by an amino acid residue comprising a side chain with a similar charge. As described above, families of amino acid residues comprising side chains with similar charges have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamine), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Alternatively, mutations can be introduced randomly along all or part of the coding sequence, such as by saturation mutagenesis, and the resulting mutants can be screened for biological activity to identify mutants that retain activity. Following mutation induction, the encoded protein can be expressed and the activity of the protein can be determined, and conservative substitutions (e.g., within groups of amino acids with similar properties and/or side chains) can be made to maintain or not significantly change the properties.
胺基酸可根據其側鏈特性之相似性分組(參見例如Lehninger, Biochemistry 73-75 (第2版, 1975))：(1)非極性：Ala (A)、Val (V)、Leu (L)、Ile (I)、Pro (P)、Phe (F)、Trp (W)、Met (M)；(2)不帶電荷的極性：Gly (G)、Ser (S)、Thr (T)、Cys (C)、Tyr (Y)、Asn (N)、Gln (Q)；(3)酸性：Asp (D)、Glu (E)；及(4)鹼性：Lys (K)、Arg (R)、His (H)。或者，天然存在的殘基可以基於共同的側鏈特性來分組：(1)疏水性：正白胺酸、Met、Ala、Val、Leu、Ile；(2)中性、親水性：Cys、Ser、Thr、Asn、Gln；(3)酸性：Asp、Glu；(4)鹼性：His、Lys、Arg；(5)影響鏈取向的殘基：Gly、Pro；及(6)芳族：Trp、Tyr、Phe。Amino acids can be grouped according to the similarity of their side chain properties (see, e.g., Lehninger, Biochemistry 73-75 (2nd ed., 1975)): (1) nonpolar: Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M); (2) uncharged polar: Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q); (3) acidic: Asp (D), Glu (E); and (4) basic: Lys (K), Arg (R), His (H). Alternatively, naturally occurring residues can be grouped based on common side chain properties: (1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) neutral, hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues affecting chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.
舉例而言，不參與維持抗體適當構形的任何半胱胺酸殘基亦可用例如另一胺基酸(諸如丙胺酸或絲胺酸)取代，以改良分子的氧化穩定性及防止異常交聯。For example, any cysteine residue that is not involved in maintaining the proper conformation of the antibody may also be substituted with, for example, another amino acid (such as alanine or serine) to improve the oxidative stability of the molecule and prevent aberrant cross-linking.
可使用此項技術中已知之方法產生變異，諸如寡核苷酸介導(定點)突變誘發、丙胺酸掃描及PCR突變誘發。可對所選殖的DNA進行定點突變誘發(參見例如Carter, 1986, Biochem J. 237:1-7；及Zoller等人, 1982, Nucl. Acids Res. 10:6487-500)、卡匣突變誘發(參見例如Wells等人, 1985, Gene 34:315-23)或其他已知技術，以產生抗-抗MSLN抗體變異體DNA。Variants can be generated using methods known in the art, such as oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR mutagenesis. The selected DNA can be subjected to site-directed mutagenesis (see, e.g., Carter, 1986, Biochem J. 237:1-7; and Zoller et al., 1982, Nucl. Acids Res. 10:6487-500), cassette mutagenesis (see, e.g., Wells et al., 1985, Gene 34:315-23), or other known techniques to generate anti-anti-MSLN antibody variant DNA.
本發明之範疇內包括抗體之共價修飾。共價修飾包括使抗體之目標胺基酸殘基與有機衍生劑反應，該有機衍生劑能夠與抗體之所選側鏈或N端或C端殘基反應。其他修飾包括麩醯胺醯基及天冬醯胺醯基殘基分別去醯胺化為對應麩胺醯基及天冬胺醯基殘基；脯胺酸及離胺酸之羥基化；絲胺醯基或蘇胺醯基殘基之羥基磷酸化；離胺酸、精胺酸及組胺酸側鏈之α-胺基之甲基化(參見例如Creighton, Proteins: Structure and Molecular Properties 79-86 (1983))；N端胺之乙醯化；及任何C端羧基之醯胺化。The scope of the present invention includes covalent modification of antibodies. Covalent modification includes reacting targeted amino acid residues of the antibody with an organic derivatizing agent that is capable of reacting with selected side chain or N-terminal or C-terminal residues of the antibody. Other modifications include deamidation of glutamido and asparaginyl residues to the corresponding glutamido and asparaginyl residues, respectively; hydroxylation of proline and lysine; hydroxyphosphorylation of seramido or threonine residues; methylation of the α-amine groups of lysine, arginine, and histidine side chains (see, e.g., Creighton, Proteins: Structure and Molecular Properties 79-86 (1983)); acetylation of the N-terminal amine; and acylation of any C-terminal carboxyl group.
本發明範疇內所包括之抗體之其他類型的共價修飾包括改變抗體或多肽之原生醣基化模式(參見例如Beck等人, 2008, Curr. Pharm. Biotechnol. 9:482-501；及Walsh, 2010, Drug Discov. Today 15:773-80)，及以例如以下文獻中所闡述之方式使抗體與多種非蛋白性聚合物(例如聚乙二醇(PEG)、聚丙二醇或聚氧化烯)之一連接：美國專利第4,640,835號、第4,496,689號、第4,301,144號、第4,670,417號、第4,791,192號或第4,179,337號。Other types of covalent modifications of antibodies included within the scope of the invention include altering the native glycosylation pattern of the antibody or polypeptide (see, e.g., Beck et al., 2008, Curr. Pharm. Biotechnol. 9:482-501; and Walsh, 2010, Drug Discov. Today 15:773-80), and linking the antibody to one of a variety of nonproteinaceous polymers (e.g., polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes) in a manner such as described in U.S. Pat. Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192, or 4,179,337.
在某些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:7中所闡述之重鏈具有一定同源性或一致性的重鏈及與如SEQ ID NO:8中所闡述之輕鏈具有一定同源性或一致性的輕鏈。具有同源性或一致性之重鏈/輕鏈的此類實施例進一步提供如下。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:7中所闡述之重鏈具有大於70%同源性或一致性的重鏈。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:7中所闡述之重鏈具有大於75%同源性或一致性的重鏈。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:7中所闡述之重鏈具有大於80%同源性或一致性的重鏈。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:7中所闡述之重鏈具有大於85%同源性或一致性的重鏈。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:7中所闡述之重鏈具有大於90%同源性或一致性的重鏈。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:7中所闡述之重鏈具有大於95%同源性或一致性的重鏈。在某些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:7中所闡述之重鏈具有所提供之任一種同源性或一致性的重鏈，其中CDR (CDR-H1、CDR-H2及CDR-H3)與如SEQ ID NO:7中所闡述之重鏈中的CDR一致。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:8中所闡述之輕鏈具有大於70%同源性或一致性的輕鏈。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:8中所闡述之輕鏈具有大於75%同源性或一致性的輕鏈。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:8中所闡述之輕鏈具有大於80%同源性或一致性的輕鏈。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:8中所闡述之輕鏈具有大於85%同源性或一致性的輕鏈。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:8中所闡述之輕鏈具有大於90%同源性或一致性的輕鏈。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:8中所闡述之輕鏈具有大於95%同源性或一致性的輕鏈。在某些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:8中所闡述之輕鏈具有所提供之任一種同源性或一致性的輕鏈，其中CDR (CDR-L1、CDR-L2及CDR-L3)與如SEQ ID NO:8中所闡述之輕鏈中的CDR一致。在某些實施例中，本文所提供之抗體或抗原結合片段包含如此段落中所提供之任何同源輕鏈與任何同源重鏈的任何組合或排列。In certain embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain having a certain homology or identity to the heavy chain as described in SEQ ID NO:7 and a light chain having a certain homology or identity to the light chain as described in SEQ ID NO:8. Such embodiments of heavy/light chains having homology or identity are further provided as follows. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain having greater than 70% homology or identity to the heavy chain as described in SEQ ID NO:7. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain having greater than 75% homology or identity to the heavy chain as described in SEQ ID NO:7. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain having greater than 80% homology or identity to the heavy chain as set forth in SEQ ID NO: 7. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain having greater than 85% homology or identity to the heavy chain as set forth in SEQ ID NO: 7. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain having greater than 90% homology or identity to the heavy chain as set forth in SEQ ID NO: 7. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain having greater than 95% homology or identity to the heavy chain as set forth in SEQ ID NO: 7. In certain embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain having any of the provided homologies or identities to the heavy chain as set forth in SEQ ID NO: 7, wherein the CDRs (CDR-H1, CDR-H2, and CDR-H3) are identical to the CDRs in the heavy chain as set forth in SEQ ID NO: 7. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain having greater than 70% homology or identity to the light chain as set forth in SEQ ID NO: 8. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain having greater than 75% homology or identity to the light chain as set forth in SEQ ID NO: 8. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain having greater than 80% homology or identity to the light chain as described in SEQ ID NO: 8. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain having greater than 85% homology or identity to the light chain as described in SEQ ID NO: 8. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain having greater than 90% homology or identity to the light chain as described in SEQ ID NO: 8. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain having greater than 95% homology or identity to the light chain as described in SEQ ID NO: 8. In certain embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain having any of the provided homologies or identities to the light chain as set forth in SEQ ID NO: 8, wherein the CDRs (CDR-L1, CDR-L2, and CDR-L3) are identical to the CDRs in the light chain as set forth in SEQ ID NO: 8. In certain embodiments, the antibodies or antigen-binding fragments provided herein comprise any combination or arrangement of any homologous light chain and any homologous heavy chain as provided in this paragraph.
在某些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:22中所闡述之重鏈可變區具有一定同源性或一致性的重鏈可變區及與如SEQ ID NO:23中所闡述之輕鏈可變區具有一定同源性或一致性的輕鏈可變區。具有同源性或一致性之重鏈可變區及輕鏈可變區的此類實施例進一步提供如下。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:22中所闡述之重鏈可變區具有大於70%同源性或一致性的重鏈可變區。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:22中所闡述之重鏈可變區具有大於75%同源性或一致性的重鏈可變區。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:22中所闡述之重鏈可變區具有大於80%同源性或一致性的重鏈可變區。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:22中所闡述之重鏈可變區具有大於85%同源性或一致性的重鏈可變區。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:22中所闡述之重鏈可變區具有大於90%同源性或一致性的重鏈可變區。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:22中所闡述之重鏈可變區具有大於95%同源性或一致性的重鏈可變區。在某些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:22中所闡述之重鏈可變區具有所提供之任一種同源性或一致性的重鏈可變區，其中CDR (CDR-H1、CDR-H2及CDR-H3)與如SEQ ID NO:22中所闡述之重鏈可變區中的CDR一致。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:23中所闡述之輕鏈可變區具有大於70%同源性或一致性的輕鏈可變區。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:23中所闡述之輕鏈可變區具有大於75%同源性或一致性的輕鏈可變區。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:23中所闡述之輕鏈可變區具有大於80%同源性或一致性的輕鏈可變區。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:23中所闡述之輕鏈可變區具有大於85%同源性或一致性的輕鏈可變區。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:23中所闡述之輕鏈可變區具有大於90%同源性或一致性的輕鏈可變區。在一些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:23中所闡述之輕鏈可變區具有大於95%同源性或一致性的輕鏈可變區。在某些實施例中，本文所提供之抗體或抗原結合片段包含與如SEQ ID NO:23中所闡述之輕鏈可變區具有所提供之任一種同源性或一致性的輕鏈可變區，其中CDR (CDR-L1、CDR-L2及CDR-L3)與如SEQ ID NO:23中所闡述之輕鏈可變區中的CDR一致。在某些實施例中，本文所提供之抗體或抗原結合片段包含如此段落中所提供之任何同源輕鏈可變區與任何同源重鏈可變區的任何組合或排列。In certain embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain variable region having a certain homology or identity with the heavy chain variable region as described in SEQ ID NO: 22 and a light chain variable region having a certain homology or identity with the light chain variable region as described in SEQ ID NO: 23. Such embodiments of heavy chain variable regions and light chain variable regions having homology or identity are further provided as follows. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain variable region having greater than 70% homology or identity with the heavy chain variable region as described in SEQ ID NO: 22. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain variable region having greater than 75% homology or identity with the heavy chain variable region as described in SEQ ID NO: 22. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain variable region having greater than 80% homology or identity to the heavy chain variable region as set forth in SEQ ID NO: 22. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain variable region having greater than 85% homology or identity to the heavy chain variable region as set forth in SEQ ID NO: 22. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain variable region having greater than 90% homology or identity to the heavy chain variable region as set forth in SEQ ID NO: 22. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain variable region having greater than 95% homology or identity to the heavy chain variable region as set forth in SEQ ID NO: 22. In certain embodiments, the antibodies or antigen-binding fragments provided herein comprise a heavy chain variable region having any of the provided homologies or identities to the heavy chain variable region as set forth in SEQ ID NO: 22, wherein the CDRs (CDR-H1, CDR-H2, and CDR-H3) are identical to the CDRs in the heavy chain variable region as set forth in SEQ ID NO: 22. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain variable region having greater than 70% homology or identity to the light chain variable region as set forth in SEQ ID NO: 23. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain variable region having greater than 75% homology or identity to the light chain variable region as set forth in SEQ ID NO: 23. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain variable region having greater than 80% homology or identity to the light chain variable region as set forth in SEQ ID NO: 23. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain variable region having greater than 85% homology or identity to the light chain variable region as set forth in SEQ ID NO: 23. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain variable region having greater than 90% homology or identity to the light chain variable region as set forth in SEQ ID NO: 23. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain variable region having greater than 95% homology or identity to the light chain variable region as set forth in SEQ ID NO: 23. In certain embodiments, the antibodies or antigen-binding fragments provided herein comprise a light chain variable region having any of the provided homologies or identities to the light chain variable region as set forth in SEQ ID NO: 23, wherein the CDRs (CDR-L1, CDR-L2, and CDR-L3) are identical to the CDRs in the light chain variable region as set forth in SEQ ID NO: 23. In certain embodiments, the antibodies or antigen-binding fragments provided herein comprise any combination or arrangement of any cognate light chain variable region and any cognate heavy chain variable region as provided in this paragraph.
在一些實施例中，本文所提供之抗連接素-4抗體包含以登錄號：PTA-11267寄存於美國菌種保藏中心(American Type Culture Collection，ATCC)之融合瘤所產生的稱為Ha22-2(2,4)6.1之抗體的重鏈及輕鏈CDR區，或胺基酸序列與Ha22-2(2,4)6.1之重鏈及輕鏈CDR區之胺基酸序列同源的重鏈及輕鏈CDR區，且其中抗體保持以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之稱為Ha22-2(2,4)6.1之抗連接素-4抗體的所需功能特性。In some embodiments, the anti-nexin-4 antibodies provided herein comprise the heavy chain and light chain CDR regions of the antibody called Ha22-2(2,4)6.1 produced by the fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267, or the heavy chain and light chain CDR regions whose amino acid sequences are homologous to the amino acid sequences of the heavy chain and light chain CDR regions of Ha22-2(2,4)6.1, and wherein the antibody retains the desired functional properties of the anti-nexin-4 antibody called Ha22-2(2,4)6.1 produced by the fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267.
在一些實施例中，本文所提供之抗連接素-4抗體包含以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之稱為Ha22-2(2,4)6.1之抗體的重鏈及輕鏈CDR區(CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3)，或由與Ha22-2(2,4)6.1之重鏈及輕鏈CDR區之胺基酸序列同源的胺基酸序列組成的重鏈及輕鏈CDR區，且其中抗體保持以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之稱為Ha22-2(2,4)6.1之抗連接素-4抗體的所需功能特性。In some embodiments, the anti-nexin-4 antibodies provided herein comprise the heavy chain and light chain CDR regions (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3) of the antibody called Ha22-2(2,4)6.1 produced by the fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267, or the heavy chain and light chain CDR regions consisting of amino acid sequences homologous to the amino acid sequences of the heavy chain and light chain CDR regions of Ha22-2(2,4)6.1, and wherein the antibody retains the desired functional properties of the anti-nexin-4 antibody called Ha22-2(2,4)6.1 produced by the fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267.
在一些實施例中，本文所提供之抗體或其抗原結合片段包含人源化重鏈可變區及人源化輕鏈可變區，其中： (a)重鏈可變區包含CDR (CDR-H1、CDR-H2及CDR-H3)，該等CDR包含以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體中所示的重鏈可變區CDR胺基酸序列； (b)輕鏈可變區包含CDR (CDR-L1、CDR-L2及CDR-L3)，該等CDR包含以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體中所示的輕鏈可變區CDR胺基酸序列。In some embodiments, the antibodies or antigen-binding fragments thereof provided herein comprise a humanized heavy chain variable region and a humanized light chain variable region, wherein:(a) the heavy chain variable region comprises CDRs (CDR-H1, CDR-H2, and CDR-H3), wherein the CDRs comprise the heavy chain variable region CDR amino acid sequences shown in an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under the accession number: PTA-11267;(b) the light chain variable region comprises CDRs (CDR-L1, CDR-L2, and CDR-L3), wherein the CDRs comprise the light chain variable region CDR amino acid sequences shown in an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under the accession number: PTA-11267.
在一些實施例中，本文所提供之抗體或其抗原結合片段包含人源化重鏈可變區及人源化輕鏈可變區，其中： (a)重鏈可變區包含CDR (CDR-H1、CDR-H2及CDR-H3)，該等CDR由以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體中所示的重鏈可變區CDR胺基酸序列組成； (b)輕鏈可變區包含CDR (CDR-L1、CDR-L2及CDR-L3)，該等CDR由以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體中所示的輕鏈可變區CDR胺基酸序列組成。In some embodiments, the antibodies or antigen-binding fragments thereof provided herein comprise a humanized heavy chain variable region and a humanized light chain variable region, wherein:(a) the heavy chain variable region comprises CDRs (CDR-H1, CDR-H2, and CDR-H3), which are composed of the heavy chain variable region CDR amino acid sequences shown in the antibody produced by the fusion tumor deposited with the American Type Culture Collection (ATCC) under the accession number: PTA-11267;(b) the light chain variable region comprises CDRs (CDR-L1, CDR-L2, and CDR-L3), which are composed of the light chain variable region CDR amino acid sequences shown in the antibody produced by the fusion tumor deposited with the American Type Culture Collection (ATCC) under the accession number: PTA-11267.
在一些實施例中，本文所提供之抗連接素-4抗體包含以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之稱為Ha22-2(2,4)6.1之抗體的重鏈及輕鏈可變區，或胺基酸序列與Ha22-2(2,4)6.1之重鏈及輕鏈可變區之胺基酸序列同源的重鏈及輕鏈可變區，且其中該等抗體保持本文所提供之抗連接素-4抗體的所需功能特性。在一些實施例中，本文所提供之抗連接素-4抗體包含以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之稱為Ha22-2(2,4)6.1之抗體的重鏈及輕鏈可變區，或由與Ha22-2(2,4)6.1之重鏈及輕鏈可變區之胺基酸序列同源之胺基酸序列組成的重鏈及輕鏈可變區，且其中該等抗體保持本文所提供之抗連接素-4抗體的所需功能特性。可選擇恆定區之任何子類作為本發明抗體之恆定區。在一個實施例中，可使用人類IgG1恆定區作為重鏈恆定區且使用人類Igκ恆定區作為輕鏈恆定區。In some embodiments, the anti-nexin-4 antibodies provided herein comprise the heavy chain and light chain variable regions of the antibody called Ha22-2(2,4)6.1 produced by the hybridoma deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267, or the heavy chain and light chain variable regions whose amino acid sequences are homologous to the heavy chain and light chain variable regions of Ha22-2(2,4)6.1, and wherein the antibodies retain the desired functional properties of the anti-nexin-4 antibodies provided herein. In some embodiments, the anti-nexin-4 antibodies provided herein comprise the heavy chain and light chain variable regions of an antibody called Ha22-2(2,4)6.1 produced by a hybridoma deposited with the American Type Culture Collection (ATCC) under the accession number PTA-11267, or heavy chain and light chain variable regions composed of amino acid sequences homologous to the amino acid sequences of the heavy chain and light chain variable regions of Ha22-2(2,4)6.1, and wherein the antibodies retain the desired functional properties of the anti-nexin-4 antibodies provided herein. Any subclass of constant regions can be selected as the constant region of the antibodies of the present invention. In one embodiment, a human IgG1 constant region can be used as a heavy chain constant region and a human Igκ constant region can be used as a light chain constant region.
在一些實施例中，本文所提供之抗連接素-4抗體包含以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之稱為Ha22-2(2,4)6.1之抗體的重鏈及輕鏈，或胺基酸序列與Ha22-2(2,4)6.1之重鏈及輕鏈之胺基酸序列同源的重鏈及輕鏈，且其中該等抗體保持本文所提供之抗連接素-4抗體的所需功能特性。在一些實施例中，本文所提供之抗連接素-4抗體包含以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之稱為Ha22-2(2,4)6.1之抗體的重鏈及輕鏈，或由與Ha22-2(2,4)6.1之重鏈及輕鏈胺基酸序列同源之胺基酸序列組成的重鏈及輕鏈，且其中該等抗體保持本文所提供之抗連接素-4抗體的所需功能特性。In some embodiments, the anti-nexin-4 antibodies provided herein comprise the heavy chain and light chain of the antibody called Ha22-2(2,4)6.1 produced by the hybridoma deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267, or the heavy chain and light chain whose amino acid sequences are homologous to the heavy chain and light chain of Ha22-2(2,4)6.1, and wherein the antibodies retain the desired functional properties of the anti-nexin-4 antibodies provided herein. In some embodiments, the anti-nexin-4 antibodies provided herein comprise the heavy chain and light chain of the antibody called Ha22-2(2,4)6.1 produced by the hybridoma deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267, or the heavy chain and light chain composed of amino acid sequences homologous to the heavy chain and light chain amino acid sequences of Ha22-2(2,4)6.1, and wherein the antibodies retain the desired functional properties of the anti-nexin-4 antibodies provided herein.
在一些實施例中，本文所提供之抗體或其抗原結合片段包含重鏈可變區及輕鏈可變區，其中： (a)該重鏈可變區包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的重鏈可變區胺基酸序列至少80%同源或一致的胺基酸序列；且 (b)該輕鏈可變區包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的輕鏈可變區胺基酸序列至少80%同源或一致的胺基酸序列。In some embodiments, the antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region and a light chain variable region, wherein:(a) the heavy chain variable region comprises an amino acid sequence that is at least 80% homologous or identical to the amino acid sequence of the heavy chain variable region of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267; and(b) the light chain variable region comprises an amino acid sequence that is at least 80% homologous or identical to the amino acid sequence of the light chain variable region of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267.
在某些實施例中，本文所提供之抗體或抗原結合片段包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的重鏈可變區胺基酸序列具有一定同源性或一致性的重鏈可變區，及與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的輕鏈可變區胺基酸序列具有一定同源性或一致性的輕鏈可變區。具有同源性或一致性之重鏈可變區及輕鏈可變區的此類實施例進一步提供如下。在一些實施例中，重鏈可變區包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的重鏈可變區胺基酸序列至少85%同源或一致的胺基酸序列。在其他實施例中，重鏈可變區包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的重鏈可變區胺基酸序列至少90%同源或一致的胺基酸序列。在又其他實施例中，重鏈可變區包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的重鏈可變區胺基酸序列至少95%同源或一致的胺基酸序列。在其他實施例中，重鏈可變區可與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的重鏈可變區胺基酸序列85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同源或一致。在一些實施例中，輕鏈可變區包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的輕鏈可變區胺基酸序列至少85%同源或一致的胺基酸序列。在其他實施例中，輕鏈可變區包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的輕鏈可變區胺基酸序列至少90%同源或一致的胺基酸序列。在又其他實施例中，輕鏈可變區包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的輕鏈可變區胺基酸序列至少95%同源或一致的胺基酸序列。在其他實施例中，輕鏈可變區可與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的輕鏈可變區胺基酸序列85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同源或一致。在某些實施例中，本文所提供之抗體或抗原結合片段包含如此段落中所提供之任何同源輕鏈可變區與任何同源重鏈可變區的任何組合或排列。In certain embodiments, the antibodies or antigen-binding fragments provided herein include a heavy chain variable region having a certain homology or identity with the heavy chain variable region amino acid sequence of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267, and a light chain variable region having a certain homology or identity with the light chain variable region amino acid sequence of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. Such embodiments of heavy chain variable regions and light chain variable regions having homology or identity are further provided as follows. In some embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 85% homologous or consistent with the amino acid sequence of the heavy chain variable region of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In other embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 90% homologous or consistent with the amino acid sequence of the heavy chain variable region of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In yet other embodiments, the heavy chain variable region comprises an amino acid sequence that is at least 95% homologous or consistent with the amino acid sequence of the heavy chain variable region of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In other embodiments, the heavy chain variable region may be 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous or identical to the heavy chain variable region amino acid sequence of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In some embodiments, the light chain variable region comprises an amino acid sequence that is at least 85% homologous or identical to the light chain variable region amino acid sequence of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In other embodiments, the light chain variable region comprises an amino acid sequence that is at least 90% homologous or identical to the amino acid sequence of the light chain variable region of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In yet other embodiments, the light chain variable region comprises an amino acid sequence that is at least 95% homologous or identical to the amino acid sequence of the light chain variable region of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In other embodiments, the light chain variable region may be 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous or identical to the light chain variable region amino acid sequence of the antibody produced by the fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In certain embodiments, the antibodies or antigen-binding fragments provided herein include any combination or arrangement of any homologous light chain variable region and any homologous heavy chain variable region as provided in this paragraph.
在其他實施例中，本文提供之抗體或其抗原結合片段包含重鏈及輕鏈，其中： (a)該重鏈包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的重鏈胺基酸序列至少80%同源或一致的胺基酸序列；且 (b)該輕鏈包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的輕鏈胺基酸序列至少80%同源或一致的胺基酸序列。In other embodiments, the antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain and a light chain, wherein:(a) the heavy chain comprises an amino acid sequence that is at least 80% homologous or identical to the heavy chain amino acid sequence of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267; and(b) the light chain comprises an amino acid sequence that is at least 80% homologous or identical to the light chain amino acid sequence of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267.
在某些實施例中，本文所提供之抗體或抗原結合片段包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的重鏈胺基酸序列具有一定同源性或一致性的重鏈，及與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的輕鏈胺基酸序列具有一定同源性或一致性的輕鏈。具有同源性或一致性之重鏈及輕鏈的此類實施例進一步提供如下。在一些實施例中，重鏈包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的重鏈胺基酸序列至少85%同源或一致的胺基酸序列。在其他實施例中，重鏈包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的重鏈胺基酸序列至少90%同源或一致的胺基酸序列。在又其他實施例中，重鏈包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的重鏈胺基酸序列至少95%同源或一致的胺基酸序列。在其他實施例中，重鏈可與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的重鏈胺基酸序列85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同源或一致。在一些實施例中，輕鏈包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的輕鏈胺基酸序列至少85%同源或一致的胺基酸序列。在其他實施例中，輕鏈包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的輕鏈胺基酸序列至少90%同源或一致的胺基酸序列。在又其他實施例中，輕鏈包含與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的輕鏈胺基酸序列至少95%同源或一致的胺基酸序列。在其他實施例中，輕鏈可與以登錄號：PTA-11267寄存於美國菌種保藏中心(ATCC)之融合瘤所產生之抗體的輕鏈胺基酸序列85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同源或一致。在某些實施例中，本文所提供之抗體或抗原結合片段包含如此段落中所提供之任何同源輕鏈與任何同源重鏈的任何組合或排列。In certain embodiments, the antibodies or antigen-binding fragments provided herein include a heavy chain having a certain homology or consistency with the heavy chain amino acid sequence of an antibody produced by a fusion tumor deposited at the American Type Culture Collection (ATCC) with accession number: PTA-11267, and a light chain having a certain homology or consistency with the light chain amino acid sequence of an antibody produced by a fusion tumor deposited at the American Type Culture Collection (ATCC) with accession number: PTA-11267. Such embodiments of heavy chains and light chains with homology or consistency are further provided as follows. In some embodiments, the heavy chain includes an amino acid sequence that is at least 85% homologous or consistent with the heavy chain amino acid sequence of an antibody produced by a fusion tumor deposited at the American Type Culture Collection (ATCC) with accession number: PTA-11267. In other embodiments, the rechain comprises an amino acid sequence that is at least 90% homologous or identical to the heavy chain amino acid sequence of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In yet other embodiments, the rechain comprises an amino acid sequence that is at least 95% homologous or identical to the heavy chain amino acid sequence of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In other embodiments, the heavy chain may be 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous or identical to the heavy chain amino acid sequence of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In some embodiments, the light chain comprises an amino acid sequence that is at least 85% homologous or identical to the light chain amino acid sequence of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In other embodiments, the light chain comprises an amino acid sequence that is at least 90% homologous or identical to the light chain amino acid sequence of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In yet other embodiments, the light chain comprises an amino acid sequence that is at least 95% homologous or identical to the amino acid sequence of the light chain of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In other embodiments, the light chain may be 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous or identical to the amino acid sequence of the light chain of an antibody produced by a fusion tumor deposited with the American Type Culture Collection (ATCC) under Accession No.: PTA-11267. In certain embodiments, the antibodies or antigen-binding fragments provided herein include any combination or arrangement of any homologous light chain and any homologous heavy chain as provided in this paragraph.
在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12中之特定抗原決定基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之VC1域。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之VC1域，但不結合至C1C2域。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第1個至第147個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至位於191P4D12之第1個至第147個胺基酸殘基中的抗原決定基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第1個至第10個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第11個至第20個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第21個至第30個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第31個至第40個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第41個至第50個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第51個至第60個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第61個至第70個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第71個至第80個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第81個至第90個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第91個至第100個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第101個至第110個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第111個至第120個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第121個至第130個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第131個至第140個胺基酸殘基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12之第141個至第147個胺基酸殘基。本文所提供之抗體或其抗原結合片段之某些實施例的結合抗原決定基已加以測定且描述於WO 2012/047724中，該文獻以全文引用的方式併入本文中。In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to a specific antigenic determinant in 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the VC1 domain of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the VC1 domain of 191P4D12, but do not bind to the C1C2 domain. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 1st to 147th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to an antigenic determinant located in the 1st to 147th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 1st to 10th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 11th to 20th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 21st to 30th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 31st to 40th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 41st to 50th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 51st to 60th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 61st to 70th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 71st to 80th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 81st to 90th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 91st to 100th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 101st to 110th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 111th to 120th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 121st to 130th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 131st to 140th amino acid residues of 191P4D12. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to the 141st to 147th amino acid residues of 191P4D12. The binding antigenic determinants of certain embodiments of the antibodies or antigen-binding fragments thereof provided herein have been determined and described in WO 2012/047724, which is incorporated herein by reference in its entirety.
在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12中之抗原決定基，該等抗原決定基為人體中所觀測之191P4D12變異體之間共同的抗原決定基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12中的抗原決定基，該等抗原決定基為人體中所觀測到之191P4D12多態性之間共同的抗原決定基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12中的抗原決定基，該等抗原決定基為人類癌症中所觀測到之191P4D12多態性之間共同的抗原決定基。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12中的抗原決定基，從而結合、內化、破壞或調節191P4Dl2或191P4D12變異體的生物功能。在一些實施例中，本文所提供之抗體或其抗原結合片段結合至191P4D12中的抗原決定基，從而破壞191P4D12與配位體、受質及結合搭配物之間的相互作用。In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to an antigenic determinant in 191P4D12 that is common among 191P4D12 variants observed in humans. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to an antigenic determinant in 191P4D12 that is common among 191P4D12 polymorphisms observed in humans. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to an antigenic determinant in 191P4D12 that is common among 191P4D12 polymorphisms observed in human cancers. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to an antigenic determinant in 191P4D12, thereby binding, internalizing, disrupting or modulating the biological function of 191P4D12 or a 191P4D12 variant. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein bind to an antigenic determinant in 191P4D12, thereby disrupting the interaction between 191P4D12 and a ligand, substrate, or binding partner.
本文所提供的經工程改造之抗體包括已對VH及/或VL內之構架殘基進行修飾(例如以改良抗體之特性)的抗體。通常，進行此類構架修飾以降低抗體之免疫原性。舉例而言，一種方法為使一或多個構架殘基「回復突變」成相應生殖系序列。更特定而言，已經歷體細胞突變之抗體可含有與衍生抗體之生殖系序列不同的構架殘基。此類殘基可藉由比較抗體構架序列與衍生抗體之生殖系序列來鑑別。為了使構架區序列恢復其生殖系組態，體細胞突變可藉由例如定點突變誘發或PCR介導之突變誘發而「回復突變」成生殖系序列(例如白胺酸「回復突變」成甲硫胺酸)。本發明亦意欲涵蓋此類「回復突變」抗體。The engineered antibodies provided herein include antibodies to which the framework residues in VH and/or VL have been modified (e.g., to improve the properties of the antibody). Typically, such framework modifications are performed to reduce the immunogenicity of the antibody. For example, one method is to "revert mutation" of one or more framework residues to the corresponding germline sequence. More specifically, an antibody that has undergone somatic cell mutation may contain framework residues that are different from the germline sequence of the derived antibody. Such residues can be identified by comparing the antibody framework sequence with the germline sequence of the derived antibody. In order to restore the germline configuration of the framework region sequence, somatic cell mutations can be "reverted mutation" to the germline sequence (e.g., leucine "reverts mutation" to methionine) by, for example, site-directed mutagenesis induction or PCR-mediated mutagenesis induction. The present invention is also intended to encompass such "reverted mutation" antibodies.
另一類型之構架修飾涉及使構架區內或甚至一或多個CDR區內之一或多個殘基突變，以移除T細胞抗原決定基，以藉此降低抗體之潛在免疫原性。此方法亦稱為「去免疫」，且進一步詳細描述於Carr等人之美國專利公開案第2003/0153043號中。Another type of framework modification involves mutating one or more residues within the framework region or even within one or more CDR regions to remove T cell antigenic determinants to thereby reduce the potential immunogenicity of the antibody. This approach is also known as "deimmunization" and is further described in detail in U.S. Patent Publication No. 2003/0153043 to Carr et al.
除在構架或CDR區內達成修飾之外或作為其替代方式，可對本發明之抗體進行工程改造以將修飾納入Fc區內，從而典型地改變抗體的一或多種功能特性，諸如血清半衰期、補體結合、Fc受體結合，及/或抗原依賴性細胞的細胞毒性。另外，本文所提供之抗191P4D12抗體可經化學修飾(例如一或多個化學部分可連接至抗體)或經修飾以改變其醣基化，從而再次改變抗體之一或多種功能特性。此等實施例各進一步詳細描述於下文中。In addition to or as an alternative to modifications in the framework or CDR regions, the antibodies of the present invention may be engineered to incorporate modifications into the Fc region, thereby typically changing one or more functional properties of the antibody, such as serum half-life, complement binding, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity. In addition, the anti-191P4D12 antibodies provided herein may be chemically modified (e.g., one or more chemical moieties may be attached to the antibody) or modified to alter its glycosylation, thereby again changing one or more functional properties of the antibody. Each of these embodiments is described in further detail below.
在一個實施例中，CH1之鉸鏈區經修飾以使得鉸鏈區中之半胱胺酸殘基數目改變，例如增加或減少。此方法進一步描述於Bodmer等人之美國專利第5,677,425號中。改變CH1鉸鏈區中之半胱胺酸殘基數目，以例如促進輕鏈及重鏈之組裝或增加或降低抗191P4D12抗體之穩定性。In one embodiment, the hinge region of CH1 is modified so that the number of cysteine residues in the hinge region is changed, for example, increased or decreased. This method is further described in U.S. Patent No. 5,677,425 to Bodmer et al. The number of cysteine residues in the hinge region of CH1 is changed, for example, to promote the assembly of the light chain and the heavy chain or to increase or decrease the stability of the anti-191P4D12 antibody.
在另一實施例中，抗體之Fc鉸鏈區經突變以縮短抗191P4D12抗體之生物半衰期。更特定言之，將一或多個胺基酸突變引入Fc鉸鏈片段之CH2-CH3域界面區以使得抗體對葡萄球菌蛋白A (SpA)的結合相對於原生Fc鉸鏈域SpA結合減弱。此方法進一步詳細描述於Ward等人之美國專利第6,165,745號中。In another embodiment, the Fc hinge region of the antibody is mutated to shorten the biological half-life of the anti-191P4D12 antibody. More specifically, one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc hinge fragment so that the antibody binds to Staphylococcal protein A (SpA) attenuated relative to native Fc hinge domain SpA binding. This method is further described in detail in U.S. Patent No. 6,165,745 to Ward et al.
在另一實施例中，抗191P4D12抗體經修飾以延長其生物半衰期。可執行多種方法。舉例而言，可如Ward之美國專利第6,277,375號中所描述，引入突變。或者，為了延長生物半衰期，可在抗體的CH1或CL區內進行改變以含有獲自IgG之Fc區之CH2域之兩個環的救助受體結合抗原決定基，如Presta等人之美國專利第5,869,046號及第6,121,022號中所述。In another embodiment, the anti-191P4D12 antibody is modified to extend its biological half-life. A variety of methods can be performed. For example, mutations can be introduced as described in Ward's U.S. Patent No. 6,277,375. Alternatively, in order to extend the biological half-life, changes can be made in the CH1 or CL region of the antibody to contain salvage receptor binding antigenic determinants obtained from two loops of the CH2 domain of the Fc region of IgG, as described in Presta et al. U.S. Patent Nos. 5,869,046 and 6,121,022.
在又其他實施例中，藉由用不同胺基酸殘基置換至少一個胺基酸殘基來改變Fc區，以改變抗體之效應功能。舉例而言，選自特定胺基酸殘基之一或多個胺基酸可經不同胺基酸殘基置換，使得抗體針對效應配位體之親和力改變但保留親本抗體之抗原結合能力。親和力改變之效應配位體可為例如Fc受體或補體之C1組分。此方法進一步詳細描述於Winter等人之美國專利第5,624,821號及第5,648,260號中。In yet other embodiments, the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to change the effector function of the antibody. For example, one or more amino acids selected from a specific amino acid residue can be replaced by a different amino acid residue so that the affinity of the antibody for the effector ligand is changed but the antigen binding ability of the parent antibody is retained. The effector ligand with changed affinity can be, for example, an Fc receptor or the C1 component of a complement. This method is further described in detail in U.S. Patent Nos. 5,624,821 and 5,648,260 to Winter et al.
抗191P4D12抗體與191P4D12相關蛋白之反應性可藉由多種熟知方式(包括西方墨點法、免疫沈澱、ELISA及FACS分析)，適當時使用191P4D12相關蛋白、191P4D12表現細胞或其提取物來確立。191P4D12抗體或其片段可用可偵測標記物加以標記或與第二分子結合。適合的可偵測標記物包括(但不限於)放射性同位素、螢光化合物、生物發光化合物、化學發光化合物、金屬螯合劑或酶。此外，使用此項技術中一般已知之方法，來產生對兩種或更多種191P4D12抗原決定基具有特異性之雙特異性抗體。亦可藉由此項技術中已知之交聯技術(例如Wolff等人, Cancer Res. 53: 2560-2565)來產生均二聚抗體。The reactivity of anti-191P4D12 antibodies to 191P4D12-related proteins can be established by a variety of well-known methods, including Western blot, immunoprecipitation, ELISA, and FACS analysis, using 191P4D12-related proteins, 191P4D12-expressing cells, or extracts thereof, as appropriate. The 191P4D12 antibody or fragment thereof can be labeled with a detectable marker or conjugated to a second molecule. Suitable detectable markers include, but are not limited to, radioisotopes, fluorescent compounds, bioluminescent compounds, chemiluminescent compounds, metal chelators, or enzymes. In addition, bispecific antibodies specific for two or more 191P4D12 antigenic determinants are generated using methods generally known in the art. Homodimeric antibodies may also be generated by cross-linking techniques known in the art (eg, Wolff et al., Cancer Res. 53: 2560-2565).
在又另一個特定實施例中，本文所提供之抗191P4D12抗體為包含稱為Ha22-2(2,4)6.1之抗體之重鏈及輕鏈的抗體。Ha22-2(2,4)6.1之重鏈由範圍自SEQ ID NO:7之第20位E殘基至第466位K殘基內的胺基酸序列組成；且Ha22-2(2,4)6.1之輕鏈由範圍自SEQ ID NO:8之第23位D殘基至第236位C殘基內的胺基酸序列組成。In yet another specific embodiment, the anti-191P4D12 antibody provided herein is an antibody comprising a heavy chain and a light chain of an antibody called Ha22-2(2,4)6.1. The heavy chain of Ha22-2(2,4)6.1 consists of an amino acid sequence ranging from the 20th E residue to the 466th K residue of SEQ ID NO:7; and the light chain of Ha22-2(2,4)6.1 consists of an amino acid sequence ranging from the 23rd D residue to the 236th C residue of SEQ ID NO:8.
產生稱為Ha22-2(2,4)6.1之抗體的融合瘤於2010年8月18日寄送(經由Federal Express)至美國菌種保藏中心(ATCC)(P.O. Box 1549, Manassas, VA 20108)，且被指定登錄號PTA-11267。The fusion tumor producing the antibody designated Ha22-2(2,4)6.1 was sent (via Federal Express) to the American Type Culture Collection (ATCC) (P.O. Box 1549, Manassas, VA 20108) on August 18, 2010 and was assigned accession number PTA-11267.
抗連接素-4抗體的其他實施例已描述於美國專利第8,637,642號及國際申請案第PCT/US2019/056214號(公開案第WO2020/117373號)，該兩者以其全文引用之方式併入本文中。5.3.2細胞毒性劑(藥物單元)Other embodiments of anti-nectin-4 antibodies are described in U.S. Patent No. 8,637,642 and International Application No. PCT/US2019/056214 (Publication No. WO2020/117373), both of which are incorporated herein by reference in their entirety.5.3.2Cytotoxic Agents(Drug Units)
由於本文提供之方法中使用的ADC包含與細胞毒性劑結合的抗體或其抗原結合片段，因此本發明進一步提供細胞毒性劑之各種實施例作為該等方法中使用之ADC的一部分。在本文所提供之方法(包括章節5.2中所提供的方法)的各種實施例中，作為本文向該等方法提供之任一種ADC之一部分的細胞毒性劑包含微管蛋白破裂劑、由微管蛋白破裂劑組成或為微管蛋白破裂劑。在一個實施例中，細胞毒性劑為微管蛋白破裂劑。在一些實施例中，微管蛋白破裂劑選自由以下組成之群：海兔毒素(dolastatin)、奧瑞他汀(auristatin)、哈米特林(hemiasterlin)、長春花生物鹼(vinca alkaloid)、類美登素(maytansinoid)、艾瑞布林(eribulin)、秋水仙鹼(colchicine)、普羅布林(plocabulin)、福莫普辛(phomopsin)、埃坡黴素(epothilone)、念珠藻素(cryptophycin)及紫杉烷(taxane)。在一個特定實施例中，微管蛋白破裂劑為奧瑞他汀。在另一特定實施例中，奧瑞他汀為單甲基奧瑞他汀E (MMAE)、單甲基奧瑞他汀F (MMAF)、AFP或奧瑞他汀T。在又另一個特定實施例中，奧瑞他汀為單甲基奧瑞他汀E (MMAE)。Since the ADC used in the methods provided herein comprises an antibody or antigen-binding fragment thereof bound to a cytotoxic agent, the present invention further provides various embodiments of a cytotoxic agent as part of the ADC used in the methods. In various embodiments of the methods provided herein (including the methods provided in Section 5.2), the cytotoxic agent as part of any ADC provided herein for the methods comprises, consists of, or is a tubulin disrupting agent. In one embodiment, the cytotoxic agent is a tubulin disrupting agent. In some embodiments, the tubulin disrupting agent is selected from the group consisting of dolastatin, auristatin, hemiasterlin, vinca alkaloid, maytansinoid, eribulin, colchicine, plocabulin, phomopsin, epothilone, cryptophycin, and taxane. In a specific embodiment, the tubulin disrupting agent is auristatin. In another specific embodiment, auristatin is monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), AFP, or auristatin T. In yet another specific embodiment, auristatin is monomethyl auristatin E (MMAE).
在本文所提供之方法(包括章節5.2中所提供之方法)的各種實施例中，作為本文向該等方法提供之任一種ADC之一部分的細胞毒性劑包含選自以下的任何藥劑、由選自以下的任何藥劑組成或為選自以下的任何藥劑：美國專利第8,637,642號及國際申請案第PCT/US2019/056214號(公開案第WO2020/117373號)中所描述的細胞毒性劑，該兩者以全文引用之方式併入本文中。In various embodiments of the methods provided herein, including the methods provided in Section 5.2, the cytotoxic agent as part of any ADC provided herein for such methods comprises, consists of, or is any agent selected from the following: cytotoxic agents described in U.S. Patent No. 8,637,642 and International Application No. PCT/US2019/056214 (Publication No. WO2020/117373), both of which are incorporated herein by reference in their entirety.
在一些實施例中，奧瑞他汀為MMAE (其中波浪線指示與抗體藥物結合物之連接子的共價連接)。MMAEIn some embodiments, the auristatin is MMAE (wherein the wavy line indicates the covalent attachment to the linker of the antibody drug conjugate). MMAE
在一些實施例中，包含MMAE及連接子組分(本文中進一步描述)的一個例示性實施例具有以下結構(其中L表示抗體(例如抗連接素-4抗體或其抗原結合片段)且p在1至12範圍內)：In some embodiments, an exemplary embodiment comprising MMAE and a linker component (described further herein) has the following structure (wherein L represents an antibody (e.g., an anti-nexin-4 antibody or an antigen-binding fragment thereof) and p ranges from 1 to 12):
在前一段落所描述之式的一些實施例中，p的範圍為1至20、1至19、1至18、1至17、1至16、1至15、1至14、1至13、1至12、1至11、1至10、1至9、1至8、1至7、1至6、1至5、1至4、1至3或1至2。在前一段落所描述之式的一些實施例中，p的範圍為2至20、2至19、2至18、2至17、2至16、2至15、2至14、2至13、2至12、2至11、2至10、2至9、2至8、2至7、2至6、2至5、2至4或2至3。在前一段落所描述之式的一些實施例中，p的範圍為3至20、3至19、3至18、3至17、3至16、3至15、3至14、3至13、3至12、3至11、3至10、3至9、3至8、3至7、3至6、3至5或3至4。在前一段落所描述之式的一些實施例中，p為約1。在前一段落所描述之式的一些實施例中，p為約2。在前一段落所描述之式的一些實施例中，p為約3。在前一段落所描述之式的一些實施例中，p為約4。在前一段落所描述之式的一些實施例中，p為約3.8。在前一段落所描述之式的一些實施例中，p為約5。在前一段落所描述之式的一些實施例中，p為約6。在前一段落所描述之式的一些實施例中，p為約7。在前一段落所描述之式的一些實施例中，p為約8。在前一段落所描述之式的一些實施例中，p為約9。在前一段落所描述之式的一些實施例中，p為約10。在前一段落所描述之式的一些實施例中，p為約11。在前一段落所描述之式的一些實施例中，p為約12。在前一段落所描述之式的一些實施例中，p為約13。在前一段落所描述之式的一些實施例中，p為約14。在前一段落所描述之式的一些實施例中，p為約15。在前一段落所描述之式的一些實施例中，p為約16。在前一段落所描述之式的一些實施例中，p為約17。在前一段落所描述之式的一些實施例中，p為約18。在前一段落所描述之式的一些實施例中，p為約19。在前一段落所描述之式的一些實施例中，p為約20。In some embodiments of the formula described in the preceding paragraph, p ranges from 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments of the formula described in the preceding paragraph, p ranges from 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, 2 to 13, 2 to 12, 2 to 11, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3. In some embodiments of the formula described in the preceding paragraph, p ranges from 3 to 20, 3 to 19, 3 to 18, 3 to 17, 3 to 16, 3 to 15, 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 3 to 4. In some embodiments of the formula described in the preceding paragraph, p is about 1. In some embodiments of the formula described in the preceding paragraph, p is about 2. In some embodiments of the formula described in the preceding paragraph, p is about 3. In some embodiments of the formula described in the preceding paragraph, p is about 4. In some embodiments of the formula described in the preceding paragraph, p is about 3.8. In some embodiments of the formula described in the preceding paragraph, p is about 5. In some embodiments of the formula described in the preceding paragraph, p is about 6. In some embodiments of the formula described in the preceding paragraph, p is about 7. In some embodiments of the formula described in the preceding paragraph, p is about 8. In some embodiments of the formula described in the preceding paragraph, p is about 9. In some embodiments of the formula described in the preceding paragraph, p is about 10. In some embodiments of the formula described in the preceding paragraph, p is about 11. In some embodiments of the formula described in the preceding paragraph, p is about 12. In some embodiments of the formula described in the preceding paragraph, p is about 13. In some embodiments of the formula described in the preceding paragraph, p is about 14. In some embodiments of the formula described in the preceding paragraph, p is about 15. In some embodiments of the formula described in the preceding paragraph, p is about 16. In some embodiments of the formula described in the preceding paragraph, p is about 17. In some embodiments of the formula described in the preceding paragraph, p is about 18. In some embodiments of the formula described in the preceding paragraph, p is about 19. In some embodiments of the formula described in the preceding paragraph, p is about 20.
通常，基於肽之藥物單元可藉由在兩個或更多個胺基酸及/或肽片段之間形成肽鍵來製備。此類肽鍵可例如根據肽化學領域中熟知的液相合成方法(參見E. Schröder及K. Lübke, 「The Peptides」, 第1卷, 第76-136頁, 1965, Academic Press)製備。奧瑞他汀/海兔毒素藥物單元可根據以下文獻之方法製備：US 5635483；US 5780588；Pettit等人(1989) J. Am. Chem. Soc. 111:5463-5465；Pettit等人(1998) Anti-Cancer Drug Design 13:243-277；Pettit, G. R.等人, Synthesis, 1996, 719-725；Pettit等人(1996) J. Chem. Soc. Perkin Trans. 1 5:859-863；及Doronina (2003) Nat Biotechnol 21(7):778-784。Typically, peptide-based drug units can be prepared by forming a peptide bond between two or more amino acids and/or peptide fragments. Such peptide bonds can be prepared, for example, according to liquid phase synthesis methods well known in the field of peptide chemistry (see E. Schröder and K. Lübke, "The Peptides", Vol. 1, pp. 76-136, 1965, Academic Press). The auristatin/dolastatin drug unit can be prepared according to the methods of the following references: US 5635483; US 5780588; Pettit et al. (1989) J. Am. Chem. Soc. 111:5463-5465; Pettit et al. (1998) Anti-Cancer Drug Design 13:243-277; Pettit, G. R. et al., Synthesis, 1996, 719-725; Pettit et al. (1996) J. Chem. Soc. Perkin Trans. 1 5:859-863; and Doronina (2003) Nat Biotechnol 21(7):778-784.
細胞毒性劑的其他實施例已描述於美國專利第8,637,642號及國際申請案第PCT/US2019/056214號(公開案第WO2020/117373號)，該兩者以其全文引用之方式併入本文中。5.3.3連接子Other embodiments of cytotoxic agents are described in U.S. Patent No. 8,637,642 and International Application No. PCT/US2019/056214 (Publication No. WO2020/117373), both of which are incorporated herein by reference in their entirety.5.3.3Linker
通常，抗體藥物結合物在藥物單元(例如MMAE)與抗體單元(例如抗191P4D12抗體或其抗原結合片段)之間包含連接子單元。在一些實施例中，連接子在細胞內條件下可裂解，使得連接子在細胞內環境中裂解而自抗體釋放藥物單元。在又其他實施例中，連接子單元不可裂解且(例如)藉由抗體降解來釋放藥物。在一些實施例中，連接子可藉由細胞內環境中(例如溶酶體或核內體或胞膜窖內)存在之裂解劑裂解。連接子可為例如可由細胞內肽酶或蛋白酶(包括(但不限於)溶酶體或內體蛋白酶)裂解之肽基連接子。舉例而言，可使用可由硫醇依賴性蛋白酶組織蛋白酶B裂解的肽基連接子(例如Phe-Leu或Gly-Phe-Leu-Gly連接子(SEQ ID NO:15))，該組織蛋白酶B在癌組織中高度表現。在一些實施例中，肽基連接子之長度為至少兩個胺基酸或至少三個胺基酸。在其他實施例中，可裂解連接子為pH敏感的，亦即在某些pH值下對水解敏感。通常，pH敏感性連接子可在酸性條件下水解。舉例而言，可使用在溶酶體中可水解之酸不穩定連接子(例如腙、半卡巴腙、硫半卡巴肼、順式烏頭酸醯胺、原酸酯、縮醛、縮酮或其類似物)。在又其他實施例中，連接子在還原條件下可裂解(例如二硫化物連接子)。此項技術中已知多種二硫化物連接子，包括例如可使用SATA (N-丁二醯亞胺基-S-乙醯基硫基乙酸酯)、SPDP (N-丁二醯亞胺基-3-(2-吡啶基二硫基)丙酸酯)、SPDB (N-丁二醯亞胺基-3-(2-吡啶基二硫基)丁酸酯)及SMPT (N-丁二醯亞胺基-氧基羰基-α-甲基-α-(2-吡啶基-二硫基)甲苯)、SPDB與SMPT形成的彼等物。Typically, the antibody-drug conjugate includes a linker unit between a drug unit (e.g., MMAE) and an antibody unit (e.g., an anti-191P4D12 antibody or an antigen-binding fragment thereof). In some embodiments, the linker is cleavable under intracellular conditions, so that the linker is cleaved in the intracellular environment and releases the drug unit from the antibody. In yet other embodiments, the linker unit is not cleavable and (for example) releases the drug by antibody degradation. In some embodiments, the linker can be cleaved by a cleavage agent present in the intracellular environment (e.g., a lysosome or endosome or caveolae). The linker can be, for example, a peptidyl linker that can be cleaved by an intracellular peptidase or protease (including, but not limited to, a lysosomal or endosomal protease). For example, a peptidyl linker (e.g., a Phe-Leu or Gly-Phe-Leu-Gly linker (SEQ ID NO: 15)) that is cleavable by the thiol-dependent protease cathepsin B, which is highly expressed in cancer tissues, can be used. In some embodiments, the peptidyl linker is at least two amino acids or at least three amino acids in length. In other embodiments, the cleavable linker is pH sensitive, that is, sensitive to hydrolysis at certain pH values. Typically, pH-sensitive linkers can be hydrolyzed under acidic conditions. For example, an acid-labile linker (e.g., a hydrazone, semicarbazone, thiosemicarbazide, cis-arutanamide, orthoester, acetal, ketone, or the like) that is hydrolyzable in lysosomes can be used. In yet other embodiments, the linker is cleavable under reducing conditions (e.g., a disulfide linker). A variety of disulfide linkers are known in the art, including, for example, those that can be formed using SATA (N-succinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio) propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio) butyrate), and SMPT (N-succinimidyl-oxycarbonyl-α-methyl-α-(2-pyridyl-dithio) toluene), SPDB and SMPT.
「連接子單元」(LU)為可用於將藥物單元與抗體單元連接以形成抗體藥物結合物之雙官能化合物。在一些實施例中，連接子單元具有下式： -Aa-Ww-Yy- 其中：-A-為延伸子單元， a為0或1， 各-W-獨立地為胺基酸單元， w為0至12範圍內之整數， -Y-為自我分解型間隔子單元，且 y為0、1或2。A "Linker unit" (LU) is a bifunctional compound that can be used to link a drug unit to an antibody unit to form an antibody drug conjugate. In some embodiments, the Linker unit has the following formula:-Aa -Ww -Yy- wherein: -A- is a Stretcher unit, a is 0 or 1, each -W- is independently an amino acid unit, w is an integer in the range of 0 to 12, -Y- is a self-immolative Spacer unit, and y is 0, 1 or 2.
在一些實施例中，a為0或1，w為0或1，且y為0、1或2。在一些實施例中，a為0或1，w為0或1，且y為0或1。在一些實施例中，當w為1至12時，y為1或2。在一些實施例中，w為2至12且y為1或2。在一些實施例中，a為1且w及y為0。連接子以及延伸子單元、胺基酸單元與間隔子單元中之每一者已描述於美國專利第8,637,642號及國際申請案第PCT/US2019/056214號(公開案第WO2020/117373號)中，該兩者以全文引用之方式併入本文中。In some embodiments, a is 0 or 1, w is 0 or 1, and y is 0, 1 or 2. In some embodiments, a is 0 or 1, w is 0 or 1, and y is 0 or 1. In some embodiments, when w is 1 to 12, y is 1 or 2. In some embodiments, w is 2 to 12 and y is 1 or 2. In some embodiments, a is 1 and w and y are 0. The linker and each of the stretcher unit, amino acid unit, and spacer unit have been described in U.S. Patent No. 8,637,642 and International Application No. PCT/US2019/056214 (Publication No. WO2020/117373), both of which are incorporated herein by reference in their entirety.
抗體-藥物結合物之實施例可包括：其中w及y各自為0、1或2，及其中w及y各自為0，及5.3.4藥物負載Examples of antibody-drug conjugates may include: where w and y are each 0, 1, or 2, and Where w and y are each 0, and5.3.4Drug Load
藥物負載由p表示且為分子中每個抗體之藥物單元平均數目。藥物負載可在每個抗體1至20個藥物單元(D)範圍內。本文提供之ADC包括與一系列藥物單元(例如1至20個)結合之抗體或抗原結合片段之集合。在經由結合反應製備ADC時，每個抗體的藥物單元平均數目可藉由諸如質譜法及ELISA分析之習知方式表徵。亦可根據p來測定ADC之定量分佈。在一些情況下，將p為特定值的均質ADC自具有其他藥物負載之ADC分離、純化及表徵可藉由諸如電泳之方式來達成。Drug loading is represented by p and is the average number of drug units per antibody in the molecule. Drug loading can range from 1 to 20 drug units (D) per antibody. The ADCs provided herein include a collection of antibodies or antigen-binding fragments bound to a range of drug units (e.g., 1 to 20). When preparing ADCs by binding reactions, the average number of drug units per antibody can be characterized by known methods such as mass spectrometry and ELISA analysis. The quantitative distribution of ADCs can also be determined based on p. In some cases, separation, purification, and characterization of homogeneous ADCs with a particular value of p from ADCs with other drug loadings can be achieved by methods such as electrophoresis.
在某些實施例中，本文所提供之ADC的藥物負載範圍為1至20。在某些實施例中，本文所提供之ADC的藥物負載範圍為1至18。在某些實施例中，本文所提供之ADC的藥物負載範圍為1至15。在某些實施例中，本文所提供之ADC的藥物負載範圍為1至12。在某些實施例中，本文所提供之ADC的藥物負載範圍為1至10。在某些實施例中，本文所提供之ADC的藥物負載範圍為1至9。在某些實施例中，本文所提供之ADC的藥物負載範圍為1至8。在某些實施例中，本文所提供之ADC的藥物負載範圍為1至7。在某些實施例中，本文所提供之ADC的藥物負載範圍為1至6。在某些實施例中，本文所提供之ADC的藥物負載範圍為1至5。在某些實施例中，本文所提供之ADC的藥物負載範圍為1至4。在某些實施例中，本文所提供之ADC的藥物負載範圍為1至3。在某些實施例中，本文所提供之ADC的藥物負載範圍為2至12。在某些實施例中，本文所提供之ADC的藥物負載範圍為2至10。在某些實施例中，本文所提供之ADC的藥物負載範圍為2至9。在某些實施例中，本文所提供之ADC的藥物負載範圍為2至8。在某些實施例中，本文所提供之ADC的藥物負載範圍為2至7。在某些實施例中，本文所提供之ADC的藥物負載範圍為2至6。在某些實施例中，本文所提供之ADC的藥物負載範圍為2至5。在某些實施例中，本文所提供之ADC的藥物負載範圍為2至4。在某些實施例中，本文所提供之ADC的藥物負載範圍為3至12。在某些實施例中，本文所提供之ADC的藥物負載範圍為3至10。在某些實施例中，本文所提供之ADC的藥物負載範圍為3至9。在某些實施例中，本文所提供之ADC的藥物負載範圍為3至8。在某些實施例中，本文所提供之ADC的藥物負載範圍為3至7。在某些實施例中，本文所提供之ADC的藥物負載範圍為3至6。在某些實施例中，本文所提供之ADC的藥物負載範圍為3至5。在某些實施例中，本文所提供之ADC的藥物負載範圍為3至4。In certain embodiments, the ADCs provided herein have a drug loading ranging from 1 to 20. In certain embodiments, the ADCs provided herein have a drug loading ranging from 1 to 18. In certain embodiments, the ADCs provided herein have a drug loading ranging from 1 to 15. In certain embodiments, the ADCs provided herein have a drug loading ranging from 1 to 12. In certain embodiments, the ADCs provided herein have a drug loading ranging from 1 to 10. In certain embodiments, the ADCs provided herein have a drug loading ranging from 1 to 9. In certain embodiments, the ADCs provided herein have a drug loading ranging from 1 to 8. In certain embodiments, the ADCs provided herein have a drug loading ranging from 1 to 7. In certain embodiments, the ADCs provided herein have a drug loading ranging from 1 to 6. In certain embodiments, the ADCs provided herein have a drug loading ranging from 1 to 5. In certain embodiments, the ADCs provided herein have a drug loading ranging from 1 to 4. In certain embodiments, the ADCs provided herein have a drug loading ranging from 1 to 3. In certain embodiments, the ADCs provided herein have a drug loading ranging from 2 to 12. In certain embodiments, the ADCs provided herein have a drug loading ranging from 2 to 10. In certain embodiments, the ADCs provided herein have a drug loading ranging from 2 to 9. In certain embodiments, the ADCs provided herein have a drug loading ranging from 2 to 8. In certain embodiments, the ADCs provided herein have a drug loading ranging from 2 to 7. In certain embodiments, the ADCs provided herein have a drug loading ranging from 2 to 6. In certain embodiments, the ADCs provided herein have a drug loading ranging from 2 to 5. In certain embodiments, the ADCs provided herein have a drug loading ranging from 2 to 4. In certain embodiments, the ADCs provided herein have a drug loading ranging from 3 to 12. In certain embodiments, the ADCs provided herein have a drug loading ranging from 3 to 10. In certain embodiments, the ADCs provided herein have a drug loading ranging from 3 to 9. In certain embodiments, the ADCs provided herein have a drug loading ranging from 3 to 8. In certain embodiments, the ADCs provided herein have a drug loading ranging from 3 to 7. In certain embodiments, the ADCs provided herein have a drug loading ranging from 3 to 6. In certain embodiments, the ADCs provided herein have a drug loading ranging from 3 to 5. In certain embodiments, the drug loading of the ADCs provided herein ranges from 3 to 4.
在某些實施例中，本文所提供之ADC的藥物負載範圍為1至約8；約2至約6；約3至約5；約3至約4；約3.1至約3.9；約3.2至約3.8；約3.2至約3.7；約3.2至約3.6；約3.3至約3.8；或約3.3至約3.7。In certain embodiments, the drug loading of the ADCs provided herein ranges from 1 to about 8; about 2 to about 6; about 3 to about 5; about 3 to about 4; about 3.1 to about 3.9; about 3.2 to about 3.8; about 3.2 to about 3.7; about 3.2 to about 3.6; about 3.3 to about 3.8; or about 3.3 to about 3.7.
在某些實施例中，本文所提供之ADC的藥物負載為約1、約2、約3、約4、約5、約6、約7、約8、約9、約10、約11、約12或更多。在一些實施例中，本文所提供之ADC的藥物負載為約3.1、約3.2、約3.3、約3.4、約3.5、約3.6、約3.7、約3.8或約3.9。In certain embodiments, the drug loading of the ADC provided herein is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12 or more. In some embodiments, the drug loading of the ADC provided herein is about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, or about 3.9.
在一些實施例中，本文所提供之ADC的藥物負載範圍為2至20、2至19、2至18、2至17、2至16、2至15、2至14或2至13。在一些實施例中，本文所提供之ADC的藥物負載範圍為3至20、3至19、3至18、3至17、3至16、3至15、3至14或3至13。在一些實施例中，本文所提供之ADC的藥物負載為約1。在一些實施例中，本文所提供之ADC的藥物負載為約2。在一些實施例中，本文所提供之ADC的藥物負載為約3。在一些實施例中，本文所提供之ADC的藥物負載為約4。在一些實施例中，本文所提供之ADC的藥物負載為約3.8。在一些實施例中，本文所提供之ADC的藥物負載為約5。在一些實施例中，本文所提供之ADC的藥物負載為約6。在一些實施例中，本文所提供之ADC的藥物負載為約7。在一些實施例中，本文所提供之ADC的藥物負載為約8。在一些實施例中，本文所提供之ADC的藥物負載為約9。在一些實施例中，本文所提供之ADC的藥物負載為約10。在一些實施例中，本文所提供之ADC的藥物負載為約11。在一些實施例中，本文所提供之ADC的藥物負載為約12。在一些實施例中，本文所提供之ADC的藥物負載為約13。在一些實施例中，本文所提供之ADC的藥物負載為約14。在一些實施例中，本文所提供之ADC的藥物負載為約15。在一些實施例中，本文所提供之ADC的藥物負載為約16。在一些實施例中，本文所提供之ADC的藥物負載為約17。在一些實施例中，本文所提供之ADC的藥物負載為約18。在一些實施例中，本文所提供之ADC的藥物負載為約19。在一些實施例中，本文所提供之ADC的藥物負載為約20。In some embodiments, the drug loading of the ADCs provided herein ranges from 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, or 2 to 13. In some embodiments, the drug loading of the ADCs provided herein ranges from 3 to 20, 3 to 19, 3 to 18, 3 to 17, 3 to 16, 3 to 15, 3 to 14, or 3 to 13. In some embodiments, the drug loading of the ADCs provided herein is about 1. In some embodiments, the drug loading of the ADCs provided herein is about 2. In some embodiments, the drug loading of the ADCs provided herein is about 3. In some embodiments, the drug loading of the ADCs provided herein is about 4. In some embodiments, the drug loading of the ADCs provided herein is about 3.8. In some embodiments, the drug loading of the ADC provided herein is about 5. In some embodiments, the drug loading of the ADC provided herein is about 6. In some embodiments, the drug loading of the ADC provided herein is about 7. In some embodiments, the drug loading of the ADC provided herein is about 8. In some embodiments, the drug loading of the ADC provided herein is about 9. In some embodiments, the drug loading of the ADC provided herein is about 10. In some embodiments, the drug loading of the ADC provided herein is about 11. In some embodiments, the drug loading of the ADC provided herein is about 12. In some embodiments, the drug loading of the ADC provided herein is about 13. In some embodiments, the drug loading of the ADC provided herein is about 14. In some embodiments, the drug loading of the ADC provided herein is about 15. In some embodiments, the drug loading of the ADC provided herein is about 16. In some embodiments, the drug loading of the ADC provided herein is about 17. In some embodiments, the drug loading of the ADC provided herein is about 18. In some embodiments, the drug loading of the ADC provided herein is about 19. In some embodiments, the drug loading of the ADC provided herein is about 20.
在某些實施例中，在結合反應期間，使少於理論最大值之藥物單元與抗體結合。抗體可含有例如與藥物-連接子中間物或連接子試劑不反應的離胺酸殘基。一般而言，抗體不含有可與藥物單元連接之許多游離的反應性半胱胺酸硫醇基；實際上，抗體中之大部分半胱胺酸硫醇殘基以二硫橋鍵形式存在。在某些實施例中，抗體可用諸如二硫蘇糖醇(DTT)或三羰基乙基膦(TCEP)之還原劑在部分或完全還原條件下還原，產生反應性半胱胺酸硫醇基。在某些實施例中，抗體經歷變性條件，以顯露反應性親核基團，諸如離胺酸或半胱胺酸。在一些實施例中，經由抗體單元上之離胺酸殘基來結合連接子單元或藥物單元。在一些實施例中，經由抗體單元上之半胱胺酸殘基來結合連接子單元或藥物單元。In certain embodiments, less than the theoretical maximum number of drug units are allowed to bind to the antibody during the binding reaction. Antibodies may contain, for example, lysine residues that are unreactive with drug-linker intermediates or linker reagents. Generally, antibodies do not contain many free reactive cysteine thiol groups to which drug units may be attached; in fact, most cysteine thiol residues in antibodies exist as disulfide bridges. In certain embodiments, antibodies may be reduced with a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP) under partial or full reducing conditions to generate reactive cysteine thiol groups. In certain embodiments, antibodies are subjected to denaturing conditions to reveal reactive nucleophilic groups such as lysine or cysteine. In some embodiments, the linker unit or drug unit is conjugated via a lysine residue on the antibody unit. In some embodiments, the linker unit or drug unit is conjugated via a cysteine residue on the antibody unit.
在一些實施例中，與連接子單元藥物單元連接之胺基酸係在抗體或其抗原結合片段之重鏈中。在一些實施例中，與連接子單元或藥物單元連接之胺基酸係在抗體或其抗原結合片段之輕鏈中。在一些實施例中，與連接子單元或藥物單元連接之胺基酸係在抗體或其抗原結合片段之鉸鏈區中。在一些實施例中，與連接子單元或藥物單元連接之胺基酸係在抗體或其抗原結合片段之Fc區中。在其他實施例中，與連接子單元或藥物單元連接之胺基酸係在抗體或其抗原結合片段之恆定區(例如重鏈之CH1、CH2或CH3，或輕鏈之CH1)中。在又其他實施例中，與連接子單元或藥物單元連接之胺基酸係在抗體或其抗原結合片段之VH構架區中。在又其他實施例中，連接至連接子單元或藥物單元之胺基酸係在抗體或其抗原結合片段之VL構架區中。In some embodiments, the amino acid to which the linker unit drug unit is linked is in the heavy chain of an antibody or an AF thereof. In some embodiments, the amino acid to which the linker unit or drug unit is linked is in the light chain of an antibody or an AF thereof. In some embodiments, the amino acid to which the linker unit or drug unit is linked is in the hinge region of an antibody or an AF thereof. In some embodiments, the amino acid to which the linker unit or drug unit is linked is in the Fc region of an antibody or an AF thereof. In other embodiments, the amino acid to which the linker unit or drug unit is linked is in the constant region (e.g., CH1, CH2, or CH3 of the heavy chain, or CH1 of the light chain) of an antibody or an AF thereof. In yet other embodiments, the amino acid linked to the Linker unit or the Drug unit is in the VH framework region of an antibody or an antigen-binding fragment thereof. In yet other embodiments, the amino acid linked to the Linker unit or the Drug unit is in the VL framework region of an antibody or an antigen-binding fragment thereof.
ADC之負載(藥物/抗體比率)可以不同方式控制，例如：(i)限制藥物-連接子中間物或連接子試劑相對於抗體之莫耳濃度過量；(ii)限制結合反應時間或溫度；(iii)用於半胱胺酸硫醇修飾之部分或限制性還原條件；(iv)藉由重組技術對抗體之胺基酸序列進行工程改造，使得半胱胺酸殘基之數目及位置經修改以控制連接子-藥物連接之數目及/或位置(諸如本文及WO2006/034488 (以全文引用的方式併入本文中)所揭示而製備之thioMab或thioFab)。The loading (drug/antibody ratio) of the ADC can be controlled in various ways, for example: (i) limiting the molar excess of drug-linker intermediate or linker reagent relative to the antibody; (ii) limiting the binding reaction time or temperature; (iii) partial or limiting reducing conditions for cysteine thiol modification; (iv) engineering the amino acid sequence of the antibody by recombinant technology so that the number and position of cysteine residues are modified to control the number and/or position of linker-drug linkages (such as thioMabs or thioFabs prepared as disclosed herein and WO2006/034488 (incorporated herein by reference in their entirety)).
應瞭解，若超過一個親核基團與藥物-連接子中間物或連接子試劑反應，隨後與藥物單元試劑反應，則所得產物為ADC化合物的混合物，其中存在一或多個連接至抗體單元之藥物單元的分佈。混合物中每個抗體的藥物平均數目可藉由對抗體具有特異性且對藥物具有特異性之雙重ELISA抗體分析來計算。混合物中的個別ADC分子可藉由質譜法鑑別且藉由HPLC (例如疏水相互作用層析)來分離(參見例如Hamblett, K.J.等人「Effect of drug loading on the pharmacology, pharmacokinetics, and toxicity of an anti-CD30 antibody-drug conjugate」, 摘要編號624, 美國癌症研究學會(American Association for Cancer Research), 2004年年會, 2004年3月27-31日, AACR論文集, 第45卷, 2004年3月；Alley, S.C.等人「Controlling the location of drug attachment in antibody-drug conjugates」, 摘要編號627, 美國癌症研究學會, 2004年年會, 2004年3月27-31日, AACR論文集, 第45卷, 2004年3月)。在某些實施例中，具有單一負載值之均質ADC可藉由電泳或層析自結合混合物分離。It will be appreciated that if more than one nucleophilic group is reacted with a drug-linker intermediate or linker reagent, which is then reacted with a drug unit reagent, the resulting product is a mixture of ADC compounds in which there is a distribution of one or more drug units linked to antibody units. The average number of drugs per antibody in the mixture can be calculated by a duplex ELISA antibody assay specific for the antibody and specific for the drug. Individual ADC molecules in a mixture can be identified by mass spectrometry and separated by HPLC (e.g., hydrophobic interaction chromatography) (see, e.g., Hamblett, K.J. et al., “Effect of drug loading on the pharmacology, pharmacokinetics, and toxicity of an anti-CD30 antibody-drug conjugate,” Abstract No. 624, American Association for Cancer Research, 2004 Annual Meeting, March 27-31, 2004, AACR Proceedings, Vol. 45, March 2004; Alley, S.C. et al., “Controlling the location of drug attachment in antibody-drug conjugates,” Abstract No. 627, American Association for Cancer Research, 2004 Annual Meeting, March 27-31, 2004, AACR Proceedings, Vol. 45, March 2004). In certain embodiments, homogeneous ADCs having a single loading value can be separated from a binding mixture by electrophoresis or chromatography.
用於製備、篩選及表徵抗體藥物結合物方法係一般熟習此項技術者已知的，例如美國專利案第8,637,642號中所描述，該案以全文引用之方式併入本文中。Methods for preparing, screening, and characterizing antibody-drug conjugates are known to those of ordinary skill in the art, such as described in U.S. Patent No. 8,637,642, which is incorporated herein by reference in its entirety.
在一些實施例中，用於本文提供之方法之抗體藥物結合物為AGS-22M6E，其係根據美國專利案第8,637,642號中所描述之方法製備且具有下式：其中L為Ha22-2(2,4)6.1，且p為1至20。In some embodiments, the antibody drug conjugate used in the methods provided herein is AGS-22M6E, which is prepared according to the method described in U.S. Patent No. 8,637,642 and has the following formula: Wherein L is Ha22-2(2,4)6.1, and p is 1 to 20.
在一些實施例中，p範圍為1至20、1至10、1至9、1至8、1至7、1至6、1至5、1至4、1至3或1至2。在一些實施例中，p範圍為2至10、2至9、2至8、2至7、2至6、2至5、2至4或2至3。在其他實施例中，p為約1。在其他實施例中，p為約2。在其他實施例中，p為約3。在其他實施例中，p為約4。在其他實施例中，p為約5。在其他實施例中，p為約6。在其他實施例中，p為約7。在其他實施例中，p為約8。在其他實施例中，p為約9。在其他實施例中，p為約10。在一些實施例中，p為約3.1。在一些實施例中，p為約3.2。在一些實施例中，p為約3.3。在一些實施例中，p為約3.4。在一些實施例中，p為約3.5。在其他實施例中，p為約3.6。在一些實施例中，p為約3.7。在一些實施例中，p為約3.8。在一些實施例中，p為約3.9。在一些實施例中，p為約4.0。在一些實施例中，p為約4.1。在一些實施例中，p為約4.2。在一些實施例中，p為約4.3。在一些實施例中，p為約4.4。在一些實施例中，p為約4.5。在其他實施例中，p為約4.6。在一些實施例中，p為約4.7。在一些實施例中，p為約4.8。在一些實施例中，p為約4.9。在一些實施例中，p為約5.0。In some embodiments, p ranges from 1 to 20, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, p ranges from 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3. In other embodiments, p is about 1. In other embodiments, p is about 2. In other embodiments, p is about 3. In other embodiments, p is about 4. In other embodiments, p is about 5. In other embodiments, p is about 6. In other embodiments, p is about 7. In other embodiments, p is about 8. In other embodiments, p is about 9. In other embodiments, p is about 10. In some embodiments, p is about 3.1. In some embodiments, p is about 3.2. In some embodiments, p is about 3.3. In some embodiments, p is about 3.4. In some embodiments, p is about 3.5. In other embodiments, p is about 3.6. In some embodiments, p is about 3.7. In some embodiments, p is about 3.8. In some embodiments, p is about 3.9. In some embodiments, p is about 4.0. In some embodiments, p is about 4.1. In some embodiments, p is about 4.2. In some embodiments, p is about 4.3. In some embodiments, p is about 4.4. In some embodiments, p is about 4.5. In other embodiments, p is about 4.6. In some embodiments, p is about 4.7. In some embodiments, p is about 4.8. In some embodiments, p is about 4.9. In some embodiments, p is about 5.0.
在一些實施例中，本文所提供之方法中使用的ADC係恩諾單抗維多汀。恩諾單抗維多汀為一種ADC，其包含經由蛋白酶可裂解連接子與微管破裂劑(MMAE)結合的完全人類免疫球蛋白G1κ (IgG1Κ)抗體(Challita-Eid PM等人, Cancer Res. 2016;76(10):3003-13)。恩諾單抗維多汀如下誘導抗腫瘤活性：結合至細胞表面上之191P4D12蛋白質，引起ADC-191P4D12複合物內化，接著運輸至溶酶體隔室，在該隔室中經由蛋白水解裂解連接子而釋放MMAE。細胞內釋放MMAE隨後干擾微管蛋白聚合，引起G2/M期細胞週期阻滯及細胞凋亡性細胞死亡(Francisco JA等人, Blood. 2003年8月15日;102(4):1458-65)。In some embodiments, the ADC used in the methods provided herein is enrokumab vedotin. Enrokumab vedotin is an ADC comprising a fully human immunoglobulin G1κ (IgG1κ ) antibody conjugated to a microtubule disrupting agent (MMAE) via a protease-cleavable linker (Challita-Eid PM et al., Cancer Res. 2016;76(10):3003-13). Enrokumab vedotin induces anti-tumor activity by binding to the 191P4D12 protein on the cell surface, causing internalization of the ADC-191P4D12 complex, followed by transport to the lysosomal compartment, where the MMAE is released by proteolytic cleavage of the linker. Intracellular release of MMAE subsequently interferes with tubulin polymerization, causing G2/M cell cycle arrest and apoptotic cell death (Francisco JA et al., Blood. 2003 Aug 15;102(4):1458-65).
如上文及美國專利第8,637,642號中所描述，AGS-22M6E為來源於鼠類融合瘤細胞株之ADC。恩諾單抗維多汀為中國倉鼠卵巢(CHO)細胞株來源的AGS-22M6E ADC等效物且為用於人類療法之例示性產品。恩諾單抗維多汀具有與AGS-22M6E相同的胺基酸序列、連接子及細胞毒性藥物。恩諾單抗維多汀與AGS-22M6E之間的可比較性係經由深入分析及生物表徵研究，諸如與191P4D12之結合親和力、活體外細胞毒性及活體內抗腫瘤活性確定。As described above and in U.S. Patent No. 8,637,642, AGS-22M6E is an ADC derived from a murine fusion tumor cell line. Enromax Vedotin is an AGS-22M6E ADC equivalent derived from a Chinese Hamster Ovary (CHO) cell line and is an exemplary product for human therapy. Enromax Vedotin has the same amino acid sequence, linker, and cytotoxic drug as AGS-22M6E. The comparability between Enromax Vedotin and AGS-22M6E was determined through in-depth analysis and biocharacterization studies, such as binding affinity to 191P4D12, in vitro cytotoxicity, and in vivo antitumor activity.
在一個實施例中，本文所提供之ADC為恩諾單抗維多汀，亦稱為EV、PADCEV、AGS-22M6E、AGS-22C3E、ASG-22C3E。恩諾單抗維多汀包括抗191P4D12抗體，其中該抗體或其抗原結合片段包含含有SEQ ID NO:7之胺基酸殘基20至胺基酸殘基466的重鏈及含有SEQ ID NO:8之胺基酸殘基23至胺基酸殘基236的輕鏈。In one embodiment, the ADC provided herein is enrokumab vedotin, also known as EV, PADCEV, AGS-22M6E, AGS-22C3E, ASG-22C3E. Enrokumab vedotin includes an anti-191P4D12 antibody, wherein the antibody or an antigen-binding fragment thereof comprises a heavy chain containing amino acid residue 20 to amino acid residue 466 of SEQ ID NO:7 and a light chain containing amino acid residue 23 to amino acid residue 236 of SEQ ID NO:8.
恩諾單抗維多汀為針對連接素-4之抗體-藥物結合物(ADC)，其包含經由蛋白酶可裂解之順丁烯二醯亞胺基己醯基纈胺酸-瓜胺酸(vc)連接子(SGD-1006)與小分子微管破裂劑單甲基奧瑞他汀E (MMAE)結合的完全人類抗連接素-4 IgG1κ單株抗體(AGS-22C3)。結合發生在包含抗體之鏈間二硫鍵之半胱胺酸殘基上，產生藥物:抗體比為約3.8:1的產物。分子量為約152 kDa。Ennosumab Vedotin is an antibody-drug conjugate (ADC) targeting nectin-4, which comprises a fully human anti-nectin-4 IgG1κ monoclonal antibody (AGS-22C3) conjugated to a small molecule microtubule disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable cis-butylenediimidohexanoylvaleric acid-citrulline (vc) linker (SGD-1006). Binding occurs at the cysteine residue containing the interchain disulfide bond of the antibody, resulting in a product with a drug:antibody ratio of approximately 3.8:1. The molecular weight is approximately 152 kDa.
恩諾單抗維多汀具有以下結構式：Ennosumab vedotin has the following structural formula:
約4分子之MMAE與各抗體分子連接。藉由化學結合抗體及小分子組分，產生恩諾單抗維多汀。抗體由哺乳動物(中國倉鼠卵巢)細胞產生，且小分子組分藉由化學合成產生。Approximately 4 molecules of MMAE are linked to each antibody molecule. Ennotumab vedotin is produced by chemically combining the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule component is produced by chemical synthesis.
恩諾單抗維多汀注射劑係以無菌、不含防腐劑的白色至灰白色凍乾粉末形式提供於單次劑量小瓶中供靜脈內使用。供應呈20 mg/小瓶及30 mg/小瓶形式之恩諾單抗維多汀，且需要用USP注射用無菌水(分別2.3 mL及3.3 mL)復原，產生最終濃度為10 mg/mL的透明至略微乳白色、無色至略微黃色的溶液。在復原之後，各小瓶允許抽取2 mL (20 mg)及3 mL (30 mg)。每毫升復原溶液含有10 mg恩諾單抗維多汀、組胺酸(1.4 mg)、單水合組胺酸鹽酸鹽(2.31 mg)、聚山梨醇酯20 (0.2 mg)及二水合海藻糖(55 mg)，pH為6.0。5.4醫藥組合物Enrotumab vedotin injection is supplied as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use. Enrotumab vedotin is supplied as 20 mg/vial and 30 mg/vial and requires reconstitution with USP Sterile Water for Injection (2.3 mL and 3.3 mL, respectively) to produce a clear to slightly opalescent, colorless to slightly yellow solution with a final concentration of 10 mg/mL. After reconstitution, each vial allows for the withdrawal of 2 mL (20 mg) and 3 mL (30 mg). Each mL of reconstituted solution contains 10 mg of enrotumab vedotin, histidine (1.4 mg), histidine hydrochloride monohydrate (2.31 mg), polysorbate 20 (0.2 mg), and trehalose dihydrate (55 mg) at a pH of 6.0.5.4Pharmaceutical compositions
在本文所提供之方法的某些實施例中，該等方法中使用之活性成分(諸如ADC及派姆單抗)以「醫藥組合物」形式提供。此類醫藥組合物包括本文所提供之抗體藥物結合物，及一或多種醫藥學上可接受或生理學上可接受之賦形劑。在一些實施例中，抗體藥物結合物與檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如派姆單抗)組合或分開提供。在一些實施例中，抗體藥物結合物與派姆單抗組合或分開提供。亦提供一種組合物，其包含抗體藥物結合物及派姆單抗以及一或多種醫藥學上可接受或生理學上可接受之賦形劑。在特定實施例中，抗體藥物結合物及派姆單抗以治療可接受量存在。在某些實施例中，抗體藥物結合物及派姆單抗與一或多種額外藥劑組合或分開提供。亦提供一種組合物，其包含此類一或多種額外藥劑及一或多種醫藥學上可接受或生理學上可接受之賦形劑。在特定實施例中，抗體藥物結合物及額外藥劑以治療可接受量存在。可根據本文提供之方法及用途來使用醫藥組合物。因此，舉例而言，可向個體離體或活體內投與醫藥組合物，以便實踐本文提供之治療方法及用途。本文所提供之醫藥組合物可經調配以與預期方法或投藥途徑相容；例示性投藥途徑在本文中闡述。In certain embodiments of the methods provided herein, the active ingredients used in the methods (such as ADC and pembrolizumab) are provided in the form of a "pharmaceutical composition." Such pharmaceutical compositions include the antibody drug conjugates provided herein, and one or more pharmaceutically acceptable or physiologically acceptable excipients. In some embodiments, the antibody drug conjugate is provided in combination or separately with a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as pembrolizumab). In some embodiments, the antibody drug conjugate is provided in combination or separately with pembrolizumab. A composition is also provided, comprising an antibody drug conjugate and pembrolizumab and one or more pharmaceutically acceptable or physiologically acceptable excipients. In specific embodiments, the antibody drug conjugate and pembrolizumab are present in therapeutically acceptable amounts. In certain embodiments, the antibody-drug conjugate and pembrolizumab are provided in combination or separately with one or more additional agents. Also provided is a composition comprising such one or more additional agents and one or more pharmaceutically acceptable or physiologically acceptable excipients. In specific embodiments, the antibody-drug conjugate and the additional agent are present in therapeutically acceptable amounts. The pharmaceutical compositions can be used according to the methods and uses provided herein. Thus, for example, the pharmaceutical compositions can be administered to an individual ex vivo or in vivo in order to practice the treatment methods and uses provided herein. The pharmaceutical compositions provided herein can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are described herein.
在一些實施例中，提供調節癌症或腫瘤之抗體藥物結合物及派姆單抗的醫藥組合物。In some embodiments, pharmaceutical compositions of cancer or tumor modulating antibody drug conjugates and pembrolizumab are provided.
在本文所提供之方法的某些實施例中，包含ADC及派姆單抗之醫藥組合物可進一步包含本文所揭示或熟習此項技術者已知的其他治療活性劑或化合物，該等其他治療活性劑或化合物可用於治療或預防如本文所闡述之各種疾病及病症(例如癌症)。如上文所闡述，額外治療活性劑或化合物可存在於獨立醫藥組合物中。In certain embodiments of the methods provided herein, the pharmaceutical compositions comprising ADC and pembrolizumab may further comprise other therapeutic agents or compounds disclosed herein or known to those skilled in the art, which may be used to treat or prevent various diseases and conditions (e.g., cancer) as described herein. As described above, the additional therapeutic agents or compounds may be present in separate pharmaceutical compositions.
醫藥組合物通常包含治療有效量之本文提供之抗體藥物結合物中之至少一者及派姆單抗以及一或多種醫藥學上可接受之調配藥劑。在某些實施例中，醫藥組合物進一步包含一或多種本文所描述之額外藥劑。The pharmaceutical composition generally comprises a therapeutically effective amount of at least one of the antibody-drug conjugates provided herein and pembrolizumab and one or more pharmaceutically acceptable formulation agents. In certain embodiments, the pharmaceutical composition further comprises one or more additional agents described herein.
在一個實施例中，醫藥組合物包含本文所提供之抗體藥物結合物及派姆單抗。在一些實施例中，醫藥組合物包含治療有效量之本文所提供的抗體藥物結合物及派姆單抗。在某些實施例中，醫藥組合物包含醫藥學上可接受之賦形劑。In one embodiment, the pharmaceutical composition comprises an antibody-drug conjugate provided herein and pembrolizumab. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an antibody-drug conjugate provided herein and pembrolizumab. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient.
在一些實施例中，本文所提供之醫藥組合物中的抗體藥物結合物係選自上述章節5.3中所述的抗體藥物結合物。In some embodiments, the antibody-drug conjugate in the pharmaceutical compositions provided herein is selected from the antibody-drug conjugates described in Section 5.3 above.
在某些實施例中，醫藥組合物包含本文所提供之抗體藥物結合物，其量使得投與個體之抗體藥物結合物的劑量為約0.1 mg/kg、約0.5 mg/kg、約0.75 mg/kg、約1 mg/kg、約1.25 mg/kg、約1.5 mg/kg、約2 mg/kg、約2.5 mg/kg、約3 mg/kg、約4 mg/kg、約5 mg/kg、約10 mg/kg、約15 mg/kg、約20 mg/kg、約25 mg/kg、約30 mg/kg、約35 mg/kg、約40 mg/kg、約45 mg/kg、約50 mg/kg、約55 mg/kg、約60 mg/kg、約65 mg/kg、約70 mg/kg、約75 mg/kg、約80 mg/kg、約85 mg/kg、約90 mg/kg、約95 mg/kg、約100 mg/kg。In certain embodiments, the pharmaceutical composition comprises an antibody drug conjugate provided herein in an amount such that the dosage of the antibody drug conjugate administered to a subject is about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg.
在某些實施例中，醫藥組合物包含本文所提供之抗體藥物結合物，其量使得投與個體之抗體藥物結合物的劑量為0.1 mg/kg、0.5 mg/kg、0.75 mg/kg、1 mg/kg、1.25 mg/kg、1.5 mg/kg、2 mg/kg、2.5 mg/kg、3 mg/kg、4 mg/kg、5 mg/kg、10 mg/kg、15 mg/kg、20 mg/kg、25 mg/kg、30 mg/kg、35 mg/kg、40 mg/kg、45 mg/kg、50 mg/kg、55 mg/kg、60 mg/kg、65 mg/kg、70 mg/kg、75 mg/kg、80 mg/kg、85 mg/kg、90 mg/kg、95 mg/kg、100 mg/kg。In certain embodiments, the pharmaceutical composition comprises an antibody drug conjugate provided herein in an amount such that the dosage of the antibody drug conjugate administered to a subject is 0.1 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 1.25 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg.
在某些實施例中，醫藥組合物包含本文所提供之抗體藥物結合物，其量使得投與個體之抗體藥物結合物的劑量為每公斤個體體重約0.1 mg至約100 mg。在一些實施例中，投與患者的劑量為每公斤個體體重約1 mg至約75 mg。在一些實施例中，投與患者的劑量在每公斤個體體重約1 mg與約20 mg之間，諸如每公斤個體體重約1 mg至約5 mg。In certain embodiments, the pharmaceutical composition comprises an antibody-drug conjugate provided herein in an amount such that the dosage of the antibody-drug conjugate administered to a subject is about 0.1 mg to about 100 mg per kg of subject weight. In some embodiments, the dosage administered to a patient is about 1 mg to about 75 mg per kg of subject weight. In some embodiments, the dosage administered to a patient is between about 1 mg and about 20 mg per kg of subject weight, such as about 1 mg to about 5 mg per kg of subject weight.
在某些實施例中，醫藥組合物包含本文所提供之抗體藥物結合物，其量使得投與個體之抗體藥物結合物的劑量為每公斤個體體重0.1 mg至100 mg。在一些實施例中，投與患者的劑量為每公斤個體體重1 mg至75 mg。在一些實施例中，投與患者的劑量在每公斤個體體重1 mg與20 mg之間，諸如每公斤個體體重1 mg至5 mg。In certain embodiments, the pharmaceutical composition comprises an antibody-drug conjugate provided herein in an amount such that the dosage of the antibody-drug conjugate administered to an individual is 0.1 mg to 100 mg per kg of individual body weight. In some embodiments, the dosage administered to a patient is 1 mg to 75 mg per kg of individual body weight. In some embodiments, the dosage administered to a patient is between 1 mg and 20 mg per kg of individual body weight, such as 1 mg to 5 mg per kg of individual body weight.
在某些實施例中，醫藥組合物包含濃度為0.1-100 mg/mL之抗體藥物結合物。在一些實施例中，醫藥組合物包含濃度為1至20 mg/mL之抗體藥物結合物。在其他實施例中，醫藥組合物包含濃度為5至15 mg/mL之抗體藥物結合物。在其他實施例中，醫藥組合物包含濃度為8至12 mg/mL之抗體藥物結合物。在其他實施例中，醫藥組合物包含濃度為9至11 mg/mL之抗體藥物結合物。在一些實施例中，醫藥組合物包含濃度為約9.5 mg/mL之抗體藥物結合物。在一些實施例中，醫藥組合物包含濃度為約9.6 mg/mL之抗體藥物結合物。在一些實施例中，醫藥組合物包含濃度為約9.7 mg/mL之抗體藥物結合物。在一些實施例中，醫藥組合物包含濃度為約9.8 mg/mL之抗體藥物結合物。在一些實施例中，醫藥組合物包含濃度為約9.9 mg/mL之抗體藥物結合物。在又其他實施例中，醫藥組合物包含濃度為約10 mg/mL之抗體藥物結合物。在又其他實施例中，醫藥組合物包含濃度為約10.1 mg/mL之抗體藥物結合物。在一些實施例中，醫藥組合物包含濃度為約10.2 mg/mL之抗體藥物結合物。在一些實施例中，醫藥組合物包含濃度為約10.3 mg/mL之抗體藥物結合物。在一些實施例中，醫藥組合物包含濃度為約10.3 mg/mL之抗體藥物結合物。在一些實施例中，醫藥組合物包含濃度為約10.4 mg/mL之抗體藥物結合物。在一些實施例中，醫藥組合物包含濃度為約10.5 mg/mL之抗體藥物結合物。 在一些實施例中，本文所提供之醫藥組合物包含L-組胺酸、TWEEN-20及二水合海藻糖或蔗糖中之至少一者。在一些實施例中，本文所提供之醫藥組合物進一步包含鹽酸(HCl)或丁二酸。In certain embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of 0.1-100 mg/mL. In some embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of 1 to 20 mg/mL. In other embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of 5 to 15 mg/mL. In other embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of 8 to 12 mg/mL. In other embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of 9 to 11 mg/mL. In some embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of about 9.5 mg/mL. In some embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of about 9.6 mg/mL. In some embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of about 9.7 mg/mL. In some embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of about 9.8 mg/mL. In some embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of about 9.9 mg/mL. In yet other embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of about 10 mg/mL. In yet other embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of about 10.1 mg/mL. In some embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of about 10.2 mg/mL. In some embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of about 10.3 mg/mL. In some embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of about 10.3 mg/mL. In some embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of about 10.4 mg/mL. In some embodiments, the pharmaceutical composition comprises an antibody-drug conjugate at a concentration of about 10.5 mg/mL.In some embodiments, the pharmaceutical composition provided herein comprises L-histidine, TWEEN-20, and at least one of trehalose dihydrate or sucrose. In some embodiments, the pharmaceutical composition provided herein further comprises hydrochloric acid (HCl) or succinic acid.
在某些實施例中，醫藥組合物包含約100 mg、約150 mg、約200 mg、約250 mg、約300 mg、約350 mg、約400 mg、約450 mg或約500 mg之量的派姆單抗。在特定實施例中，醫藥組合物包含約200 mg之量的派姆單抗。In certain embodiments, the pharmaceutical composition comprises about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg of pembrolizumab. In a specific embodiment, the pharmaceutical composition comprises about 200 mg of pembrolizumab.
在某些實施例中，醫藥組合物包含100 mg、150 mg、200 mg、250 mg、300 mg、350 mg、約400 mg、450 mg或500 mg之量的派姆單抗。在特定實施例中，醫藥組合物包含200 mg之量的派姆單抗。In certain embodiments, the pharmaceutical composition comprises 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, about 400 mg, 450 mg, or 500 mg of pembrolizumab. In a specific embodiment, the pharmaceutical composition comprises 200 mg of pembrolizumab.
在某些實施例中，醫藥組合物包含約100 mg至約500 mg、約150 mg至約500 mg、約200 mg至約500 mg、約250 mg至約500 mg、約300 mg至約500 mg、約350 mg至約500 mg、約400 mg至約500 mg或約450 mg至約500 mg之量的派姆單抗。在某些實施例中，醫藥組合物包含約100 mg至約450 mg、約100 mg至約400 mg、約100 mg至約350 mg、約100 mg至約300 mg、約100 mg至約250 mg、約100 mg至約200 mg或約100 mg至約150 mg之量的派姆單抗。在某些實施例中，醫藥組合物包含約150 mg至約450 mg、約150 mg至約400 mg、約150 mg至約350 mg、約200 mg至約450 mg、約200 mg至約400 mg、約200 mg至約300 mg或約200 mg至約250 mg之量的派姆單抗。In certain embodiments, the pharmaceutical composition comprises an amount of pembrolizumab of about 100 mg to about 500 mg, about 150 mg to about 500 mg, about 200 mg to about 500 mg, about 250 mg to about 500 mg, about 300 mg to about 500 mg, about 350 mg to about 500 mg, about 400 mg to about 500 mg, or about 450 mg to about 500 mg. In certain embodiments, the pharmaceutical composition comprises an amount of pembrolizumab of about 100 mg to about 450 mg, about 100 mg to about 400 mg, about 100 mg to about 350 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, or about 100 mg to about 150 mg. In certain embodiments, the pharmaceutical composition comprises pembrolizumab in an amount of about 150 mg to about 450 mg, about 150 mg to about 400 mg, about 150 mg to about 350 mg, about 200 mg to about 450 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, or about 200 mg to about 250 mg.
在某些實施例中，醫藥組合物包含100 mg至500 mg、150 mg至500 mg、200 mg至500 mg、250 mg至500 mg、300 mg至500 mg、350 mg至500 mg、400 mg至500 mg或450 mg至500 mg之量的派姆單抗。在某些實施例中，醫藥組合物包含100 mg至450 mg、100 mg至400 mg、100 mg至350 mg、100 mg至300 mg、100 mg至250 mg、100 mg至200 mg或100 mg至150 mg之量的派姆單抗。在某些實施例中，醫藥組合物包含150 mg至450 mg、150至400 mg、150至350 mg、200 mg至450 mg、200 mg至400 mg、200 mg至300 mg或200 mg至250 mg之量的派姆單抗。In certain embodiments, the pharmaceutical composition comprises 100 mg to 500 mg, 150 mg to 500 mg, 200 mg to 500 mg, 250 mg to 500 mg, 300 mg to 500 mg, 350 mg to 500 mg, 400 mg to 500 mg, or 450 mg to 500 mg of pembrolizumab. In certain embodiments, the pharmaceutical composition comprises 100 mg to 450 mg, 100 mg to 400 mg, 100 mg to 350 mg, 100 mg to 300 mg, 100 mg to 250 mg, 100 mg to 200 mg, or 100 mg to 150 mg of pembrolizumab. In certain embodiments, the pharmaceutical composition comprises pembrolizumab in an amount of 150 mg to 450 mg, 150 to 400 mg, 150 to 350 mg, 200 mg to 450 mg, 200 mg to 400 mg, 200 mg to 300 mg, or 200 mg to 250 mg.
在一些實施例中，適用於本文所提供之醫藥組合物中的L-組胺酸濃度在5與50 mM之間的範圍內。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度在10與40 mM之間的範圍內。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度在15與35 mM之間的範圍內。In some embodiments, the concentration of L-histidine suitable for use in the pharmaceutical compositions provided herein is in the range of between 5 and 50 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is in the range of between 10 and 40 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is in the range of between 15 and 35 mM.
在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度在15與30 mM之間的範圍內。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度在15與25 mM之間的範圍內。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度在15與35 mM之間的範圍內。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度為約16 mM。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度為約17 mM。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度為約18 mM。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度為約19 mM。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度為約20 mM。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度為約21 mM。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度為約22 mM。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度為約23 mM。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度為約24 mM。在一些實施例中，本文所提供之醫藥組合物中的L-組胺酸濃度為約25 mM。In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is in the range of 15 to 30 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is in the range of 15 to 25 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is in the range of 15 to 35 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is about 16 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is about 17 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is about 18 mM. In some embodiments, the concentration of L-histidine in the pharmaceutical compositions provided herein is about 19 mM. In some embodiments, the concentration of L-histamine in the pharmaceutical compositions provided herein is about 20 mM. In some embodiments, the concentration of L-histamine in the pharmaceutical compositions provided herein is about 21 mM. In some embodiments, the concentration of L-histamine in the pharmaceutical compositions provided herein is about 22 mM. In some embodiments, the concentration of L-histamine in the pharmaceutical compositions provided herein is about 23 mM. In some embodiments, the concentration of L-histamine in the pharmaceutical compositions provided herein is about 24 mM. In some embodiments, the concentration of L-histamine in the pharmaceutical compositions provided herein is about 25 mM.
在一些實施例中，適用於本文所提供之醫藥組合物中的TWEEN-20濃度在0.001至0.1% (v/v)之範圍內。在另一實施例中，TWEEN-20之濃度在0.0025至0.075% (v/v)之範圍內。在一個實施例中，TWEEN-20之濃度在0.005至0.05% (v/v)之範圍內。在另一實施例中，TWEEN-20之濃度在0.0075至0.025% (v/v)之範圍內。在另一實施例中，TWEEN-20之濃度在0.0075至0.05% (v/v)之範圍內。在另一實施例中，TWEEN-20之濃度在0.01至0.03% (v/v)之範圍內。在一個特定實施例中，TWEEN-20之濃度為約0.01% (v/v)。在一個特定實施例中，TWEEN-20之濃度為約0.015% (v/v)。在一個特定實施例中，TWEEN-20之濃度為約0.016% (v/v)。在一個特定實施例中，TWEEN-20之濃度為約0.017% (v/v)。在一個特定實施例中，TWEEN-20之濃度為約0.018% (v/v)。在一個特定實施例中，TWEEN-20之濃度為約0.019% (v/v)。在一個特定實施例中，TWEEN-20之濃度為約0.02% (v/v)。在一個特定實施例中，TWEEN-20之濃度為約0.021% (v/v)。在一個特定實施例中，TWEEN-20之濃度為約0.022% (v/v)。在一個特定實施例中，TWEEN-20之濃度為約0.023% (v/v)。在一個特定實施例中，TWEEN-20之濃度為約0.024% (v/v)。在一個特定實施例中，TWEEN-20之濃度為約0.025% (v/v)。In some embodiments, the concentration of TWEEN-20 suitable for use in the pharmaceutical compositions provided herein is in the range of 0.001 to 0.1% (v/v). In another embodiment, the concentration of TWEEN-20 is in the range of 0.0025 to 0.075% (v/v). In one embodiment, the concentration of TWEEN-20 is in the range of 0.005 to 0.05% (v/v). In another embodiment, the concentration of TWEEN-20 is in the range of 0.0075 to 0.025% (v/v). In another embodiment, the concentration of TWEEN-20 is in the range of 0.0075 to 0.05% (v/v). In another embodiment, the concentration of TWEEN-20 is in the range of 0.01 to 0.03% (v/v). In a specific embodiment, the concentration of TWEEN-20 is about 0.01% (v/v). In a specific embodiment, the concentration of TWEEN-20 is about 0.015% (v/v). In a specific embodiment, the concentration of TWEEN-20 is about 0.016% (v/v). In a specific embodiment, the concentration of TWEEN-20 is about 0.017% (v/v). In a specific embodiment, the concentration of TWEEN-20 is about 0.018% (v/v). In a specific embodiment, the concentration of TWEEN-20 is about 0.019% (v/v). In a particular embodiment, the concentration of TWEEN-20 is about 0.02% (v/v). In a particular embodiment, the concentration of TWEEN-20 is about 0.021% (v/v). In a particular embodiment, the concentration of TWEEN-20 is about 0.022% (v/v). In a particular embodiment, the concentration of TWEEN-20 is about 0.023% (v/v). In a particular embodiment, the concentration of TWEEN-20 is about 0.024% (v/v). In a particular embodiment, the concentration of TWEEN-20 is about 0.025% (v/v).
在一個實施例中，適用於本文所提供之醫藥組合物中的二水合海藻糖濃度在1%與20% (w/v)之間的範圍內。在另一實施例中，二水合海藻糖之濃度在2%至15% (w/v)之範圍內。在一個實施例中，二水合海藻糖之濃度在3%至10% (w/v)之範圍內。在另一實施例中，二水合海藻糖之濃度在4%至9% (w/v)之範圍內。在另一實施例中，二水合海藻糖之濃度在4%至8% (w/v)之範圍內。在另一實施例中，二水合海藻糖之濃度在4%至7% (w/v)之範圍內。在另一實施例中，二水合海藻糖之濃度在4%至6% (w/v)之範圍內。在另一實施例中，二水合海藻糖之濃度在4.5%至6% (w/v)之範圍內。在另一實施例中，二水合海藻糖之濃度為約4.6% (w/v)。在另一實施例中，二水合海藻糖之濃度為約4.7% (w/v)。在另一實施例中，二水合海藻糖之濃度為約4.8% (w/v)。在另一實施例中，二水合海藻糖之濃度為約4.9% (w/v)。在另一實施例中，二水合海藻糖之濃度為約5.0% (w/v)。在另一實施例中，二水合海藻糖之濃度為約5.1% (w/v)。在另一實施例中，二水合海藻糖之濃度為約5.2% (w/v)。在另一實施例中，二水合海藻糖之濃度為約5.3% (w/v)。在另一實施例中，二水合海藻糖之濃度為約5.4% (w/v)。在另一實施例中，二水合海藻糖之濃度為約5.5% (w/v)。在另一實施例中，二水合海藻糖之濃度為約5.6% (w/v)。在另一實施例中，二水合海藻糖之濃度為約5.7% (w/v)。在另一實施例中，二水合海藻糖之濃度為約5.8% (w/v)。在另一實施例中，二水合海藻糖之濃度為約5.9% (w/v)。在另一實施例中，二水合海藻糖之濃度為約6.0% (w/v)。在另一實施例中，二水合海藻糖之濃度為約6.1% (w/v)。在另一實施例中，二水合海藻糖之濃度為約6.2% (w/v)。在另一實施例中，二水合海藻糖之濃度為約6.3% (w/v)。在另一實施例中，二水合海藻糖之濃度為約6.4% (w/v)。在另一實施例中，二水合海藻糖之濃度為約6.5% (w/v)。In one embodiment, the concentration of dihydrated trehalose suitable for use in the pharmaceutical compositions provided herein is in the range of 1% to 20% (w/v). In another embodiment, the concentration of dihydrated trehalose is in the range of 2% to 15% (w/v). In one embodiment, the concentration of dihydrated trehalose is in the range of 3% to 10% (w/v). In another embodiment, the concentration of dihydrated trehalose is in the range of 4% to 9% (w/v). In another embodiment, the concentration of dihydrated trehalose is in the range of 4% to 8% (w/v). In another embodiment, the concentration of dihydrated trehalose is in the range of 4% to 7% (w/v). In another embodiment, the concentration of trehalose dihydrate is in the range of 4% to 6% (w/v). In another embodiment, the concentration of trehalose dihydrate is in the range of 4.5% to 6% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 4.6% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 4.7% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 4.8% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 4.9% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.0% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.1% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.2% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.3% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.4% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.5% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.6% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.7% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.8% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 5.9% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 6.0% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 6.1% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 6.2% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 6.3% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 6.4% (w/v). In another embodiment, the concentration of trehalose dihydrate is about 6.5% (w/v).
在某些實施例中，二水合海藻糖之莫耳濃度為50至300 mM。在其他實施例中，二水合海藻糖之莫耳濃度為75至250 mM。在一些實施例中，二水合海藻糖之莫耳濃度為100至200 mM。在其他實施例中，二水合海藻糖之莫耳濃度為130至150 mM。在一些實施例中，二水合海藻糖之莫耳濃度為135至150 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約135 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約136 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約137 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約138 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約139 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約140 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約141 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約142 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約143 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約144 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約145 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約146 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約150 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約151 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約151 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約152 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約153 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約154 mM。在某些實施例中，二水合海藻糖之莫耳濃度為約155 mM。In certain embodiments, the molar concentration of trehalose dihydrate is 50 to 300 mM. In other embodiments, the molar concentration of trehalose dihydrate is 75 to 250 mM. In some embodiments, the molar concentration of trehalose dihydrate is 100 to 200 mM. In other embodiments, the molar concentration of trehalose dihydrate is 130 to 150 mM. In some embodiments, the molar concentration of trehalose dihydrate is 135 to 150 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 135 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 136 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 137 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 138 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 139 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 140 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 141 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 142 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 143 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 144 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 145 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 146 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 150 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 151 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 151 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 152 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 153 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 154 mM. In certain embodiments, the molar concentration of trehalose dihydrate is about 155 mM.
在一個實施例中，適用於本文所提供之醫藥組合物中的蔗糖濃度在1%與20% (w/v)之間的範圍內。在另一實施例中，蔗糖之濃度在2%至15% (w/v)之範圍內。在一個實施例中，蔗糖之濃度在3%至10% (w/v)之範圍內。在另一實施例中，蔗糖之濃度在4%至9% (w/v)之範圍內。在另一實施例中，蔗糖之濃度在4%至8% (w/v)之範圍內。在另一實施例中，蔗糖之濃度在4%至7% (w/v)之範圍內。在另一實施例中，蔗糖之濃度在4%至6% (w/v)之範圍內。在另一實施例中，蔗糖之濃度在4.5%至6% (w/v)之範圍內。在另一實施例中，蔗糖之濃度為約4.6% (w/v)。在另一實施例中，蔗糖之濃度為約4.7% (w/v)。在另一實施例中，蔗糖之濃度為約4.8% (w/v)。在另一實施例中，蔗糖之濃度為約4.9% (w/v)。在另一實施例中，蔗糖之濃度為約5.0% (w/v)。在另一實施例中，蔗糖之濃度為約5.1% (w/v)。在另一實施例中，蔗糖之濃度為約5.2% (w/v)。在另一實施例中，蔗糖之濃度為約5.3% (w/v)。在另一實施例中，蔗糖之濃度為約5.4% (w/v)。在另一實施例中，蔗糖之濃度為約5.5% (w/v)。在另一實施例中，蔗糖之濃度為約5.6% (w/v)。在另一實施例中，蔗糖之濃度為約5.7% (w/v)。在另一實施例中，蔗糖之濃度為約5.8% (w/v)。在另一實施例中，蔗糖之濃度為約5.9% (w/v)。在另一實施例中，蔗糖之濃度為約6.0% (w/v)。在另一實施例中，蔗糖之濃度為約6.1% (w/v)。在另一實施例中，蔗糖之濃度為約6.2% (w/v)。在另一實施例中，蔗糖之濃度為約6.3% (w/v)。在另一實施例中，蔗糖之濃度為約6.4% (w/v)。在另一實施例中，蔗糖之濃度為約6.5% (w/v)。In one embodiment, the concentration of sucrose suitable for use in the pharmaceutical compositions provided herein is in the range of 1% to 20% (w/v). In another embodiment, the concentration of sucrose is in the range of 2% to 15% (w/v). In one embodiment, the concentration of sucrose is in the range of 3% to 10% (w/v). In another embodiment, the concentration of sucrose is in the range of 4% to 9% (w/v). In another embodiment, the concentration of sucrose is in the range of 4% to 8% (w/v). In another embodiment, the concentration of sucrose is in the range of 4% to 7% (w/v). In another embodiment, the concentration of sucrose is in the range of 4% to 6% (w/v). In another embodiment, the concentration of sucrose is in the range of 4.5% to 6% (w/v). In another embodiment, the concentration of sucrose is about 4.6% (w/v). In another embodiment, the concentration of sucrose is about 4.7% (w/v). In another embodiment, the concentration of sucrose is about 4.8% (w/v). In another embodiment, the concentration of sucrose is about 4.9% (w/v). In another embodiment, the concentration of sucrose is about 5.0% (w/v). In another embodiment, the concentration of sucrose is about 5.1% (w/v). In another embodiment, the concentration of sucrose is about 5.2% (w/v). In another embodiment, the concentration of sucrose is about 5.3% (w/v). In another embodiment, the concentration of sucrose is about 5.4% (w/v). In another embodiment, the concentration of sucrose is about 5.5% (w/v). In another embodiment, the concentration of sucrose is about 5.6% (w/v). In another embodiment, the concentration of sucrose is about 5.7% (w/v). In another embodiment, the concentration of sucrose is about 5.8% (w/v). In another embodiment, the concentration of sucrose is about 5.9% (w/v). In another embodiment, the concentration of sucrose is about 6.0% (w/v). In another embodiment, the concentration of sucrose is about 6.1% (w/v). In another embodiment, the concentration of sucrose is about 6.2% (w/v). In another embodiment, the concentration of sucrose is about 6.3% (w/v). In another embodiment, the concentration of sucrose is about 6.4% (w/v). In another embodiment, the concentration of sucrose is about 6.5% (w/v).
在某些實施例中，蔗糖之莫耳濃度為50至300 mM。在其他實施例中，蔗糖之莫耳濃度為75至250 mM。在一些實施例中，蔗糖之莫耳濃度為100至200 mM。在其他實施例中，蔗糖之莫耳濃度為130至150 mM。在一些實施例中，蔗糖之莫耳濃度為135至150 mM。在某些實施例中，蔗糖之莫耳濃度為約135 mM。在某些實施例中，蔗糖之莫耳濃度為約136 mM。在某些實施例中，蔗糖之莫耳濃度為約137 mM。在某些實施例中，蔗糖之莫耳濃度為約138 mM。在某些實施例中，蔗糖之莫耳濃度為約139 mM。在某些實施例中，蔗糖之莫耳濃度為約140 mM。在某些實施例中，蔗糖之莫耳濃度為約141 mM。在某些實施例中，蔗糖之莫耳濃度為約142 mM。在某些實施例中，蔗糖之莫耳濃度為約143 mM。在某些實施例中，蔗糖之莫耳濃度為約144 mM。在某些實施例中，蔗糖之莫耳濃度為約145 mM。在某些實施例中，蔗糖之莫耳濃度為約146 mM。在某些實施例中，蔗糖之莫耳濃度為約150 mM。在某些實施例中，蔗糖之莫耳濃度為約151 mM。在某些實施例中，蔗糖之莫耳濃度為約151 mM。在某些實施例中，蔗糖之莫耳濃度為約152 mM。在某些實施例中，蔗糖之莫耳濃度為約153 mM。在某些實施例中，蔗糖之莫耳濃度為約154 mM。在某些實施例中，蔗糖之莫耳濃度為約155 mM。In some embodiments, the molar concentration of sucrose is 50 to 300 mM. In other embodiments, the molar concentration of sucrose is 75 to 250 mM. In some embodiments, the molar concentration of sucrose is 100 to 200 mM. In other embodiments, the molar concentration of sucrose is 130 to 150 mM. In some embodiments, the molar concentration of sucrose is 135 to 150 mM. In some embodiments, the molar concentration of sucrose is about 135 mM. In some embodiments, the molar concentration of sucrose is about 136 mM. In some embodiments, the molar concentration of sucrose is about 137 mM. In some embodiments, the molar concentration of sucrose is about 138 mM. In some embodiments, the molar concentration of sucrose is about 139 mM. In some embodiments, the molar concentration of sucrose is about 140 mM. In some embodiments, the molar concentration of sucrose is about 141 mM. In some embodiments, the molar concentration of sucrose is about 142 mM. In some embodiments, the molar concentration of sucrose is about 143 mM. In some embodiments, the molar concentration of sucrose is about 144 mM. In some embodiments, the molar concentration of sucrose is about 145 mM. In some embodiments, the molar concentration of sucrose is about 146 mM. In some embodiments, the molar concentration of sucrose is about 150 mM. In some embodiments, the molar concentration of sucrose is about 151 mM. In some embodiments, the molar concentration of sucrose is about 151 mM. In some embodiments, the molar concentration of sucrose is about 152 mM. In some embodiments, the molar concentration of sucrose is about 153 mM. In some embodiments, the molar concentration of sucrose is about 154 mM. In some embodiments, the molar concentration of sucrose is about 155 mM.
在一些實施例中，本文所提供之醫藥組合物包含HCl。在其他實施例中，本文所提供之醫藥組合物包含丁二酸。In some embodiments, the pharmaceutical compositions provided herein include HCl. In other embodiments, the pharmaceutical compositions provided herein include succinic acid.
在一些實施例中，本文所提供之醫藥組合物具有5.5至6.5範圍內之pH。在其他實施例中，本文所提供之醫藥組合物具有5.7至6.3範圍內之pH。在一些實施例中，本文所提供之醫藥組合物的pH為約5.7。在一些實施例中，本文所提供之醫藥組合物的pH為約5.8。在一些實施例中，本文所提供之醫藥組合物的pH為約5.9。在一些實施例中，本文所提供之醫藥組合物的pH為約6.0。在一些實施例中，本文所提供之醫藥組合物的pH為約6.1。在一些實施例中，本文所提供之醫藥組合物的pH為約6.2。在一些實施例中，本文所提供之醫藥組合物的pH為約6.3。In some embodiments, the pharmaceutical compositions provided herein have a pH in the range of 5.5 to 6.5. In other embodiments, the pharmaceutical compositions provided herein have a pH in the range of 5.7 to 6.3. In some embodiments, the pH of the pharmaceutical compositions provided herein is about 5.7. In some embodiments, the pH of the pharmaceutical compositions provided herein is about 5.8. In some embodiments, the pH of the pharmaceutical compositions provided herein is about 5.9. In some embodiments, the pH of the pharmaceutical compositions provided herein is about 6.0. In some embodiments, the pH of the pharmaceutical compositions provided herein is about 6.1. In some embodiments, the pH of the pharmaceutical compositions provided herein is about 6.2. In some embodiments, the pH of the pharmaceutical compositions provided herein is about 6.3.
在一些實施例中，pH係在室溫下獲得。在其他實施例中，pH係在15℃至27℃下獲得。在又其他實施例中，pH係在4℃下獲得。在又其他實施例中，pH係在25℃下獲得。In some embodiments, the pH is obtained at room temperature. In other embodiments, the pH is obtained at 15°C to 27°C. In still other embodiments, the pH is obtained at 4°C. In still other embodiments, the pH is obtained at 25°C.
在一些實施例中，藉由HCl調節pH。在一些實施例中，醫藥組合物包含HCl，且醫藥組合物在室溫下具有5.5至6.5範圍內的pH。在一些實施例中，醫藥組合物包含HCl，且醫藥組合物在室溫下具有5.7至6.3範圍內的pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在室溫下具有約5.7之pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在室溫下具有約5.8之pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在室溫下具有約5.9之pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在室溫下具有約6.0之pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在室溫下具有約6.1之pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在室溫下具有約6.2之pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在室溫下具有約6.3之pH。In some embodiments, the pH is adjusted by HCl. In some embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH in the range of 5.5 to 6.5 at room temperature. In some embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH in the range of 5.7 to 6.3 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 5.7 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 5.8 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 5.9 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 6.0 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 6.1 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 6.2 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 6.3 at room temperature.
在一些實施例中，醫藥組合物包含HCl，且醫藥組合物在15℃至27℃下具有5.5至6.5範圍內的pH。在一些實施例中，醫藥組合物包含HCl，且醫藥組合物在15℃至27℃下具有5.7至6.3範圍內的pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在15℃至27℃下具有約5.7之pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在15℃至27℃下具有約5.8之pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在15℃至27℃下具有約5.9之pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在15℃至27℃下具有約6.0之pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在15℃至27℃下具有約6.1之pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在15℃至27℃下具有約6.2之pH。在一些更特定實施例中，醫藥組合物包含HCl，且醫藥組合物在15℃至27℃下具有約6.3之pH。In some embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH in the range of 5.5 to 6.5 at 15°C to 27°C. In some embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH in the range of 5.7 to 6.3 at 15°C to 27°C. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 5.7 at 15°C to 27°C. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 5.8 at 15°C to 27°C. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 5.9 at 15°C to 27°C. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 6.0 at 15°C to 27°C. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 6.1 at 15° C. to 27° C. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 6.2 at 15° C. to 27° C. In some more specific embodiments, the pharmaceutical composition comprises HCl, and the pharmaceutical composition has a pH of about 6.3 at 15° C. to 27° C.
在一些實施例中，藉由丁二酸調節pH。在一些實施例中，醫藥組合物包含丁二酸，且醫藥組合物在室溫下具有5.5至6.5範圍內之pH。在一些實施例中，醫藥組合物包含丁二酸，且醫藥組合物在室溫下具有5.7至6.3範圍內之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在室溫下具有約5.7之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在室溫下具有約5.8之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在室溫下具有約5.9之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在室溫下具有約6.0之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在室溫下具有約6.1之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在室溫下具有約6.2之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在室溫下具有約6.3之pH。In some embodiments, pH is adjusted by succinic acid. In some embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH in the range of 5.5 to 6.5 at room temperature. In some embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH in the range of 5.7 to 6.3 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 5.7 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 5.8 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 5.9 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 6.0 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 6.1 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 6.2 at room temperature. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 6.3 at room temperature.
在一些實施例中，醫藥組合物包含丁二酸，且醫藥組合物在15℃至27℃下具有5.5至6.5範圍內之pH。在一些實施例中，醫藥組合物包含丁二酸，且醫藥組合物在15℃至27℃下具有5.7至6.3範圍內之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在15℃至27℃下具有約5.7之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在15℃至27℃下具有約5.8之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在15℃至27℃下具有約5.9之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在15℃至27℃下具有約6.0之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在15℃至27℃下具有約6.1之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在15℃至27℃下具有約6.2之pH。在一些更特定實施例中，醫藥組合物包含丁二酸，且醫藥組合物在15℃至27℃下具有約6.3之pH。In some embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH in the range of 5.5 to 6.5 at 15°C to 27°C. In some embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH in the range of 5.7 to 6.3 at 15°C to 27°C. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 5.7 at 15°C to 27°C. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 5.8 at 15°C to 27°C. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 5.9 at 15°C to 27°C. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 6.0 at 15°C to 27°C. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 6.1 at 15° C. to 27° C. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 6.2 at 15° C. to 27° C. In some more specific embodiments, the pharmaceutical composition comprises succinic acid, and the pharmaceutical composition has a pH of about 6.3 at 15° C. to 27° C.
在一些特定實施例中，本文所提供之醫藥組合物包含約20 mM L-組胺酸、約0.02% (w/v) TWEEN-20，及約5.5% (w/v)二水合海藻糖或約5% (w/v)蔗糖中之至少一者。在一些實施例中，本文所提供之醫藥組合物進一步包含HCl或丁二酸。在一些實施例中，在室溫下pH為約6.0。在一些實施例中，在25℃下pH為約6.0。In some specific embodiments, the pharmaceutical compositions provided herein comprise about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, and at least one of about 5.5% (w/v) trehalose dihydrate or about 5% (w/v) sucrose. In some embodiments, the pharmaceutical compositions provided herein further comprise HCl or succinic acid. In some embodiments, the pH is about 6.0 at room temperature. In some embodiments, the pH is about 6.0 at 25°C.
在一些特定實施例中，本文所提供之醫藥組合物包含約20 mM L-組胺酸、約0.02% (w/v) TWEEN-20、約5.5% (w/v)二水合海藻糖及HCl。在一些實施例中，在室溫下pH為約6.0。在一些實施例中，在25℃下pH為約6.0。In some specific embodiments, the pharmaceutical compositions provided herein comprise about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.5% (w/v) trehalose dihydrate, and HCl. In some embodiments, the pH is about 6.0 at room temperature. In some embodiments, the pH is about 6.0 at 25°C.
在一些特定實施例中，本文所提供之醫藥組合物包含約20 mM L-組胺酸、約0.02% (w/v) TWEEN-20、約5% (w/v)蔗糖及HCl。在一些實施例中，在室溫下pH為約6.0。在一些實施例中，在25℃下pH為約6.0。In some specific embodiments, the pharmaceutical compositions provided herein comprise about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5% (w/v) sucrose, and HCl. In some embodiments, the pH is about 6.0 at room temperature. In some embodiments, the pH is about 6.0 at 25°C.
在其他特定實施例中，本文所提供之醫藥組合物包含約20 mM L-組胺酸、約0.02% (w/v) TWEEN-20、約5.5% (w/v)二水合海藻糖及丁二酸。在一些實施例中，在室溫下pH為約6.0。在一些實施例中，在25℃下pH為約6.0。In other specific embodiments, the pharmaceutical compositions provided herein comprise about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.5% (w/v) trehalose dihydrate, and succinic acid. In some embodiments, the pH is about 6.0 at room temperature. In some embodiments, the pH is about 6.0 at 25°C.
在一些特定實施例中，本文所提供之醫藥組合物包含約20 mM L-組胺酸、約0.02% (w/v) TWEEN-20、約5% (w/v)蔗糖及丁二酸。在一些實施例中，在室溫下pH為約6.0。在一些實施例中，在25℃下pH為約6.0。In some specific embodiments, the pharmaceutical compositions provided herein comprise about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5% (w/v) sucrose and succinic acid. In some embodiments, the pH is about 6.0 at room temperature. In some embodiments, the pH is about 6.0 at 25°C.
在一特定實施例中，本文所提供的包含 (a) 抗體藥物結合物，其包含以下結構：其中L-表示抗體或其抗原結合片段(例如抗連接素-4抗體或其抗原結合片段)且p為1至10；及 (b) 醫藥學上可接受之賦形劑，其包含約20 mM L-組胺酸、約0.02% (w/v) TWEEN-20、約5.5% (w/v)二水合海藻糖及HCl，其中抗體藥物結合物之濃度為約10 mg/mL，且其中在25℃下pH為約6.0。In a specific embodiment, provided herein is (a) an antibody-drug conjugate comprising the following structure: wherein L- represents an antibody or an antigen-binding fragment thereof (e.g., an anti-nectin-4 antibody or an antigen-binding fragment thereof) and p is 1 to 10; and (b) a pharmaceutically acceptable excipient comprising about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.5% (w/v) trehalose dihydrate, and HCl, wherein the concentration of the antibody drug conjugate is about 10 mg/mL, and wherein the pH is about 6.0 at 25°C.
在另一特定實施例中，本文所提供之醫藥組合物包含： (a) 抗體藥物結合物，其包含以下結構：其中L-表示抗體或其抗原結合片段(例如抗連接素-4抗體或其抗原結合片段)且p為1至10；及 (b) 醫藥學上可接受之賦形劑，其包含約20 mM L-組胺酸、約0.02% (w/v) TWEEN-20、約5.5% (w/v)二水合海藻糖及丁二酸， 其中抗體藥物結合物之濃度為約10 mg/mL，且其中在25℃下pH為約6.0。In another specific embodiment, the pharmaceutical composition provided herein comprises: (a) an antibody-drug conjugate comprising the following structure: wherein L- represents an antibody or an antigen-binding fragment thereof (e.g., an anti-nectin-4 antibody or an antigen-binding fragment thereof) and p is 1 to 10; and (b) a pharmaceutically acceptable excipient comprising about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.5% (w/v) trehalose dihydrate, and succinic acid, wherein the concentration of the antibody-drug conjugate is about 10 mg/mL, and wherein the pH is about 6.0 at 25°C.
在又另一特定實施例中，本文所提供之醫藥組合物包含： (a) 抗體藥物結合物，其包含以下結構：其中L-表示抗體或其抗原結合片段(例如抗連接素-4抗體或其抗原結合片段)且p為1至10；及 (b) 醫藥學上可接受之賦形劑，其包含約20 mM L-組胺酸、約0.02% (w/v) TWEEN-20、約5.0% (w/v)蔗糖及HCl， 其中抗體藥物結合物之濃度為約10 mg/mL，且其中在25℃下pH為約6.0。In yet another specific embodiment, the pharmaceutical composition provided herein comprises: (a) an antibody-drug conjugate comprising the following structure: wherein L- represents an antibody or an antigen-binding fragment thereof (e.g., an anti-nectin-4 antibody or an antigen-binding fragment thereof) and p is 1 to 10; and (b) a pharmaceutically acceptable excipient comprising about 20 mM L-histidine, about 0.02% (w/v) TWEEN-20, about 5.0% (w/v) sucrose, and HCl, wherein the concentration of the antibody drug conjugate is about 10 mg/mL, and wherein the pH is about 6.0 at 25°C.
儘管提供某些數字(及其數值範圍)，但應瞭解，在某些實施例中，亦考慮該等數字(或數值範圍)之例如2%、5%、10%、15%或20%以內的數值。Although certain numbers (and numerical ranges thereof) are provided, it should be understood that in certain embodiments, values within, for example, 2%, 5%, 10%, 15% or 20% of such numbers (or numerical ranges) are also contemplated.
媒劑中之主溶劑在本質上可為水性或非水性的。另外，媒劑可含有用於調節或維持醫藥組合物之pH、容積滲透濃度、黏度、無菌或穩定性的醫藥學上可接受之其他賦形劑。在某些實施例中，醫藥學上可接受之媒劑為水性緩衝液。在其他實施例中，媒劑包含例如氯化鈉及/或檸檬酸鈉。The main solvent in the medium can be aqueous or non-aqueous in nature. In addition, the medium may contain other pharmaceutically acceptable excipients for adjusting or maintaining the pH, volume osmotic concentration, viscosity, sterility or stability of the pharmaceutical composition. In certain embodiments, the pharmaceutically acceptable medium is an aqueous buffer. In other embodiments, the medium comprises, for example, sodium chloride and/or sodium citrate.
本文所提供之醫藥組合物可含有用於調節或維持如本文所述之抗體藥物結合物及/或另一種藥劑之釋放速率的醫藥學上可接受之又其他調配劑。此類調配劑包括熟習製備持續釋放型調配物之技術者已知之彼等物質。關於醫藥學上及生理學上可接受之調配劑的其他參考文獻，參見例如Remington's Pharmaceutical Sciences, 第18版(1990, Mack Publishing Co., Easton, Pa. 18042), 第1435-1712頁, The Merck Index, 第12版(1996, Merck Publishing Group, Whitehouse, NJ)；及Pharmaceutical Principles of Solid Dosage Forms (1993, Technonic Publishing Co., Inc., Lancaster, Pa.)。適合投與的其他醫藥組合物為此項技術中已知的，且適用於本文所提供之方法及組合物中。The pharmaceutical compositions provided herein may contain other pharmaceutically acceptable formulations for regulating or maintaining the release rate of the antibody-drug conjugates and/or another agent as described herein. Such formulations include those known to those skilled in the art of preparing sustained-release formulations. For other references to pharmaceutically and physiologically acceptable formulations, see, for example, Remington's Pharmaceutical Sciences, 18th edition (1990, Mack Publishing Co., Easton, Pa. 18042), pages 1435-1712, The Merck Index, 12th edition (1996, Merck Publishing Group, Whitehouse, NJ); and Pharmaceutical Principles of Solid Dosage Forms (1993, Technonic Publishing Co., Inc., Lancaster, Pa.). Other pharmaceutical compositions suitable for administration are known in the art and are suitable for use in the methods and compositions provided herein.
在一些實施例中，本文所提供之醫藥組合物呈液體形式。在其他實施例中，本文所提供之醫藥組合物為凍乾的。In some embodiments, the pharmaceutical compositions provided herein are in liquid form. In other embodiments, the pharmaceutical compositions provided herein are lyophilized.
醫藥組合物可經調配以與其預期投藥途徑相容。因此，醫藥組合物包括適合於藉由包括以下之途徑投與之賦形劑：非經腸(例如皮下(s.c.)、靜脈內、肌肉內或腹膜內)、皮內、經口(例如攝取)、吸入、腔內、顱內及經皮(局部)。本文闡述其他例示性投與途徑。The pharmaceutical composition can be formulated to be compatible with its intended route of administration. Thus, the pharmaceutical composition includes dosage forms suitable for administration by routes including parenteral (e.g., subcutaneous (s.c.), intravenous, intramuscular or intraperitoneal), intradermal, oral (e.g., ingestion), inhalation, intracavity, intracranial, and transdermal (topical). Other exemplary routes of administration are described herein.
醫藥組合物可呈無菌可注射水性或油性懸浮液形式。此懸浮液可使用本文所揭示或熟習此項技術者已知之適合分散劑或濕潤劑及懸浮劑調配。無菌可注射製劑亦可為存在於非經腸可接受之無毒稀釋劑或溶劑中的無菌可注射溶液或懸浮液，例如1,3-丁二醇中之溶液。可採用的可接受之稀釋劑、溶劑及分散介質包括水、林格氏溶液(Ringer's solution)、等張氯化鈉溶液、Cremophor EL™ (BASF，Parsippany，NJ)或磷酸鹽緩衝鹽水(PBS)、乙醇、多元醇(例如丙三醇、丙二醇及液體聚乙二醇)及其適合混合物。另外，無菌不揮發性油習知地用作溶劑或懸浮介質。出於此目的，可採用任何溫和的不揮發性油，包括合成單甘油酯或二甘油酯。此外，諸如油酸之脂肪酸可用於製備可注射劑。特定可注射調配物之延長吸收可藉由包括延遲吸收之試劑(例如單硬脂酸鋁或明膠)來達成。The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. Such suspensions may be prepared using suitable dispersants or wetting agents and suspending agents disclosed herein or known to those skilled in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in parenterally acceptable nontoxic diluents or solvents, such as solutions in 1,3-butanediol. Acceptable diluents, solvents and dispersion media that may be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol) and suitable mixtures thereof. In addition, sterile, non-volatile oils are known to be used as solvents or suspending media. For this purpose, any bland, non-volatile oil may be employed, including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may be used to prepare injectables. Prolonged absorption of a particular injectable formulation may be achieved by including an agent that delays absorption, such as aluminum monostearate or gelatin.
在一個實施例中，本文所提供之醫藥組合物可藉由注射、輸注或植入、以非經腸方式投與，用於局部或全身投與。如本文所用，非經腸投與包括靜脈內、動脈內、腹膜內、鞘內、腦室內、尿道內、胸骨內、顱內、肌肉內、滑膜內及皮下投與。In one embodiment, the pharmaceutical compositions provided herein can be administered parenterally by injection, infusion or implantation for local or systemic administration. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.
在一個實施例中，本文所提供之醫藥組合物可以調配成適於非經腸投與之任何劑型，包括溶液、懸浮液、乳液、微胞、脂質體、微球體、奈米系統，及適於在注射之前溶解於或懸浮於液體中的固體形式。此類劑型可根據熟習醫藥科學技術者已知之習知方法製備(參見例如Remington,TheScienceandPracticeofPharmacy, 見上文)。In one embodiment, the pharmaceutical compositions provided herein can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for dissolving or suspending in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, e.g., Remington,TheScienceandPracticeofPharmacy , supra).
在一個實施例中，意欲非經腸投與之醫藥組合物可包括一或多種醫藥學上可接受之載劑及賦形劑，包括(但不限於)水性媒劑、水混溶性媒劑、非水性媒劑、對抗微生物生長之抗微生物劑或防腐劑、穩定劑、溶解度增強劑、等張劑、緩衝劑、抗氧化劑、局部麻醉劑、懸浮劑及分散劑、濕潤劑或乳化劑、錯合劑、鉗合劑或螯合劑、低溫保護劑、凍乾保護劑、增稠劑、pH調節劑及惰性氣體。In one embodiment, a pharmaceutical composition intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including but not limited to aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to combat microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, clamping or chelating agents, cryoprotectants, lyoprotectants, thickeners, pH adjusters, and inert gases.
在一個實施例中，適合的水性媒劑包括(但不限於)水、鹽水、生理鹽水或磷酸鹽緩衝鹽水(PBS)、氯化鈉注射液、林格氏注射液、等張右旋糖注射液、無菌水注射液、右旋糖及乳酸林格氏注射液。非水性媒劑包括(但不限於)植物來源之不揮發油，蓖麻油、玉米油、棉籽油、橄欖油、花生油、薄荷油、紅花油、芝麻油、大豆油、氫化植物油、氫化大豆油，及椰子油之中鏈三酸甘油酯，及棕櫚籽油。水混溶性媒劑包括(但不限於)乙醇、1,3-丁二醇、液體聚乙二醇(例如聚乙二醇300及聚乙二醇400)、丙二醇、甘油、N-甲基-2-吡咯啶酮、N,N-二甲基乙醯胺及二甲亞碸。In one embodiment, suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous vehicles include, but are not limited to, non-volatile oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, medium-chain triglycerides of coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butylene glycol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol,N -methyl-2-pyrrolidone,N,N -dimethylacetamide, and dimethyl sulfoxide.
在一個實施例中，適合的抗微生物劑或防腐劑包括(但不限於)苯酚、甲酚、汞劑、苯甲醇、氯丁醇、對羥基苯甲酸甲酯及對羥基苯甲酸丙酯、硫柳汞、苯紮氯銨(例如苄索氯銨)、對羥基苯甲酸甲酯及對羥基苯甲酸丙酯以及山梨酸。適合的等張劑包括(但不限於)氯化鈉、甘油及右旋糖。適合的緩衝劑包括(但不限於)磷酸鹽及檸檬酸鹽。適合的抗氧化劑為如本文所描述之抗氧化劑，包括亞硫酸氫鹽及偏亞硫酸氫鈉。適合的局部麻醉劑包括(但不限於)鹽酸普魯卡因(procaine hydrochloride)。適合的懸浮劑及分散劑為如本文所描述之懸浮劑及分散劑，包括羧甲基纖維素鈉、羥丙基甲基纖維素及聚乙烯吡咯啶酮。適合的乳化劑包括本文中所描述之彼等乳化劑，包括聚氧化乙烯脫水山梨糖醇單月桂酸酯、聚氧化乙烯脫水山梨糖醇單油酸酯80及油酸三乙醇胺。適合的鉗合劑或螯合劑包括(但不限於) EDTA。適合的pH值調節劑包括(但不限於)氫氧化鈉、鹽酸、檸檬酸及乳酸。適合的錯合劑包括(但不限於)環糊精，包括α-環糊精、β-環糊精、羥丙基-β-環糊精、磺基丁醚-β-環糊精及磺基丁醚7-β-環糊精(CAPTISOL®, CyDex, Lenexa, KS)。In one embodiment, suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzoyl chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and dextrose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants are those described herein, including bisulfites and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending agents and dispersing agents are those described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable chelating agents or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).
在一個實施例中，本文所提供之醫藥組合物可調配成以單次劑量或多次劑量投與。單次劑量調配物係封裝於安瓿、小瓶或注射器中。多次劑量非經腸調配物可含有抑制細菌或抑制真菌濃度之抗微生物劑。如此項技術中已知及實踐，所有非經腸調配物必須為無菌的。In one embodiment, the pharmaceutical compositions provided herein can be formulated for administration in a single dose or multiple doses. Single dose formulations are packaged in ampoules, vials, or syringes. Multiple dose parenteral formulations may contain antimicrobial agents at bacteriostatic or fungistatic concentrations. As known and practiced in the art, all parenteral formulations must be sterile.
在一個實施例中，醫藥組合物係以即用型無菌溶液形式提供。在另一實施例中，醫藥組合物以待在使用之前用媒劑復原之無菌乾燥可溶產品形式提供，包括凍乾粉末及皮下錠劑。在又另一實施例中，醫藥組合物以即用型無菌懸浮液形式提供。在又另一實施例中，醫藥組合物以待在使用之前用媒劑復原之無菌乾燥不可溶產品形式提供。在再一實施例中，醫藥組合物以即用型無菌乳液形式提供。In one embodiment, the pharmaceutical composition is provided in the form of a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided in the form of a sterile dry soluble product to be reconstituted with a vehicle before use, including lyophilized powders and subcutaneous tablets. In yet another embodiment, the pharmaceutical composition is provided in the form of a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided in the form of a sterile dry insoluble product to be reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical composition is provided in the form of a ready-to-use sterile emulsion.
在一個實施例中，本文所提供之醫藥組合物可調配為速釋型或調節釋放劑型，包括延遲釋放、持續釋放、脈衝釋放、控制釋放、靶向釋放及程式化釋放形式。In one embodiment, the pharmaceutical compositions provided herein can be formulated as immediate release or modified release, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.
適於藉由添加水來製備水性懸浮液之可分散散劑及粒劑提供與分散劑或濕潤劑、懸浮劑及一或多種防腐劑摻合之活性成分。適合的分散劑或濕潤劑及懸浮劑例示於本文中。Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersant or wetting agent, a suspending agent and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified herein.
醫藥組合物亦可包括賦形劑以保護組合物免於快速降解或自身體排出，諸如控制釋放型調配物，包括植入物、脂質體、水凝膠、前藥及微囊封遞送系統。舉例而言，時間延遲材料，諸如單硬脂酸甘油酯或硬脂酸甘油酯，可單獨或與蠟組合使用。可注射醫藥組合物之延長吸收可藉由包括吸收延遲劑(例如單硬脂酸鋁或明膠)來達成。微生物作用之預防可藉由各種抗細菌及抗真菌劑來達成，例如對羥苯甲酸酯、氯丁醇、酚、抗壞血酸、硫柳汞及其類似物。The pharmaceutical composition may also include a formulation to protect the composition from rapid degradation or excretion from the body, such as a controlled release formulation, including implants, liposomes, hydrogels, prodrugs, and microencapsulated delivery systems. For example, a time delay material, such as glyceryl monostearate or glyceryl stearate, can be used alone or in combination with a wax. Prolonged absorption of the injectable pharmaceutical composition may be achieved by including an absorption delaying agent, such as aluminum monostearate or gelatin. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
本文所提供之醫藥組合物可在-80℃、4℃、25℃或37℃下儲存。The pharmaceutical compositions provided herein can be stored at -80°C, 4°C, 25°C or 37°C.
可藉由冷凍乾燥本文所提供之液體醫藥組合物來製備凍乾組合物。在一個特定實施例中，本文所提供之醫藥組合物為凍乾醫藥組合物。在一些實施例中，醫藥調配物為凍乾粉末，其可經復原以用於以溶液、乳液及其他混合物形式投與。其亦可復原且調配成固體或凝膠形式。A lyophilized composition can be prepared by freeze drying a liquid pharmaceutical composition provided herein. In a specific embodiment, the pharmaceutical composition provided herein is a lyophilized pharmaceutical composition. In some embodiments, the pharmaceutical formulation is a lyophilized powder, which can be reconstituted for administration in the form of solutions, emulsions, and other mixtures. It can also be reconstituted and formulated into a solid or gel form.
在一些實施例中，本文所提供之凍乾調配物的製備包括將經調配的本體溶液(bulk solution)分批凍乾、無菌過濾，裝填於小瓶中，將小瓶在冷凍乾燥室中冷凍，隨後凍乾、塞緊及蓋緊。In some embodiments, the preparation of the lyophilized formulations provided herein comprises batch lyophilization of the formulated bulk solution, aseptic filtration, filling into vials, freezing the vials in a freeze dryer, followed by lyophilization, stoppering and capping.
凍乾器可用於製備凍乾調配物。舉例而言，可採用VirTis Genesis型號EL試驗單元。該單元併有腔室，該腔室具有三個處理擱架(至約0.4平方公尺之總可用擱架面積)、外部冷凝器及機械真空泵系統。級聯式機械製冷允許擱架冷卻至-70℃或更低，且允許外部冷凝器冷卻至-90℃或更低。擱架溫度及室壓自動地分別控制在+/-0.5℃及+/-2微米(毫托)。該單元配備有真空電容壓力計、皮冉尼真空計(Pirani vacuum gauge)、壓力轉換器(量測範圍：0至1個大氣壓)及相對濕度感測器。A freeze dryer can be used to prepare freeze dried formulations. For example, a VirTis Genesis model EL test unit can be used. The unit incorporates a chamber with three processing racks (to a total available rack area of approximately 0.4 m2), an external condenser, and a mechanical vacuum pump system. Cascaded mechanical refrigeration allows the racks to be cooled to -70°C or lower, and the external condenser to be cooled to -90°C or lower. The rack temperature and chamber pressure are automatically controlled at +/-0.5°C and +/-2 microns (mTorr), respectively. The unit is equipped with a vacuum capacitance pressure gauge, a Pirani vacuum gauge, a pressure transducer (measuring range: 0 to 1 atmosphere), and a relative humidity sensor.
凍乾粉末可藉由將本文所提供的抗體藥物結合物或其醫藥學上可接受的衍生物溶解於適合溶劑中來製備。在一些實施例中，凍乾粉末為無菌的。隨後將溶液無菌過濾，隨後在熟習此項技術者已知之標準條件下凍乾，得到所需調配物。在一個實施例中，將所得溶液分配至小瓶中凍乾。各小瓶含有單次劑量或多次劑量之抗體藥物結合物。凍乾粉末可在適當條件下儲存，諸如在約4℃至室溫下儲存。The lyophilized powder can be prepared by dissolving the antibody-drug conjugate provided herein or a pharmaceutically acceptable derivative thereof in a suitable solvent. In some embodiments, the lyophilized powder is sterile. The solution is then aseptically filtered and then lyophilized under standard conditions known to those skilled in the art to obtain the desired formulation. In one embodiment, the resulting solution is dispensed into vials and lyophilized. Each vial contains a single dose or multiple doses of the antibody-drug conjugate. The lyophilized powder can be stored under appropriate conditions, such as at about 4°C to room temperature.
用注射用水復原此凍乾粉末得到用於非經腸投與之調配物。復原時，將凍乾粉末添加至無菌水或其他適合賦形劑中。此量可憑經驗確定且根據特定需要進行調整。Reconstitute this lyophilized powder with water for injection to obtain a formulation for parenteral administration. When reconstituted, add the lyophilized powder to sterile water or other suitable formulation. This amount can be determined empirically and adjusted according to specific needs.
例示性復原程序說明如下：(1)將5 mL或3 mL注射器裝配一個18或20號針並用注射用水(WFI)級水填充該注射器；(2)使用注射器刻度量測適量之WFI，確保注射器不含氣泡；(3)將針插入穿過橡膠塞；(4)將注射器之全部內容物沿瓶壁向下分配至容器中，移出注射器及針且放入利器容器中；(4)持續渦旋小瓶以小心地溶解整個小瓶內容物直至完全復原為止(例如約20-40秒)，並使可導致起泡的對蛋白質溶液之過多攪動減到最少。An exemplary reconstitution procedure is as follows: (1) Fit a 5 mL or 3 mL syringe with an 18 or 20 gauge needle and fill the syringe with water for injection (WFI) grade water; (2) Measure the appropriate amount of WFI using the syringe scale, ensuring that the syringe does not contain air bubbles; (3) Insert the needle through the rubber stopper; (4) Dispense the entire contents of the syringe down the vial wall into the container, remove the syringe and needle and place in a sharps container; (4) Continue vortexing the vial to carefully dissolve the entire vial contents until fully reconstituted (e.g., about 20-40 seconds) and minimize excessive agitation of the protein solution that could cause foaming.
在一些實施例中，本文所提供之醫藥組合物係以乾燥無菌凍乾粉末或無水濃縮物形式在氣密密封式容器中供應，且可以用例如水或鹽水復原至適當濃度以向個體投與。在某些實施例中，抗體藥物結合物係以乾燥無菌凍乾粉末形式以以下之單位劑量在氣密密封式容器中供應：至少0.1 mg、至少0.5 mg、至少1 mg、至少2 mg、至少3 mg、至少5 mg、至少10 mg、至少15 mg、至少25 mg、至少30 mg、至少35 mg、至少45 mg、至少50 mg、至少60 mg、至少75 mg、至少80 mg、至少85 mg、至少90 mg、至少95 mg或至少100 mg。凍乾之抗體藥物結合物可在2與8℃之間儲存於其初始容器中，且抗體藥物結合物可在復原後12小時內，諸如6小時內、5小時內、3小時內或1小時內投與。在一個替代實施例中，包含本文所提供之抗體藥物結合物的醫藥組合物以液體形式、於指示抗體藥物結合物之量及濃度的氣密密封式容器中供應。在某些實施例中，液體形式之抗體藥物結合物係在氣密密封式容器中以以下劑量供應：至少0.1 mg/ml、至少0.5 mg/ml、至少1 mg/ml、至少5 mg/ml、至少10 mg/ml、至少15 mg/ml、至少25 mg/ml、至少30 mg/ml、至少40 mg/ml、至少50 mg/ml、至少60 mg/ml、至少70 mg/ml、至少80 mg/ml、至少90 mg/ml或至少100 mg/ml。In some embodiments, the pharmaceutical compositions provided herein are supplied in a hermetically sealed container as a dry sterile lyophilized powder or anhydrous concentrate, and can be reconstituted with, for example, water or saline to an appropriate concentration for administration to an individual. In certain embodiments, the antibody-drug conjugate is supplied in a hermetically sealed container as a dry sterile lyophilized powder in the following unit doses: at least 0.1 mg, at least 0.5 mg, at least 1 mg, at least 2 mg, at least 3 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 45 mg, at least 50 mg, at least 60 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg. The lyophilized antibody-drug conjugate can be stored in its original container at between 2 and 8° C., and the antibody-drug conjugate can be administered within 12 hours, such as within 6 hours, within 5 hours, within 3 hours, or within 1 hour after reconstitution. In an alternative embodiment, a pharmaceutical composition comprising an antibody-drug conjugate provided herein is supplied in liquid form in a hermetically sealed container indicating the amount and concentration of the antibody-drug conjugate. In certain embodiments, the antibody-drug conjugate in liquid form is provided in a hermetically sealed container at a dosage of at least 0.1 mg/ml, at least 0.5 mg/ml, at least 1 mg/ml, at least 5 mg/ml, at least 10 mg/ml, at least 15 mg/ml, at least 25 mg/ml, at least 30 mg/ml, at least 40 mg/ml, at least 50 mg/ml, at least 60 mg/ml, at least 70 mg/ml, at least 80 mg/ml, at least 90 mg/ml, or at least 100 mg/ml.
醫藥組合物的其他實施例已描述於美國專利第8,637,642號及國際申請案第PCT/US2019/056214號(公開案第WO2020/117373號)，該兩者以其全文引用之方式併入本文中。5.5組合治療方法Other embodiments of pharmaceutical compositions are described in U.S. Patent No. 8,637,642 and International Application No. PCT/US2019/056214 (Publication No. WO2020/117373), both of which are incorporated herein by reference in their entirety.5.5Combination Therapy Methods
使用本文所提供之醫藥組合物與化學療法或放射或兩者之組合來抑制腫瘤細胞生長之方法包含在開始化學療法或放射療法之前、期間或之後以及其任何組合(亦即，在開始化學療法及/或放射療法之前及期間、之前及之後、期間及之後，或之前、期間及之後)，投與本發明醫藥組合物。視治療方案及特定患者需要而定，以將提供最有效治療且最終延長患者生命之方式進行該方法。此類組合療法的其他實施例已描述於美國專利第8,637,642號及國際申請案第PCT/US2019/056214號(公開案第WO2020/117373號)，該兩者以其全文引用之方式併入本文中。5.6免疫檢查點抑制劑(例如派姆單抗)之劑量Methods of inhibiting tumor cell growth using the pharmaceutical compositions provided herein in combination with chemotherapy or radiation or both include administering the pharmaceutical compositions of the present invention before, during, or after the initiation of chemotherapy or radiation therapy, and any combination thereof (i.e., before and during, before and after, during and after, or before, during, and after the initiation of chemotherapy and/or radiation therapy). Depending on the treatment regimen and the specific patient needs, the method is performed in a manner that will provide the most effective treatment and ultimately prolong the patient's life. Other embodiments of such combination therapies are described in U.S. Patent No. 8,637,642 and International Application No. PCT/US2019/056214 (Publication No. WO2020/117373), both of which are incorporated herein by reference in their entirety.5.6Dosage ofImmune Checkpoint Inhibitors(e.g., Pembrolizumab)
在一些實施例中，本文所提供之各種方法之檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)的量係藉由標準臨床技術確定。In some embodiments, the amount of a checkpoint inhibitor (e.g., a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) in the various methods provided herein is determined by standard clinical techniques.
檢查點抑制劑之劑量產生約0.1 μg/ml至約450 μg/ml之血清效價，且在一些實施例中，為了預防及/或治療癌症，可向人類投與至少0.1 μg/ml、至少0.2 μg/ml、至少0.4 μg/ml、至少0.5 μg/ml、至少0.6 μg/ml、至少0.8 μg/ml、至少1 μg/ml、至少1.5 μg/ml，諸如至少2 μg/ml、至少5 μg/ml、至少10 μg/ml、至少15 μg/ml、至少20 μg/ml、至少25 μg/ml、至少30 μg/ml、至少35 μg/ml、至少40 μg/ml、至少50 μg/ml、至少75 μg/ml、至少100 μg/ml、至少125 μg/ml、至少150 μg/ml、至少200 μg/ml、至少250 μg/ml、至少300 μg/ml、至少350 μg/ml、至少400 μg/ml或至少450 μg/ml。應瞭解，檢查點抑制劑的精確使用劑量亦視投藥途徑及個體之癌症嚴重度而定，且應根據從醫者之判斷及各患者的情形決定。The dosage of the checkpoint inhibitor produces a serum titer of about 0.1 μg/ml to about 450 μg/ml, and in some embodiments, for the prevention and/or treatment of cancer, at least 0.1 μg/ml, at least 0.2 μg/ml, at least 0.4 μg/ml, at least 0.5 μg/ml, at least 0.6 μg/ml, at least 0.8 μg/ml, at least 1 μg/ml, at least 1.5 μg/ml, such as at least 2 μg/ml, at least 5 μg/ml, at least 10 μg/ml, at least 15 μg/ml, at least 20 μg/ml, at least 25 μg/ml, at least 30 μg/ml, at least 35 μg/ml, at least 40 μg/ml, at least 50 μg/ml, at least 75 μg/ml, at least 100 μg/ml, at least 125 μg/ml, at least 150 μg/ml, at least 160 μg/ml, at least 170 μg/ml, at least 180 μg/ml, at least 190 μg/ml, at least 200 μg/ml, at least 250 μg/ml, at least 300 μg/ml, at least 350 μg/ml, at least 400 μg/ml, at least 5 ... μg/ml, at least 200 μg/ml, at least 250 μg/ml, at least 300 μg/ml, at least 350 μg/ml, at least 400 μg/ml or at least 450 μg/ml. It should be understood that the exact dosage of the checkpoint inhibitor also depends on the route of administration and the severity of the individual's cancer, and should be determined based on the judgment of the practitioner and the circumstances of each patient.
在一些實施例中，投與患者的檢查點抑制劑(例如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)之劑量通常為每公斤個體體重0.1 mg至100 mg。在一些實施例中，投與患者的劑量為每公斤個體體重約1 mg至約75 mg。在一些實施例中，投與患者的劑量在每公斤個體體重1 mg與20 mg之間，諸如每公斤個體體重1 mg至5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約1 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約1.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約2 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約2.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約3 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約3.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約4 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約4.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約5.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約6 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約6.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約7 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約7.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約8 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約8.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約9.0 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約10.0 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約15.0 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約20.0 mg。In some embodiments, the dose of a checkpoint inhibitor (e.g., a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti-PD-1 antibody, such as pembrolizumab) administered to a patient is typically 0.1 mg to 100 mg per kilogram of individual body weight. In some embodiments, the dose administered to a patient is about 1 mg to about 75 mg per kilogram of individual body weight. In some embodiments, the dose administered to a patient is between 1 mg and 20 mg per kilogram of individual body weight, such as 1 mg to 5 mg per kilogram of individual body weight. In some embodiments, the dose administered to a patient is about 1 mg per kilogram of individual body weight. In some embodiments, the dose administered to a patient is about 1.5 mg per kilogram of individual body weight. In some embodiments, the dose administered to a patient is about 2 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 2.5 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 3 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 3.5 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 4 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 4.5 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 5 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 5.5 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 6 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 6.5 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 7 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 7.5 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 8 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 8.5 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 9.0 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 10.0 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 15.0 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 20.0 mg per kilogram of individual body weight.
在某些實施例中，檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以約100 mg、約150 mg、約200 mg、約250 mg、約300 mg、約350 mg、約400 mg、約450 mg或約500 mg之劑量投與。在特定實施例中，檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以約200 mg之劑量投與。In certain embodiments, a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti-PD-1 antibody, such as pembrolizumab) is administered in an amount of about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. In a specific embodiment, a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti-PD-1 antibody, such as pembrolizumab) is administered in an amount of about 200 mg.
在某些實施例中，檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以約100 mg、150 mg、200 mg、250 mg、300 mg、350 mg、400 mg、450 mg或500 mg之劑量投與。在特定實施例中，檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以約200 mg之劑量投與。在特定實施例中，派姆單抗係以約200 mg之劑量投與。In certain embodiments, a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti-PD-1 antibody, such as pembrolizumab) is administered in an amount of about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. In specific embodiments, a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti-PD-1 antibody, such as pembrolizumab) is administered in an amount of about 200 mg. In specific embodiments, pembrolizumab is administered in an amount of about 200 mg.
在某些實施例中，檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以約100 mg至約500 mg、約150 mg至約500 mg、約200 mg至約500 mg、約250 mg至約500 mg、約300 mg至約500 mg、約350 mg至約500 mg、約400 mg至約500 mg或約450 mg至約500 mg之劑量投與。在某些實施例中，檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以約100 mg至約450 mg、約100 mg至約400 mg、約100 mg至約350 mg、約100 mg至約300 mg、約100 mg至約250 mg、約100 mg至約200 mg或約100 mg至約150 mg之劑量投與。在某些實施例中，檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以約150 mg至約450 mg、約150 mg至約400 mg、約150 mg至約350 mg、約200 mg至約450 mg、約200 mg至約400 mg、約200 mg至約300 mg或約200 mg至約250 mg之劑量投與。In certain embodiments, a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered in an amount of about 100 mg to about 500 mg, about 150 mg to about 500 mg, about 200 mg to about 500 mg, about 250 mg to about 500 mg, about 300 mg to about 500 mg, about 350 mg to about 500 mg, about 400 mg to about 500 mg, or about 450 mg to about 500 mg. In certain embodiments, a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered in an amount of about 100 mg to about 450 mg, about 100 mg to about 400 mg, about 100 mg to about 350 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, or about 100 mg to about 150 mg. In certain embodiments, a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered in an amount of about 150 mg to about 450 mg, about 150 mg to about 400 mg, about 150 mg to about 350 mg, about 200 mg to about 450 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, or about 200 mg to about 250 mg.
在某些實施例中，檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以100 mg至500 mg、150 mg至500 mg、200 mg至500 mg、250 mg至500 mg、300 mg至500 mg、350 mg至500 mg、400 mg至500 mg或450 mg至500 mg之劑量投與。在某些實施例中，檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以100 mg至450 mg、100 mg至400 mg、100 mg至350 mg、100 mg至300 mg、100 mg至250 mg、100 mg至200 mg或100 mg至150 mg之劑量投與。在某些實施例中，檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以150 mg至450 mg、150 mg至400 mg、150 mg至350 mg、200 mg至450 mg、200 mg至400 mg、200 mg至300 mg或200 mg至250 mg之劑量投與。In certain embodiments, a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered in a dose of 100 mg to 500 mg, 150 mg to 500 mg, 200 mg to 500 mg, 250 mg to 500 mg, 300 mg to 500 mg, 350 mg to 500 mg, 400 mg to 500 mg, or 450 mg to 500 mg. In certain embodiments, a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered in a dose of 100 mg to 450 mg, 100 mg to 400 mg, 100 mg to 350 mg, 100 mg to 300 mg, 100 mg to 250 mg, 100 mg to 200 mg, or 100 mg to 150 mg. In certain embodiments, a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 antibody, e.g., pembrolizumab) is administered in a dose of 150 mg to 450 mg, 150 mg to 400 mg, 150 mg to 350 mg, 200 mg to 450 mg, 200 mg to 400 mg, 200 mg to 300 mg, or 200 mg to 250 mg.
在一些實施例中，(a)檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以約100 mg至約400 mg之劑量投與；及(b)在步驟(a)之後，抗PD-1抗體每40至45天以約300 mg至約500 mg之劑量向個體投與。在一些實施例中，(a)檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以約100 mg至約300 mg之劑量投與；及(b)在步驟(a)之後，抗PD-1抗體每40至45天以約350 mg至約450 mg之劑量向個體投與。在一些實施例中，(a)檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以約150 mg至約250 mg之劑量投與；及(b)在步驟(a)之後，抗PD-1抗體每40至45天以約350 mg至約450 mg之劑量向個體投與。在某些實施例中，(a)檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以約200 mg之劑量投與；及(b)在步驟(a)之後，抗PD-1抗體每42天以約400 mg之劑量向個體投與。In some embodiments, (a) the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti-PD-1 antibody, such as pembrolizumab) is administered in an amount of about 100 mg to about 400 mg; and (b) after step (a), the anti-PD-1 antibody is administered to the subject at a dose of about 300 mg to about 500 mg every 40 to 45 days. In some embodiments, (a) the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti-PD-1 antibody, such as pembrolizumab) is administered in an amount of about 100 mg to about 300 mg; and (b) after step (a), the anti-PD-1 antibody is administered to the subject at a dose of about 350 mg to about 450 mg every 40 to 45 days. In some embodiments, (a) the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti-PD-1 antibody, such as pembrolizumab) is administered at a dose of about 150 mg to about 250 mg; and (b) after step (a), the anti-PD-1 antibody is administered to the subject at a dose of about 350 mg to about 450 mg every 40 to 45 days. In certain embodiments, (a) the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti-PD-1 antibody, such as pembrolizumab) is administered at a dose of about 200 mg; and (b) after step (a), the anti-PD-1 antibody is administered to the subject at a dose of about 400 mg every 42 days.
在一些實施例中，(a)檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以100 mg至400 mg之劑量投與；及(b)在步驟(a)之後，抗PD-1抗體每40至45天以300 mg至500 mg之劑量向個體投與。在一些實施例中，(a)檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以100 mg至300 mg之劑量投與；及(b)在步驟(a)之後，抗PD-1抗體每40至45天以350 mg至450 mg之劑量向個體投與。在一些實施例中，(a)檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以150 mg至250 mg之劑量投與；及(b)在步驟(a)之後，抗PD-1抗體每40至45天以350 mg至450 mg之劑量向個體投與。在某些實施例中，(a)檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如抗PD-1抗體，例如派姆單抗)係以200 mg之劑量投與；及(b)在步驟(a)之後，抗PD-1抗體每42天以400 mg之劑量向個體投與。In some embodiments, (a) the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti-PD-1 antibody, such as pembrolizumab) is administered at a dose of 100 mg to 400 mg; and (b) after step (a), the anti-PD-1 antibody is administered to the subject at a dose of 300 mg to 500 mg every 40 to 45 days. In some embodiments, (a) the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti-PD-1 antibody, such as pembrolizumab) is administered at a dose of 100 mg to 300 mg; and (b) after step (a), the anti-PD-1 antibody is administered to the subject at a dose of 350 mg to 450 mg every 40 to 45 days. In some embodiments, (a) the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti-PD-1 antibody, such as pembrolizumab) is administered at a dose of 150 mg to 250 mg; and (b) after step (a), the anti-PD-1 antibody is administered to the subject at a dose of 350 mg to 450 mg every 40 to 45 days. In certain embodiments, (a) the checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as an anti-PD-1 antibody, such as pembrolizumab) is administered at a dose of 200 mg; and (b) after step (a), the anti-PD-1 antibody is administered to the subject at a dose of 400 mg every 42 days.
在一些實施例中，派姆單抗係以約200 mg之劑量投與。在一些實施例中，派姆單抗每3週以約200 mg之劑量投與。在一些實施例中，派姆單抗在各3週週期之第1天以約200 mg之劑量投與。In some embodiments, pembrolizumab is administered at a dose of about 200 mg. In some embodiments, pembrolizumab is administered at a dose of about 200 mg every 3 weeks. In some embodiments, pembrolizumab is administered at a dose of about 200 mg on day 1 of each 3-week cycle.
在一些實施例中，派姆單抗係以約400 mg之劑量投與。在一些實施例中，派姆單抗每6週以約400 mg之劑量投與。在一些實施例中，派姆單抗在各6週週期之第1天以約400 mg之劑量投與。In some embodiments, pembrolizumab is administered at a dose of about 400 mg. In some embodiments, pembrolizumab is administered at a dose of about 400 mg every 6 weeks. In some embodiments, pembrolizumab is administered at a dose of about 400 mg on day 1 of each 6-week cycle.
在一些實施例中，派姆單抗係以約2 mg/kg之劑量投與。在一些實施例中，派姆單抗每三週以約2 mg/kg之劑量投與。在一些實施例中，派姆單抗在各3週週期之第1天以約2 mg/kg之劑量投與。在特定實施例中，患者為兒科患者。In some embodiments, pembrolizumab is administered at a dose of about 2 mg/kg. In some embodiments, pembrolizumab is administered at a dose of about 2 mg/kg every three weeks. In some embodiments, pembrolizumab is administered at a dose of about 2 mg/kg on day 1 of each 3-week cycle. In specific embodiments, the patient is a pediatric patient.
在一些實施例中，派姆單抗以30分鐘(-5分鐘/+10分鐘)靜脈內輸注形式投與。在一個實施例中，所選劑量之派姆單抗藉由IV輸注經25與40分鐘之間或約30分鐘的時段投與。In some embodiments, pembrolizumab is administered as a 30 minute (-5 minutes/+10 minutes) intravenous infusion. In one embodiment, the selected dose of pembrolizumab is administered by IV infusion over a period of between 25 and 40 minutes or about 30 minutes.
在一個態樣中，派姆單抗與醫藥學上可接受之載劑或稀釋劑一起包括於醫藥組合物中，且可包括額外醫藥學上可接受之賦形劑。In one aspect, pembrolizumab is included in a pharmaceutical composition together with a pharmaceutically acceptable carrier or diluent, and may include additional pharmaceutically acceptable excipients.
在特定實施例中，患者為成年患者。在特定實施例中，患者為成年患者，其中該成年患者為18歲或更大。5.7用於該等方法的ADC之劑量In certain embodiments, the patient is an adult patient. In certain embodiments, the patient is an adult patient, wherein the adult patient is 18 years of age or older.5.7Dosage ofADCfor use in the methods
在一些實施例中，將有效預防及/或治療癌症的預防劑或治療劑(例如本文所提供之抗體藥物結合物)或本文所提供之醫藥組合物的量可藉由標準臨床技術確定。In some embodiments, the amount of a prophylactic or therapeutic agent (e.g., an antibody-drug conjugate provided herein) or a pharmaceutical composition provided herein that will be effective in preventing and/or treating cancer can be determined by standard clinical techniques.
在一些實施例中，方法中的ADC (其各種劑量描述於本章節(章節5.7))為恩諾單抗維多汀(EV)。In some embodiments, the ADC in the method (various dosages of which are described in this section (Section 5.7)) is enrofloxacin (EV).
相應地，為了預防及/或治療癌症，可向人類投與含有一定劑量之抗體藥物結合物的醫藥組合物，該劑量產生的血清效價為約0.1 μg/ml至約450 μg/ml且在一些實施例中為至少0.1 μg/ml、至少0.2 μg/ml、至少0.4 μg/ml、至少0.5 μg/ml、至少0.6 μg/ml、至少0.8 μg/ml、至少1 μg/ml、至少1.5 μg/ml，諸如至少2 μg/ml、至少5 μg/ml、至少10 μg/ml、至少15 μg/ml、至少20 μg/ml、至少25 μg/ml、至少30 μg/ml、至少35 μg/ml、至少40 μg/ml、至少50 μg/ml、至少75 μg/ml、至少100 μg/ml、至少125 μg/ml、至少150 μg/ml、至少200 μg/ml、至少250 μg/ml、至少300 μg/ml、至少350 μg/ml、至少400 μg/ml或至少450 μg/ml。應瞭解，調配物中的精確使用劑量亦視投藥途徑及個體之癌症嚴重度而定，且應根據從醫者之判斷及各患者的情形決定。Accordingly, for the prevention and/or treatment of cancer, a pharmaceutical composition containing an amount of an antibody-drug conjugate that produces a serum titer of about 0.1 μg/ml to about 450 μg/ml and in some embodiments is at least 0.1 μg/ml, at least 0.2 μg/ml, at least 0.4 μg/ml, at least 0.5 μg/ml, at least 0.6 μg/ml, at least 0.8 μg/ml, at least 1 μg/ml, at least 1.5 μg/ml, such as at least 2 μg/ml, at least 5 μg/ml, at least 10 μg/ml, at least 15 μg/ml, at least 20 μg/ml, at least 25 μg/ml, at least 30 μg/ml, at least 35 μg/ml, at least 40 μg/ml, at least 50 μg/ml, at least 75 μg/ml, at least 100 μg/ml, at least 150 μg/ml, at least 200 μg/ml, at least 250 μg/ml, at least 300 μg/ml, at least 350 μg/ml, at least 400 μg/ml, at least 5 ... μg/ml, at least 125 μg/ml, at least 150 μg/ml, at least 200 μg/ml, at least 250 μg/ml, at least 300 μg/ml, at least 350 μg/ml, at least 400 μg/ml or at least 450 μg/ml. It should be understood that the exact dosage used in the formulation also depends on the route of administration and the severity of the individual's cancer, and should be determined according to the judgment of the practitioner and the circumstances of each patient.
可利用來源於活體外或動物模型測試系統之劑量反應曲線外推出有效劑量。Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
對於包含本文所提供之抗體藥物結合物的醫藥組合物，投與患者之抗體藥物結合物的劑量通常為每公斤個體體重0.1 mg至100 mg。在一些實施例中，投與患者的劑量為每公斤個體體重約1 mg至約75 mg。在一些實施例中，投與患者的劑量在每公斤個體體重1 mg與20 mg之間，諸如每公斤個體體重1 mg至5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約0.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約0.75 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約1 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約1.25 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約1.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約2 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約2.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約3 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約3.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約4 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約4.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約5.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約6 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約6.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約7 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約7.5 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約8 mg。在一些實施例中，投與患者之劑量為每公斤個體體重約8.5 mg。For pharmaceutical compositions comprising the antibody-drug conjugates provided herein, the dosage of the antibody-drug conjugate administered to the patient is generally 0.1 mg to 100 mg per kilogram of individual body weight. In some embodiments, the dosage administered to the patient is about 1 mg to about 75 mg per kilogram of individual body weight. In some embodiments, the dosage administered to the patient is between 1 mg and 20 mg per kilogram of individual body weight, such as 1 mg to 5 mg per kilogram of individual body weight. In some embodiments, the dosage administered to the patient is about 0.5 mg per kilogram of individual body weight. In some embodiments, the dosage administered to the patient is about 0.75 mg per kilogram of individual body weight. In some embodiments, the dosage administered to the patient is about 1 mg per kilogram of individual body weight. In some embodiments, the dosage administered to the patient is about 1.25 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 1.5 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 2 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 2.5 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 3 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 3.5 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 4 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 4.5 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 5 mg per kilogram of individual body weight. In some embodiments, the dose administered to the patient is about 5.5 mg per kilogram of individual body weight. In some embodiments, the dose administered to a patient is about 6 mg per kg of individual body weight. In some embodiments, the dose administered to a patient is about 6.5 mg per kg of individual body weight. In some embodiments, the dose administered to a patient is about 7 mg per kg of individual body weight. In some embodiments, the dose administered to a patient is about 7.5 mg per kg of individual body weight. In some embodiments, the dose administered to a patient is about 8 mg per kg of individual body weight. In some embodiments, the dose administered to a patient is about 8.5 mg per kg of individual body weight.
在一些實施例中，調配成本文所提供之醫藥組合物的抗體藥物結合物係基於患者在基線時之實際體重投與，且除非患者體重相對於前一週期之基線變化≥10%或滿足劑量調整準則，否則劑量將不變。在一些實施例中，除非患者體重大於100 kg，否則將使用實際體重，在此類情況下，劑量將基於100 kg體重計算。在一些實施例中，對於接受1.00 mg/kg劑量含量之患者而言，最大劑量為100 mg；且對於接受1.25 mg/kg劑量含量之患者而言，最大劑量為125 mg。In some embodiments, the antibody-drug conjugate formulated in the pharmaceutical composition provided herein is administered based on the patient's actual weight at baseline, and the dose will not change unless the patient's weight changes by ≥10% from the baseline of the previous cycle or the dose adjustment criteria are met. In some embodiments, the actual weight will be used unless the patient weighs more than 100 kg, in which case the dose will be calculated based on a body weight of 100 kg. In some embodiments, for patients receiving a 1.00 mg/kg dose level, the maximum dose is 100 mg; and for patients receiving a 1.25 mg/kg dose level, the maximum dose is 125 mg.
在一個實施例中，將約100 mg/kg或更低、約75 mg/kg或更低、約50 mg/kg或更低、約25 mg/kg或更低、約10 mg/kg或更低、約5 mg/kg或更低、約1.5 mg/kg或更低、約1.25 mg/kg或更低、約1 mg/kg或更低、約0.75 mg/kg或更低、約0.5 mg/kg或更低、或約0.1 mg/kg或更低劑量的調配成本發明醫藥組合物之抗體藥物結合物投與5次、4次、3次、2次或1次以治療癌症。在一些實施例中，包含本文所提供之抗體藥物結合物的醫藥組合物投與約1-12次，其中該等劑量可視需要投與，例如每週一次、兩週一次、每月一次、兩月一次、三月一次等，如醫師所決定。在一些實施例中，可以較大頻率(例如3-6次)投與較低劑量(例如0.1-15 mg/kg)。在其他實施例中，可以較小頻率(例如1-3次)投與較高劑量(例如25-100 mg/kg)。In one embodiment, the antibody drug conjugate of the pharmaceutical composition of the invention is administered 5 times, 4 times, 3 times, 2 times, or 1 time to treat cancer. In some embodiments, the pharmaceutical composition comprising the antibody drug conjugate provided herein is administered about 1-12 times, wherein the dosage can be administered as needed, for example, once a week, once every two weeks, once a month, once every two months, once every three months, etc., as determined by the physician. In some embodiments, a lower dose (e.g., 0.1-15 mg/kg) can be administered more frequently (e.g., 3-6 times). In other embodiments, a higher dose (e.g., 25-100 mg/kg) can be administered less frequently (e.g., 1-3 times).
在一些實施例中，為了預防及/或治療癌症，在一定時段內(例如一年)，每兩週週期(例如約14天)期間將調配成本文所提供之醫藥組合物的單次劑量之抗體藥物結合物投與患者1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25或26次，其中該劑量選自由以下組成之群：約0.1 mg/kg、約0.5 mg/kg、約0.75 mg/kg、約1 mg/kg、約1.25 mg/kg、約1.5 mg/kg、約2 mg/kg、約2.5 mg/kg、約3 mg/kg、約4 mg/kg、約5 mg/kg、約10 mg/kg、約15 mg/kg、約20 mg/kg、約25 mg/kg、約30 mg/kg、約35 mg/kg、約40 mg/kg、約45 mg/kg、約50 mg/kg、約55 mg/kg、約60 mg/kg、約65 mg/kg、約70 mg/kg、約75 mg/kg、約80 mg/kg、約85 mg/kg、約90 mg/kg、約95 mg/kg、約100 mg/kg或其組合(亦即，按月給與的各劑量可相同或可不相同)。In some embodiments, for the prevention and/or treatment of cancer, a single dose of an antibody drug conjugate formulated as a pharmaceutical composition provided herein is administered to a patient 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 times during every two-week cycle (e.g., about 14 days) over a certain period of time (e.g., one year), wherein the dose is selected from the group consisting of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 [0013] In some embodiments, the dosage may be about 100 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, or a combination thereof (i.e., the amounts of each dose given monthly may be the same or different).
在一些實施例中，為了預防及/或治療癌症，在一定時段(例如一年)內，在每三週週期(例如約21天)期間，將調配成本文所提供之醫藥組合物之抗體藥物結合物的單次劑量投與患者1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25或26次，其中該劑量選自由以下組成之群：約0.1 mg/kg、約0.5 mg/kg、約0.75 mg/kg、約1 mg/kg、約1.25 mg/kg、約1.5 mg/kg、約2 mg/kg、約2.5 mg/kg、約3 mg/kg、約4 mg/kg、約5 mg/kg、約10 mg/kg、約15 mg/kg、約20 mg/kg、約25 mg/kg、約30 mg/kg、約35 mg/kg、約40 mg/kg、約45 mg/kg、約50 mg/kg、約55 mg/kg、約60 mg/kg、約65 mg/kg、約70 mg/kg、約75 mg/kg、約80 mg/kg、約85 mg/kg、約90 mg/kg、約95 mg/kg、約100 mg/kg或其組合(亦即，按月給與的各劑量可相同或可不相同)。In some embodiments, for the prevention and/or treatment of cancer, a single dose of an antibody drug conjugate formulated as a pharmaceutical composition provided herein is administered to a patient 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 times during every three-week cycle (e.g., about 21 days) over a certain period of time (e.g., one year), wherein the dose is selected from the group consisting of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 [0013] In some embodiments, the dosage may be about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, or a combination thereof (i.e., the amounts of each dose given monthly may be the same or different).
在一些實施例中，為了預防及/或治療癌症，在一定時段(例如一年)內，在每四週週期(例如約28天)期間，將調配成本文所提供之醫藥組合物之抗體藥物結合物的單次劑量投與患者1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25或26次，其中該劑量選自由以下組成之群：約0.1 mg/kg、約0.5 mg/kg、約0.75 mg/kg、約1 mg/kg、約1.25 mg/kg、約1.5 mg/kg、約2 mg/kg、約2.5 mg/kg、約3 mg/kg、約4 mg/kg、約5 mg/kg、約10 mg/kg、約15 mg/kg、約20 mg/kg、約25 mg/kg、約30 mg/kg、約35 mg/kg、約40 mg/kg、約45 mg/kg、約50 mg/kg、約55 mg/kg、約60 mg/kg、約65 mg/kg、約70 mg/kg、約75 mg/kg、約80 mg/kg、約85 mg/kg、約90 mg/kg、約95 mg/kg、約100 mg/kg或其組合(亦即，按月給與的各劑量可相同或可不相同)。In some embodiments, for the prevention and/or treatment of cancer, a single dose of an antibody drug conjugate formulated in a pharmaceutical composition provided herein is administered to a patient 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 times during every four-week cycle (e.g., about 28 days) over a period of time (e.g., one year), wherein the dose is selected from the group consisting of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 About 150 mg/kg, about 200 mg/kg, about 250 mg/kg, about 300 mg/kg, about 350 mg/kg, about 400 mg/kg, about 450 mg/kg, about 500 mg/kg, about 550 mg/kg, about 600 mg/kg, about 650 mg/kg, about 700 mg/kg, about 750 mg/kg, about 800 mg/kg, about 850 mg/kg, about 900 mg/kg, about 950 mg/kg, about 1000 mg/kg, or a combination thereof (i.e., the amounts of each dose given monthly may be the same or different).
在另一實施例中，為了預防及/或治療癌症，在一定時段(例如一年)內，每隔約一個月(例如約30天)將調配成本文所提供之醫藥組合物之抗體藥物結合物的單次劑量投與患者1、2、3、4、5、6、7、8、9、10、11或12次，其中該劑量選自由以下組成之群：約0.1 mg/kg、約0.5 mg/kg、約0.75 mg/kg、約1 mg/kg、約1.25 mg/kg、約1.5 mg/kg、約2 mg/kg、約2.5 mg/kg、約3 mg/kg、約4 mg/kg、約5 mg/kg、約10 mg/kg、約15 mg/kg、約20 mg/kg、約25 mg/kg、約30 mg/kg、約35 mg/kg、約40 mg/kg、約45 mg/kg、約50 mg/kg、約55 mg/kg、約60 mg/kg、約65 mg/kg、約70 mg/kg、約75 mg/kg、約80 mg/kg、約85 mg/kg、約90 mg/kg、約95 mg/kg、約100 mg/kg或其組合(亦即，按月給與的各劑量可相同或可不相同)。In another embodiment, for the prevention and/or treatment of cancer, a single dose of the antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered to a patient 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 times every about one month (e.g., about 30 days) over a certain period of time (e.g., one year), wherein the dose is selected from the group consisting of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 In some embodiments, the dosage may be about 100 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, or a combination thereof (i.e., the dosages given monthly may be the same or different).
在另一實施例中，為了預防及/或治療癌症，在一定時段(例如一年)內，每隔約兩個月(例如約60天)，將調配成本文所提供之醫藥組合物之抗體藥物結合物的單次劑量投與患者1、2、3、4、5或6次，其中該劑量係選自由以下組成之群：約0.1 mg/kg、約0.5 mg/kg、約0.75 mg/kg、約1 mg/kg、約1.25 mg/kg、約1.5 mg/kg、約2 mg/kg、約2.5 mg/kg、約3 mg/kg、約4 mg/kg、約5 mg/kg、約10 mg/kg、約15 mg/kg、約20 mg/kg、約25 mg/kg、約30 mg/kg、約35 mg/kg、約40 mg/kg、約45 mg/kg、約50 mg/kg、約55 mg/kg、約60 mg/kg、約65 mg/kg、約70 mg/kg、約75 mg/kg、約80 mg/kg、約85 mg/kg、約90 mg/kg、約95 mg/kg、約100 mg/kg或其組合(亦即，按月給與的各劑量可相同或可不相同)。In another embodiment, for the prevention and/or treatment of cancer, a single dose of the antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered to a patient 1, 2, 3, 4, 5 or 6 times every about two months (e.g., about 60 days) over a certain period of time (e.g., one year), wherein the dose is selected from the group consisting of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, or a combination thereof (i.e., the monthly doses may be the same or different).
在又另一實施例中，為了預防及/或治療癌症，在一定時段(例如一年)內，每隔約三個月(例如約120天)，將調配成本文所提供之醫藥組合物之抗體藥物結合物的單次劑量投與患者1、2、3或4次，其中該劑量選自由以下組成之群：約0.1 mg/kg、約0.5 mg/kg、約0.75 mg/kg、約1 mg/kg、約1.25 mg/kg、約1.5 mg/kg、約2 mg/kg、約2.5 mg/kg、約3 mg/kg、約4 mg/kg、約5 mg/kg、約10 mg/kg、約15 mg/kg、約20 mg/kg、約25 mg/kg、約30 mg/kg、約35 mg/kg、約40 mg/kg、約45 mg/kg、約50 mg/kg、約55 mg/kg、約60 mg/kg、約65 mg/kg、約70 mg/kg、約75 mg/kg、約80 mg/kg、約85 mg/kg、約90 mg/kg、約95 mg/kg、約100 mg/kg或其組合(亦即，按月給與的各劑量可相同或可不相同)。In yet another embodiment, for the prevention and/or treatment of cancer, a single dose of the antibody drug conjugate formulated in the pharmaceutical composition provided herein is administered to a patient 1, 2, 3 or 4 times every about three months (e.g., about 120 days) over a certain period of time (e.g., one year), wherein the dose is selected from the group consisting of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, or a combination thereof (i.e., the monthly doses may be the same or different).
在某些實施例中，調配成本文所提供之醫藥組合物的一定劑量之抗體藥物結合物投與患者的途徑為鼻內、肌肉內、靜脈內、皮下或其組合，但本文所述之其他途徑亦為可接受的。各劑量可或可不藉由相同投藥途徑投與。在一些實施例中，調配成本文所提供之醫藥組合物的抗體藥物結合物可在一或多種其他治療劑之其他劑量的同時或之後，經由多種投藥途徑投與。In certain embodiments, a dose of an antibody-drug conjugate formulated in a pharmaceutical composition provided herein is administered to a patient intranasally, intramuscularly, intravenously, subcutaneously, or a combination thereof, but other routes described herein are also acceptable. Each dose may or may not be administered by the same route of administration. In some embodiments, an antibody-drug conjugate formulated in a pharmaceutical composition provided herein may be administered by a variety of routes of administration simultaneously with or after other doses of one or more other therapeutic agents.
在一些更特定實施例中，調配成本文所提供之醫藥組合物的抗體藥物結合物係以每公斤個體體重約0.5 mg、約0.75 mg、約1 mg、約1.25 mg或約1.5 mg之劑量、藉由靜脈內(IV)注射或輸注投與。In some more specific embodiments, the antibody-drug conjugate formulated in the pharmaceutical compositions provided herein is administered by intravenous (IV) injection or infusion at a dose of about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, or about 1.5 mg per kg of individual body weight.
在一些更特定實施例中，調配成本文所提供之醫藥組合物的抗體藥物結合物係以每公斤個體體重約0.5 mg、約0.75 mg、約1 mg、約1.25 mg或約1.5 mg劑量，藉由靜脈內(IV)注射或輸注約30分鐘投與，每三週週期投與兩次。在一些實施例中，調配成醫藥組合物之抗體藥物結合物係藉由在每三週週期之第1天及第8天靜脈內(IV)注射或輸注約30分鐘投與。在一些實施例中，該方法進一步包含每三週週期藉由靜脈內(IV)注射或輸注一或多次來投與免疫檢查點抑制劑。在一些實施例中，該方法進一步包含每三週週期之第1天藉由靜脈內(IV)注射或輸注來投與免疫檢查點抑制劑。在一些實施例中，免疫檢查點抑制劑為派姆單抗，且其中派姆單抗以約200 mg之量投與約30分鐘。在一些實施例中，抗體藥物結合物投與患有局部晚期尿路上皮癌或膀胱癌的患者，該等患者在用另一種癌症療法治療期間或之後，已顯示疾病惡化或復發。在一些實施例中，方法中的ADC (其各種劑量描述於本段落)為恩諾單抗維多汀(EV)。In some more specific embodiments, the antibody-drug conjugate formulated into the pharmaceutical composition provided herein is administered at a dose of about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, or about 1.5 mg per kg of individual body weight by intravenous (IV) injection or infusion for about 30 minutes, twice every three cycles. In some embodiments, the antibody-drug conjugate formulated into the pharmaceutical composition is administered by intravenous (IV) injection or infusion for about 30 minutes on the 1st and 8th day of each three-cycle cycle. In some embodiments, the method further comprises administering an immune checkpoint inhibitor by intravenous (IV) injection or infusion one or more times every three cycles. In some embodiments, the method further comprises administering an immune checkpoint inhibitor by intravenous (IV) injection or infusion on day 1 of each three-week cycle. In some embodiments, the immune checkpoint inhibitor is pembrolizumab, and wherein the pembrolizumab is administered in an amount of about 200 mg for about 30 minutes. In some embodiments, the antibody drug conjugate is administered to patients with locally advanced urothelial carcinoma or bladder cancer who have shown disease worsening or recurrence during or after treatment with another cancer therapy. In some embodiments, the ADC in the method (various doses of which are described in this paragraph) is enrotumumab vedotin (EV).
在其他更特定的實施例中，調配成本文所提供之醫藥組合物的抗體藥物結合物係以每公斤個體體重約0.5 mg、約0.75 mg、約1 mg、約1.25 mg或約1.5 mg的劑量、藉由靜脈內(IV)注射或輸注投與約30分鐘，每四週週期投與三次。在一些實施例中，調配成醫藥組合物之抗體藥物結合物係在每28天(四週)週期之第1天、第8天及第15天投與。在一些實施例中，調配成醫藥組合物之抗體藥物結合物係在每28天(四週)週期之第1天、第8天及第15天，藉由靜脈內(IV)注射或輸注經約30分鐘投與。在一些實施例中，該方法進一步包含每四週週期藉由靜脈內(IV)注射或輸注來投與免疫檢查點抑制劑一或多次。在一些實施例中，免疫檢查點抑制劑為派姆單抗。在其他實施例中，免疫檢查點抑制劑為阿特珠單抗。在一些實施例中，抗體藥物結合物投與患有尿路上皮癌或膀胱癌的患者，該等患者在用另一種癌症療法治療期間或之後，已顯示疾病惡化或復發。在一些實施例中，抗體藥物結合物投與患有轉移性尿路上皮癌或膀胱癌的患者，該等患者在另一種癌症療法治療期間或之後，已顯示疾病惡化或復發。在一些實施例中，抗體藥物結合物投與患有局部晚期尿路上皮癌或膀胱癌的患者，該等患者在用另一種癌症療法治療期間或之後，已顯示疾病惡化或復發。在一些實施例中，方法中的ADC (其各種劑量描述於本段落)為恩諾單抗維多汀(EV)。In other more specific embodiments, the antibody-drug conjugate formulated into the pharmaceutical composition provided herein is administered by intravenous (IV) injection or infusion for about 30 minutes at a dose of about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, or about 1.5 mg per kg of individual body weight, three times per four-week cycle. In some embodiments, the antibody-drug conjugate formulated into the pharmaceutical composition is administered on the 1st day, the 8th day, and the 15th day of each 28-day (four-week) cycle. In some embodiments, the antibody-drug conjugate formulated into the pharmaceutical composition is administered by intravenous (IV) injection or infusion over about 30 minutes on the 1st day, the 8th day, and the 15th day of each 28-day (four-week) cycle. In some embodiments, the method further comprises administering an immune checkpoint inhibitor by intravenous (IV) injection or infusion one or more times every four weeks. In some embodiments, the immune checkpoint inhibitor is pembrolizumab. In other embodiments, the immune checkpoint inhibitor is atezolizumab. In some embodiments, the antibody drug conjugate is administered to patients with urothelial carcinoma or bladder cancer who have shown disease worsening or recurrence during or after treatment with another cancer therapy. In some embodiments, the antibody drug conjugate is administered to patients with metastatic urothelial carcinoma or bladder cancer who have shown disease worsening or recurrence during or after treatment with another cancer therapy. In some embodiments, the antibody drug conjugate is administered to patients with locally advanced urothelial carcinoma or bladder cancer who have shown disease progression or recurrence during or after treatment with another cancer therapy. In some embodiments, the ADC in the method (various doses of which are described in this paragraph) is enrotumomab vedotin (EV).
在本文所提供之各種方法的一些實施例中，ADC的投與劑量為每公斤個體體重約0.25至約10 mg、每公斤個體體重約0.25至約5 mg、每公斤個體體重約0.25至約2.5 mg、每公斤個體體重約0.25至約1.25 mg、每公斤個體體重約0.5至約10 mg、每公斤個體體重約0.5至約5 mg、每公斤個體體重約0.5至約2.5 mg、每公斤個體體重約0.5至約1.25 mg、每公斤個體體重約0.75至約10 mg、每公斤個體體重約0.75至約5 mg、每公斤個體體重約0.75至約2.5 mg，或每公斤個體體重約0.75至約1.25 mg。在一些實施例中，ADC係以每公斤個體體重約1至約10 mg的劑量投與。在某些實施例中，ADC係以每公斤個體體重約1至約5 mg之劑量投與。在一些實施例中，ADC係以每公斤個體體重約1至約2.5 mg的劑量投與。在其他實施例中，ADC係以每公斤個體體重約1至約1.25 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重約0.25 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重約0.5 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重約0.75 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重約1.0 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重約1.25 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重約1.5 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重約1.75 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重約2.0 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重約2.25 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重約2.5 mg的劑量投與。In some embodiments of the various methods provided herein, the ADC is administered in an amount of about 0.25 to about 10 mg/kg of individual body weight, about 0.25 to about 5 mg/kg of individual body weight, about 0.25 to about 2.5 mg/kg of individual body weight, about 0.25 to about 1.25 mg/kg of individual body weight, about 0.5 to about 10 mg/kg of individual body weight, about 0.5 to about 5 mg/kg of individual body weight, about 0.5 to about 2.5 mg/kg of individual body weight, about 0.5 to about 1.25 mg/kg of individual body weight, about 0.75 to about 10 mg/kg of individual body weight, about 0.75 to about 5 mg/kg of individual body weight, about 0.75 to about 2.5 mg/kg of individual body weight, or about 0.75 to about 1.25 mg/kg of individual body weight. In some embodiments, the ADC is administered at a dose of about 1 to about 10 mg per kilogram of individual body weight. In certain embodiments, the ADC is administered at a dose of about 1 to about 5 mg per kilogram of individual body weight. In some embodiments, the ADC is administered at a dose of about 1 to about 2.5 mg per kilogram of individual body weight. In other embodiments, the ADC is administered at a dose of about 1 to about 1.25 mg per kilogram of individual body weight. In some embodiments, the ADC is administered at a dose of about 0.25 mg per kilogram of individual body weight. In some embodiments, the ADC is administered at a dose of about 0.5 mg per kilogram of individual body weight. In some embodiments, the ADC is administered at a dose of about 0.75 mg per kilogram of individual body weight. In some embodiments, the ADC is administered at a dose of about 1.0 mg per kilogram of individual body weight. In some embodiments, the ADC is administered at a dose of about 1.25 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of about 1.5 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of about 1.75 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of about 2.0 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of about 2.25 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of about 2.5 mg per kg of individual body weight.
在本文所提供之各種方法的某些實施例中，ADC的投與劑量為每公斤個體體重0.25至10 mg、每公斤個體體重0.25至5 mg、每公斤個體體重0.25至2.5 mg、每公斤個體體重0.25至1.25 mg、每公斤個體體重0.5至10 mg、每公斤個體體重0.5至5 mg、每公斤個體體重0.5至2.5 mg、每公斤個體體重0.5至1.25 mg、每公斤個體體重0.75至10 mg、每公斤個體體重0.75至5 mg、每公斤個體體重0.75至2.5 mg，或每公斤個體體重0.75至1.25 mg。在一些實施例中，ADC係以每公斤個體體重1至10 mg的劑量投與。在某些實施例中，ADC係以每公斤個體體重1至5 mg之劑量投與。在其他實施例中，ADC係以每公斤個體體重1至2.5 mg的劑量投與。在其他實施例中，ADC係以每公斤個體體重1至1.25 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重0.25 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重0.5 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重0.75 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重1.0 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重1.25 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重1.5 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重1.75 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重2.0 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重2.25 mg的劑量投與。在一些實施例中，ADC係以每公斤個體體重2.5 mg的劑量投與。In certain embodiments of the various methods provided herein, the ADC is administered in an amount of 0.25 to 10 mg/kg, 0.25 to 5 mg/kg, 0.25 to 2.5 mg/kg, 0.25 to 1.25 mg/kg, 0.5 to 10 mg/kg, 0.5 to 5 mg/kg, 0.5 to 2.5 mg/kg, 0.5 to 1.25 mg/kg, 0.75 to 10 mg/kg, 0.75 to 5 mg/kg, 0.75 to 2.5 mg/kg, or 0.75 to 1.25 mg/kg. In some embodiments, the ADC is administered in an amount of 1 to 10 mg/kg. In certain embodiments, the ADC is administered at a dose of 1 to 5 mg per kg of individual body weight. In other embodiments, the ADC is administered at a dose of 1 to 2.5 mg per kg of individual body weight. In other embodiments, the ADC is administered at a dose of 1 to 1.25 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of 0.25 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of 0.5 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of 0.75 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of 1.0 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of 1.25 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of 1.5 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of 1.75 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of 2.0 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of 2.25 mg per kg of individual body weight. In some embodiments, the ADC is administered at a dose of 2.5 mg per kg of individual body weight.
在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第一次劑量為每公斤個體體重約0.25至約10 mg、每公斤個體體重約0.25至約5 mg、每公斤個體體重約0.25至約2.5 mg、每公斤個體體重約0.25至約1.25 mg、每公斤個體體重約0.5至約10 mg、每公斤個體體重約0.5至約5 mg、每公斤個體體重約0.5至約2.5 mg、每公斤個體體重約0.5至約1.25 mg、每公斤個體體重約0.75至約10 mg、每公斤個體體重約0.75至約5 mg、每公斤個體體重約0.75至約2.5 mg，或每公斤個體體重約0.75至約1.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第一次劑量為每公斤個體體重約1至約10 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第一次劑量為每公斤個體體重約1至約5 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第一次劑量為每公斤個體體重約1至約2.5 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第一次劑量為每公斤個體體重約1至約1.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第一次劑量為每公斤個體體重約0.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第一次劑量為每公斤個體體重約0.5 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重約0.75 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重約1.0 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重約1.25 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重約1.5 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重約1.75 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重約2.0 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重約2.25 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重或約2.5 mg的劑量。In some embodiments of the various methods provided herein, including those requiring a first and a second dose, the first dose of the ADC is from about 0.25 to about 10 mg/kg of individual body weight, from about 0.25 to about 5 mg/kg of individual body weight, from about 0.25 to about 2.5 mg/kg of individual body weight, from about 0.25 to about 1.25 mg/kg of individual body weight, from about 0.5 to about 10 mg/kg of individual body weight, from about 0.5 to about 5 mg/kg of individual body weight, from about 0.5 to about 2.5 mg/kg of individual body weight, from about 0.5 to about 1.25 mg/kg of individual body weight, from about 0.75 to about 10 mg/kg of individual body weight, from about 0.75 to about 5 mg/kg of individual body weight, from about 0.75 to about 2.5 mg/kg of individual body weight, or from about 0.75 to about 1.25 mg/kg of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the first dose of ADC is a dose of about 1 to about 10 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the first dose of ADC is a dose of about 1 to about 5 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the first dose of ADC is a dose of about 1 to about 2.5 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the first dose of ADC is a dose of about 1 to about 1.25 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring the first and second doses), the first dose of ADC is a dose of about 0.25 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring the first and second doses), the first dose of ADC is a dose of about 0.5 mg per kilogram of individual body weight. In some embodiments, the first dose of ADC is a dose of about 0.75 mg per kilogram of individual body weight. In some embodiments, the first dose of ADC is a dose of about 1.0 mg per kilogram of individual body weight. In some embodiments, the first dose of ADC is a dose of about 1.25 mg per kilogram of individual body weight. In some embodiments, the first dose of ADC is a dose of about 1.5 mg per kilogram of individual body weight. In some embodiments, the first dose of ADC is about 1.75 mg per kg of individual body weight. In some embodiments, the first dose of ADC is about 2.0 mg per kg of individual body weight. In some embodiments, the first dose of ADC is about 2.25 mg per kg of individual body weight. In some embodiments, the first dose of ADC is about 2.5 mg per kg of individual body weight.
在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的某些實施例中，ADC的第一次劑量為每公斤個體體重0.25至10 mg、每公斤個體體重0.25至5 mg、每公斤個體體重0.25至2.5 mg、每公斤個體體重0.25至1.25 mg、每公斤個體體重0.5至10 mg、每公斤個體體重0.5至5 mg、每公斤個體體重0.5至2.5 mg、每公斤個體體重0.5至1.25 mg、每公斤個體體重0.75至10 mg、每公斤個體體重0.75至5 mg、每公斤個體體重0.75至2.5 mg，或每公斤個體體重0.75至1.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的某些實施例中，ADC的第一次劑量為每公斤個體體重1至10 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第一次劑量為每公斤個體體重1至5 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第一次劑量為每公斤個體體重1至2.5 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第一次劑量為每公斤個體體重1至1.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第一次劑量為每公斤個體體重0.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第一次劑量為每公斤個體體重0.5 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重0.75 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重1.0 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重1.25 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重1.5 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重1.75 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重2.0 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重2.25 mg的劑量。在一些實施例中，ADC的第一次劑量為每公斤個體體重2.5 mg的劑量。In certain embodiments of the various methods provided herein, including those requiring a first and a second dose, the first dose of the ADC is 0.25 to 10 mg/kg of individual body weight, 0.25 to 5 mg/kg of individual body weight, 0.25 to 2.5 mg/kg of individual body weight, 0.25 to 1.25 mg/kg of individual body weight, 0.5 to 10 mg/kg of individual body weight, 0.5 to 5 mg/kg of individual body weight, 0.5 to 2.5 mg/kg of individual body weight, 0.5 to 1.25 mg/kg of individual body weight, 0.75 to 10 mg/kg of individual body weight, 0.75 to 5 mg/kg of individual body weight, 0.75 to 2.5 mg/kg of individual body weight, or 0.75 to 1.25 mg/kg of individual body weight. In certain embodiments of the various methods provided herein (including those methods requiring a first and second dose), the first dose of ADC is a dose of 1 to 10 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the first dose of ADC is a dose of 1 to 5 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the first dose of ADC is a dose of 1 to 2.5 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the first dose of ADC is a dose of 1 to 1.25 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring the first and second doses), the first dose of ADC is a dose of 0.25 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring the first and second doses), the first dose of ADC is a dose of 0.5 mg per kilogram of individual body weight. In some embodiments, the first dose of ADC is a dose of 0.75 mg per kilogram of individual body weight. In some embodiments, the first dose of ADC is a dose of 1.0 mg per kilogram of individual body weight. In some embodiments, the first dose of ADC is a dose of 1.25 mg per kilogram of individual body weight. In some embodiments, the first dose of ADC is a dose of 1.5 mg per kilogram of individual body weight. In some embodiments, the first dose of ADC is 1.75 mg per kg of individual body weight. In some embodiments, the first dose of ADC is 2.0 mg per kg of individual body weight. In some embodiments, the first dose of ADC is 2.25 mg per kg of individual body weight. In some embodiments, the first dose of ADC is 2.5 mg per kg of individual body weight.
在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約0.1 mg至約2 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約0.1 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約0.2 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約0.25 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約0.3 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約0.4 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約0.5 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約0.6 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約0.7 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約0.75 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約0.8 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約0.9 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約1 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約1.1 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約1.2 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約1.25 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約1.3 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約1.4 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約1.5 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約1.6 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約1.7 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約1.75 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約1.8 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約1.9 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重約2 mg。In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 0.1 mg to about 2 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 0.1 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 0.2 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 0.25 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 0.3 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 0.4 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 0.5 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 0.6 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 0.7 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 0.75 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 0.8 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 0.9 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 1 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 1.1 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 1.2 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 1.25 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 1.3 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 1.4 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 1.5 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 1.6 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 1.7 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 1.75 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 1.8 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is about 1.9 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of ADC is about 2 mg/kg of subject body weight less than the first dose.
在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的某些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重0.1 mg至2 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重0.1 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重0.2 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重0.25 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重0.3 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重0.4 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重0.5 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重0.6 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重0.7 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重0.75 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重0.8 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重0.9 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重1 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重1.1 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重1.2 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重1.25 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重1.3 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重1.4 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重1.5 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重1.6 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重1.7 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重1.75 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重1.8 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重1.9 mg。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量比第一次劑量低每公斤個體體重2 mg。In certain embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 0.1 mg to 2 mg lower per kilogram of individual body weight than the first dose. In certain embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 0.1 mg lower per kilogram of individual body weight than the first dose. In certain embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 0.2 mg lower per kilogram of individual body weight than the first dose. In certain embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 0.25 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 0.3 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 0.4 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 0.5 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 0.6 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 0.7 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 0.75 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 0.8 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 0.9 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 1 mg per kilogram of individual body weight lower than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 1.1 mg per kilogram of individual body weight lower than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 1.2 mg per kilogram of individual body weight lower than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 1.25 mg per kilogram of individual body weight lower than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 1.3 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 1.4 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 1.5 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 1.6 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 1.7 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 1.75 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 1.8 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is 1.9 mg lower per kilogram of individual body weight than the first dose. In some embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of ADC is 2 mg/kg of subject body weight less than the first dose.
在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約0.25至約10 mg、每公斤個體體重約0.25至約5 mg、每公斤個體體重約0.25至約2.5 mg、每公斤個體體重約0.25至約1.25 mg、每公斤個體體重約0.5至約10 mg、每公斤個體體重約0.5至約5 mg、每公斤個體體重約0.5至約2.5 mg、每公斤個體體重約0.5至約1.25 mg、每公斤個體體重約0.75至約10 mg、每公斤個體體重約0.75至約5 mg、每公斤個體體重約0.75至約2.5 mg，或每公斤個體體重約0.75至約1.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約1至約10 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約1至約5 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約1至約2.5 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約1至約1.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約0.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約0.5 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約0.75 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約1.0 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約1.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約1.5 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約1.75 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約2.0 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約2.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重約2.5 mg的劑量。In some embodiments of the various methods provided herein, including those requiring a first and a second dose, the second dose of the ADC is from about 0.25 to about 10 mg/kg of individual body weight, from about 0.25 to about 5 mg/kg of individual body weight, from about 0.25 to about 2.5 mg/kg of individual body weight, from about 0.25 to about 1.25 mg/kg of individual body weight, from about 0.5 to about 10 mg/kg of individual body weight, from about 0.5 to about 5 mg/kg of individual body weight, from about 0.5 to about 2.5 mg/kg of individual body weight, from about 0.5 to about 1.25 mg/kg of individual body weight, from about 0.75 to about 10 mg/kg of individual body weight, from about 0.75 to about 5 mg/kg of individual body weight, from about 0.75 to about 2.5 mg/kg of individual body weight, or from about 0.75 to about 1.25 mg/kg of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of about 1 to about 10 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of about 1 to about 5 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of about 1 to about 2.5 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of about 1 to about 1.25 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of about 0.25 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of about 0.5 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of about 0.75 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of about 1.0 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of about 1.25 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of about 1.5 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of about 1.75 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of about 2.0 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and a second dose), the second dose of ADC is a dose of about 2.25 mg per kg of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and a second dose), the second dose of ADC is a dose of about 2.5 mg per kg of individual body weight.
在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的某些實施例中，ADC的第二次劑量為每公斤個體體重0.25至10 mg、每公斤個體體重0.25至5 mg、每公斤個體體重0.25至2.5 mg、每公斤個體體重0.25至1.25 mg、每公斤個體體重0.5至10 mg、每公斤個體體重0.5至5 mg、每公斤個體體重0.5至2.5 mg、每公斤個體體重0.5至1.25 mg、每公斤個體體重0.75至10 mg、每公斤個體體重0.75至5 mg、每公斤個體體重0.75至2.5 mg，或每公斤個體體重0.75至1.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的某些實施例中，ADC的第二次劑量為每公斤個體體重1至10 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重1至5 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重1至2.5 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重1至1.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重0.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重0.5 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重0.75 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重1.0 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重1.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重1.5 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重1.75 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重2.0 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重2.25 mg的劑量。在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的一些實施例中，ADC的第二次劑量為每公斤個體體重2.5 mg的劑量。In certain embodiments of the various methods provided herein, including those requiring a first and second dose, the second dose of ADC is 0.25 to 10 mg/kg of individual body weight, 0.25 to 5 mg/kg of individual body weight, 0.25 to 2.5 mg/kg of individual body weight, 0.25 to 1.25 mg/kg of individual body weight, 0.5 to 10 mg/kg of individual body weight, 0.5 to 5 mg/kg of individual body weight, 0.5 to 2.5 mg/kg of individual body weight, 0.5 to 1.25 mg/kg of individual body weight, 0.75 to 10 mg/kg of individual body weight, 0.75 to 5 mg/kg of individual body weight, 0.75 to 2.5 mg/kg of individual body weight, or 0.75 to 1.25 mg/kg of individual body weight. In certain embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of 1 to 10 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of 1 to 5 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of 1 to 2.5 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of 1 to 1.25 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of 0.25 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of 0.5 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of 0.75 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of 1.0 mg per kilogram of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of 1.25 mg per kg of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of 1.5 mg per kg of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of 1.75 mg per kg of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and second dose), the second dose of ADC is a dose of 2.0 mg per kg of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and a second dose), the second dose of ADC is a dose of 2.25 mg per kg of individual body weight. In some embodiments of the various methods provided herein (including those methods requiring a first and a second dose), the second dose of ADC is a dose of 2.5 mg per kg of individual body weight.
在本文所提供之各種方法(包括需要第一次及第二次劑量的彼等方法)的某些實施例中，ADC的第二次劑量與ADC的第一次劑量相同。In certain embodiments of the various methods provided herein, including those methods requiring a first and a second dose, the second dose of ADC is the same as the first dose of ADC.
在本文所提供之方法的一些實施例中，ADC係藉由靜脈內(IV)注射或輸注投與。在一個實施例中，ADC的第一次劑量係藉由IV注射投與。在另一實施例中，ADC的第一次劑量係藉由IV輸注投與。在又另一實施例中，ADC的第二次劑量係藉由IV注射投與。在又另一實施例中，ADC的第二次劑量係藉由IV注射輸注投與。在一個實施例中，ADC的第一次劑量係藉由IV注射投與且ADC的第二次劑量係藉由IV注射投與。在另一實施例中，ADC的第一次劑量係藉由IV輸注投與且ADC的第二次劑量係藉由IV注射投與。在又另一實施例中，ADC的第二次劑量係藉由IV注射投與且ADC的第二次劑量係藉由IV注射輸注投與。在又另一實施例中，ADC的第二次劑量係藉由IV注射輸注投與且ADC的第二次劑量係藉由IV注射輸注投與。在一些實施例中，方法中的ADC (其各種劑量描述於本段落)為恩諾單抗維多汀(EV)。In some embodiments of the methods provided herein, the ADC is administered by intravenous (IV) injection or infusion. In one embodiment, the first dose of the ADC is administered by IV injection. In another embodiment, the first dose of the ADC is administered by IV infusion. In yet another embodiment, the second dose of the ADC is administered by IV injection. In yet another embodiment, the second dose of the ADC is administered by IV injection infusion. In one embodiment, the first dose of the ADC is administered by IV injection and the second dose of the ADC is administered by IV injection. In another embodiment, the first dose of the ADC is administered by IV infusion and the second dose of the ADC is administered by IV injection. In yet another embodiment, the second dose of the ADC is administered by IV injection and the second dose of the ADC is administered by IV injection infusion. In yet another embodiment, the second dose of the ADC is administered by IV injection infusion and the second dose of the ADC is administered by IV injection infusion. In some embodiments, the ADC in the method (various doses of which are described in this paragraph) is enrotumomab vedotin (EV).
在本文所提供之方法的某些實施例中，ADC係藉由IV注射或輸注、每四週週期投與三次。在本文所提供之方法的一些實施例中，ADC的第一次劑量係藉由IV注射或輸注、每四週週期投與三次。在本文所提供之方法的一些實施例中，ADC的第二次劑量係藉由IV注射或輸注、每四週週期投與三次。在本文所提供之方法的一些實施例中，ADC的第一次劑量係藉由IV注射或輸注、每四週週期投與三次，且ADC的第二次劑量係藉由IV注射或輸注、每四週週期投與三次。在一些實施例中，方法中的ADC (其各種劑量描述於本段落)為恩諾單抗維多汀(EV)。In certain embodiments of the methods provided herein, the ADC is administered three times per four-cycle cycle by IV injection or infusion. In some embodiments of the methods provided herein, the first dose of the ADC is administered three times per four-cycle cycle by IV injection or infusion. In some embodiments of the methods provided herein, the second dose of the ADC is administered three times per four-cycle cycle by IV injection or infusion. In some embodiments of the methods provided herein, the first dose of the ADC is administered three times per four-cycle cycle by IV injection or infusion, and the second dose of the ADC is administered three times per four-cycle cycle by IV injection or infusion. In some embodiments, the ADC in the method (various doses of which are described in this paragraph) is enromax vedotin (EV).
在本文所提供之方法的一些實施例中，ADC係藉由IV注射或輸注、在每四週週期的第1、8及15天投與。在一些實施例中，ADC的第一次劑量係藉由IV注射或輸注、在每四週週期的第1、8及15天投與。在一些實施例中，ADC的第二次劑量係藉由IV注射或輸注、在每四週週期的第1、8及15天投與。在一些實施例中，ADC的第一次劑量係藉由IV注射或輸注、在每四週週期的第1、8及15天投與，且ADC的第二次劑量係藉由IV注射或輸注、在每四週週期的第1、8及15天投與。在一些實施例中，方法中的ADC (其各種劑量描述於本段落)為恩諾單抗維多汀(EV)。In some embodiments of the methods provided herein, the ADC is administered by IV injection or infusion on days 1, 8, and 15 of each four-week cycle. In some embodiments, the first dose of the ADC is administered by IV injection or infusion on days 1, 8, and 15 of each four-week cycle. In some embodiments, the second dose of the ADC is administered by IV injection or infusion on days 1, 8, and 15 of each four-week cycle. In some embodiments, the first dose of the ADC is administered by IV injection or infusion on days 1, 8, and 15 of each four-week cycle, and the second dose of the ADC is administered by IV injection or infusion on days 1, 8, and 15 of each four-week cycle. In some embodiments, the ADC in the method (various doses of which are described in this paragraph) is enrotumab vedotin (EV).
在本文所提供之方法的某些實施例中，ADC係藉由IV注射或輸注約30分鐘、每四週週期投與三次。在一些實施例中，ADC的第一次劑量係藉由IV注射或輸注約30分鐘、每四週週期投與三次。在一些實施例中，ADC的第二次劑量係藉由IV注射或輸注約30分鐘、每四週週期投與三次。在一些實施例中，ADC的第一次劑量係藉由IV注射或輸注約30分鐘、每四週週期投與三次，且ADC的第二次劑量係藉由IV注射或輸注約30分鐘、每四週週期投與三次。在一些實施例中，方法中的ADC (其各種劑量描述於本段落)為恩諾單抗維多汀(EV)。In certain embodiments of the methods provided herein, the ADC is administered three times per four-week cycle by IV injection or infusion over about 30 minutes. In some embodiments, the first dose of the ADC is administered three times per four-week cycle by IV injection or infusion over about 30 minutes. In some embodiments, the second dose of the ADC is administered three times per four-week cycle by IV injection or infusion over about 30 minutes. In some embodiments, the first dose of the ADC is administered three times per four-week cycle by IV injection or infusion over about 30 minutes, and the second dose of the ADC is administered three times per four-week cycle by IV injection or infusion over about 30 minutes. In some embodiments, the ADC in the method (various doses of which are described in this paragraph) is enromax vedotin (EV).
在本文所提供之方法的一些實施例中，ADC係藉由IV注射或輸注約30分鐘、在每四週週期的第1、8及15天投與。在本文所提供之方法的一些實施例中，ADC的第一次劑量係IV注射或輸注約30分鐘、在每四週週期的第1、8及15天投與。在本文所提供之方法的一些實施例中，ADC的第二次劑量係藉由IV注射或輸注約30分鐘、在每四週週期的第1、8及15天投與。在本文所提供之方法的一些實施例中，ADC的第一次劑量係藉由IV注射或輸注約30分鐘、在每四週週期的第1、8及15天投與，且ADC的第二次劑量係藉由IV注射或輸注約30分鐘、在每四週週期的第1、8及15天投與。在一些實施例中，方法中的ADC (其各種劑量描述於本段落)為恩諾單抗維多汀(EV)。In some embodiments of the methods provided herein, the ADC is administered by IV injection or infusion over about 30 minutes on days 1, 8, and 15 of each four-cycle cycle. In some embodiments of the methods provided herein, the first dose of the ADC is administered by IV injection or infusion over about 30 minutes on days 1, 8, and 15 of each four-cycle cycle. In some embodiments of the methods provided herein, the second dose of the ADC is administered by IV injection or infusion over about 30 minutes on days 1, 8, and 15 of each four-cycle cycle. In some embodiments of the methods provided herein, the first dose of the ADC is administered by IV injection or infusion over about 30 minutes on days 1, 8, and 15 of each four-cycle cycle, and the second dose of the ADC is administered by IV injection or infusion over about 30 minutes on days 1, 8, and 15 of each four-cycle cycle. In some embodiments, the ADC in the method (various dosages of which are described in this paragraph) is enrofloxacin (EV).
在其他更特定實施例中，調配成本文所提供之醫藥組合物的抗體藥物結合物係以每公斤個體體重約1 mg、1.25 mg或約1.5 mg之劑量、藉由靜脈內(IV)注射或輸注約30分鐘、每28天週期投與三次。在一些實施例中，調配成醫藥組合物之抗體藥物結合物係藉由靜脈內(IV)注射或輸注約30分鐘、在每28天週期的第1、8及15天投與。在一些實施例中，該方法進一步包含每四週週期藉由靜脈內(IV)注射或輸注來投與免疫檢查點抑制劑一或多次。在本文所提供之方法的一些實施例中，在28天週期內投與ADC三次。在本文所提供之方法的一些實施例中，在28天週期之第1、8及15天投與ADC。在一些實施例中，方法中的ADC (其各種劑量描述於本段落)為恩諾單抗維多汀(EV)。In other more specific embodiments, the antibody drug conjugate formulated into the pharmaceutical composition provided herein is administered three times per 28-day cycle by intravenous (IV) injection or infusion for about 30 minutes at a dose of about 1 mg, 1.25 mg, or about 1.5 mg per kilogram of individual body weight. In some embodiments, the antibody drug conjugate formulated into the pharmaceutical composition is administered by intravenous (IV) injection or infusion for about 30 minutes on the 1st, 8th, and 15th days of each 28-day cycle. In some embodiments, the method further comprises administering an immune checkpoint inhibitor one or more times per four-cycle cycle by intravenous (IV) injection or infusion. In some embodiments of the methods provided herein, the ADC is administered three times in a 28-day cycle. In some embodiments of the methods provided herein, the ADC is administered on days 1, 8, and 15 of a 28-day cycle. In some embodiments, the ADC in the methods (various doses of which are described in this paragraph) is enrofloxacin (EV).
在本文所提供之方法的一個特定實施例中，ADC具有以下結構：其中L-表示該抗體或其抗原結合片段且p為約3至約4，該抗體包含重鏈，該重鏈包含SEQ ID NO:7之第20個胺基酸(麩胺酸)至第466個胺基酸(離胺酸)範圍內的胺基酸序列；及輕鏈，該輕鏈包含SEQ ID NO:8之第23個胺基酸(天冬胺酸)至第236個胺基酸(半胱胺酸)範圍內的胺基酸序列，其中該ADC係以每公斤該個體體重約1.25 mg的劑量投與，且其中該劑量係在每四週週期之第1、8及15天藉由IV注射或輸注經約30分鐘投與。5.8組合療法In a specific embodiment of the method provided herein, the ADC has the following structure: wherein L- represents the antibody or an antigen-binding fragment thereof and p is about 3 to about 4, the antibody comprises a heavy chain comprising an amino acid sequence ranging from the 20th amino acid (glutamine) to the 466th amino acid (lysine) of SEQ ID NO:7; and a light chain comprising an amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8, wherein the ADC is administered at a dose of about 1.25 mg per kilogram of body weight of the individual, and wherein the dose is administered by IV injection or infusion over about 30 minutes on days 1, 8, and 15 of each four-week cycle.5.8Combination Therapy
本文提供使用抗體藥物結合物(其中抗體藥物結合物包含結合至191P4D12之抗體或其抗原結合片段與單甲基奧瑞他汀E (MMAE)之一或多個單元的結合物)組合檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如派姆單抗)以治療個體之癌症的組合療法。在本文所揭示之任一實施例中，檢查點抑制劑可為派姆單抗。Provided herein are combination therapies for treating cancer in an individual using an antibody drug conjugate (wherein the antibody drug conjugate comprises a conjugate of an antibody or antigen-binding fragment thereof that binds to 191P4D12 and one or more units of monomethyl auristatin E (MMAE)) in combination with a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, e.g., pembrolizumab). In any of the embodiments disclosed herein, the checkpoint inhibitor may be pembrolizumab.
在一些實施例中，投與醫藥學上有效量之抗體藥物結合物。在一些實施例中，投與醫藥學上有效量之檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如派姆單抗)。在一些實施例中，投與醫藥學上有效量之抗體藥物結合物且投與醫藥學上有效量之檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如派姆單抗)。在一些實施例中，投與醫藥學上有效量之抗體藥物結合物且投與醫藥學上有效量之派姆單抗。在一些實施例中，投與有效量之抗體藥物結合物且投與有效量之檢查點抑制劑(諸如PD-1抑制劑或PD-L1抑制劑，例如派姆單抗)。在一些實施例中，投與有效量之抗體藥物結合物且投與有效量之派姆單抗。In some embodiments, a pharmaceutically effective amount of an antibody-drug conjugate is administered. In some embodiments, a pharmaceutically effective amount of a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as pembrolizumab) is administered. In some embodiments, a pharmaceutically effective amount of an antibody-drug conjugate is administered and a pharmaceutically effective amount of a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as pembrolizumab) is administered. In some embodiments, a pharmaceutically effective amount of an antibody-drug conjugate is administered and a pharmaceutically effective amount of pembrolizumab is administered. In some embodiments, an effective amount of an antibody-drug conjugate is administered and an effective amount of a checkpoint inhibitor (such as a PD-1 inhibitor or a PD-L1 inhibitor, such as pembrolizumab) is administered. In some embodiments, an effective amount of an antibody drug conjugate is administered and an effective amount of pembrolizumab is administered.
在一些實施例中，個體為人類。在一些實施例中，個體為診斷患有癌症之個體，該癌症例如尿路上皮癌、膀胱癌、腎盂癌、輸尿管癌、尿道癌、局部晚期癌、轉移性癌症、局部晚期尿路上皮癌、不可切除性局部晚期尿路上皮癌、轉移性尿路上皮癌、局部晚期膀胱癌或轉移性膀胱癌。In some embodiments, the subject is a human. In some embodiments, the subject is a subject diagnosed with cancer, such as urothelial carcinoma, bladder cancer, renal pelvic cancer, ureteral cancer, urethral cancer, locally advanced cancer, metastatic cancer, locally advanced urothelial carcinoma, unresectable locally advanced urothelial carcinoma, metastatic urothelial carcinoma, locally advanced bladder cancer, or metastatic bladder cancer.
將有效預防及/或治療癌症的本文所提供之抗體藥物結合物或派姆單抗或醫藥組合物的量可藉由標準臨床技術確定。另外，可視情況採用活體外分析幫助鑑別最佳劑量範圍。調配物中的精確使用劑量亦視投藥途徑及癌症嚴重度而定，且在一些實施例中，應根據從醫者之判斷及各患者的情形決定。The amount of the antibody drug conjugate or pembrolizumab or pharmaceutical composition provided herein that will be effective in preventing and/or treating cancer can be determined by standard clinical techniques. In addition, in vitro assays can be used to help identify optimal dosage ranges as appropriate. The exact dosage used in the formulation also depends on the route of administration and the severity of the cancer, and in some embodiments, should be determined based on the judgment of the practitioner and the circumstances of each patient.
在一些實施例中，本文所提供之抗體藥物結合物作為組合物的一部分投與個體。在一些實施例中，組合物為章節5.4中所描述之醫藥組合物。In some embodiments, the antibody drug conjugates provided herein are administered to a subject as part of a composition. In some embodiments, the composition is a pharmaceutical composition as described in Section 5.4.
在一些實施例中，抗體藥物結合物及派姆單抗可調配成不同醫藥組合物且向有需要之個體分開投與。在其他實施例中，抗體藥物結合物及派姆單抗在同一醫藥組合物中一起投與。In some embodiments, the antibody drug conjugate and pembrolizumab can be formulated into different pharmaceutical compositions and administered separately to individuals in need thereof. In other embodiments, the antibody drug conjugate and pembrolizumab are administered together in the same pharmaceutical composition.
在其他實施例中，抗體藥物結合物及派姆單抗同時投與。術語「同時」意謂在相同時間或在相差短時段內，舉例而言，小於1小時、小於2小時、小於3小時、小於4小時或小於12小時。In other embodiments, the antibody drug conjugate and pembrolizumab are administered simultaneously. The term "simultaneously" means at the same time or within a short time period, for example, less than 1 hour, less than 2 hours, less than 3 hours, less than 4 hours, or less than 12 hours.
在一些實施例中，抗體藥物結合物及派姆單抗不同時投與，而是兩種化合物在不同時間投與。In some embodiments, the antibody drug conjugate and pembrolizumab are not administered at the same time, but rather the two compounds are administered at different times.
在一些實施例中，派姆單抗在投與抗體藥物結合物之前投與。In some embodiments, pembrolizumab is administered prior to administration of the antibody drug conjugate.
在一些實施例中，派姆單抗在投與抗體藥物結合物之後投與。In some embodiments, pembrolizumab is administered after administration of the antibody drug conjugate.
在某些實施例中，在投與抗體藥物結合物之前，個體先前已以派姆單抗治療。In certain embodiments, the subject has been previously treated with pembrolizumab prior to administration of the antibody drug conjugate.
在某些實施例中，在投與派姆單抗之前，個體先前已以抗體藥物結合物治療。In certain embodiments, the subject has been previously treated with an antibody-drug conjugate prior to administration of pembrolizumab.
在某些實施例中，在共同投與抗體藥物結合物及派姆單抗之前，個體先前未以派姆單抗治療。In certain embodiments, the individual has not been previously treated with pembrolizumab prior to co-administration of the antibody drug conjugate and pembrolizumab.
在某些實施例中，抗體藥物結合物與派姆單抗之共同投與為伴隨投與。In certain embodiments, co-administration of an antibody drug conjugate and pembrolizumab is concomitant administration.
在某些實施例中，共同投與抗體藥物結合物及派姆單抗在醫藥學上有效治療癌症。In certain embodiments, co-administration of an antibody drug conjugate and pembrolizumab is medically effective for treating cancer.
本文所揭示之任何量或劑量之抗體藥物結合物可與本文所揭示之任何量或劑量之派姆單抗組合投與。在一些實施例中，抗體藥物結合物及派姆單抗在給藥期期間至少投與一次。如本文所用之給藥期意謂在其期間至少投與一次各治療劑的時段。給藥週期可為約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30天。在一些實施例中，給藥週期為1、2、3、4、5、6、7、8、9或10週。在某些實施例中，給藥期為給藥週期。Any amount or dosage of the Antibody Drug Conjugate disclosed herein may be administered in combination with any amount or dosage of pembrolizumab disclosed herein. In some embodiments, the Antibody Drug Conjugate and pembrolizumab are administered at least once during a dosing period. As used herein, a dosing period means a time period during which each therapeutic agent is administered at least once. The dosing cycle may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days. In some embodiments, the dosing cycle is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks. In certain embodiments, the dosing period is a dosing cycle.
治療劑(本文所提供之抗體藥物結合物及/或派姆單抗)可以單次劑量(例如單次彈丸注射)遞送或隨時間推移(例如隨時間推移連續輸注或隨時間推移分次彈丸注射劑量)遞送。若需要，可重複投與藥劑，例如直至患者經歷穩定疾病或消退，或直至患者經歷疾病惡化或不可接受的毒性。藉由此項技術中已知之方法來確定穩定疾病或缺乏，諸如評估患者症狀、體檢及觀測已使用X射線、CAT、PET、MRI掃描成像之腫瘤或其他通常公認的評估模式。The therapeutic agent (antibody drug conjugate provided herein and/or pembrolizumab) can be delivered in a single dose (e.g., a single bolus injection) or over time (e.g., continuous infusion over time or divided bolus injections over time). If necessary, the agent can be administered repeatedly, for example, until the patient experiences stable disease or regression, or until the patient experiences disease worsening or unacceptable toxicity. Stable disease or the absence thereof is determined by methods known in the art, such as assessment of patient symptoms, physical examination, and observation of the tumor that has been imaged using X-ray, CAT, PET, MRI scans, or other generally recognized assessment modalities.
治療劑(本文所提供之抗體藥物結合物及/或派姆單抗)可每日投與一次(QD)，或分成多次日劑量，諸如每日兩次(BID)、每日三次(TID)及每日四次(QID)。此外，投藥可為連續性的(亦即，在連續日中的每一日，或每日)、或間歇性的，例如以週期方式(亦即，包括數天、數週或數月之停藥休息期)。如本文所用，術語「每日」欲意謂治療化合物每日投與一次或超過一次，舉例而言，持續一段時間。術語「連續」欲意謂每日投與治療化合物持續例如至少10天的不間斷期間。如本文所使用之術語「間歇性」或「間歇地」欲意謂以規則或不規則時間間隔停止及起始。舉例而言，化合物之間歇性投與為每週一天至六天投與，以週期投與(例如，每日投與持續兩個至八個連續週，接著為不投與至多一週之休息期)或以隔日投與。The therapeutic agent (antibody drug conjugates and/or pembrolizumab provided herein) can be administered once daily (QD), or divided into multiple daily doses, such as twice daily (BID), three times daily (TID), and four times daily (QID). In addition, administration can be continuous (i.e., on consecutive days, or every day), or intermittent, such as in a cyclic manner (i.e., including rest periods of several days, weeks, or months). As used herein, the term "daily" is intended to mean that the therapeutic compound is administered once or more than once a day, for example, for a period of time. The term "continuously" is intended to mean that the therapeutic compound is administered daily for an uninterrupted period of, for example, at least 10 days. As used herein, the term "intermittent" or "intermittently" is intended to mean stopping and starting at regular or irregular time intervals. For example, intermittent administration of a compound is administration one to six days per week, in cycles (e.g., daily administration for two to eight consecutive weeks, followed by a rest period of up to one week without administration), or in alternate days.
在一些實施例中，投與頻率在約日劑量至約月劑量之範圍內。在某些實施例中，投與為一天一次、一天兩次、一天三次、一天四次、每隔一天一次、每隔一天兩次、每隔一天三次、每隔一天四次、一週兩次、一週三次、一週四次、一週五次、一週一次、每兩週一次、每三週一次或每四週一次。In some embodiments, the frequency of administration is in the range of about a daily dose to about a monthly dose. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice every other day, three times every other day, four times every other day, twice a week, three times a week, four times a week, five times a week, once a week, once every two weeks, once every three weeks, or once every four weeks.
在某些實施例中，化合物每天一次、一天兩次、一天三次或一天四次投與，持續一天至六個月、一週至三個月、一週至四週、一週至三週或一週至兩週。In certain embodiments, the compound is administered once a day, twice a day, three times a day, or four times a day for one day to six months, one week to three months, one week to four weeks, one week to three weeks, or one week to two weeks.
在一些實施例中，本文所提供之抗體藥物結合物以治療有效量投與且派姆單抗以治療有效量投與。抗體藥物結合物之治療有效量可為本文所揭示之抗體藥物結合物的任何量或劑量。派姆單抗之治療有效量可為本文所揭示之派姆單抗的任何量或劑量。在某些實施例中，本文所揭示之任何量或劑量之抗體藥物結合物可與本文所揭示之任何量或劑量之派姆單抗組合投與(參見例如章節5.2.1.3、5.4及5.7)。In some embodiments, an Antibody Drug Conjugate provided herein is administered in a therapeutically effective amount and pembrolizumab is administered in a therapeutically effective amount. The therapeutically effective amount of the Antibody Drug Conjugate can be any amount or dosage of the Antibody Drug Conjugate disclosed herein. The therapeutically effective amount of pembrolizumab can be any amount or dosage of pembrolizumab disclosed herein. In certain embodiments, any amount or dosage of the Antibody Drug Conjugate disclosed herein can be administered in combination with any amount or dosage of pembrolizumab disclosed herein (see, e.g., Sections 5.2.1.3, 5.4, and 5.7).
抗體藥物結合物及/或派姆單抗可根據體重(mg/kg)或體表面積(BSA) (mg/m2)投與或給與。作為意欲為說明性而非限制性之實例，全球平均身體質量已計算為62 kg。參見Walpole等人, 2012,BMC Public Health, 12:439 (doi: 10.1186/1471-2458-12-439)。The antibody drug conjugate and/or pembrolizumab may be administered or dosed based on body weight (mg/kg) or body surface area (BSA) (mg/m2 ). As an example, which is intended to be illustrative and not limiting, the global average body mass has been calculated to be 62 kg. See Walpole et al., 2012,BMC Public Health , 12:439 (doi: 10.1186/1471-2458-12-439).
在某些實施例中，本文所提供之抗體藥物結合物係以約0.1 mg/kg、約0.5 mg/kg、約0.75 mg/kg、約1 mg/kg、約1.25 mg/kg、約1.5 mg/kg、約2 mg/kg、約2.5 mg/kg、約3 mg/kg、約4 mg/kg、約5 mg/kg、約10 mg/kg、約15 mg/kg、約20 mg/kg、約25 mg/kg、約30 mg/kg、約35 mg/kg、約40 mg/kg、約45 mg/kg、約50 mg/kg、約55 mg/kg、約60 mg/kg、約65 mg/kg、約70 mg/kg、約75 mg/kg、約80 mg/kg、約85 mg/kg、約90 mg/kg、約95 mg/kg、約100 mg/kg之劑量投與。In certain embodiments, the antibody drug conjugates provided herein are administered in an amount of about 0.1 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg.
在某些實施例中，本文所提供之抗體藥物結合物係以每公斤個體體重約0.1 mg至約100 mg之劑量投與。在一些實施例中，本文所提供之抗體藥物結合物係以每公斤個體體重約1 mg至約75 mg之劑量投與。在一些實施例中，本文所提供之抗體藥物結合物係以每公斤個體體重約1 mg與約20 mg之間，諸如每公斤個體體重約1 mg至約5 mg、每公斤個體體重約1 mg至約4 mg、每公斤個體體重約1 mg至約3 mg或每公斤個體體重約1 mg至約2 mg之劑量投與。In certain embodiments, the antibody-drug conjugates provided herein are administered in an amount of about 0.1 mg to about 100 mg per kilogram of individual body weight. In some embodiments, the antibody-drug conjugates provided herein are administered in an amount of about 1 mg to about 75 mg per kilogram of individual body weight. In some embodiments, the antibody-drug conjugates provided herein are administered in an amount of between about 1 mg and about 20 mg per kilogram of individual body weight, such as about 1 mg to about 5 mg per kilogram of individual body weight, about 1 mg to about 4 mg per kilogram of individual body weight, about 1 mg to about 3 mg per kilogram of individual body weight, or about 1 mg to about 2 mg per kilogram of individual body weight.
在某些實施例中，派姆單抗係以約100 mg、約150 mg、約200 mg、約250 mg、約300 mg、約350 mg、約400 mg、約450 mg或約500 mg之劑量投與。在特定實施例中，派姆單抗係以約200 mg之劑量投與。In certain embodiments, pembrolizumab is administered at a dose of about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. In a specific embodiment, pembrolizumab is administered at a dose of about 200 mg.
在某些實施例中，派姆單抗係以約100 mg至約500 mg、約150 mg至約500 mg、約200 mg至約500 mg、約250 mg至約500 mg、約300 mg至約500 mg、約350 mg至約500 mg、約400 mg至約500 mg或約450 mg至約500 mg之劑量投與。在某些實施例中，派姆單抗係以約100 mg至約450 mg、約100 mg至約400 mg、約100 mg至約350 mg、約100 mg至約300 mg、約100 mg至約250 mg、約100 mg至約200 mg或約100 mg至約150 mg之劑量投與。在某些實施例中，派姆單抗係以約150 mg至約450 mg、約150 mg至約400 mg、約150 mg至約350 mg、約200 mg至約450 mg、約200 mg至約400 mg、約200 mg至約300 mg或約200 mg至約250 mg之劑量投與。In certain embodiments, pembrolizumab is administered in an amount of about 100 mg to about 500 mg, about 150 mg to about 500 mg, about 200 mg to about 500 mg, about 250 mg to about 500 mg, about 300 mg to about 500 mg, about 350 mg to about 500 mg, about 400 mg to about 500 mg, or about 450 mg to about 500 mg. In certain embodiments, pembrolizumab is administered in an amount of about 100 mg to about 450 mg, about 100 mg to about 400 mg, about 100 mg to about 350 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, or about 100 mg to about 150 mg. In certain embodiments, pembrolizumab is administered in an amount of about 150 mg to about 450 mg, about 150 mg to about 400 mg, about 150 mg to about 350 mg, about 200 mg to about 450 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, or about 200 mg to about 250 mg.
在一些實施例中，本文所提供之抗體藥物結合物在各14天、21天、28天、35天或42天治療週期期間每日投與。在一些實施例中，抗體藥物結合物在14天治療週期中投與1、2、3、4、5、6、7、8、9、10、11、12、13或14天。在一些實施例中，抗體藥物結合物在21天(亦即3週)治療週期中投與1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21天。在一些實施例中，抗體藥物結合物在28天治療週期中投與1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27或28天。在一些實施例中，抗體藥物結合物在35天治療週期中投與1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34或35天。在一些實施例中，抗體藥物結合物在42天治療週期中投與1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41或42天。在一些實施例中，抗體藥物結合物在21天治療週期中之1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21天投與。在某些實施例中，抗體藥物結合物在21天治療週期之第1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20及/或21天投與。在特定實施例中，抗體藥物結合物在21天治療週期之第1天及第8天投與。在一些實施例中，抗體藥物結合物投與至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39或40個治療週期。In some embodiments, the antibody drug conjugates provided herein are administered daily during each 14-day, 21-day, 28-day, 35-day, or 42-day treatment cycle. In some embodiments, the antibody drug conjugates are administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days in a 14-day treatment cycle. In some embodiments, the antibody drug conjugates are administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days in a 21-day (i.e., 3-week) treatment cycle. In some embodiments, the antibody drug conjugate is administered on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 of a 28-day treatment cycle. In some embodiments, the antibody drug conjugate is administered on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 of a 35-day treatment cycle. In some embodiments, the antibody drug conjugate is administered on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 of a 42 day treatment cycle. In some embodiments, the antibody drug conjugate is administered on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 of a 21 day treatment cycle. In certain embodiments, the antibody drug conjugate is administered on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and/or 21 of a 21 day treatment cycle. In specific embodiments, the antibody drug conjugate is administered on days 1 and 8 of a 21 day treatment cycle. In some embodiments, the antibody drug conjugate is administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 treatment cycles.
在一些實施例中，抗體藥物結合物在各14天、21天、28天、35天或42天治療週期期間每日投與一次、兩次、三次或四次。在一些實施例中，抗體藥物結合物在各14天治療週期中之1、2、3、4、5、6、7、8、9、10、11、12、13或14天每日投與一次、兩次、三次或四次。在一些實施例中，抗體藥物結合物在各21天治療週期中之1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21天每日投與一次、兩次、三次或四次。在一些實施例中，抗體藥物結合物在各28天治療週期中之1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27或28天每日投與一次、兩次、三次或四次。在一些實施例中，抗體藥物結合物在各35天治療週期中之1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34或35天每日投與一次、兩次、三次或四次。在一些實施例中，抗體藥物結合物在各42天治療週期中之1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41或42天每日投與一次、兩次、三次或四次。在某些實施例中，抗體藥物結合物在各21天治療週期中之2天每日投與一次、兩次、三次或四次。In some embodiments, the Antibody Drug Conjugate is administered once, twice, three times, or four times daily during each 14-day, 21-day, 28-day, 35-day, or 42-day treatment cycle. In some embodiments, the Antibody Drug Conjugate is administered once, twice, three times, or four times daily on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of each 14-day treatment cycle. In some embodiments, the Antibody Drug Conjugate is administered once, twice, three times, or four times daily on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days of each 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered once, twice, three times, or four times daily on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 of each 28-day treatment cycle. In some embodiments, the antibody drug conjugate is administered once, twice, three times, or four times daily on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 of each 35-day treatment cycle. In some embodiments, the antibody drug conjugate is administered once, twice, three times, or four times daily on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 of each 42-day treatment cycle. In certain embodiments, the antibody drug conjugate is administered once, twice, three times, or four times daily on day 2 of each 21-day treatment cycle.
在某些實施例中，抗體藥物結合物在各21天治療週期中之2天以約1.25 mg/kg之日劑量投與。在某些實施例中，抗體藥物結合物在各21天治療週期之第1天及第8天以約1.25 mg/kg之日劑量投與。在某些實施例中，抗體藥物結合物在各21天治療週期之第1天及第8天以約1.25 mg/kg之日劑量藉由靜脈內注射或輸注投與。在某些實施例中，抗體藥物結合物在各21天治療週期之第1天及第8天以約1.25 mg/kg之日劑量藉由靜脈內輸注投與。In certain embodiments, the antibody drug conjugate is administered at a daily dose of about 1.25 mg/kg on 2 days of each 21-day treatment cycle. In certain embodiments, the antibody drug conjugate is administered at a daily dose of about 1.25 mg/kg on Day 1 and Day 8 of each 21-day treatment cycle. In certain embodiments, the antibody drug conjugate is administered by intravenous injection or infusion at a daily dose of about 1.25 mg/kg on Day 1 and Day 8 of each 21-day treatment cycle. In certain embodiments, the antibody drug conjugate is administered by intravenous infusion at a daily dose of about 1.25 mg/kg on Day 1 and Day 8 of each 21-day treatment cycle.
在一些實施例中，抗體藥物結合物經靜脈內投與。在一些實施例中，抗體藥物結合物藉由靜脈內注射或輸注投與。在一些實施例中，抗體藥物結合物藉由靜脈內輸注投與。在一些實施例中，抗體藥物結合物以30分鐘(-5分鐘/+10分鐘)靜脈內輸注形式投與。在一個實施例中，所選劑量之抗體藥物結合物藉由靜脈內輸注經25與40分鐘之間或約30分鐘(-5分鐘/+10分鐘)之時段投與。In some embodiments, the antibody drug conjugate is administered intravenously. In some embodiments, the antibody drug conjugate is administered by intravenous injection or infusion. In some embodiments, the antibody drug conjugate is administered by intravenous infusion. In some embodiments, the antibody drug conjugate is administered as a 30 minute (-5 minutes/+10 minutes) intravenous infusion. In one embodiment, the selected dose of the antibody drug conjugate is administered by intravenous infusion over a period of between 25 and 40 minutes or about 30 minutes (-5 minutes/+10 minutes).
在一些實施例中，派姆單抗在各14天、21天、28天、35天或42天治療週期期間每日投與。在一些實施例中，派姆單抗在14天治療週期中投與1、2、3、4、5、6、7、8、9、10、11、12、13或14天。在一些實施例中，派姆單抗在21天(亦即3週)治療週期中投與1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21天。在一些實施例中，派姆單抗在28天治療週期中投與1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27或28天。在一些實施例中，派姆單抗在35天治療週期中投與1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34或35天。在一些實施例中，派姆單抗在42天治療週期中投與1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41或42天。在一些實施例中，派姆單抗在21天治療週期中之1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21天投與。在某些實施例中，派姆單抗在21天治療週期之第1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20及/或21天投與。在特定實施例中，派姆單抗在21天治療週期之第1天投與。在一些實施例中，派姆單抗投與至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39或40個治療週期。In some embodiments, pembrolizumab is administered daily during each 14-day, 21-day, 28-day, 35-day, or 42-day treatment cycle. In some embodiments, pembrolizumab is administered on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days in a 14-day treatment cycle. In some embodiments, pembrolizumab is administered on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days in a 21-day (i.e., 3-week) treatment cycle. In some embodiments, pembrolizumab is administered on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 of a 28-day treatment cycle. In some embodiments, pembrolizumab is administered on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 of a 35-day treatment cycle. In some embodiments, pembrolizumab is administered on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 of a 42 day treatment cycle. In some embodiments, pembrolizumab is administered on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 of a 21 day treatment cycle. In certain embodiments, pembrolizumab is administered on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and/or 21 of a 21 day treatment cycle. In specific embodiments, pembrolizumab is administered on day 1 of a 21 day treatment cycle. In some embodiments, pembrolizumab is administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 treatment cycles.
在一些實施例中，派姆單抗在各14天、21天、28天、35天或42天治療週期期間每日投與一次、兩次、三次或四次。在一些實施例中，派姆單抗在各14天治療週期中之1、2、3、4、5、6、7、8、9、10、11、12、13或14天每日投與一次、兩次、三次或四次。在一些實施例中，派姆單抗在各21天治療週期中之1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21天每日投與一次、兩次、三次或四次。在一些實施例中，派姆單抗在各28天治療週期中之1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27或28天每日投與一次、兩次、三次或四次。在一些實施例中，派姆單抗在各35天治療週期中之1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34或35天每日投與一次、兩次、三次或四次。在一些實施例中，派姆單抗在各42天治療週期中之1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41或42天每日投與一次、兩次、三次或四次。在某些實施例中，派姆單抗在各21天治療週期之1天每日投與一次、兩次、三次或四次。In some embodiments, pembrolizumab is administered once, twice, three times, or four times daily during each 14-day, 21-day, 28-day, 35-day, or 42-day treatment cycle. In some embodiments, pembrolizumab is administered once, twice, three times, or four times daily on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 of each 14-day treatment cycle. In some embodiments, pembrolizumab is administered once, twice, three times, or four times daily on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 of each 21-day treatment cycle. In some embodiments, pembrolizumab is administered once, twice, three times, or four times daily on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 of each 28-day treatment cycle. In some embodiments, pembrolizumab is administered once, twice, three times, or four times daily on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 of each 35-day treatment cycle. In some embodiments, pembrolizumab is administered once, twice, three times, or four times daily on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 of each 42-day treatment cycle. In certain embodiments, pembrolizumab is administered once, twice, three times, or four times daily on day 1 of each 21-day treatment cycle.
在某些實施例中，派姆單抗在各21天治療週期中之1天以約200 mg之日劑量投與。在某些實施例中，派姆單抗在各21天治療週期之第1天以約200 mg之日劑量投與。在某些實施例中，派姆單抗在各21天治療週期之第1天以約200 mg之日劑量以靜脈內輸注形式投與。在某些實施例中，派姆單抗在各21天治療週期之第1天以約200 mg之日劑量藉由靜脈內輸注投與。In certain embodiments, pembrolizumab is administered at a daily dose of about 200 mg on day 1 of each 21-day treatment cycle. In certain embodiments, pembrolizumab is administered at a daily dose of about 200 mg on day 1 of each 21-day treatment cycle. In certain embodiments, pembrolizumab is administered as an intravenous infusion at a daily dose of about 200 mg on day 1 of each 21-day treatment cycle. In certain embodiments, pembrolizumab is administered by intravenous infusion at a daily dose of about 200 mg on day 1 of each 21-day treatment cycle.
在一些實施例中，派姆單抗經靜脈內投與。在一些實施例中，派姆單抗以靜脈內輸注形式投與。在一些實施例中，派姆單抗藉由靜脈內輸注投與。在一些實施例中，派姆單抗以30分鐘(-5分鐘/+10分鐘)靜脈內輸注形式投與。In some embodiments, pembrolizumab is administered intravenously. In some embodiments, pembrolizumab is administered as an intravenous infusion. In some embodiments, pembrolizumab is administered by intravenous infusion. In some embodiments, pembrolizumab is administered as a 30 minute (-5 minutes/+10 minutes) intravenous infusion.
在一些實施例中，抗體藥物結合物在21天治療週期之至多2天向個體投與，且派姆單抗在21天治療週期之1天向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天向個體投與，且派姆單抗在21天治療週期之第1天向個體投與。In some embodiments, the antibody drug conjugate is administered to a subject on up to 2 days of a 21 day treatment cycle, and pembrolizumab is administered to a subject on day 1 of a 21 day treatment cycle. In some embodiments, the antibody drug conjugate is administered to a subject on days 1 and 8 of a 21 day treatment cycle, and pembrolizumab is administered to a subject on day 1 of a 21 day treatment cycle.
在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.0 mg/kg至約5 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天以約100 mg至約300 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.0 mg/kg至約5 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與之後30分鐘以約100 mg至約300 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.0 mg/kg至約5 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與完成後30分鐘以約100 mg至約300 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.0 mg/kg至約5 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天以約100 mg至約300 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.0 mg/kg至約5 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與之後30分鐘以約100 mg至約300 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.0 mg/kg至約5 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與完成後30分鐘以約100 mg至約300 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.0 mg/kg至約5 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與之後30分鐘以約100 mg至約300 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.0 mg/kg至約5 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與完成後30分鐘以約100 mg至約300 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.0 mg/kg至約5 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天以約100 mg至約300 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.0 mg/kg至約5 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與之後30分鐘以約100 mg至約300 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.0 mg/kg至約5 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與完成後30分鐘以約100 mg至約300 mg之劑量以30分鐘靜脈內輸注形式向個體投與。In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of about 1.0 mg/kg to about 5 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of about 100 mg to about 300 mg on day 1 of a 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of about 1.0 mg/kg to about 5 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of about 100 mg to about 300 mg 30 minutes after administration of the antibody drug conjugate on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of about 1.0 mg/kg to about 5 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of about 100 mg to about 300 mg 30 minutes after completion of administration of the antibody drug conjugate on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion on Days 1 and 8 of a 21-day treatment cycle at a dose of about 1.0 mg/kg to about 5 mg/kg, and pembrolizumab is administered to the subject by intravenous infusion on Day 1 of a 21-day treatment cycle at a dose of about 100 mg to about 300 mg. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion on Days 1 and 8 of a 21-day treatment cycle at a dose of about 1.0 mg/kg to about 5 mg/kg, and pembrolizumab is administered to the subject by intravenous infusion on Day 1 of the 21-day treatment cycle at a dose of about 100 mg to about 300 mg 30 minutes after administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion on Days 1 and 8 of a 21-day treatment cycle at a dose of about 1.0 mg/kg to about 5 mg/kg, and pembrolizumab is administered to the subject by intravenous infusion on Day 1 of the 21-day treatment cycle at a dose of about 100 mg to about 300 mg 30 minutes after completion of administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject as a 30-minute intravenous infusion at a dose of about 1.0 mg/kg to about 5 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as a 30-minute intravenous infusion on day 1 of the 21-day treatment cycle at a dose of about 100 mg to about 300 mg 30 minutes after administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject as a 30-minute intravenous infusion at a dose of about 1.0 mg/kg to about 5 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as a 30-minute intravenous infusion on day 1 of the 21-day treatment cycle at a dose of about 100 mg to about 300 mg 30 minutes after completion of administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject as a 30-minute intravenous infusion at a dose of about 1.0 mg/kg to about 5 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject as a 30-minute intravenous infusion on Day 1 of a 21-day treatment cycle at a dose of about 100 mg to about 300 mg. In some embodiments, the antibody drug conjugate is administered to the subject as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day treatment cycle at a dose of about 1.0 mg/kg to about 5 mg/kg, and pembrolizumab is administered to the subject as a 30-minute intravenous infusion on Day 1 of the 21-day treatment cycle at a dose of about 100 mg to about 300 mg 30 minutes after the administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day treatment cycle at a dose of about 1.0 mg/kg to about 5 mg/kg, and pembrolizumab is administered to the subject as a 30-minute intravenous infusion on Day 1 of the 21-day treatment cycle at a dose of about 100 mg to about 300 mg 30 minutes after completion of administration of the antibody drug conjugate.
在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.0 mg/kg至5 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天以100 mg至300 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.0 mg/kg至5 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與之後30分鐘以100 mg至300 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.0 mg/kg至5 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與完成後30分鐘以100 mg至300 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.0 mg/kg至5 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天以100 mg至300 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.0 mg/kg至5 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與之後30分鐘以100 mg至300 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.0 mg/kg至5 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與完成後30分鐘以100 mg至300 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.0 mg/kg至5 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與之後30分鐘以100 mg至300 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.0 mg/kg至5 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與完成後30分鐘以100 mg至300 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.0 mg/kg至5 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天以100 mg至300 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.0 mg/kg至5 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與之後30分鐘以100 mg至300 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.0 mg/kg至5 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與完成後30分鐘以100 mg至300 mg之劑量以30分鐘靜脈內輸注形式向個體投與。In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of 1.0 mg/kg to 5 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of 100 mg to 300 mg on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of 1.0 mg/kg to 5 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of 100 mg to 300 mg on day 1 of the 21-day treatment cycle 30 minutes after the administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of 1.0 mg/kg to 5 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of 100 mg to 300 mg 30 minutes after completion of administration of the antibody drug conjugate on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion at a dose of 1.0 mg/kg to 5 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject by intravenous infusion at a dose of 100 mg to 300 mg on Day 1 of a 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion at a dose of 1.0 mg/kg to 5 mg/kg on Day 1 and Day 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject by intravenous infusion at a dose of 100 mg to 300 mg 30 minutes after administration of the antibody drug conjugate on Day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion at a dose of 1.0 mg/kg to 5 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject by intravenous infusion at a dose of 100 mg to 300 mg 30 minutes after completion of administration of the antibody drug conjugate on Day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as a 30-minute intravenous infusion at a dose of 1.0 mg/kg to 5 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as a 30-minute intravenous infusion at a dose of 100 mg to 300 mg 30 minutes after administration of the antibody drug conjugate on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as a 30-minute intravenous infusion at a dose of 1.0 mg/kg to 5 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as a 30-minute intravenous infusion on day 1 of the 21-day treatment cycle at a dose of 100 mg to 300 mg 30 minutes after completion of administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg to 5 mg/kg as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of 100 mg to 300 mg as a 30-minute intravenous infusion on Day 1 of a 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as a 30-minute intravenous infusion at a dose of 1.0 mg/kg to 5 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject as a 30-minute intravenous infusion at a dose of 100 mg to 300 mg 30 minutes after administration of the antibody drug conjugate on Day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as a 30-minute intravenous infusion at a dose of 1.0 mg/kg to 5 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject as a 30-minute intravenous infusion at a dose of 100 mg to 300 mg on Day 1 of the 21-day treatment cycle 30 minutes after completion of administration of the antibody drug conjugate.
在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.25 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天以約200 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.25 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與之後30分鐘以約200 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.25 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與完成後30分鐘以約200 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.25 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天以約200 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.25 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與之後30分鐘以約200 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.25 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與完成後30分鐘以約200 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.25 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與之後30分鐘以約200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.25 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與完成後30分鐘以約200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.25 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天以約200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.25 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與之後30分鐘以約200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.25 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與完成後30分鐘以約200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of about 1.25 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of about 200 mg on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of about 1.25 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of about 200 mg 30 minutes after administration of the antibody drug conjugate on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of about 1.25 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of about 200 mg 30 minutes after completion of administration of the antibody drug conjugate on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion on days 1 and 8 of a 21-day treatment cycle at a dose of about 1.25 mg/kg, and pembrolizumab is administered to the subject by intravenous infusion on day 1 of the 21-day treatment cycle at a dose of about 200 mg. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion at a dose of about 1.25 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject by intravenous infusion at a dose of about 200 mg 30 minutes after administration of the antibody drug conjugate on Day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion at a dose of about 1.25 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject by intravenous infusion at a dose of about 200 mg 30 minutes after completion of administration of the antibody drug conjugate on Day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg as a 30-minute intravenous infusion on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of about 200 mg as a 30-minute intravenous infusion on day 1 of the 21-day treatment cycle 30 minutes after administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg as a 30-minute intravenous infusion on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of about 200 mg as a 30-minute intravenous infusion on day 1 of the 21-day treatment cycle 30 minutes after completion of administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of about 200 mg as a 30-minute intravenous infusion on Day 1 of a 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of about 200 mg as a 30-minute intravenous infusion on Day 1 of the 21-day treatment cycle 30 minutes after administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of about 1.25 mg/kg as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of about 200 mg as a 30-minute intravenous infusion on Day 1 of the 21-day treatment cycle 30 minutes after completion of administration of the antibody drug conjugate.
在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.25 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天以200 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.25 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與之後30分鐘以200 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.25 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與完成後30分鐘以200 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.25 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天以200 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.25 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與之後30分鐘以200 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.25 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與完成後30分鐘以200 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.25 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與之後30分鐘以200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.25 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與完成後30分鐘以200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.25 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天以200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.25 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與之後30分鐘以200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.25 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與完成後30分鐘以200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of 1.25 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of 200 mg on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of 1.25 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of 200 mg 30 minutes after administration of the antibody drug conjugate on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of 1.25 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of 200 mg 30 minutes after completion of administration of the antibody drug conjugate on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion on days 1 and 8 of a 21-day treatment cycle at a dose of 1.25 mg/kg, and pembrolizumab is administered to the subject by intravenous infusion on day 1 of the 21-day treatment cycle at a dose of 200 mg. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion at a dose of 1.25 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject by intravenous infusion at a dose of 200 mg 30 minutes after administration of the antibody drug conjugate on Day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion at a dose of 1.25 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject by intravenous infusion at a dose of 200 mg 30 minutes after completion of administration of the antibody drug conjugate on Day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg as a 30-minute intravenous infusion on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of 200 mg as a 30-minute intravenous infusion on day 1 of the 21-day treatment cycle 30 minutes after administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg as a 30-minute intravenous infusion on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of 200 mg as a 30-minute intravenous infusion on day 1 of the 21-day treatment cycle 30 minutes after completion of administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg as a 30-minute intravenous infusion on days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of 200 mg as a 30-minute intravenous infusion on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of 200 mg as a 30-minute intravenous infusion on Day 1 of the 21-day treatment cycle 30 minutes after administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of 1.25 mg/kg as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of 200 mg as a 30-minute intravenous infusion on Day 1 of the 21-day treatment cycle 30 minutes after completion of administration of the antibody drug conjugate.
在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.0 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天以約200 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.0 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與之後30分鐘以約200 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.0 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與完成後30分鐘以約200 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.0 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天以約200 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.0 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與之後30分鐘以約200 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.0 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與完成後30分鐘以約200 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.0 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與之後30分鐘以約200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以約1.0 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與完成後30分鐘以約200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.0 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天以約200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.0 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與之後30分鐘以約200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以約1.0 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與完成後30分鐘以約200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of about 1.0 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of about 200 mg on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of about 1.0 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of about 200 mg 30 minutes after administration of the antibody drug conjugate on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of about 1.0 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of about 200 mg 30 minutes after completion of administration of the antibody drug conjugate on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion on days 1 and 8 of a 21-day treatment cycle at a dose of about 1.0 mg/kg, and pembrolizumab is administered to the subject by intravenous infusion on day 1 of the 21-day treatment cycle at a dose of about 200 mg. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion at a dose of about 1.0 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject by intravenous infusion at a dose of about 200 mg 30 minutes after administration of the antibody drug conjugate on Day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion at a dose of about 1.0 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject by intravenous infusion at a dose of about 200 mg 30 minutes after completion of administration of the antibody drug conjugate on Day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg as a 30-minute intravenous infusion on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of about 200 mg as a 30-minute intravenous infusion on day 1 of the 21-day treatment cycle 30 minutes after administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg as a 30-minute intravenous infusion on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of about 200 mg as a 30-minute intravenous infusion on day 1 of the 21-day treatment cycle 30 minutes after completion of administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of about 200 mg as a 30-minute intravenous infusion on Day 1 of a 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of about 200 mg as a 30-minute intravenous infusion 30 minutes after administration of the antibody drug conjugate on Day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of about 1.0 mg/kg as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of about 200 mg as a 30-minute intravenous infusion on Day 1 of the 21-day treatment cycle 30 minutes after completion of administration of the antibody drug conjugate.
在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.0 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天以200 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.0 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與之後30分鐘以200 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.0 mg/kg之劑量以靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與完成後30分鐘以200 mg之劑量以靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.0 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天以200 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.0 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與之後30分鐘以200 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.0 mg/kg之劑量藉由靜脈內輸注向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與完成後30分鐘以200 mg之劑量藉由靜脈內輸注向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.0 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與之後30分鐘以200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之至多2天以1.0 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之1天在抗體藥物結合物的投與完成後30分鐘以200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.0 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天以200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.0 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與之後30分鐘以200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。在一些實施例中，抗體藥物結合物在21天治療週期之第1天及第8天以1.0 mg/kg之劑量以30分鐘靜脈內輸注形式向個體投與，且派姆單抗在21天治療週期之第1天在抗體藥物結合物的投與完成後30分鐘以200 mg之劑量以30分鐘靜脈內輸注形式向個體投與。In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of 1.0 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of 200 mg on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of 1.0 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of 200 mg 30 minutes after administration of the antibody drug conjugate on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject as an intravenous infusion at a dose of 1.0 mg/kg on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject as an intravenous infusion at a dose of 200 mg 30 minutes after completion of administration of the antibody drug conjugate on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion at a dose of 1.0 mg/kg on days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject by intravenous infusion at a dose of 200 mg on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion at a dose of 1.0 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject by intravenous infusion at a dose of 200 mg 30 minutes after administration of the antibody drug conjugate on Day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject by intravenous infusion at a dose of 1.0 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject by intravenous infusion at a dose of 200 mg 30 minutes after completion of administration of the antibody drug conjugate on Day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg as a 30-minute intravenous infusion on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of 200 mg as a 30-minute intravenous infusion on day 1 of the 21-day treatment cycle 30 minutes after administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg as a 30-minute intravenous infusion on up to 2 days of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of 200 mg as a 30-minute intravenous infusion on day 1 of the 21-day treatment cycle 30 minutes after completion of administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg as a 30-minute intravenous infusion on days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of 200 mg as a 30-minute intravenous infusion on day 1 of the 21-day treatment cycle. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of 200 mg as a 30-minute intravenous infusion on Day 1 of the 21-day treatment cycle 30 minutes after administration of the antibody drug conjugate. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of 1.0 mg/kg as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day treatment cycle, and pembrolizumab is administered to the subject at a dose of 200 mg as a 30-minute intravenous infusion on Day 1 of the 21-day treatment cycle 30 minutes after completion of administration of the antibody drug conjugate.
在本文所揭示之任何實施例中，術語「治療週期」與「週期」可互換。5.9生物標記物測定方法In any embodiment disclosed herein, the terms "treatment cycle" and "cycle" are interchangeable.5.9Biomarker Assay Methods
本發明規定，本文所提供之任一種標記物的表現可藉由本領域中已知之各種方法測定。在一些實施例中，標記物的表現可根據自標記基因轉錄之mRNA的量或相對量測定。在一個實施例中，標記基因的表現可根據由標記基因編碼之蛋白質產物的量或相對量測定。在另一實施例中，標記基因的表現可根據由標記基因編碼之蛋白質產物所誘導的生物學或化學反應水平來測定。另外，在某些實施例中，標記基因的表現可根據與標記基因之表現相關之一或多種基因的表現來測定。The present invention provides that the expression of any marker provided herein can be measured by various methods known in the art. In some embodiments, the expression of the marker can be measured according to the amount or relative amount of the mRNA transcribed from the marker gene. In one embodiment, the expression of the marker gene can be measured according to the amount or relative amount of the protein product encoded by the marker gene. In another embodiment, the expression of the marker gene can be measured according to the biological or chemical reaction level induced by the protein product encoded by the marker gene. In addition, in certain embodiments, the expression of the marker gene can be measured according to the expression of one or more genes related to the expression of the marker gene.
如上文所描述，標記基因之基因轉錄本(例如mRNA)的含量或量可用作標記基因之表現量的指示。此項技術中已知多種不同的PCR或qPCR方案，包括本文中例示的彼等方案。在一些實施例中，多種PCR或qPCR方法應用於或經調適而用於測定各種標記基因的mRNA含量。定量PCR (qPCR)(亦稱為即時PCR)應用於且經調適而用於一些實施例中，原因在於其不僅提供定量的量測結果，而且減少時間及污染。如本文所用，「定量PCR」(或「qPCR」)係指如正發生之PCR擴增進度之直接監測，而無需對反應產物重複取樣。在定量PCR中，反應產物在其產生時可以經由信號傳導機制(例如螢光)加以監測且在信號上升而高於背景含量、但在反應達到平穩階段之前加以追蹤。為達成可偵測或「臨限」螢光含量所需的循環數目在PCR過程開始時直接隨著可擴增的目標濃度而變化，從而允許量測信號強度，以便即時量測樣品中之目標核酸量。當應用qPCR測定mRNA表現量時，mRNA逆轉錄為DNA之額外步驟係在qPCR分析之前執行。PCR方法之實例可見於文獻中(Wong等人, BioTechniques 39:75-85 (2005)；D'haene等人, Methods 50:262-270 (2010))，該文獻以全文引用的方式併入本文中。PCR分析之實例亦可見於美國專利第6,927,024號中，其以全文引用的方式併入本文中。RT-PCR方法之實例可見於美國專利第7,122,799號中，其以全文引用的方式併入本文中。螢光原位PCR方法描述於美國專利第7,186,507號中，其以全文引用的方式併入本文中。As described above, the content or amount of the gene transcript (e.g., mRNA) of the marker gene can be used as an indication of the amount of expression of the marker gene. A variety of different PCR or qPCR protocols are known in the art, including those illustrated herein. In some embodiments, a variety of PCR or qPCR methods are applied to or adapted to measure the mRNA content of various marker genes. Quantitative PCR (qPCR) (also known as real-time PCR) is applied to and adapted for use in some embodiments because it not only provides quantitative measurement results, but also reduces time and pollution. As used herein, "quantitative PCR" (or "qPCR") refers to direct monitoring of the progress of PCR amplification as it is occurring, without the need for repeated sampling of the reaction products. In quantitative PCR, the reaction products can be monitored as they are produced via a signaling mechanism (e.g., fluorescence) and tracked as the signal rises above background levels but before the reaction reaches a plateau. The number of cycles required to achieve a detectable or "threshold" level of fluorescence varies directly with the amplifiable target concentration at the beginning of the PCR process, allowing the signal intensity to be measured in real time to measure the amount of target nucleic acid in a sample. When qPCR is used to measure mRNA expression, an additional step of reverse transcription of the mRNA into DNA is performed prior to qPCR analysis. Examples of PCR methods can be found in the literature (Wong et al., BioTechniques 39:75-85 (2005); D'haene et al., Methods 50:262-270 (2010)), which are incorporated herein by reference in their entirety. Examples of PCR analysis can also be found in U.S. Patent No. 6,927,024, which is incorporated herein by reference in its entirety. Examples of RT-PCR methods can be found in U.S. Patent No. 7,122,799, which is incorporated herein by reference in its entirety. Fluorescent in situ PCR methods are described in U.S. Patent No. 7,186,507, which is incorporated herein by reference in its entirety.
在一個特定實施例中，可如下進行qPCR以測定或量測標記基因之mRNA含量。簡言之，測定標記基因及一或多種管家基因之複製qPCR反應的平均Ct (循環臨限)值(或在本文中可互換地稱為Cq (定量循環))。標記基因之平均Ct值接著可以利用以下例示公式以管家基因之Ct值標準化：標記基因ΔCt = (標記基因之平均Ct - 管家基因A之平均Ct)。接著可以利用相對標記基因ΔCt測定標記基因mRNA的相對含量，例如藉由使用mRNA表現公式=2-ΔCt。關於Ct及Cq值之概述，參見MIQE指南(Bustin等人, The MIQE Guidelines: Minimum Information for Publication of Quantitative Real-Time PCR Experiments, Clinical Chemistry 55:4 (2009))。In a specific embodiment, qPCR can be performed as follows to determine or measure the mRNA content of the marker gene. In short, the average Ct (cycle threshold) value (or interchangeably referred to herein as Cq (quantitative cycle)) of the replicate qPCR reactions of the marker gene and one or more housekeeping genes is determined. The average Ct value of the marker gene can then be standardized with the Ct value of the housekeeping gene using the following exemplary formula: marker gene ΔCt = (average Ct of marker gene - average Ct of housekeeping gene A). The relative content of the marker gene mRNA can then be determined using the relative marker gene ΔCt, for example by using the mRNA expression formula = 2-ΔCt . For an overview of Ct and Cq values, see the MIQE guidelines (Bustin et al., The MIQE Guidelines: Minimum Information for Publication of Quantitative Real-Time PCR Experiments, Clinical Chemistry 55:4 (2009)).
為了定量樣品中之標記基因的RNA轉錄本作為標記基因之表現的指示，亦可使用此項技術中已知之其他常用方法，包括北方墨點法及原位雜交法(Parker及Barnes, Methods in Molecular Biology 106:247-283 (1999))；核糖核酸酶保護分析(Hod, Biotechniques 13:852-854 (1992))；微陣列法(Hoheisel等人, Nature Reviews Genetics 7:200-210 (2006)；Jaluria等人, Microbial Cell Factories 6:4 (2007))；及聚合酶鏈反應(PCR)(Weis等人, Trends in Genetics 8:263-264 (1992))。RNA原位雜交(ISH)為一種分子生物學技術，其廣泛用於量測及定位細胞(諸如循環腫瘤細胞(CTC))或組織切片內的特定RNA序列，例如信使RNA (mRNA)、非編碼長RNA (lncRNA)，及微RNA (miRNA)，同時保存細胞及組織環境。ISH為一種雜交類型，其使用直接或間接標記之互補DNA或RNA股(諸如探針)結合及定位樣品(特定而言，組織或細胞(原位)的一部分或切片)中的特定核酸，諸如DNA或RNA。探針類型可為雙股DNA (dsDNA)、單股DNA (ssDNA)、單股互補RNA (sscRNA)、信使RNA (mRNA)、微RNA (miRNA)、核糖體RNA、粒線體RNA及/或合成寡核苷酸。術語「螢光原位雜交」或「FISH」係指使用螢光標記的ISH類型。術語「顯色原位雜交」或「CISH」係指使用顯色標記的ISH類型。ISH、FISH及CISH方法已為熟習此項技術者所熟知(參見例如ClinicsinLaboratoryMedicine10(1):215-236 (1990)；Insituhybridization.Apracticalapproach, Wilkinson編, IRL Press, Oxford (1992)；Schwarzacher及Heslop-Harrison,Practicalinsituhybridization, BIOS Scientific Publishers Ltd, Oxford (2000))。RNA ISH因此對細胞及組織內的基因表現提供空間-時間可視化以及定量。其已廣泛應用於研究及診斷(Hu等人,Biomark. Res.2(1):1-13, doi: 10.1186/2050-7771-2-3 (2014)；Ratan等人,Cureus9(6):e1325. doi: 10.7759/cureus.1325 (2017)；Weier等人,Expert Rev. Mol. Diagn.2(2):109-119 (2002))。螢光RNA ISH分別使用螢光染料及螢光顯微鏡進行RNA標記及偵測。螢光RNA ISH可提供四種至五種目標序列的多工處理。To quantify RNA transcripts of marker genes in a sample as an indicator of marker gene expression, other common methods known in the art may also be used, including Northern blotting and in situ hybridization (Parker and Barnes, Methods in Molecular Biology 106:247-283 (1999)); ribonuclease protection assays (Hod, Biotechniques 13:852-854 (1992)); microarrays (Hoheisel et al., Nature Reviews Genetics 7:200-210 (2006); Jaluria et al., Microbial Cell Factories 6:4 (2007)); and polymerase chain reaction (PCR) (Weis et al., Trends in Genetics 8:263-264 (1992)). RNA in situ hybridization (ISH) is a molecular biology technique that is widely used to measure and localize specific RNA sequences, such as messenger RNA (mRNA), long noncoding RNA (lncRNA), and microRNA (miRNA), within cells (such as circulating tumor cells (CTCs)) or tissue sections, while preserving the cellular and tissue context. ISH is a type of hybridization that uses directly or indirectly labeled complementary DNA or RNA strands (such as probes) to bind and localize specific nucleic acids, such as DNA or RNA, in a sample (specifically, a portion or section of a tissue or cell (in situ)). The probe type can be double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), single-stranded complementary RNA (sscRNA), messenger RNA (mRNA), microRNA (miRNA), ribosomal RNA, mitochondrial RNA, and/or synthetic oligonucleotides. The term "fluorescent in situ hybridization" or "FISH" refers to the type of ISH that uses fluorescent labels. The term "chromogenic in situ hybridization" or "CISH" refers to the type of ISH that uses chromogenic labels. ISH, FISH and CISH methods are well known to those skilled in the art (see, e.g.,ClinicsinLaboratoryMedicine 10(1):215-236 (1990);Insituhybridization.Apracticalapproach , Wilkinson, ed., IRL Press, Oxford (1992); Schwarzacher and Heslop-Harrison,Practicalinsituhybridization , BIOS Scientific Publishers Ltd, Oxford (2000)). RNA ISH therefore provides spatial-temporal visualization and quantification of gene expression in cells and tissues. It has been widely used in research and diagnosis (Hu et al.,Biomark. Res. 2(1):1-13, doi: 10.1186/2050-7771-2-3 (2014); Ratan et al.,Cureus 9(6):e1325. doi: 10.7759/cureus.1325 (2017); Weier et al.,Expert Rev. Mol. Diagn. 2(2):109-119 (2002)). Fluorescent RNA ISH uses fluorescent dyes and fluorescent microscopy for RNA labeling and detection, respectively. Fluorescent RNA ISH can provide multiplexing of four to five target sequences.
或者，樣品中之標記基因的RNA轉錄本作為標記基因表現的指示，可藉由定序技術測定。基於定序之基因表現分析的代表性方法包括基因表現系列分析(SAGE)及藉由大規模並行標誌定序(MPSS)進行之基因表現分析。Alternatively, RNA transcripts of marker genes in a sample can be determined by sequencing technology as an indicator of marker gene expression. Representative methods of sequencing-based gene expression analysis include serial analysis of gene expression (SAGE) and gene expression analysis by massive parallel marker sequencing (MPSS).
在一些實施例中，標記基因之表現可根據標記基因之RNA轉錄本(包括例如mRNA)在總轉錄RNA池中之相對豐度來測定。標記基因之RNA轉錄本的此類相對豐度可藉由稱為RNA-seq的下一代定序測定。在RNA-seq程序的一個實例中，將來自不同來源(血液、組織、細胞)的RNA純化，視情況增濃(例如利用寡核苷酸(dT)引子)，轉化為cDNA且片段化。利用隨機片段化cDNA庫產生數百萬或甚至數十億個短序列讀段。參見Zhao等人,BMCgenomics16: 97 (2015)；Zhao等人,ScientificReports8: 4781 (2018)；Shanrong Zhao等人,RNA, 在2020年4月13日提前公開, doi: 10.1261/rna.074922.120，其均以全文引用的方式併入本文中。標記基因之各mRNA轉錄本的表現量係根據標準化後定位之片段總數目測定，該總數目與其豐度水平成正比。幾種標準化方案已知且用於促進使用RNA轉錄本豐度作為用於測定基因表現的參數，包括RPKM (每百萬每千鹼基的讀段數)、FPKM (每百萬每千鹼基的片段數)及/或TPM (每百萬每千鹼基的轉錄本數)。簡言之，RPKM可如下計算：對樣品中之總讀段進行計數且將該數目除以1,000,000 (其為「每百萬」比例因子)；將讀段計數除以「每百萬」比例因子，其針對定序深度進行標準化，得到每百萬讀段數(RPM)；及將RPM值除以基因長度(千鹼基)，得到RPKM。除用片段置換讀段之外，FPKM與RPKM密切相關。RPKM用於單端RNA-seq，其中每個讀段對應於定序的單個片段。FPKM用於成對端RNA-seq，其中兩個讀段可對應於單個片段，或若一對中的一個讀段未定位，則一個讀段可對應於單個片段。TPM非常類似於RPKM及FPKM且如下計算：將讀段計數除以各基因之長度(千鹼基)，得到每千鹼基之讀段數(RPK)；對樣品的所有RPK值計數且將此數除以1,000,000，得到「每百萬」比例因子；將RPK值除以「每百萬」比例因子，得到TPM。參見Zhao等人,BMCgenomics16: 97 (2015)；Zhao等人,ScientificReports8: 4781 (2018)；Shanrong Zhao等人,RNA, 在2020年4月13日提前公開, doi: 10.1261/rna.074922.120，其均以全文引用的方式併入本文中。In some embodiments, the expression of a marker gene can be determined based on the relative abundance of RNA transcripts of the marker gene (including, for example, mRNA) in the total transcribed RNA pool. Such relative abundance of RNA transcripts of marker genes can be determined by next generation sequencing, known as RNA-seq. In one example of an RNA-seq procedure, RNA from different sources (blood, tissue, cells) is purified, optionally enriched (e.g., using oligonucleotide (dT) primers), converted to cDNA and fragmented. Millions or even billions of short sequence reads are generated using randomly fragmented cDNA libraries. See Zhao et al.,BMCgenomics 16: 97 (2015); Zhao et al.,ScientificReports 8: 4781 (2018); Shanrong Zhao et al.,RNA , published in advance on April 13, 2020, doi: 10.1261/rna.074922.120, all of which are incorporated herein by reference in their entirety. The expression level of each mRNA transcript of the marker gene is determined based on the total number of located fragments after normalization, which is proportional to its abundance level. Several normalization schemes are known and used to facilitate the use of RNA transcript abundance as a parameter for determining gene expression, including RPKM (reads per kilobase per million), FPKM (fragments per kilobase per million), and/or TPM (transcripts per kilobase per million). Briefly, RPKM can be calculated by counting the total reads in a sample and dividing that number by 1,000,000 (which is the "per million" scaling factor); dividing the read count by the "per million" scaling factor, which is normalized for sequencing depth to obtain reads per million (RPM); and dividing the RPM value by the gene length (kilobases) to obtain RPKM. FPKM is closely related to RPKM, except that reads are replaced by fragments. RPKM is used for single-end RNA-seq, where each read corresponds to a single fragment sequenced. FPKM is used for paired-end RNA-seq, where two reads can correspond to a single fragment, or if one read in a pair is not mapped, one read can correspond to a single fragment. TPM is very similar to RPKM and FPKM and is calculated as follows: divide the read count by the length of each gene in kilobases to get the number of reads per kilobase (RPK); count all RPK values for a sample and divide this number by 1,000,000 to get the "per million" scaling factor; divide the RPK value by the "per million" scaling factor to get TPM. See Zhao et al.,BMCgenomics 16: 97 (2015); Zhao et al.,ScientificReports 8: 4781 (2018); Shanrong Zhao et al.,RNA , published in advance on April 13, 2020, doi: 10.1261/rna.074922.120, all of which are incorporated herein by reference in their entirety.
在一個實施例中，標記基因的表現係藉由RNA-seq (例如TPM、RPKM及/或FPKM)測定。在一些實施例中，標記基因的表現係藉由TPM測定。在一些實施例中，標記基因的表現係藉由RPKM測定。在一些實施例中，標記基因的表現係藉由FPKM測定。In one embodiment, the expression of the marker gene is determined by RNA-seq (e.g., TPM, RPKM and/or FPKM). In some embodiments, the expression of the marker gene is determined by TPM. In some embodiments, the expression of the marker gene is determined by RPKM. In some embodiments, the expression of the marker gene is determined by FPKM.
如早先所述，可測定來自個體之樣品中之標記基因的表現。在一些實施例中，樣品為血液樣品、血清樣品、血漿樣品、體液(例如組織液，包括癌症組織液)，或組織(例如癌症組織或癌症周圍的組織)。在一些實施例中，樣品為組織樣品。在一些實施例中，組織樣品為自哺乳動物(特定言之，人類)分離或提取之組織部分。在一些實施例中，組織樣品為自哺乳動物(特定言之，人類)分離或提取之細胞群。在一些實施例中，組織樣品為獲自生檢之樣品。在某些實施例中，樣品可以獲自個體(包括人類個體)之多種器官。在一些實施例中，樣品獲自患有癌症之個體的器官。在一些實施例中，樣品獲自患有癌症之個體的患癌器官。在其他實施例中，樣品，例如參考樣品獲自患者或第二人類個體之正常器官。As described earlier, the expression of marker genes in samples from individuals can be determined. In some embodiments, the sample is a blood sample, a serum sample, a plasma sample, a body fluid (e.g., a tissue fluid, including a cancer tissue fluid), or a tissue (e.g., a cancer tissue or a tissue surrounding a cancer). In some embodiments, the sample is a tissue sample. In some embodiments, the tissue sample is a tissue portion separated or extracted from a mammal (specifically, a human). In some embodiments, the tissue sample is a cell population separated or extracted from a mammal (specifically, a human). In some embodiments, the tissue sample is a sample obtained from a biopsy. In certain embodiments, the sample can be obtained from a variety of organs of an individual (including a human individual). In some embodiments, the sample is obtained from an organ of an individual suffering from cancer. In some embodiments, the sample is obtained from a cancerous organ of an individual suffering from cancer. In other embodiments, the sample, such as a reference sample, is obtained from a normal organ of a patient or a second human individual.
在本文所提供之方法的某些實施例中，組織包括來自膀胱、輸尿管、乳房、肺、結腸、直腸、卵巢、輸卵管、食道、子宮頸、子宮內膜、皮膚、喉、骨髓、唾液腺、腎臟、前列腺、腦、脊髓、胎盤、腎上腺、胰臟、副甲狀腺、腦垂體、睪丸、甲狀腺、脾、扁桃體、胸腺、心臟、胃、小腸、肝臟、骨骼肌、周邊神經、間皮或眼的組織。In certain embodiments of the methods provided herein, the tissue includes tissue from the bladder, ureter, breast, lung, colon, rectum, ovary, fallopian tube, esophagus, cervix, endometrium, skin, larynx, bone marrow, salivary gland, kidney, prostate, brain, spinal cord, placenta, adrenal gland, pancreas, parathyroid gland, pituitary gland, testis, thyroid gland, spleen, tonsil, thymus, heart, stomach, small intestine, liver, skeletal muscle, peripheral nerve, mesothelium, or eye.
在本文所提供之方法的其他實施例中，不同標記基因的表現可藉由此項技術中已知的多種免疫分析加以偵測，包括免疫組織化學(IHC)分析、免疫墨點法分析、FACS分析及ELISA。In other embodiments of the methods provided herein, the expression of different marker genes can be detected by a variety of immunoassays known in the art, including immunohistochemistry (IHC) analysis, immunoblotting analysis, FACS analysis, and ELISA.
在多種IHC分析中，各種標記基因之表現可藉由針對由標記基因編碼之蛋白質產物的抗體偵測。組織切片之IHC染色已表明為評估或偵測樣品中蛋白質之存在的可靠方法。IHC技術利用抗體原位探測及可視化細胞抗原，其通常藉由顯色或螢光方法達成。初級抗體或抗血清，諸如特異性地靶向由標記基因編碼之蛋白質產物的多株抗血清及單株抗體，可在IHC分析中用於偵測標記基因的表現。在一些實施例中，使組織樣品與針對特定目標的初級抗體接觸足以使抗體-目標結合發生的時間。如早先更詳細地論述，該等抗體可藉由用例如放射性標記、螢光標記、半抗原標記(諸如生物素)或酶(諸如辣根過氧化酶或鹼性磷酸酶)直接標記抗體本身來偵測。或者，未標記之初級抗體與對該初級抗體具有特異性的經標記之二級抗體(包含抗血清、多株抗血清或單株抗體)結合使用。IHC方案及套組在此項技術中已熟知且可商購。用於載片製備及IHC處理之自動化系統係可商購的。Leica BOND自動染色儀及Leica Bond Refine偵測系統為此類自動化系統之實例。In a variety of IHC analyses, the expression of various marker genes can be detected by antibodies directed against the protein products encoded by the marker genes. IHC staining of tissue sections has been shown to be a reliable method for assessing or detecting the presence of proteins in samples. IHC technology utilizes antibodies to detect and visualize cellular antigens in situ, which is usually achieved by colorimetric or fluorescent methods. Primary antibodies or antisera, such as polyclonal antisera and monoclonal antibodies that specifically target the protein products encoded by the marker genes, can be used in IHC analyses to detect the expression of marker genes. In some embodiments, the tissue sample is contacted with a primary antibody directed against a specific target for a time sufficient for antibody-target binding to occur. As discussed in more detail earlier, the antibodies can be detected by directly labeling the antibodies themselves, for example, with a radioactive label, a fluorescent label, a hapten label (such as biotin), or an enzyme (such as horseradish peroxidase or alkaline phosphatase). Alternatively, an unlabeled primary antibody is used in conjunction with a labeled secondary antibody (including antisera, polyclonal antisera, or monoclonal antibodies) specific for the primary antibody. IHC protocols and kits are well known in the art and are commercially available. Automated systems for slide preparation and IHC processing are commercially available. The Leica BOND automatic stainer and the Leica Bond Refine detection system are examples of such automated systems.
在一些實施例中，在間接分析中，使用未標記之初級抗體結合經標記之二級抗體來執行IHC分析。間接分析係使用兩種抗體偵測組織樣品中由標記基因編碼的蛋白質產物。首先，將未結合的初級抗體施加至組織(第一層)，與組織樣品中的目標抗原反應。接著，施加經酶標記之二級抗體，其特異性識別初級抗體之抗體同型(第二層)。二級抗體與初級抗體反應，隨後施加受質-色素原。第二層抗體可用酶(諸如過氧化酶)標記，該酶與色素原3,3'-二胺基聯苯胺(DAB)反應，在反應位點產生棕色沈澱物。此方法由於潛在的信號經由信號放大系統放大而靈敏且通用。In some embodiments, in an indirect assay, an unlabeled primary antibody is used in conjunction with a labeled secondary antibody to perform an IHC analysis. An indirect assay uses two antibodies to detect a protein product encoded by a labeled gene in a tissue sample. First, an unbound primary antibody is applied to the tissue (first layer) to react with the target antigen in the tissue sample. Next, an enzyme-labeled secondary antibody is applied that specifically recognizes the antibody isotype of the primary antibody (second layer). The secondary antibody reacts with the primary antibody, and then the substrate - the chromogen - is applied. The second layer of antibodies can be labeled with an enzyme (such as peroxidase), which reacts with the chromogen 3,3'-diaminobenzidine (DAB) to produce a brown precipitate at the reaction site. This method is sensitive and versatile because the underlying signal is amplified by the signal amplification system.
在某些實施例中，為了增加偵測靈敏性，可以使用信號放大系統。如本文所用，「信號放大系統」意謂試劑與方法之系統，其可用於增強來自偵測所結合之初級或二級抗體的信號。信號放大系統增強目標蛋白偵測靈敏性、增強所偵測信號，且降低偵測極限之下邊界。存在若干類型的信號放大系統，包括酶標記系統及宏觀標記系統。此等系統/方法互不排斥且可以組合使用以得到相加效應。In certain embodiments, in order to increase the sensitivity of detection, a signal amplification system can be used. As used herein, a "signal amplification system" means a system of reagents and methods that can be used to enhance the signal from the primary or secondary antibody bound by the detection. The signal amplification system enhances the sensitivity of target protein detection, enhances the detected signal, and reduces the lower boundary of the detection limit. There are several types of signal amplification systems, including enzyme labeling systems and macro-labeling systems. These systems/methods are not mutually exclusive and can be used in combination to obtain an additive effect.
宏觀標記系統為附接至或併入共同支架中的標記集合，其數目為數十(例如藻膽蛋白)至數百萬(例如螢光微球體)。支架可以與目標特異性親和試劑(諸如抗體)偶聯，且併入的標記在結合後藉此一起與目標關聯。宏觀標記中的標記可為本文所述之任何標記，諸如螢光團、半抗原、酶及/或放射性同位素。在信號放大系統之一個實施例中，使用經標記之鏈聚合物所結合的二級抗體。聚合物技術係利用可與1、2、3、4、5、6、7、8、9、10、15、20、25、30、50或更多個二級抗體分子連接之經HRP酶標記之惰性「棘」聚葡萄糖分子，從而使系統甚至更靈敏。A macro-labeling system is a collection of labels attached to or incorporated into a common scaffold, the number of which ranges from tens (e.g., phycobiliprotein) to millions (e.g., fluorescent microspheres). The scaffold can be coupled to a target-specific affinity reagent (e.g., an antibody), and the incorporated labels are thereby associated with the target together after binding. The labels in the macro-labeling can be any of the labels described herein, such as fluorophores, haptens, enzymes, and/or radioisotopes. In one embodiment of the signal amplification system, a secondary antibody bound by a labeled chain polymer is used. Polymer technology utilizes inert "spike" polydextrose molecules labeled with HRP enzymes that can be linked to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 50, or more secondary antibody molecules, making the system even more sensitive.
基於酶標記系統之信號放大系統係利用酶(諸如辣根過氧化酶(HRP)或鹼性磷酸酶)之催化活性來原位產生目標蛋白或核酸序列之高密度標記。在一個實施例中，可以使用酪醯胺增強HRP信號。在此系統中，HRP以酶方式使經標記之酪醯胺衍生物轉化成反應性高、壽命短的酪醯胺基團。經標記之活性酪醯胺基團接著與HRP抗體-目標相互作用位點附近的殘基(主要為蛋白質酪胺酸殘基之苯酚部分)共價偶聯，引起該位點處之標記數目擴增且與擴散相關的信號局域化損失最小。因此，信號可以擴增1、2、3、4、5、6、7、8、9、10、15、20、25、30、50、75或100倍。如熟習此項技術者所知，酪醯胺上之標記可為本文所述之任何標記，包括螢光團、酶、半抗原、放射性同位素及/或發光器。亦可利用其他基於酶之反應產生信號放大。舉例而言，經酶標記之螢光(ELF)信號放大可利用於鹼性磷酸酶，其中鹼性磷酸酶以酶方式使弱藍色螢光受質(ELF 97磷酸酯)裂解且將其轉化成亮黃色-綠色螢光沈澱物，該沈澱物展現異常大的斯托克位移(Stokes shift)及優良的光穩定性。基於酪醯胺之信號放大系統與ELF信號放大可購自例如ThermoFisher Scientific (Waltham, MA USA 02451)。The signal amplification system based on the enzyme labeling system utilizes the catalytic activity of enzymes (such as horseradish peroxidase (HRP) or alkaline phosphatases) to generate high-density labels of target proteins or nucleic acid sequences in situ. In one embodiment, tyramide can be used to enhance the HRP signal. In this system, HRP enzymatically converts the labeled tyramide derivative into a highly reactive, short-lived tyramide group. The labeled active tyramide group is then covalently coupled to the residues (mainly the phenol part of the protein tyrosine residue) near the HRP antibody-target interaction site, causing the number of labels at the site to be expanded and the signal localization loss associated with diffusion is minimized. Thus, the signal can be amplified 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 50, 75, or 100 times. As known to those skilled in the art, the label on the tyramide can be any label described herein, including a fluorophore, an enzyme, a hapten, a radioisotope, and/or a luminescent device. Other enzyme-based reactions can also be used to generate signal amplification. For example, enzyme-labeled fluorescence (ELF) signal amplification can be used for alkaline phosphatases, which enzymatically cleave the weak blue fluorescent substrate (ELF 97 phosphate) and convert it into a bright yellow-green fluorescent precipitate that exhibits an unusually large Stokes shift and excellent photostability. Tyramide-based signal amplification systems and ELF signal amplification are commercially available from, for example, ThermoFisher Scientific (Waltham, MA USA 02451).
因此，在本文所提供之方法的一些實施例中，經由使用信號放大系統的IHC偵測標記基因之表現量。在一些實施例中，接著對試樣進行對比染色，以鑑別細胞及次細胞元件。Therefore, in some embodiments of the methods provided herein, the expression of marker genes is detected by IHC using a signal amplification system. In some embodiments, the sample is then subjected to contrast staining to identify cellular and subcellular elements.
在一些實施例中，由標記基因編碼之蛋白質產物的表現量亦可經由針對標記基因所編碼之蛋白質產物的抗體、使用免疫墨點分析加以偵測。在免疫墨點分析之一些實施例中，通常(但不一定)藉由電泳分離出蛋白質且轉印至膜(通常為硝化纖維素或PVDF膜)上。類似於IHC分析，初級抗體或抗血清，諸如特異性地靶向由標記基因編碼之蛋白質產物的多株抗血清及單株抗體，可用於偵測標記基因的表現。在一些實施例中，使膜與針對特定目標之初級抗體接觸足以發生抗體-抗原結合的時間且所結合的抗體可以藉由用例如放射性標記、螢光標記、半抗原標記(諸如生物素)或酶(諸如辣根過氧化酶或鹼性磷酸酶)直接標記初級抗體本身來偵測。在其他實施例中，在如上文所述的間接分析中，未標記之初級抗體聯合對初級抗體具有特異性之經標記之二級抗體來使用。如本文所述，二級抗體可以用例如酶或其他可偵測標記(諸如螢光標記、發光標記、比色標記，或放射性同位素)標記。免疫墨點方案及套組在此項技術中已熟知且可商購。用於免疫墨點法的自動化系統，例如用於西方墨點法的iBind Western系統(ThermoFisher, Waltham, MA USA 02451)可商購。免疫墨點法包括(但不限於)西方墨點法、細胞內西方墨點法及點漬墨法。點漬墨法為一種簡化程序，其中蛋白質樣品並非藉由電泳分離，而是直接點樣至膜上。細胞內西方墨點法包括將細胞接種於微量滴定盤中、固定/滲透細胞，及隨後用主要的經標記之初級抗體或未標記之初級抗體偵測，隨後用經標記之二級抗體偵測，如本文所述。In some embodiments, the expression of the protein product encoded by the marker gene can also be detected by using an immunoblot analysis using antibodies against the protein product encoded by the marker gene. In some embodiments of immunoblot analysis, proteins are usually (but not necessarily) separated by electrophoresis and transferred to a membrane (usually nitrocellulose or PVDF membrane). Similar to IHC analysis, primary antibodies or antisera, such as polyclonal antisera and monoclonal antibodies that specifically target the protein product encoded by the marker gene, can be used to detect the expression of the marker gene. In some embodiments, the membrane is contacted with a primary antibody directed against a specific target for a time sufficient for antibody-antigen binding to occur and the bound antibody can be detected by directly labeling the primary antibody itself with, for example, a radioactive label, a fluorescent label, a hapten label (such as biotin), or an enzyme (such as horseradish peroxidase or alkaline phosphatase). In other embodiments, an unlabeled primary antibody is used in conjunction with a labeled secondary antibody specific for the primary antibody in an indirect assay as described above. As described herein, the secondary antibody can be labeled with, for example, an enzyme or other detectable label (such as a fluorescent label, a luminescent label, a colorimetric label, or a radioisotope). Immunoblot protocols and kits are well known in the art and are commercially available. Automated systems for immunoblotting, such as the iBind Western system for Western blotting (ThermoFisher, Waltham, MA USA 02451), are commercially available. Immunoblotting includes, but is not limited to, Western blotting, in-cell Western blotting, and spot blotting. Spot blotting is a simplified procedure in which protein samples are not separated by electrophoresis but are directly spotted onto a membrane. In-cell Western blotting involves seeding cells in a microtiter plate, fixing/permeabilizing the cells, and subsequently detecting with a primary labeled primary antibody or an unlabeled primary antibody, followed by detection with a labeled secondary antibody, as described herein.
在其他實施例中，由標記基因編碼之蛋白質產物的表現量亦可使用本文所述之抗體在流式細胞分析技術分析(包括螢光活化細胞分選(FACS)分析)中偵測。類似於IHC或免疫墨點分析，可以在FACS分析中使用初級抗體或抗血清(諸如特異性靶向由標記基因編碼之蛋白質產物的多株抗血清及單株抗體)偵測蛋白質表現。在一些實施例中，細胞用針對特定目標蛋白的初級抗體染色足以發生抗體-抗原結合的時間且所結合的抗體可以藉由初級抗體上的直接標記(例如螢光標記或半抗原標記，諸如初級抗體上的生物素)來偵測。在其他實施例中，在如上文所述的間接分析中，未標記之初級抗體聯合對初級抗體具有特異性之經螢光標記之二級抗體來使用。FACS提供一種基於每種細胞之特定光散射及螢光特徵來分選或分析經螢光標記之生物細胞之混合物的方法(一次一種細胞)。因此，流式細胞儀偵測且報導經螢光染料標記之抗體的強度，其指示目標蛋白之表現量。因此，由標記基因編碼之蛋白質產物的表現量可使用針對此類蛋白質產物之抗體偵測。亦可藉由對透化細胞染色來觀測非螢光細胞質蛋白質。用於執行FACS染色及分析之方法已為熟習此項技術者熟知且描述於Teresa S. Hawley及Robert G. Hawley in Flow Cytometry Protocols, Humana Press, 2011 (ISBN 1617379506, 9781617379505)中。In other embodiments, the expression amount of the protein product encoded by the marker gene can also be detected in flow cytometric analysis (including fluorescence activated cell sorting (FACS) analysis) using the antibodies described herein. Similar to IHC or immunoblot analysis, protein expression can be detected in FACS analysis using primary antibodies or antisera (such as polyclonal antisera and monoclonal antibodies that specifically target the protein product encoded by the marker gene). In some embodiments, cells are stained with primary antibodies against specific target proteins for a time sufficient for antibody-antigen binding to occur and the bound antibody can be detected by a direct label on the primary antibody (e.g., a fluorescent label or a hapten label, such as biotin on the primary antibody). In other embodiments, in an indirect analysis as described above, an unlabeled primary antibody is used in conjunction with a fluorescently labeled secondary antibody specific for the primary antibody. FACS provides a method for sorting or analyzing a mixture of fluorescently labeled biological cells (one cell at a time) based on the specific light scattering and fluorescence characteristics of each cell. Therefore, the flow cytometer detects and reports the intensity of the antibody labeled with the fluorescent dye, which indicates the expression amount of the target protein. Therefore, the expression amount of the protein product encoded by the marker gene can be detected using antibodies against such protein products. Non-fluorescent cytoplasmic proteins can also be observed by staining permeabilized cells. Methods for performing FACS staining and analysis are well known to those skilled in the art and are described in Teresa S. Hawley and Robert G. Hawley in Flow Cytometry Protocols, Humana Press, 2011 (ISBN 1617379506, 9781617379505).
在其他實施例中，由標記基因編碼之蛋白質產物的表現量亦可使用免疫分析法偵測，諸如酶免疫分析(EIA)或ELISA。EIA與ELISA分析在此項技術中已知，例如，用於分析多種組織及樣品，包括血液、血漿、血清或骨髓。有多種ELISA分析形式可供利用，參見例如美國專利第4,016,043號、第4,424,279號及第4,018,653號，該等專利以全文引用的方式併入本文中。此等分析包括非競爭型單點及兩點或「夾心」分析，以及傳統競爭性結合分析。此等分析亦包括經標記之抗體對目標蛋白的直接結合。夾心分析為常用的分析形式。夾心分析技術存在多種變化形式。舉例而言，在典型正向分析中，將未經標記之抗體固定於固體基質上，且使待測試之樣品與經結合分子接觸。在培育適合時間段，即足以允許形成抗體-抗原複合物之時間段之後，接著添加用能夠產生可偵測信號之報導體分子標記的針對抗原具有特異性之第二抗體且培育，給予足夠的時間以形成抗體-抗原-經標記抗體之另一複合物。洗掉任何未反應之物質，且藉由觀測報導體分子所產生之信號來確定抗原之存在。結果可藉由簡單地觀測可見信號來定性，或可藉由與含有已知量之目標蛋白的對照樣品比較來定量。In other embodiments, the expression of the protein product encoded by the marker gene can also be detected using immunoassays, such as enzyme immunoassays (EIA) or ELISA. EIA and ELISA assays are known in the art, for example, for analyzing a variety of tissues and samples, including blood, plasma, serum or bone marrow. There are a variety of ELISA assay formats available, see, for example, U.S. Patent Nos. 4,016,043, 4,424,279 and 4,018,653, which are incorporated herein by reference in their entirety. Such assays include non-competitive single-point and two-point or "sandwich" assays, as well as traditional competitive binding assays. Such assays also include direct binding of labeled antibodies to target proteins. Sandwich assays are commonly used assay formats. There are many variations of sandwich assay technology. For example, in a typical forward assay, an unlabeled antibody is immobilized on a solid matrix and the sample to be tested is contacted with the bound molecule. After incubation for a suitable period of time, i.e., a period of time sufficient to allow the formation of an antibody-antigen complex, a second antibody specific for the antigen labeled with a reporter molecule capable of producing a detectable signal is then added and incubated, allowing sufficient time for another complex of antibody-antigen-labeled antibody to form. Any unreacted material is washed away, and the presence of the antigen is determined by observing the signal produced by the reporter molecule. The results can be qualitative by simply observing the visible signal, or can be quantitative by comparison with a control sample containing a known amount of the target protein.
在EIA或ELISA分析之一些實施例中，使酶與第二抗體結合。在其他實施例中，可以在ELISA分析形式中使用經螢光標記之二級抗體來代替經酶標記之二級抗體產生可偵測信號。當在特定波長之光照射下活化時，螢光染料標記之抗體吸收光能，誘導分子之可激發狀態，隨後發射可用光學顯微鏡目測偵測之特徵性顏色的光。如同EIA及ELISA，允許經螢光標記之抗體結合第一抗體-目標蛋白複合物。在洗掉未結合之試劑之後，接著使殘留三元複合物暴露於適當波長之光，觀測到的螢光指示存在所關注之目標蛋白。免疫螢光與EIA技術在此項技術中均沿用已久且揭示於本文中。In some embodiments of EIA or ELISA analysis, the enzyme is combined with a second antibody. In other embodiments, a fluorescently labeled secondary antibody can be used in the ELISA analysis format to replace the enzyme-labeled secondary antibody to produce a detectable signal. When activated under light irradiation of a specific wavelength, the fluorescent dye-labeled antibody absorbs light energy, induces the excitable state of the molecule, and then emits light of a characteristic color that can be detected by optical microscope. As with EIA and ELISA, the fluorescently labeled antibody is allowed to bind to the first antibody-target protein complex. After washing away the unbound reagent, the residual ternary complex is then exposed to light of the appropriate wavelength, and the observed fluorescence indicates the presence of the target protein of interest. Immunofluorescence and EIA techniques have been used for a long time in this technology and are disclosed herein.
對於本文所描述之免疫分析而言，可以使用多種酶或非酶標記中之任一者，只要可以分別偵測到酶活性或非酶標記即可。酶藉此產生可偵測信號，該信號可以用於偵測目標蛋白。特別適用的可偵測信號為顯色或螢光信號。因此，用作標記的特別適用酶包括可利用顯色或螢光受質的酶。此類顯色或螢光受質可以藉由酶反應轉化為容易偵測的顯色或螢光產物，該產物可以容易利用顯微法或光譜法偵測及/或定量。此類酶已為熟習此項技術者熟知，包括(但不限於)辣根過氧化酶、鹼性磷酸酶、β-半乳糖苷酶、葡萄糖氧化酶及其類似物(參見Hermanson,BioconjugateTechniques, Academic Press, San Diego (1996))。顯色或螢光受質已熟知的其他酶包括各種肽酶，其中顯色或螢光肽受質可用於偵測蛋白水解裂解反應。顯色及螢光受質在細菌診斷中的用途亦熟知，包括(但不限於)使用α-半乳糖苷酶及β-半乳糖苷酶、β-葡糖醛酸酶、6-磷酸化-β-D-半乳糖苷6-磷酸化半乳糖水解酶、β-葡糖苷酶、α-葡糖苷酶、澱粉酶、神經胺糖酸苷酶、酯酶、脂肪酶及其類似物(Manafi等人,Microbiol.Rev.55:335-348 (1991))，且顯色或螢光受質已知的此類酶可容易調適以用於本發明方法中。For the immunoassays described herein, any of a variety of enzymes or non-enzyme labels can be used, as long as the enzyme activity or non-enzyme label can be detected, respectively. The enzyme thereby produces a detectable signal that can be used to detect the target protein. Particularly suitable detectable signals are colorimetric or fluorescent signals. Therefore, particularly suitable enzymes for use as labels include enzymes that can utilize colorimetric or fluorescent substrates. Such colorimetric or fluorescent substrates can be converted into easily detectable colorimetric or fluorescent products by enzyme reactions, which can be easily detected and/or quantified using microscopy or spectroscopy. Such enzymes are well known to those skilled in the art and include, but are not limited to, horseradish peroxidase, alkaline phosphatase, β-galactosidase, glucose oxidase, and the like (see Hermanson,BioconjugateTechniques , Academic Press, San Diego (1996)). Other enzymes for which colorimetric or fluorescent substrates are known include various peptidases, wherein colorimetric or fluorescent peptide substrates can be used to detect proteolytic cleavage reactions. The use of chromogenic and fluorescent substrates in bacterial diagnostics is also well known, including but not limited to the use of α-galactosidase and β-galactosidase, β-glucuronidase, 6-phosphorylated-β-D-galactoside 6-phosphorylating galactosyl hydrolase, β-glucosidase, α-glucosidase, amylase, neuraminic acid sidase, esterase, lipase and the like (Manafi et al.,Microbiol.Rev. 55:335-348 (1991)), and such enzymes for which chromogenic or fluorescent substrates are known can be readily adapted for use in the methods ofthe present invention.
產生可偵測信號的各種顯色或螢光受質已為熟習此項技術者熟知且可商購。可用於產生可偵測信號的例示性受質包括(但不限於)辣根過氧化酶用的3,3'-二胺基聯苯胺(DAB)、3,3',5,5'-四甲基聯苯胺(TMB)、氯萘酚(Chloronaphthol)(4-CN)(4-氯-1-萘酚)、2,2'-次偶氮基-雙(3-乙基苯并噻唑啉-6-磺酸)(ABTS)、鄰苯二胺二鹽酸鹽(OPD)，及3-胺基-9-乙基咔唑(AEC)；鹼性磷酸酶用的5-溴-4-氯-3-吲哚基-1-磷酸酯(BCIP)、硝基藍四唑鎓(NBT)、快速紅(快速紅TR/AS-MX)，及對硝基苯基磷酸酯(PNPP)；β-半乳糖苷酶用的1-甲基-3-吲哚基-β-D-哌喃半乳糖苷及2-甲氧基-4-(2-硝基乙烯基)苯基β-D-哌喃半乳糖苷；β-葡糖苷酶用的2-甲氧基-4-(2-硝基乙烯基)苯基β-D-哌喃葡萄糖苷；及其類似物。例示性螢光受質包括(但不限於)鹼性磷酸酶用的4-(三氟甲基)傘形酮基磷酸酯；磷酸酶用的4-甲基傘形酮基磷酸酯雙(2-胺基-2-甲基-1,3-丙二醇)、4-甲基傘形酮基磷酸酯雙(環己基銨)及4-甲基傘形酮基磷酸酯；辣根過氧化酶用的QuantaBluTM及QuantaRedTM；β-半乳糖苷酶用的4-甲基傘形酮基β-D-哌喃半乳糖苷、螢光素二(β-D-哌喃半乳糖苷)及萘并螢光素二-(β-D-哌喃半乳糖苷)；β-葡糖苷酶用的3-乙醯基傘形酮基β-D-哌喃葡萄糖苷及4-甲基傘形酮基-β-D-哌喃葡萄糖苷；及α-半乳糖苷酶用的4-甲基傘形酮基-α-D-哌喃半乳糖苷。用於產生可偵測信號的例示性酶及受質亦描述於例如US公開案2012/0100540中。各種可偵測酶受質(包括顯色或螢光受質)已熟知且可商購(Pierce, Rockford IL; Santa Cruz Biotechnology, Dallas TX; Invitrogen, Carlsbad CA; 42 Life Science; Biocare)。一般而言，將受質轉化成產物，形成沈澱物，其沈積於目標核酸位點處。其他例示性受質包括(但不限於) HRP-綠(42 Life Science)、Betazoid DAB、Cardassian DAB、Romulin AEC、Bajoran紫、Vina綠、Deep Space Black™、Warp Red™、Biocare的Vulcan速紅及Ferangi藍(Concord CA；biocare.net/products/detection/chromogens)。Various chromogenic or fluorescent substrates that produce detectable signals are well known to those skilled in the art and are commercially available. Exemplary substrates that can be used to produce detectable signals include, but are not limited to, 3,3'-diaminobenzidine (DAB), 3,3',5,5'-tetramethylbenzidine (TMB), chloronaphthol (4-CN) (4-chloro-1-naphthol), 2,2'-azobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), o-phenylenediamine dihydrochloride (OPD), and 3-amino-9-ethylcarbazole (AEC) for horseradish peroxidase; alkaline phosphatase 5-bromo-4-chloro-3-indolyl-1-phosphate (BCIP), nitro blue tetrazolium (NBT), fast red (fast red TR/AS-MX), and p-nitrophenyl phosphate (PNPP) for β-galactosidase; 1-methyl-3-indolyl-β-D-galactopyranoside and 2-methoxy-4-(2-nitrovinyl)phenyl β-D-galactopyranoside for β-galactosidase; 2-methoxy-4-(2-nitrovinyl)phenyl β-D-glucopyranoside for β-glucosidase; and their analogs. Exemplary fluorescent substrates include, but are not limited to, 4-(trifluoromethyl) umbelliferyl ketophosphate for alkaline phosphatases; 4-methylumbelliferyl ketophosphate bis(2-amino-2-methyl-1,3-propanediol), 4-methylumbelliferyl ketophosphate bis(cyclohexylammonium), and 4-methylumbelliferyl ketophosphate for phosphatases; QuantaBlu™ and QuantaRed™ for horseradish peroxidase. ; 4-methyl umbelliferyl β-D-galactopyranoside, fluorescein di(β-D-galactopyranoside) and naphthofluorescein di-(β-D-galactopyranoside) for β-galactosidase; 3-acetyl umbelliferyl β-D-glucopyranoside and 4-methyl umbelliferyl-β-D-glucopyranoside for β-glucosidase; and 4-methyl umbelliferyl-α-D-galactopyranoside for α-galactosidase. Exemplary enzymes and substrates for generating detectable signals are also described, for example, in US Publication No. 2012/0100540. A variety of detectable enzyme substrates, including chromogenic or fluorescent substrates, are well known and commercially available (Pierce, Rockford IL; Santa Cruz Biotechnology, Dallas TX; Invitrogen, Carlsbad CA; 42 Life Science; Biocare). Generally, the substrate is converted to a product, forming a precipitate that is deposited at the target nucleic acid site. Other exemplary substrates include, but are not limited to, HRP-green (42 Life Science), Betazoid DAB, Cardassian DAB, Romulin AEC, Bajoran Purple, Vina Green, Deep Space Black™, Warp Red™, Biocare's Vulcan Fast Red, and Ferangi Blue (Concord CA; biocare.net/products/detection/chromogens).
在免疫分析之一些實施例中，可偵測標記可與可具有的初級抗體或偵測未標記之初級抗體的二級抗體直接偶聯。熟習此項技術者已熟知例示性可偵測標記，包括(但不限於)顯色或螢光標記(參見Hermanson,BioconjugateTechniques, Academic Press, San Diego (1996))。適用作標記的例示性螢光團包括但不限於玫瑰紅(rhodamine)衍生物，例如四甲基玫瑰紅、玫瑰紅B、玫瑰紅6G、磺醯玫瑰紅B、德克薩斯紅(Texas Red) (磺醯玫瑰紅101)、玫瑰紅110及其衍生物，諸如四甲基玫瑰紅-5-(或6)、麗絲胺玫瑰紅B (lissamine rhodamine B)及其類似物；7-硝基苯并-2-氧雜-1,3-二唑(NBD)；螢光素及其衍生物；萘，諸如丹醯基(5-二甲胺基萘-1-磺醯基)；香豆素衍生物，諸如7-胺基-4-甲基香豆素-3-乙酸(AMCA)、7-二乙基胺基-3-[(4'-(碘乙醯基)胺基)苯基]-4-甲基香豆素(DCIA)、Alexa fluor染料(Molecular Probes)，及其類似物；4,4-二氟-4-硼雜-3a,4a-二氮雜-s-二環戊二烯并苯(BODIPYTM)及其衍生物(Molecular Probes; Eugene Oreg.)；芘及磺化芘，諸如Cascade BlueTM及其衍生物，包括8-甲氧基芘-1,3,6-三磺酸，及其類似物；吡啶基㗁唑衍生物及達珀西(dapoxyl)衍生物(Molecular Probes)；螢光黃(3,6-二磺酸酯-4-胺基-萘二甲醯亞胺)及其衍生物；CyDyeTM螢光染料(Amersham/GE Healthcare Life Sciences；Piscataway NJ)，及其類似物。例示性發色團包括(但不限於)酚酞、孔雀綠(malachite green)、硝基芳族烴(諸如硝基苯基)、重氮染料、達波希(dabsyl)(4-二甲胺基偶氮苯-4'-磺醯基)，及其類似物。In some embodiments of immunoassays, the detectable label may be directly coupled to the primary antibody or a secondary antibody that detects the unlabeled primary antibody. Exemplary detectable labels are well known to those skilled in the art and include, but are not limited to, chromogenic or fluorescent labels (see Hermanson,BioconjugateTechniques , Academic Press, San Diego (1996)). Exemplary fluorophores suitable for use as labels include, but are not limited to, rhodamine derivatives, such as tetramethyl rose bengal, rose bengal B, rose bengal 6G, sulfonyl rose bengal B, Texas Red (sulfonyl rose bengal 101), rose bengal 110 and derivatives thereof, such as tetramethyl rose bengal-5-(or 6), lissamine rhodamine B and its analogs; 7-nitrobenz-2-oxadiazole (NBD); fluorescein and its derivatives; naphthalene, such as dansyl (5-dimethylaminonaphthalene-1-sulfonyl); coumarin derivatives, such as 7-amino-4-methylcoumarin-3-acetic acid (AMCA), 7-diethylamino-3-[(4'-(iodoacetyl)amino)phenyl]-4-methylcoumarin (DCIA), Alexa Fluor and its derivatives. fluor dyes (Molecular Probes), and their analogs; 4,4-difluoro-4-borano-3a,4a-diaza-s-dicyclopentadienylacene (BODIPY™ ) and its derivatives (Molecular Probes; Eugene Oreg.); pyrene and sulfonated pyrenes, such as Cascade Blue™ and its derivatives, including 8-methoxypyrene-1,3,6-trisulfonic acid, and its analogs; pyridyl pyrazole derivatives and dapoxyl derivatives (Molecular Probes); fluorescent yellow (3,6-disulfonate-4-amino-naphthalene dicarboxylic acid imide) and its derivatives; CyDye™ fluorescent dyes (Amersham/GE Healthcare Life Sciences; Piscataway NJ), and their analogs. Exemplary chromophores include, but are not limited to, phenolphthalein, malachite green, nitroaromatics (such as nitrophenyl), diazo dyes, dabsyl (4-dimethylaminoazobenzene-4'-sulfonyl), and the like.
可以利用熟習此項技術者熟知的方法(諸如顯微法或光譜法)使與所結合之初級或二級抗體結合的顯色或螢光可偵測信號可視化。The chromogenic or fluorescent detectable signal associated with the bound primary or secondary antibody can be visualized using methods well known to those skilled in the art, such as microscopy or spectroscopy.
此章節(章節5.8)中所提供的方法可結合此項技術中已知的各種癌症模型使用。在一個實施例中，使用小鼠異種移植癌症模型。簡言之，T-24及UM-UC-3細胞購自ATCC且使用推薦的培養基條件培養。使用pRCDCMEP-CMV-hNectin-4 EF1-Puro構築體，藉由用含有人類連接素-4的慢病毒轉導親代細胞來產生T-24 hNectin-4 (人類連接素-4)及UM-UC-3連接素-4細胞，且使用嘌呤黴素加以選擇。將T-24連接素-4 (純系1A9)細胞植入裸小鼠且經由套針繼代，允許達到約200 mm3腫瘤體積，且隨後用腹膜內(IP)單次劑量的恩諾單抗維多汀(3 mg/kg)或非結合ADC (3 mg/kg)處理，每個處理組7隻動物。使用此模型的追蹤ICD研究涉及處理後的第5天收集腫瘤用於藉由RNA-seq、流式、免疫組織化學(IHC)及Luminex進行下游分析。將腫瘤固定於福馬林中且製備成FFPE組織塊。切割4 μm塊且使用F4/80、CD11c執行免疫組織化學。免疫組織化學染色的載片切片用Leica AT2數位完整載片掃描儀掃描，且藉由使用針對連接素4、CD11c及F4/80染色定製的演算法、用Visiopharm軟體分析影像。基於染色強度及背景染色，使演算法最佳化。計算連接素4的陽性染色百分比且計算F480及CD11c的每mm2陽性細胞數。The methods provided in this section (Section 5.8) can be used in conjunction with various cancer models known in the art. In one embodiment, a mouse xenograft cancer model is used. Briefly, T-24 and UM-UC-3 cells were purchased from ATCC and cultured using recommended media conditions. T-24 hNectin-4 (human Nectin-4) and UM-UC-3 Nectin-4 cells were generated by transducing parental cells with lentivirus containing human Nectin-4 using the pRCDCMEP-CMV-hNectin-4 EF1-Puro construct and selected using puromycin. T-24 nexin-4 (clonal 1A9) cells were implanted into nude mice and passaged via trocar, allowed to reach approximately 200mm3 tumor volume, and subsequently treated with a single intraperitoneal (IP) dose of enrofloxacin (3 mg/kg) or non-conjugated ADC (3 mg/kg), 7 animals per treatment group. Follow-up ICD studies using this model involved harvesting tumors on day 5 post-treatment for downstream analysis by RNA-seq, flow cytometry, immunohistochemistry (IHC), and Luminex. Tumors were fixed in formalin and prepared as FFPE tissue blocks. 4 μm blocks were cut and immunohistochemistry was performed using F4/80, CD11c. Immunohistochemically stained slide sections were scanned with a Leica AT2 digital whole slide scanner and images were analyzed with Visiopharm software using algorithms customized for nectin 4, CD11c and F4/80 staining. The algorithm was optimized based on staining intensity and background staining. The percentage of positive staining for nectin 4 was calculated and the number of positive cells permm2 was calculated for F480 and CD11c.
將腫瘤切片溶解於細胞溶解緩衝液2 (R&D Systems®，目錄號895347)。使用MILLIPLEX MAP小鼠細胞介素/趨化介素磁珠集合(Millipore)量測腫瘤樣品中的細胞介素及趨化介素且在LUMINEX MAGPIX系統上讀取。Tumor sections were lysed in Lysis Buffer 2 (R&D Systems®, Catalog No. 895347). Interleukins and proinflammatory cytokines were measured in tumor samples using the MILLIPLEX MAP Mouse Interleukin/Protein Magnetic Bead Set (Millipore) and read on a LUMINEX MAGPIX system.
在RNA-seq分析中，使用TRIZOL Plus RNA純化套組(Life Technologies)，根據製造商方案自急驟冷凍的腫瘤中分離出RNA，從而產生高品質RNA (平均RNA完整數＞ 8)。RNA選擇方法係使用聚(A)選擇及Illumina的mRNA庫Prep套組且在單索引Hi-Seq 2×150 bp (Illumina)上讀取。使序列讀段相對於人類及小鼠總轉錄本定位且測定每百萬總讀段數。For RNA-seq analysis, RNA was isolated from snap-frozen tumors using the TRIZOL Plus RNA Purification Kit (Life Technologies) according to the manufacturer's protocol, yielding high-quality RNA (average RNA integrity number > 8). RNA selection was performed using poly(A) selection and Illumina's mRNA Library Prep Kit and read on a single index Hi-Seq 2×150 bp (Illumina). Sequence reads were mapped relative to human and mouse total transcripts and the number of total reads per million was determined.
使用肯定語言描述多個實施例來大體提供本發明。本發明亦特別包括其中特定標的物被完全或部分排除的實施例，諸如物質或材料、方法步驟及條件、方案、程序、分析法或分析。因此，儘管本文中未依本發明不包括的內容來大體表述本發明，但本文揭示了未明確包括於本發明中的態樣。The invention is generally provided by describing a number of embodiments using positive language. The invention also specifically includes embodiments in which specific subject matter is completely or partially excluded, such as substances or materials, method steps and conditions, schemes, procedures, assays or analyses. Therefore, although the invention is not generally described herein as not being included in the invention, aspects that are not expressly included in the invention are disclosed herein.
本文中描述本發明之特定實施例，包括本發明人已知之實施本發明的最佳方式。在閱讀前述描述後，所揭示實施例之變體可對於在此項技術中工作之個體變得顯而易見，且吾人預期，彼等熟習此項技術者可按需要採用此類變體。因此，希望本發明可以除本文具體描述之外的方式實施，且本發明包括隨附申請專利範圍中所述之標的物的所有變型及等效物，如適用的法律所允許。此外，除非本文另外指示或另外明顯與上下文矛盾，否則本發明涵蓋上述要素在其所有可能變化中的任何組合。Specific embodiments of the invention are described herein, including the best mode of carrying out the invention known to the inventors. Variations of the disclosed embodiments may become apparent to individuals working in this art after reading the foregoing description, and it is expected that those skilled in the art may adopt such variations as desired. Therefore, it is contemplated that the invention may be implemented in ways other than as specifically described herein, and the invention includes all variations and equivalents of the subject matter described in the accompanying claims, as permitted by applicable law. Furthermore, unless otherwise indicated herein or otherwise clearly contradicted by context, the invention encompasses any combination of the above-described elements in all possible variations thereof.
本說明書所列舉之所有公開案、專利申請案、登錄號及其他參考文獻均以全文引用之方式併入本文中，如同各個別公開案或專利申請案具體地且個別地指示以引用之方式併入一般。All publications, patent applications, accession numbers, and other references cited in this specification are incorporated herein by reference in their entirety, as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
已描述本發明之許多實施例。然而，應理解可在不脫離本發明之精神及範疇的情況下進行各種修改。6.實例Many embodiments of the present invention have been described. However, it should be understoodthat various modifications can be made without departing from the spirit and scope of the present invention.
以下為用於研究之各種方法及材料的描述，且為了向一般熟習此項技術者完整揭示及描述如何製造及使用本發明而提出，且不希望限制本發明人視為其發明的範疇，亦不希望其表示以下進行的實驗為可進行之所有實驗。應理解，以現在時態書寫之例示性描述未必進行，而是可進行該等描述以產生與本發明之教示相關之資料及其類似物。已努力確保關於所使用之數字(例如，量、溫度等)的準確性，但應考慮一些實驗性誤差及偏差。6.1實例1-恩諾單抗維多汀組合派姆單抗作為不能接受基於順鉑之化學療法的不可切除性局部晚期或轉移性尿路上皮癌(la/mUC)之患者之一線治療的1b/2期研究。6.1.1臨床研究中使用的藥物The following is a description of various methods and materials used in the studies and is presented in order to fully disclose and describe to one of ordinary skill in the art how to make and use the invention, and is not intended to limit the scope of what the inventors regard as their invention, nor is it intended to represent that the experiments performed below are all experiments that can be performed. It should be understood that exemplary descriptions written in the present tense are not necessarily performed, but rather such descriptions may be performed to generate data relevant to the teachings of the present invention and the like. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should be considered.6.1Example1- Phase1b/2 study ofenrofloxacin in combination with pembrolizumab as afirst-line treatment for patients with unresectable locally advanced or metastatic urothelial carcinoma(la/mUC) who are unable to receive cisplatin-based chemotherapy.6.1.1Drugs used in clinical studies
恩諾單抗維多汀為與微管破裂劑單甲基奧瑞他汀E (MMAE)共價連接的靶向連接素-4之單株抗體(AGS-22C3)。恩諾單抗維多汀由三種功能亞單元組成： • 完全人類IgG1K抗體(AGS-22C3)； • 微管破裂劑MMAE； • 使MMAE與AGS-22C3共價連接的蛋白酶可裂解順丁烯二醯亞胺基己醯基-纈胺酸-瓜胺酸(vc)連接子。Enromax Vedotin is a monoclonal antibody targeting nectin-4 covalently linked to the microtubule disrupting agent monomethyl auristatin E (MMAE) (AGS-22C3). Enromax Vedotin consists of three functional subunits:• Fully human IgG1K antibody (AGS-22C3);• Microtubule disrupting agent MMAE;• Protease-cleavable cis-butylenediimidohexanoyl-valine-citrulline (vc) linker that covalently links MMAE to AGS-22C3.
恩諾單抗維多汀結合連接素-4之V域(Challita-Eid等人, Cancer Res (2016); 76(10): 3003-13)。在推測的作用機制中，藥物結合細胞表面上的連接素-4蛋白且內化，從而引起vc連接子的蛋白水解裂解及MMAE的細胞內釋放。游離的MMAE隨後破壞微管蛋白聚合且導致有絲分裂阻滯。6.1.2研究概述6.1.2.1概要(i)研究藥物名稱Enrotumomab vedotin binds to the V domain of nectin-4 (Challita-Eid et al., Cancer Res (2016); 76(10): 3003-13). In the proposed mechanism of action, the drug binds to nectin-4 protein on the cell surface and is internalized, resulting in proteolytic cleavage of the vc linker and intracellular release of MMAE. Free MMAE then disrupts tubulin polymerization and causes mitotic arrest.6.1.2Study Overview6.1.2.1Overview (i)Study Drug Name
恩諾單抗維多汀(ASG-22CE) (ii)開發階段Ennotumab vedotin (ASG-22CE) (ii)Development stage
1b/2期 (iii)研究標題Phase 1b/2(iii)Study Title
恩諾單抗維多汀組合派姆單抗作為不能接受基於順鉑之化學療法的不可切除性局部晚期或轉移性尿路上皮癌(la/mUC)之患者之一線治療的1b/2期研究。 (iv)研究目標Phase 1b/2 study of enrofloxacin in combination with pembrolizumab as first-line treatment for patients with unresectable locally advanced or metastatic urothelial carcinoma (la/mUC) who are unable to receive cisplatin-based chemotherapy. (iv)Study Objectives
主要 • 評估恩諾單抗維多汀單藥療法或恩諾單抗維多汀組合派姆單抗之抗腫瘤活性，藉由盲態中央獨立評估(BICR)以根據RECIST 1.1版之ORR量測。Primary• To evaluate the anti-tumor activity of enrofloxacin monotherapy or enrofloxacin in combination with pembrolizumab, as measured by ORR according to RECIST version 1.1 by blinded independent central review (BICR).
次要 • 藉由研究者評估，根據RECIST 1.1版評估客觀反應率(ORR) • 藉由BICR及研究者評估，根據RECIST 1.1版評估反應持續時間(DOR) • 藉由BICR及研究者評估，根據RECIST 1.1版評估疾病控制率(DCR) • 藉由BICR及研究者評估，根據RECIST 1.1版評估研究療法之無惡化存活期(PFS) • 評估總存活期(OS) • 評估恩諾單抗維多汀單藥療法或恩諾單抗維多汀組合派姆單抗之安全性及耐受性Secondary• Objective response rate (ORR) by investigator assessment according to RECIST version 1.1• Duration of response (DOR) by BICR and investigator assessment according to RECIST version 1.1• Disease control rate (DCR) by BICR and investigator assessment according to RECIST version 1.1• Progression-free survival (PFS) of study therapy by BICR and investigator assessment according to RECIST version 1.1• Overall survival (OS)• Safety and tolerability of enrofloxacin monotherapy or enrofloxacin in combination with pembrolizumab
其他 • 評估藥物動力學(PK)及抗治療抗體(ATA)之發生率 • 評估連接素-4及PD-L1表現量 • 評估生物活性及疾病抗性之生物標記物及其與臨床結果量測之潛在關聯 • 藉由研究者評估來評估後續療法之PFS (PFS2) • 自患者視角評估對生活品質(QoL)及症狀(包括疼痛)之影響 • 藉由研究者評估對恩諾單抗維多汀組合派姆單抗(EV+派姆單抗組)根據iRECIST評估研究療法之ORR、DOR、DCR及PFS (v)研究群體Others • Evaluation of pharmacokinetics (PK) and incidence of anti-therapeutic antibodies (ATA) • Evaluation of nectin-4 and PD-L1 expression • Evaluation of biomarkers of biological activity and disease resistance and their potential association with clinical outcome measures • Evaluation of PFS with follow-up therapy by investigator assessment (PFS2) • Evaluation of the impact on quality of life (QoL) and symptoms (including pain) from the patient’s perspective • Evaluation of ORR, DOR, DCR and PFS of the study treatment based on iRECIST by investigator assessment for enrofloxacin combined with pembrolizumab (EV+pembrolizumab group) (v)Study population
所研究之群體包括患有la/mUC及根據RECIST 1.1版之可量測疾病的患者。其他要求包括以下：患者必須≥18歲，研究者所評估的預期壽命必須≥3個月，且美國東岸癌症臨床研究合作組織(Eastern Cooperative Oncology Group，ECOG)體能狀態為0、1或2，具有足夠的基線血液學、肝及腎功能。The population studied included patients with la/mUC and measurable disease according to RECIST version 1.1. Other requirements included the following: patients had to be ≥18 years of age, had an investigator-assessed life expectancy of ≥3 months, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, with adequate baseline hematologic, liver, and renal function.
患者不得出現正在發生的感覺或運動神經病變(2級或更高)或活動性中樞神經系統(CNS)轉移。患者先前不得針對尿路上皮癌接受恩諾單抗維多汀或其他基於單甲基奧瑞他汀E (MMAE)之抗體-藥物結合物(ADC)的治療。患者在3年內不得具有另一惡性腫瘤病史，或來自先前診斷之惡性腫瘤之殘留疾病的任何證據。若患者當前正接受針對活動性感染的全身抗微生物治療或高劑量類固醇，則亦排除在外。糖尿病不可控的患者排除在外。不可控的糖尿病定義為血紅素A1c (HbA1c) ≥8%或HbA1c 7%至＜8%與不另說明的相關糖尿病症狀(多尿症或煩渴症)。Patients must not have ongoing sensory or motor neuropathy (grade 2 or higher) or active central nervous system (CNS) metastases. Patients must not have previously received treatment with enrofloxacin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugate (ADC) for urothelial carcinoma. Patients must not have a history of another malignancy within 3 years, or any evidence of residual disease from a previously diagnosed malignancy. Patients were also excluded if they were currently receiving systemic antimicrobial therapy or high-dose steroids for active infection. Patients with uncontrolled diabetes were excluded. Uncontrolled diabetes was defined as hemoglobin A1c (HbA1c) ≥8% or HbA1c 7% to <8% with related diabetic symptoms not otherwise specified (polyuria or thirst).
患者必須能夠接受派姆單抗，且在入選時必須由於以下準則中之至少1者而不適合基於順鉑之化學療法：腎小球濾過率(GFR) ＜60 mL/min但≥30 mL/min，ECOG體能狀態為2，美國國家癌症研究所不良事件通用術語準則(National Cancer Institute Common Terminology Criteria for Adverse Events，NCI CTCAE) 4.03版≥2級聽力損失，或紐約心臟協會(New York Heart Association，NYHA) III級心臟衰竭。患者先前不得接受針對局部晚期或轉移性疾病之全身治療。患者在隨機分組之前12個月內不可先前接受過輔助/前輔助基於鉑之療法。Patients must be able to receive pembrolizumab and must be ineligible for cis-platinum-based chemotherapy at the time of enrollment due to at least 1 of the following criteria: glomerular filtration rate (GFR) <60 mL/min but ≥30 mL/min, ECOG performance status of 2, National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 grade ≥2 hearing loss, or New York Heart Association (NYHA) class III heart failure. Patients must not have received prior systemic therapy for locally advanced or metastatic disease. Patients must not have received prior adjuvant/pre-adjuvant platinum-based therapy within 12 months prior to randomization.
(vi)計劃的患者數目(vi)Planned number of patients
約150名患者入選此研究。 (vii)研究設計Approximately 150 patients were enrolled in this study. (vii)Study Design
此研究經設計以評估恩諾單抗維多汀作為單藥療法或組合派姆單抗用於治療la/mUC患者之安全性及抗腫瘤活性。此研究包括2個治療組，以1:1之比隨機分入恩諾單抗維多汀單藥療法或恩諾單抗維多汀組合派姆單抗。研究設計描繪於圖2中。This study was designed to evaluate the safety and antitumor activity of enroku as monotherapy or in combination with pembrolizumab in patients with la/mUC. The study included 2 treatment arms, randomized 1:1 to enroku monotherapy or enroku combined with pembrolizumab. The study design is depicted inFigure2 .
所有患者均接收恩諾單抗維多汀(正在研究的研究藥劑)，其在每3週週期之第1天及第8天以IV輸注形式投與。已確定在每3週週期之第1天及第8天IV恩諾單抗維多汀1.25 mg/kg的劑量含量。若SMC建議且研究試驗委託者批准，則允許恩諾單抗維多汀劑量遞減(至多2個漸減劑量含量)。All patients received enroku (investigational agent under investigation) administered as an IV infusion on Days 1 and 8 of each 3-week cycle. Enroku vedotin dose levels of 1.25 mg/kg IV on Days 1 and 8 of each 3-week cycle were established. Enroku dose reductions (up to 2 decreasing dose levels) were permitted if recommended by the SMC and approved by the study trial sponsor.
對於EV單藥組中之患者，研究者基於根據RECIST 1.1版掃描之現場評估作出治療決定。For patients in the EV monotherapy group, treatment decisions were made by the investigator based on on-site assessment of scans according to RECIST version 1.1.
患者藉由不存在或存在肝轉移及ECOG體能狀態(0相對於1/2)分層，且以1:1之比隨機分組以接受恩諾單抗維多汀單藥療法(EV單藥組)或恩諾單抗維多汀組合派姆單抗(EV+派姆單抗組)： • EV單藥組包括約75名患者。患者在每3週週期之第1天及第8天接受恩諾單抗維多汀。 • EV+派姆單抗組包括約75名患者。患者在第1天及第8天接受恩諾單抗維多汀，且在每3週週期之第1天接受派姆單抗。Patients were stratified by the absence or presence of liver metastases and ECOG performance status (0 vs. 1/2) and randomized in a 1:1 ratio to receive enroku monotherapy (EV monotherapy group) or enroku combined with pembrolizumab (EV+pembrolizumab group):• The EV monotherapy group included approximately 75 patients. Patients received enroku on days 1 and 8 of each 3-week cycle.• The EV+pembrolizumab group included approximately 75 patients. Patients received enroku on days 1 and 8, and pembrolizumab on day 1 of each 3-week cycle.
患者在電子裝置(較佳報告媒介)上完成患者報告結果(PRO)評估。僅當使用電子裝置不可行時，評估才以紙質形式或由診所工作人員藉由電話進行報告。藉由受限制的SMC持續監測安全性。Patients completed patient-reported outcome (PRO) assessments on electronic devices (preferred reporting medium). Assessments were reported on paper or by telephone by clinic staff only when use of electronic devices was not feasible. Safety was continuously monitored by restricted SMC.
在開始後續抗癌療法或在研究治療時或之後放射學確認疾病惡化(藉由研究者評估)後，根據機構指南經由成像對患者進行隨訪，但頻率不低於每12週一次，直至記錄到PFS2或患者開始另一抗癌治療，以先發生者為準。所有後續抗癌療法(包括PFS2惡化日期)均記錄在病例報告表(CRF)上。另外，治療結束(EOT)後每12週(±1週)聯絡患者一次，以瞭解後續療法時或之後的存活狀態及臨床惡化狀態。在PFS2之後，患者進入存活隨訪期，且每12週(±1週)隨訪一次存活狀態直至死亡、研究結束或撤回同意書，以先發生者為準。 (viii)測試產品、劑量及投藥模式Following initiation of subsequent anticancer therapy or radiographically confirmed disease worsening (assessed by the investigator) on or after study treatment, patients were followed by imaging according to institutional guidelines, but no less frequently than every 12 weeks, until PFS2 was documented or the patient started another anticancer therapy, whichever occurred first. All subsequent anticancer therapies (including the date of PFS2 worsening) were recorded on the case report form (CRF). In addition, patients were contacted every 12 weeks (±1 week) after end of treatment (EOT) to understand survival status and clinical worsening status on or after subsequent therapy. After PFS2, patients entered the survival follow-up period and were followed up every 12 weeks (±1 week) until death, study completion, or withdrawal of consent, whichever occurred first. (viii)Test product, dose, and mode of administration
在每3週週期之第1天及第8天，以1或1.25 mg/kg以IV輸注形式經約30分鐘投與恩諾單抗維多汀。已確定在每3週週期之第1天及第8天IV恩諾單抗維多汀1.25 mg/kg的劑量含量。若SMC建議且試驗委託者同意，則可按以下漸減劑量含量進行劑量遞減。Enrotumab vedotin is administered as an IV infusion over approximately 30 minutes at 1 or 1.25 mg/kg on Days 1 and 8 of each 3-week cycle. A dose level of 1.25 mg/kg of IV enrotumab vedotin on Days 1 and 8 of each 3-week cycle has been established. If recommended by the SMC and agreed to by the trial sponsor, dose reductions may be performed at the following decreasing dose levels.
表8顯示該研究之恩諾單抗維多汀漸減劑量含量。 表8恩諾單抗維多汀漸減劑量含量
基於基線時患者實際體重計算恩諾單抗維多汀劑量。當患者體重變化≥基線或前一個週期的10%，或滿足劑量調整準則時，重新計算劑量。使用實際重量，體重＞100 kg之患者除外；在此類情況下，基於100 kg之體重計算劑量。此研究組分中允許之最大劑量為125 mg。Enromax vedotin doses were calculated based on the patient's actual weight at baseline. Doses were recalculated when the patient's weight changed ≥10% from baseline or the previous period, or when the dose adjustment criteria were met. Actual weight was used, except for patients weighing >100 kg; in these cases, doses were calculated based on a body weight of 100 kg. The maximum dose allowed in this study component was 125 mg.
在EV+派姆單抗組中，在各3週週期之第1天，在恩諾單抗維多汀完成後約30分鐘以IV輸注形式投與派姆單抗200 mg。 (ix)治療持續時間In the EV+pembrolizumab group, pembrolizumab 200 mg was administered as an IV infusion approximately 30 minutes after completion of enrofloxacin on Day 1 of each 3-week cycle. (ix)Duration of treatment
患者繼續接受研究治療，直至放射照相上確認疾病惡化、不可接受的毒性、研究者決定、撤回同意書、開始後續抗癌療法、妊娠或試驗委託者終止研究。允許EV+派姆單抗組中具有iUPD之反應評估的患者繼續接受治療，直至由研究者在iUPD後4至9週利用後續掃描確認iCPD。Patients continued on study treatment until radiographically confirmed disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, initiation of subsequent anticancer therapy, pregnancy, or study termination by trial sponsor. Patients in the EV+pembrolizumab group who had response assessment of iUPD were allowed to continue treatment until iCPD was confirmed by the investigator using a follow-up scan 4 to 9 weeks after iUPD.
投與派姆單抗至多總共35個週期。Administer pembrolizumab for up to a total of 35 cycles.
經歷僅可歸因於派姆單抗之不可接受的毒性的患者繼續接受恩諾單抗維多汀單藥療法，直至放射照相上確認疾病惡化、不可接受的毒性、研究者決定、撤回同意書、開始後續抗癌療法、妊娠或試驗委託者終止研究。經歷僅可歸因於恩諾單抗維多汀之毒性的患者繼續接受派姆單抗單藥療法(至多35個週期)，直至疾病惡化、不可接受的毒性、研究者決定、撤回同意書、開始後續抗癌療法、妊娠或試驗委託者終止研究。 (x)功效評估Patients who experienced unacceptable toxicity attributable solely to pembrolizumab continued to receive enrofloxacin monotherapy until radiographically confirmed disease worsening, unacceptable toxicity, investigator decision, withdrawal of consent, initiation of subsequent anticancer therapy, pregnancy, or study termination by trial sponsor. Patients who experienced toxicity attributable solely to enrofloxacin continued to receive pembrolizumab monotherapy (up to 35 cycles) until disease worsening, unacceptable toxicity, investigator decision, withdrawal of consent, initiation of subsequent anticancer therapy, pregnancy, or study termination by trial sponsor. (x)Efficacy Assessments
在方案指定時間點藉由胸部、腹部及骨盆CT (使用IV造影劑)評估抗腫瘤活性之量測。若造影劑禁忌，則參閱當前的影像擷取指南(章節6.1.13)以獲得較佳掃描及造影選擇。患者在整個研究中接受相同成像方法進行反應評估。若基線時已知或在整個研究中臨床上指示不活動性腦轉移，則在疾病評估時間點重複腦部掃描(在篩選時需要)。若基線時鑑別出骨轉移，或若已知或疑似骨轉移，則在反應評估時間點重複骨掃描(在篩選時需要)。若患者在其他區域具有已知疾病或出現暗示疾病之新症狀，則應掃描該等區域。根據RECIST 1.1版確認客觀反應，在第一次記錄反應後至少4週且不超過5週重複掃描。對於EV+派姆單抗組，研究者治療決定係基於iRECIST指南。對於EV單藥組，研究者治療決定係基於RECIST 1.1版。 (xi)藥物動力學及免疫原性評估Measures of antitumor activity were assessed by CT of the chest, abdomen, and pelvis (with IV contrast) at protocol-specified time points. If contrast is contraindicated, refer to current image acquisition guidelines (Section 6.1.13) for optimal scan and contrast selection. Patients underwent the same imaging modality for response assessment throughout the study. If inactive brain metastases were known at baseline or clinically indicated throughout the study, repeat brain scans at disease assessment time points (required for screening). If bone metastases were identified at baseline, or if bone metastases were known or suspected, repeat bone scans at response assessment time points (required for screening). If patients have known disease in other areas or develop new symptoms suggestive of disease, those areas should be scanned. Objective response was confirmed according to RECIST version 1.1, with scans repeated at least 4 weeks and no more than 5 weeks after the first documented response. For the EV+pembrolizumab group, investigator treatment decisions were based on iRECIST guidelines. For the EV monotherapy group, investigator treatment decisions were based on RECIST version 1.1. (xi)Pharmacokinetic and immunogenicity assessment
在整個研究中在特定時間點收集用於PK及ATA之血液樣品。經驗證或合格的分析用於量測血清或血漿中之恩諾單抗維多汀ADC、總抗體(TAb)及MMAE的濃度。收集PK樣品且歸檔以便對伴隨藥物含量或其他恩諾單抗維多汀相關物質(諸如MMAE之循環代謝物)進行可能的分析。經驗證的分析用於確定血漿中恩諾單抗維多汀之ATA含量。收集派姆單抗之PK及ATA樣品且歸檔以便對EV+派姆單抗組進行潛在後續分析。 (xii)生物標記物評估Blood samples for PK and ATA were collected at specific time points throughout the study. Validated or qualified assays were used to measure the concentrations of enrofloxacin ADC, total antibodies (TAb), and MMAE in serum or plasma. PK samples were collected and archived for possible analysis of concomitant drug levels or other enrofloxacin-related substances (such as circulating metabolites of MMAE). Validated assays were used to determine the ATA levels of enrofloxacin in plasma. PK and ATA samples for pembrolizumab were collected and archived for potential follow-up analysis of the EV+pembrolizumab group. (xii)Biomarker Assessment
在方案指定時間點收集周邊血液、尿液及腫瘤生檢。在研究治療之前及期間監測與反應、抗性或安全性觀測結果相關之探索性、預測性及預後生物標記物。使用在RC+PLND獲得之腫瘤樣品(針對MIBC組分)以表徵臨床作用機制及抗性。Peripheral blood, urine, and tumor biopsies were collected at protocol-specified time points. Exploratory, predictive, and prognostic biomarkers associated with response, resistance, or safety observations were monitored before and during study treatment. Tumor samples obtained at RC+PLND (for MIBC components) were used to characterize clinical mechanisms of action and resistance.
需要來自診斷性TURBT試樣及RC+PLND之腫瘤組織(細針抽吸不充分)鑑別新穎生物標記物。若進行額外處理後生檢作為SOC之部分，則樣品亦可用於進一步鑑別反應之生物標記物及作用機制及對治療之抗性。Tumor tissue from diagnostic TURBT specimens and RC+PLND (fine needle aspiration is not adequate) is needed to identify novel biomarkers. If additional post-processing testing is performed as part of the SOC, the samples can also be used to further identify biomarkers of response and mechanism of action and resistance to therapy.
腫瘤組織中之生物標記物評估可包括(但不限於)基因表現(GE)及突變負荷之量測、腫瘤微環境(TME)及腫瘤亞型之表徵及藥物效應。分析可包括(但不限於)連接素-4及PD-L1之免疫組織化學(IHC)以及RNA及DNA之下一代定序(NGS)。血液樣品中之生物標記物評估可包括(但不限於)量測循環血細胞亞群中之基線及藥物誘導之變化、免疫分析及循環疾病標記物。血液及尿液分析可包括(但不限於)循環腫瘤DNA、蛋白質體方法(諸如，酶聯結免疫吸附分析(ELISA))、免疫分析作為腫瘤反應或療法抗性之標記物，及免疫功能之標記物，包括免疫細胞亞群及細胞介素之豐度。Biomarker assessment in tumor tissue may include, but is not limited to, measurement of gene expression (GE) and mutational burden, characterization of tumor microenvironment (TME) and tumor subtypes, and drug effects. Analysis may include, but is not limited to, immunohistochemistry (IHC) for nectin-4 and PD-L1, and next generation sequencing (NGS) for RNA and DNA. Biomarker assessment in blood samples may include, but is not limited to, measurement of baseline and drug-induced changes in circulating blood cell subsets, immunoassays, and circulating disease markers. Blood and urine analyses may include, but are not limited to, circulating tumor DNA, proteomic methods (e.g., enzyme-linked immunosorbent assay (ELISA)), immunoassays as markers of tumor response or resistance to therapy, and markers of immune function, including abundance of immune cell subsets and interleukins.
分析視情況存在之組織樣品提交之其他組織(例如，皮膚)中之生物標記物，包括藥物及藥品、核酸及蛋白質之組織含量，以研究與對治療之抗性或敏感性機制以及與治療相關之動態變化的可能關聯。分析方法包括IHC、DNA及RNA之NGS、T細胞受體β鏈定序、聚合酶鏈反應、流式細胞分析技術及免疫分析。 (xiii)其他評估Analysis of biomarkers in other tissues (e.g., skin) submitted as appropriate, including tissue levels of drugs and pharmaceuticals, nucleic acids, and proteins to study possible associations with mechanisms of resistance or sensitivity to therapy and dynamic changes associated with therapy. Analytical methods include IHC, NGS of DNA and RNA, T cell receptor β-chain sequencing, polymerase chain reaction, flow cytometry, and immunoassays. (xiii)Other Assessments
PRO評估包括一般及腫瘤學特異性QoL量測(分別為EuroQOL-5維[EQ 5D-5L]及歐洲癌症研究及治療組織[EORTC]核心QoL評估[QLQ C30])，以及關於疼痛之結果特異性PRO (簡要疼痛量表簡表(Brief Pain Inventory Short Form) [BPI-SF])。醫療資源利用(HRU)問卷亦旨在量測臨床試驗環境之外的臨床負擔。在第1天給藥之前、前3個週期每週一次及在研究之治療部分的剩餘時間每週期一次，在電子裝置(較佳報告媒介)上完成PRO評估。在給藥訪視日，在給藥之前完成評估。在各隨訪及各長期隨訪聯絡時完成PRO評估。僅當使用電子裝置不可行時，PRO評估才以紙質形式或由診所工作人員藉由電話進行報告。 (xiv)安全評估PRO assessments included general and oncology-specific QoL measures (EuroQOL-5 dimensions [EQ 5D-5L] and European Organization for Research and Treatment of Cancer [EORTC] Core QoL Assessment [QLQ C30], respectively), and outcome-specific PROs for pain (Brief Pain Inventory Short Form [BPI-SF]). A healthcare resource utilization (HRU) questionnaire was also designed to measure clinical burden outside of the clinical trial setting. PRO assessments were completed electronically (preferred reporting medium) prior to dosing on Day 1, weekly for the first 3 cycles, and weekly for the remainder of the treatment portion of the study. Assessments were completed prior to dosing on dosing visit days. PRO assessments were completed at each walk-in visit and at each extended walk-in contact. PRO assessments were reported in paper form or by telephone by clinic staff only when electronic devices were not feasible. (xiv)Safety Assessment
安全評估係基於經由安全監測方法所收集的資訊且包括來自所記錄AE (包括嚴重不良事件(SAE))、伴隨藥物治療、體檢結論、心臟監測及實驗室測試的資料。在研究過程中藉由SMC監測安全性。 (xv)統計方法(a)關鍵安全性終點分析Safety assessments were based on information collected through safety monitoring methods and included data from recorded AEs (including serious adverse events (SAEs)), concomitant medications, physical examination findings, cardiac monitoring, and laboratory tests. Safety was monitored during the study by the SMC. (xv)Statistical Methods (a) Key Safety Endpoint Analysis
安全性分析評估AE之類型、發生率、嚴重度、嚴重性及相關性，以及實驗室異常之類型、發生率及嚴重度。概述特別受關注之AE (AESI)的發生率、持續時間及消退。 (b)關鍵功效終點分析Safety analyses evaluated the type, incidence, severity, severity, and relevance of AEs, and the type, incidence, and severity of laboratory abnormalities. The incidence, duration, and resolution of AEs of special interest (AESIs) were summarized.(b) Key efficacy endpoint analyses
按組概述功效資料。Summarize efficacy data by group.
使用克洛珀-皮爾森方法(Clopper-Pearson methodology)，按組為FAS提供所觀測的根據RECIST 1.1版之ORR及95%信賴區間(CI)。The observed ORR and 95% confidence interval (CI) according to RECIST version 1.1 are provided for FAS by group using Clopper-Pearson methodology.
隨機分組：將患者分層且以1:1之比隨機分入EV單藥組或EV+派姆單抗組。分層因子為不存在或存在肝轉移及ECOG體能狀態(0相對於1/2)。 (b)樣本大小Randomization: Patients were stratified and randomly assigned in a 1:1 ratio to EV monotherapy or EV + pembrolizumab. Stratification factors were the absence or presence of liver metastasis and ECOG performance status (0 vs. 1/2).(b) Sample size
將約150名患者以1:1之比隨機分組以接受恩諾單抗維多汀單藥療法(EV單藥組)或恩諾單抗維多汀組合派姆單抗(EV+派姆單抗組)。Approximately 150 patients were randomized in a 1:1 ratio to receive either enroku vedotin monotherapy (EV monotherapy group) or enroku vedotin combined with pembrolizumab (EV+pembrolizumab group).
樣本大小並非基於正式假設檢定之檢定力計算，而是基於藉由95% CI表徵的ORR之估計的精確度而選擇。未執行隨機分組研究之2個組之間的正式統計比較。The sample size was not chosen based on power calculations for formal hypothesis testing but rather on the precision of the estimate of the ORR as represented by the 95% CI. No formal statistical comparisons between the 2 arms of the randomizedstudy were performed.
對於每組75名患者之樣本大小，假定ORR在50%與70%之間，雙邊95% CI概述於下表9中。 表9 Ci概述
總共約150名患者入選研究。6.1.3目標A total of approximately 150 patients were enrolled in the study.6.1.3Objectives
主要目標Main objectives
主要目標為評估恩諾單抗維多汀單藥療法或恩諾單抗維多汀組合派姆單抗之抗腫瘤活性，根據RECIST 1.1版BICR以ORR量測。The primary objective was to evaluate the antitumor activity of enrofloxacin monotherapy or enrofloxacin in combination with pembrolizumab, measured by ORR according to RECIST version 1.1 BICR.
次要目標包括：• 藉由研究者評估，根據RECIST 1.1版評估ORR， • 藉由BICR及研究者評估，根據RECIST 1.1版評估DOR， • 藉由BICR及研究者評估，根據RECIST 1.1版評估DCR， • 藉由BICR及研究者評估，根據RECIST 1.1版評估研究療法之PFS， • 評估OS， • 評估恩諾單抗維多汀單藥療法或恩諾單抗維多汀組合派姆單抗之安全性及耐受性，Secondary objectives include: • ORR by investigator assessment according to RECIST version 1.1, • DOR by BICR and investigator assessment according to RECIST version 1.1, • DCR by BICR and investigator assessment according to RECIST version 1.1, • PFS of study therapy by BICR and investigator assessment according to RECIST version 1.1, • Assess OS, • Assess the safety and tolerability of enrofloxacin monotherapy or enrofloxacin in combination with pembrolizumab,
其他目標包括：• 評估PK及ATA之發生率， • 評估連接素-4及PD-L1表現量， • 評估生物活性及疾病抗性之生物標記物及其與臨床結果量測之潛在關聯， • 藉由研究者評估來評估後續療法之PFS (PFS2)， • 自患者視角評估對QoL及症狀(包括疼痛)之影響，及 • 對於EV+派姆單抗組，藉由研究者評估根據iRECIST評估研究療法之ORR、DOR、DCR及PFS。Additional objectives include: • Assessment of the incidence of PK and ATA, • Assessment of nectin-4 and PD-L1 expression, • Assessment of biomarkers of biological activity and disease resistance and their potential association with clinical outcome measures, • Assessment of PFS with subsequent therapy (PFS2) by investigator assessment, • Assessment of the effect on QoL and symptoms (including pain) from the patient's perspective, and • For the EV+pembrolizumab group, assessment of ORR, DOR, DCR and PFS of study therapy according to iRECIST by investigator assessment.
終點End
主要終點Main destination
藉由BICR，根據RECIST 1.1版之ORR (確認)。ORR according to RECIST version 1.1 by BICR (confirmed).
次要終點• 藉由研究者評估，根據RECIST 1.1版之ORR (確認)， • 藉由BICR，根據RECIST 1.1版之DOR， • 藉由研究者評估，根據RECIST 1.1版之DOR， • 藉由BICR，根據RECIST 1.1版之DCR， • 藉由研究者評估，根據RECIST 1.1版之DCR， • 藉由BICR，根據RECIST 1.1版之PFS， • 藉由研究者，根據RECIST 1.1版之PFS， • OS， • AE的類型、發生率、嚴重度、嚴重性及相關性，及 • 實驗室異常的類型、發生率及嚴重度，Secondary endpoints : • ORR (confirmed) according to RECIST version 1.1 by investigator assessment, • DOR according to RECIST version 1.1 by BICR, • DOR according to RECIST version 1.1 by investigator assessment, • DCR according to RECIST version 1.1 by BICR, • DCR according to RECIST version 1.1 by investigator assessment, • PFS according to RECIST version 1.1 by BICR, • PFS according to RECIST version 1.1 by investigator, • OS, • Type, incidence, severity, severity, and relevance of AEs, and • Type, incidence, and severity of laboratory abnormalities,
其他終點• 恩諾單抗維多汀、MMAE及Tab的所選血漿或血清PK參數， • 針對恩諾單抗維多汀之ATA的發生率， • 臨床活性之探索性生物標記物，包括連接素-4表現及PD-L1表現狀態與反應的關係， • 藉由研究者評估之PFS2， • EQ-5D-5L、EORTC QLQ-C30及BPI-SF之PRO評估相對於基線的變化，及 • 對於EV+派姆單抗組：(1)藉由研究者評估，根據iRECIST之ORR (確認)；(2)藉由研究者評估，根據iRECIST之DOR；(2)藉由研究者評估，根據iRECIST之DCR；及(4)藉由研究者評估，根據iRECIST之PFS。6.1.4研究計劃6.1.4.1研究設計之概述Other endpoints : • Selected plasma or serum PK parameters of enrofloxacin, MMAE, and Tab, • The incidence of ATA for enrofloxacin, • Exploratory biomarkers of clinical activity, including association of nectin-4 expression and PD-L1 expression status with response, • PFS2 as assessed by investigator, • Changes from baseline in PRO assessments of EQ-5D-5L, EORTC QLQ-C30, and BPI-SF, and • For the EV+pembrolizumab group: (1) ORR according to iRECIST as assessed by investigator (confirmed); (2) DOR according to iRECIST as assessed by investigator; (3) DCR according to iRECIST as assessed by investigator; and (4) PFS according to iRECIST as assessed by investigator.6.1.4Research Plan6.1.4.1Overview of Research Design
此研究經設計以評估恩諾單抗維多汀作為單藥療法或組合派姆單抗用於治療la/mUC患者之安全性及抗腫瘤活性。This study was designed to evaluate the safety and antitumor activity of enrofloxacin as monotherapy or in combination with pembrolizumab in patients with la/mUC.
此研究包括2個治療組，以1:1之比隨機分入恩諾單抗維多汀單藥療法或恩諾單抗維多汀組合派姆單抗。參見圖2。This study included 2 treatment groups, which were randomly assigned in a 1:1 ratio to either enroku monotherapy or enroku combined with pembrolizumab. SeeFigure2 .
所有患者均接受恩諾單抗維多汀(正在研究的研究藥劑)，其在每3週週期之第1天及第8天以IV輸注形式投與。All patients received enrofloxacin (an investigational agent under investigation) as an IV infusion on Days 1 and 8 of each 3-week cycle.
每3個週期(自第1週期第1天起每9週[±1週])藉由胸部、腹部及骨盆之CT (使用IV造影劑)評估反應。若造影劑禁忌，則請參閱當前的影像擷取指南(章節6.1.13)以獲得較佳掃描及造影選擇。根據RECIST 1.1版(Eisenhauer 2009) (參見表40)確認客觀反應，在第一次記錄反應後至少4週重複掃描(需要在4至5週進行掃描)。後續反應評估根據初始時程每9週(±1週)執行，自第1週期第1天起，直至第一次給藥後1年，隨後每12週(±1週)進行。每當懷疑疾病惡化時，亦應執行腫瘤成像。Assess response by CT (with IV contrast) of the chest, abdomen, and pelvis every 3 cycles (every 9 weeks [±1 week] starting on Cycle 1 Day 1). If contrast is contraindicated, refer to current image acquisition guidelines (Section 6.1.13) for optimal scan and contrast selection. Confirm objective response according to RECIST version 1.1 (Eisenhauer 2009) (see Table 40), with scans repeated at least 4 weeks after the first documented response (scans at 4 to 5 weeks are required). Subsequent response assessments are performed according to the initial schedule every 9 weeks (±1 week), starting on Cycle 1 Day 1, until 1 year after the first dose, and then every 12 weeks (±1 week). Tumor imaging should also be performed whenever disease progression is suspected.
患者繼續接受研究治療，直至以放射照相方式確認疾病惡化、不可接受的毒性、研究者決定、撤回同意書、開始後續抗癌療法、妊娠或試驗委託者終止研究。一旦患者接受了35次派姆單抗投藥(約2年)，則中止派姆單抗治療。Patients continued to receive study treatment until radiographically confirmed disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, initiation of subsequent anticancer therapy, pregnancy, or study termination by trial sponsors. Pembrolizumab treatment was discontinued once patients had received 35 doses of pembrolizumab (approximately 2 years).
在研究治療期間，對未惡化之非目標骨病灶進行的姑息性放射治療不視為後續抗癌療法；然而，對任何目標病灶之放射治療均為後續抗癌療法。根據iRECIST指南(Seymour 2017) (章節6.1.15)在療法中具有iUPD之患者繼續接受研究治療，直至由研究者在iUPD後4至9週利用後續掃描確認惡化(iCPD)。Palliative radiation therapy to non-target bone lesions that did not worsen during study treatment was not considered subsequent anticancer therapy; however, radiation therapy to any target lesion was considered subsequent anticancer therapy. Patients with iUPD on therapy continued on study treatment until investigator-confirmed progression (iCPD) using a follow-up scan 4 to 9 weeks after iUPD according to iRECIST guidelines (Seymour 2017) (Section 6.1.15).
出於除以放射照相方式確認疾病惡化或撤回同意書之外的原因中止研究治療之患者在前一次反應評估掃描後每9週(±1週)繼續接受反應評估，直至第一次給藥後1年，隨後每12週(±1週)接受反應評估。掃描一直進行到研究者確定EV單藥組之患者根據RECIST 1.1版具有放射學確認的PD、開始後續抗癌療法、死亡、研究結束或患者撤回同意書，以先發生者為準。Patients who discontinued study treatment for reasons other than radiographically confirmed disease progression or withdrawal of consent continued to receive response assessments every 9 weeks (±1 week) after the previous response assessment scan until 1 year after the first dose and every 12 weeks (±1 week) thereafter. Scans were performed until the investigator determined that a patient in the EV monotherapy group had radiographically confirmed PD according to RECIST version 1.1, started subsequent anticancer therapy, died, ended the study, or the patient withdrew consent, whichever occurred first.
在研究治療時或之後發生惡化及研究治療中止後，每12週(±1週)隨訪患者以獲得關於後續抗癌療法之資訊，且評估存活狀態直至死亡、研究結束或患者撤回同意書，以先發生者為準。關於研究中之患者流程圖，參見圖3。After progression on or after study treatment and discontinuation of study treatment, patients were followed every 12 weeks (±1 week) to obtain information on subsequent anticancer therapy, and survival status was assessed until death, study completion, or patient withdrawal of consent, whichever occurred first. SeeFigure3 for a flow chart of patients in the study.
在開始後續抗癌療法後或在研究治療時或之後根據RECIST 1.1版(EV單藥組)或根據iRECIST (EV+派姆單抗組)以放射學方式確認疾病惡化(藉由研究者評估)後，根據機構指南經由成像對患者進行隨訪，但頻率不低於每12週一次，直至記錄到PFS2或患者開始另一抗癌治療，以先發生者為準。所有後續抗癌療法(包括PFS2惡化日期)均記錄在病例報告表(CRF)上。另外，治療結束(EOT)後每12週(±1週)聯絡患者一次，以瞭解後續療法時或之後的存活狀態及臨床惡化狀態。在PFS2之後，患者進入存活隨訪期，且每12週(±1週)隨訪一次存活狀態直至死亡、研究結束或撤回同意書，以先發生者為準。每週期完成患者報告的結果評估(QLQ-C-30、EQ-5D-5L、BPI-SF、HRU)。Patients were followed by imaging according to institutional guidelines, but no less frequently than every 12 weeks, until PFS2 was documented or the patient started another anticancer treatment, whichever occurred first, after starting subsequent anticancer therapy or after radiologically confirmed disease worsening (by investigator assessment) according to RECIST version 1.1 (EV monotherapy group) or iRECIST (EV+pembrolizumab group) during or after study treatment. All subsequent anticancer therapies (including the date of PFS2 deterioration) were recorded on the case report form (CRF). In addition, patients were contacted every 12 weeks (±1 week) after the end of treatment (EOT) to understand survival status and clinical deterioration status at or after subsequent therapy. After PFS2, patients entered the survival follow-up period and were followed up every 12 weeks (±1 week) for survival status until death, end of study, or withdrawal of consent, whichever occurred first. Patient-reported outcome assessments (QLQ-C-30, EQ-5D-5L, BPI-SF, HRU) were completed every cycle.
在EV+派姆單抗組中，經歷僅可歸因於派姆單抗之不可接受的毒性的患者繼續接受恩諾單抗維多汀單藥療法，直至以放射照相方式確認疾病惡化、不可接受的毒性、研究者決定、撤回同意書、開始後續抗癌療法、妊娠或試驗委託者終止研究。EV+派姆單抗組中經歷僅可歸因於恩諾單抗維多汀之毒性的患者繼續接受派姆單抗單藥療法(至多35個週期)，直至疾病惡化、不可接受的毒性、研究者決定、撤回同意書、開始後續抗癌療法、妊娠或試驗委託者終止研究。In the EV+pembrolizumab group, patients who experienced unacceptable toxicity attributable solely to pembrolizumab continued to receive enrofloxacin monotherapy until radiographically confirmed disease worsening, unacceptable toxicity, investigator decision, withdrawal of consent, initiation of subsequent anticancer therapy, pregnancy, or study discontinuation by trial sponsors. Patients in the EV+pembrolizumab group who experienced toxicity attributable solely to enrofloxacin continued to receive pembrolizumab monotherapy (up to 35 cycles) until disease worsening, unacceptable toxicity, investigator decision, withdrawal of consent, initiation of subsequent anticancer therapy, pregnancy, or study discontinuation by trial sponsors.
在研究過程中藉由SMC監測安全性，以確定是否出現任何新的安全性信號表明此並非可耐受的組合或時程(參見章節6.1.4.1)。藉由受限制的SMC持續監測安全性。Safety was monitored by the SMC during the study to determine if any new safety signals emerged that indicated that the combination or schedule was not tolerated (see Section 6.1.4.1). Safety was monitored continuously by a restricted SMC.
不存在派姆單抗之劑量遞增或降低。There was no dose escalation or reduction of pembrolizumab.
將約150名不適合基於順鉑之化學療法且先前未接受過針對局部晚期或轉移性疾病之全身治療的患者藉由不存在或存在肝轉移及ECOG體能狀態(0相對於1/2)進行分層，且以1:1之比隨機分組以接受恩諾單抗維多汀單藥療法(EV單藥組)或恩諾單抗維多汀組合派姆單抗(EV+派姆單抗組)。 • EV單藥組包括約75名患者。患者在各3週週期之第1天及第8天接受恩諾單抗維多汀(1.25 mg/kg IV)。 • EV+派姆單抗組包括約75名患者。患者在第1天接受恩諾單抗維多汀(1.25 mg/kg IV)，隨後為派姆單抗(200 mg IV)，且在各3週週期之第8天投與單獨的恩諾單抗維多汀。投與派姆單抗至多總共35個週期。Approximately 150 patients who were ineligible for cisplatin-based chemotherapy and had not received prior systemic therapy for locally advanced or metastatic disease were stratified by the absence or presence of liver metastases and ECOG performance status (0 vs. 1/2) and randomized 1:1 to receive enrofloxacin monotherapy (EV monotherapy group) or enrofloxacin in combination with pembrolizumab (EV+pembrolizumab group).• The EV monotherapy group included approximately 75 patients. Patients received enrofloxacin (1.25 mg/kg IV) on days 1 and 8 of each 3-week cycle.• The EV+pembrolizumab group included approximately 75 patients. Patients received enrofloxacin (1.25 mg/kg IV) on day 1, followed by pembrolizumab (200 mg IV), and enrofloxacin alone was administered on day 8 of each 3-week cycle. Pembrolizumab was administered for up to a total of 35 cycles.
藉由受限制的SMC持續監測安全性。6.1.4.2研究設計之討論及基本原理Safety was continuously monitored through restricted SMC.6.1.4.2Discussion and rationale of study design
恩諾單抗維多汀+派姆單抗相對於恩諾單抗維多汀之評估使得可產生關於當前組合的額外資料，以及提供關於在一線情況下不適合順鉑的la/mUC患者中來自恩諾單抗維多汀單藥療法之活性貢獻的資訊。隨機分組確保各組中之患者的基線特徵可比。Evaluation of enroku + pembrolizumab versus enroku alone allows for the generation of additional data on the current combination and provides information on the contribution of activity from enroku monotherapy in patients with la/mUC who are not candidates for cisplatin in the first-line setting. Randomization ensured that the baseline characteristics of patients in each group were comparable.
(i)將患者分配至治療組之方法(i) Methods of assigning patients to treatment groups
將患者藉由不存在或存在肝轉移及ECOG體能狀態(0相對於1/2)分層，且基於章節6.1.8.3中詳述之分層因子以1:1之比隨機分入EV單藥組或EV+派姆單抗組。 (ii)盲法Patients were stratified by the absence or presence of liver metastases and ECOG performance status (0 vs. 1/2) and randomly assigned in a 1:1 ratio to EV alone or EV + pembrolizumab based on the stratification factors detailed in Section 6.1.8.3.(ii) Blind method
此為開放標記研究。6.1.5研究群體6.1.5.1納入準則This is an open label study.6.1.5Study population6.1.5.1Inclusion criteria
患者必須患有組織學記錄的局部晚期或轉移性尿路上皮(先前稱為移行細胞)癌(亦即，膀胱癌、腎盂癌、輸尿管癌或尿道癌)。具有鱗狀分化或混合細胞類型的患者符合條件。患有可以治癒意圖進行切除之局部晚期疾病的患者不符合條件。Patients must have histologically documented locally advanced or metastatic urothelial (formerly transitional cell) carcinoma (ie, bladder, renal pelvis, ureter, or urethra). Patients with squamous differentiation or mixed cell types are eligible. Patients with locally advanced disease that can be resected with curative intent are not eligible.
患者必須符合CPI療法條件。Patients must meet the CPI treatment criteria.
患者在入選時必須由於以下準則中之至少1者而不適合基於順鉑之化學療法： • 腎小球濾過率(GFR)＜60 mL/min但≥30 mL/min (藉由科克羅夫特-高爾特公式、腎病膳食改良[MDRD]或24小時尿液量測) • ECOG體能狀態為2 (關於ECOG 2個體之額外準則，參考納入準則#6) • NCI CTCAE 4.03版≥2級聽力損失 • NYHA III級心臟衰竭 患者先前不得接受針對局部晚期或轉移性疾病之全身治療。患者在隨機分組之前12個月內不可先前接受過輔助/前輔助基於鉑之療法。Patients must be ineligible for cisplatin-based chemotherapy at the time of inclusion due to at least 1 of the following criteria:• Glomerular filtration rate (GFR) <60 mL/min but ≥30 mL/min (by Cockcroft-Gault formula, Modification of Diet in Renal Disease [MDRD], or 24-hour urine measurement)• ECOG performance status 2 (for additional criteria for ECOG 2 individuals, see inclusion criteria #6)• NCI CTCAE version 4.03 grade 2 hearing loss ≥2• NYHA class III heart failurePatients must not have received prior systemic therapy for locally advanced or metastatic disease. Patients must not have received prior adjuvant/pre-adjuvant platinum-based therapy within 12 months prior to randomization.
最小年齡為18歲。Minimum age is 18 years old.
患者必須患有根據RECIST 1.1版(Eisenhauer等人, Eur. J. Cancer (2009); 45(2): 228-47)之可量測疾病。先前照射區域中的病灶必須已惡化至視為可量測的。Patients must have measurable disease according to RECIST version 1.1 (Eisenhauer et al., Eur. J. Cancer (2009); 45(2): 228-47). Lesions in previously irradiated areas must have progressed to be considered measurable.
ECOG體能狀態為0、1或2。 • ECOG體能狀態為2之個體必須另外符合以下準則： i.血紅素≥ 10 g/dL ii. GFR ≥ 50 mL/min iii.不可具有NYHA III級心臟衰竭ECOG performance status is 0, 1, or 2.• Individuals with ECOG performance status of 2 must also meet the following criteria:i. Hemoglobin ≥ 10 g/dLii. GFR ≥ 50 mL/miniii. Must not have NYHA class III heart failure
如研究者所評估，≥3個月的預期壽命。Life expectancy of ≥3 months as assessed by the investigator.
具有如表10中所定義之足夠的器官功能。必須在開始研究治療之前7天內收集試樣。 表10足夠的器官功能定義
具有生育潛力之女性個體係已經歷初潮且未進行手術絕育(例如，子宮切除術、雙側輸卵管切除術、雙側卵巢切除術)或尚未完成停經之任何出生為女性的人。停經在臨床上定義為45歲以上的人在不存在其他生物學、生理或藥理學病因之情況下閉經12個月。具有生育潛力之女性個體必須符合以下條件： • 同意在研究期間及最後一次劑量之研究藥物之後的至少6個月內不嘗試懷孕。 • 在第1天之前3天內必須具有陰性尿液或血清妊娠測試(最低敏感性25 mIU/mL或等效單位的β人類絨毛膜激性腺素[β-hCG])。具有假陽性結果且陰性妊娠狀態記錄驗證的女性個體有資格入選。 • 若異性戀活躍，則必須始終使用高效的生育控制方法，其中在篩選開始、整個研究時段且在最後一次劑量之研究藥物之後至少6個月失敗率低於1% (如章節6.1.14中所描述)。 • 女性個體必須同意在篩選開始及整個研究時段且在最後一次劑量之研究藥物之後至少6個月不哺乳或捐獻卵。Female subjects of childbearing potential are any natal female who has experienced menarche and has not undergone surgical sterilization (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has not completed menopause. Menopause is clinically defined as the absence of menstruation for 12 months in the absence of other biological, physiological, or pharmacological causes in individuals 45 years of age or older. Female subjects of childbearing potential must meet the following criteria: • Agree not to attempt pregnancy during the study and for at least 6 months after the last dose of study drug. • Must have a negative urine or serum pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) within 3 days prior to Day 1. Female subjects with a false-positive result verified by documented negative pregnancy status are eligible.• If heterosexually active, must use a highly effective method of birth control with a failure rate of less than 1% at screening, throughout the study, and for at least 6 months after the last dose of study drug (as described in Section 6.1.14).• Female subjects must agree not to breastfeed or donate eggs at screening, throughout the study, and for at least 6 months after the last dose of study drug.
可生育兒童之男性個體係具有睪丸且尚未進行手術絕育(例如，輸精管結紮，接著進行臨床測試證明該手術有效)之任何出生為男性的人。可生育兒童之男性個體必須符合以下條件： • 在篩選時開始及整個研究時段，以及最後一次劑量之研究藥物之後至少6個月，不得捐獻精子。男性個體被告知研究治療對生殖功能及生育力的負面風險。在治療之前，應建議男性個體尋求關於生育力保存及精子低溫保存之資訊。 • 必須始終使用高效的生育控制方法，其中在篩選開始及整個研究時段繼續且在最後一次劑量之研究藥物之後至少6個月失敗率低於1% (如章節6.1.14中所描述)。 • 具有妊娠或哺乳配偶之男性個體必須在整個研究時段及最後一次劑量之研究藥物之後至少6個月始終使用2個避孕選項中之一者，以防止在妊娠期間或配偶哺乳期間二次暴露於精液(如章節6.1.14中所描述)。A male subject of reproductive potential is any person born male who has testicles and has not undergone surgical sterilization (e.g., vasectomy followed by clinical testing demonstrating that the procedure is effective). Male subjects of reproductive potential must meet the following criteria:• Must not donate sperm beginning at screening and throughout the study, and for at least 6 months after the last dose of study drug. Male subjects are informed of the negative risks of study treatment on reproductive function and fertility. Prior to treatment, male subjects should be advised to seek information about fertility preservation and sperm cryopreservation.• Must use a highly effective method of birth control with a failure rate of less than 1% at screening and throughout the study period and for at least 6 months after the last dose of study drug (as described in Section 6.1.14).• Male subjects with a pregnant or breastfeeding partner must use one of 2 contraceptive options throughout the study period and for at least 6 months after the last dose of study drug to prevent secondary exposure to semen during pregnancy or if the partner is breastfeeding (as described in Section 6.1.14).
患者必須提供書面知情同意書。6.1.5.2排除準則Patients must provide written informed consent.6.1.5.2Exclusion criteria
先前接受過CPI治療。CPI定義為PD-1抑制劑、PD-L1抑制劑或PD-L2抑制劑(包括(但不限於)阿特珠單抗、派姆單抗、納武單抗、德瓦魯單抗或阿維魯單抗)。Prior treatment with a CPI. CPIs were defined as PD-1 inhibitors, PD-L1 inhibitors, or PD-L2 inhibitors (including but not limited to atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab).
先前接受過任何針對另一刺激性或共抑制性T細胞受體之藥劑(包括(但不限於) CD137促效劑、CTLA 4抑制劑或OX-40促效劑)的治療。正在發生的2級或更高的感覺或運動神經病變。Prior treatment with any agent that targets another stimulatory or co-inhibitory T-cell receptor (including but not limited to CD137 agonists, CTLA 4 inhibitors, or OX-40 agonists). Ongoing Grade 2 or higher sensory or motor neuropathy.
活動性中樞神經系統[CNS]轉移。若所有以下內容皆為真，則容許CNS轉移經治療的患者參與研究： a. CNS轉移在篩選之前已臨床上穩定至少6週，且基線掃描未展示新轉移或擴大轉移的證據。 b.若需要類固醇治療CNS轉移，則患者服用穩定劑量＜10 mg/天之普賴松或等效物，持續至少2週。 c.患者未患軟腦膜疾病。Active central nervous system [CNS] metastases. Patients with treated CNS metastases were allowed to participate in the study if all of the following were true:a. The CNS metastases had been clinically stable for at least 6 weeks prior to screening, and baseline scans showed no evidence of new or enlarging metastases.b. If steroids were required for CNS metastases, patients were on a stable dose of <10 mg/day of prazosin or equivalent for at least 2 weeks.c. Patients did not have meningeal disease.
正在發生的與先前治療(包括放射治療或手術)相關的臨床顯著毒性(2級或更高)。Ongoing clinically significant toxicity (grade 2 or higher) related to prior treatment (including radiation therapy or surgery).
不包括患有需要高劑量類固醇(＞10 mg/天普賴松或等效物)或其他免疫抑制性藥品之病狀的患者。在不存在活動性自體免疫性疾病的情況下，允許吸入或局部類固醇。Patients with conditions requiring high-dose steroids (>10 mg/day of prazosin or equivalent) or other immunosuppressive medications were excluded. Inhaled or topical steroids were permitted in the absence of active autoimmune disease.
先前使用恩諾單抗維多汀或其他基於MMAE之ADC治療尿路上皮癌。Previous treatment of urothelial carcinoma with enrofloxacin or other MMAE-based ADCs.
個體在第一次給與研究藥物之前的3年內具有另一侵襲性惡性腫瘤的病史，或先前診斷之惡性疾病之殘留疾病的任何證據。允許患有非黑色素瘤皮膚癌或任何類型之原位癌(若進行完全切除術)之個體。Subjects with a history of another invasive malignancy within 3 years prior to the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Subjects with non-melanoma skin cancer or any type of carcinoma in situ (if completely excised) were permitted.
在進入研究前至少1年以明確意圖(以手術方式或用放射療法)治療之前列腺癌(T2NXMX或更低，其中格里森評分≤7)的病史為可接受的，其限制條件為個體視為無前列腺癌，且滿足以下準則： a.經歷根除性前列腺切除術之參與者必須具有不可偵測之PSA持續＞1年且在篩選具有不可偵測之PSA。 b.接受過放射之參與者的PSA倍增時間必須＞1年(基於至少3個相隔＞1個月確定的值)且總PSA值不滿足生物化學復發之菲尼克斯準則(亦即，高於最低點＜2.0 ng/mL)。A history of prostate cancer (T2NXMX or lower with a Gleason score ≤7) treated with explicit intent (surgery or with radiation) at least 1 year prior to study entry was acceptable, provided that the individual was considered free of prostate cancer and met the following criteria:a. Participants who had undergone radical prostatectomy must have an undetectable PSA for >1 year and an undetectable PSA at screening.b. Participants who had received radiation must have a PSA doubling time >1 year (based on at least 3 values determined >1 month apart) and a total PSA value that did not meet the Phoenix criteria for biochemical recurrence (i.e., <2.0 ng/mL above nadir).
主動監測的患有未經治療的低風險前列腺癌(格里森評分≤6)且PSA倍增時間＞1年(基於至少3個相隔＞1個月的值)的參與者亦符合條件。Participants on active surveillance with untreated low-risk prostate cancer (Gleason score ≤ 6) and a PSA doubling time > 1 year (based on at least 3 values separated by > 1 month) were also eligible.
在恩諾單抗維多汀首次給與時，當前針對活動性感染(病毒、細菌或真菌)接受全身抗微生物治療。允許常規的抗微生物預防。Current systemic antimicrobial therapy for active infection (viral, bacterial, or fungal) at the time of first dose of enrofloxacin. Routine antimicrobial prophylaxis is permitted.
B型肝炎表面抗原及/或抗B型肝炎核心抗體陽性患者；允許聚合酶鏈反應(PCR)分析呈陰性的患者進行普遍預防或使用先發性方法。該方法根據接受抗癌療法之患者的地區或國家指南選擇。Patients who are positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody; patients who are negative by polymerase chain reaction (PCR) analysis are allowed to proceed with universal prophylaxis or use a preemptive approach. The approach is selected according to regional or national guidelines for patients receiving anticancer therapy.
活動性C型肝炎感染或已知的人類免疫缺乏病毒(HIV)感染。若已針對C型肝炎感染接受治療性治療的患者已記錄有12週的持續病毒學反應，則該等患者被允許。除非當地衛生當局強制要求，否則不需要HIV測試。Active hepatitis C infection or known human immunodeficiency virus (HIV) infection. Patients who have been receiving therapeutic treatment for hepatitis C infection are allowed if they have documented a sustained virologic response for 12 weeks. HIV testing is not required unless mandated by local health authorities.
具有活動性肺結核之患者。Patients with active pulmonary tuberculosis.
在第一次給與恩諾單抗維多汀之前的6個月內記錄有腦血管事件(中風或短暫局部缺血發作)、不穩定型心絞痛、心肌梗塞或符合NYHA IV級(參見章節6.1.11)之心臟症狀(包括充血性心臟衰竭)的病史。允許具有NYHA III級之患者。Documented history of cerebrovascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with NYHA class IV (see section 6.1.11) (including congestive heart failure) within 6 months before the first dose of enrofloxacin. Patients with NYHA class III are permitted.
在研究藥物第一次給與之前的2週內接受過放射治療或大手術。在開始研究治療之前，患者必須已自干預之毒性及/或併發症充分恢復。Radiation therapy or major surgery within 2 weeks prior to the first dose of study drug. Patients must have adequately recovered from toxicity and/or complications of the intervention before starting study treatment.
在第一次給與研究藥物之前4週未完成的化學療法、生物製劑或排除準則2號未另外禁止的研究性藥劑治療。Uncompleted chemotherapy, biologics, or treatment with investigational agents not otherwise prohibited by Exclusion Criterion 2 4 weeks prior to the first dose of study drug.
已知對恩諾單抗維多汀或對恩諾單抗維多汀藥物調配物中所含的任何賦形劑(包括組胺酸、二水合海藻糖，及聚山梨醇酯20)重度(≥3級)超敏反應。已知對派姆單抗或對派姆單抗藥物調配物中所含的任何賦形劑重度(≥3級)超敏反應。Known severe (≥Grade 3) hypersensitivity reaction to enrofloxacin or to any excipient contained in the enrofloxacin drug formulation (including histidine, trehalose dihydrate, and polysorbate 20). Known severe (≥Grade 3) hypersensitivity reaction to pembrolizumab or to any excipient contained in the pembrolizumab drug formulation.
出現活動性角膜炎或角膜潰瘍的患者。出現淺表性點狀角膜炎的患者若在研究者看來，其病症得到充分治療，則係允許的。Patients with active keratitis or corneal ulcers. Patients with superficial punctate keratitis were permitted if, in the investigator's opinion, their condition was adequately treated.
具有在過去2年內需要進行全身治療(亦即，使用疾病調節劑、皮質類固醇或免疫抑制性藥物)之活動性自體免疫性疾病。替代療法(例如針對腎上腺或垂體機能不全之甲狀腺素、胰島素或生理皮質類固醇替代療法)不視為全身治療形式且予以允許。Active autoimmune disease requiring systemic treatment (i.e., use of disease modifying agents, corticosteroids, or immunosuppressive drugs) within the past 2 years. Alternative therapies (e.g., thyroid hormone, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) are not considered a form of systemic treatment and are permitted.
特發性肺纖維化病史；機化性肺炎、藥物誘導之肺炎、特發性肺炎或篩檢胸部CT掃描時活動性肺炎之證據。History of idiopathic pulmonary fibrosis; evidence of organizing pneumonia, drug-induced pneumonia, idiopathic pneumonia, or active pneumonia on screening chest CT scan.
先前同種異體幹細胞或實體器官移植。Previous allogeneic stem cell or solid organ transplantation.
在第一次給與研究藥物之前的30天內投與減毒活疫苗。活疫苗之實例包括(但不限於)以下：麻疹、流行性腮腺炎、風疹、水痘/帶狀疱疹(雞痘)、黃熱病、狂犬病、BCG及傷寒疫苗。用於注射之季節性流感疫苗一般為滅活病毒疫苗且予以允許；然而，鼻內流感疫苗(例如FluMist®)為減毒活疫苗且不予允許。Live attenuated vaccines were administered within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccines. Seasonal influenza vaccines for injection are generally killed virus vaccines and are permitted; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not permitted.
在研究者看來，損害患者接受或耐受計劃治療及隨訪能力的其他潛在醫學病狀；任何已知的會干擾配合研究要求的精神或物質濫用障礙。Other potential medical conditions that, in the opinion of the investigator, impair the patient's ability to receive or tolerate planned treatment and follow-up visits; Any known psychiatric or substance abuse disorder that would interfere with compliance with the study requirements.
糖尿病不可控的患者。不可控的糖尿病定義為血紅素A1c (HbA1c) ≥8%或HbA1c 7%至＜8%與不另說明的相關糖尿病症狀(多尿症或煩渴症)。6.1.6治療6.1.6.1所投與之治療Patients with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥8% or HbA1c 7% to <8% and related diabetes symptoms not otherwise specified (polyuria or thirst).6.1.6Treatment6.1.6.1Treatment administered
此研究中之患者(EV單藥組或EV+派姆單抗組)在每3週週期之第1天及第8天接受以IV輸注形式經30分鐘投與的1.25 mg/kg恩諾單抗維多汀。Patients in this study (EV alone or EV + pembrolizumab) received 1.25 mg/kg of enrofloxacin as an IV infusion over 30 minutes on Days 1 and 8 of each 3-week cycle.
在各3週週期之第1天，在恩諾單抗維多汀完成後約30分鐘以IV輸注形式經30分鐘投與派姆單抗200 mg (若隨機分入EV+派姆單抗組)。6.1.6.2研究性研究藥物(i)描述-恩諾單抗維多汀On Day 1 of each 3-week cycle, pembrolizumab 200 mg was administered as an IV infusion over 30 minutes approximately 30 minutes after completion of enrofloxacin (if randomized to EV+pembrolizumab).6.1.6.2Investigational Study Drug (i)Description-Enrofloxacin
藉由使含有MMAE與連接子亞單元的化學中間物與抗體之半胱胺酸殘基結合來產生恩諾單抗維多汀。所得ADC含有平均3.8個藥物分子/抗體。恩諾單抗維多汀藥品為無菌、無防腐劑的白色至灰白色凍乾粉末，經復原以供IV投與。恩諾單抗維多汀於30 mg單次劑量小瓶中供應。 (ii)劑量及投藥Enromax is produced by conjugating a chemical intermediate containing MMAE and a linker subunit to a cysteine residue of an antibody. The resulting ADC contains an average of 3.8 drug molecules per antibody. Enromax drug product is a sterile, preservative-free, white to off-white lyophilized powder that is reconstituted for IV administration. Enromax is supplied in a 30 mg single-dose vial. (ii)Dosage and Administration
在每3週週期之第1天及第8天，經約30分鐘以IV輸注形式投與恩諾單抗維多汀。Enrotumab vedotin is administered as an IV infusion over approximately 30 minutes on Days 1 and 8 of each 3-week cycle.
在不存在IRR下，應計算所有患者之輸注速率，以達成大致30分鐘輸注時段。恩諾單抗維多汀不得以IV推注或彈丸注射形式投與。恩諾單抗維多汀不應與其他藥品混合。恩諾單抗維多汀的劑量必須間隔至少1週(7天)。In the absence of an IRR, the infusion rate for all patients should be calculated to achieve an approximate 30-minute infusion period. Enrotumab vedotin should not be administered as an IV push or bolus. Enrotumab vedotin should not be mixed with other medicinal products. Doses of Enrotumab vedotin must be spaced at least 1 week (7 days) apart.
基於基線時患者實際體重計算恩諾單抗維多汀劑量。當患者體重變化≥基線或前一個週期的10%，或滿足劑量調整準則時，應重新計算劑量。使用實際重量，體重＞100 kg之患者除外；在此類情況下，基於100 kg之體重計算劑量。此研究中允許之最大劑量為125 mg。Enromax vedotin doses were calculated based on the patient's actual weight at baseline. Dosages should be recalculated when the patient's weight changes by ≥10% from baseline or the previous period, or when the dose adjustment criteria are met. Actual weight was used, except for patients weighing >100 kg; in these cases, doses were calculated based on a body weight of 100 kg. The maximum dose allowed in this study was 125 mg.
對於體重相對於基線或前一週期的變化≥10%的患者，必須調整劑量。患者體重在如事件時程中所描述之所有相關評估窗期間量測，且另外根據機構標準(若適用)進行量測。體重變化＜10%時，允許根據機構標準進行其他劑量調整。Dose adjustments must be made for patients with a change in body weight of ≥10% from baseline or the previous period. Patient weight was measured during all relevant assessment windows as described in the event schedule and additionally according to institutional criteria, if applicable. Other dose adjustments based on institutional criteria were permitted for weight changes <10%.
在恩諾單抗維多汀投與期間應觀測患者，且在前3個週期期間，在輸注之後觀測患者至少60分鐘。根據機構標準，應在整個研究中給與符合最佳患者照護之所有支持性措施。Patients should be observed during enrofloxacin administration and for at least 60 minutes after infusion during the first 3 cycles. All supportive measures consistent with optimal patient care should be administered throughout the study, per institutional standards.
在投與期間及投與後之任何時間，應密切監測輸注部位之發紅、腫脹、疼痛及感染情況。應建議患者在投與時或輸注之後即時報告發紅或不適。遵循機構指南投與化學治療劑，且按照機構標準及如「Chemotherapy and Biotherapy Guidelines and Recommendations for Practice」(Polovich 2014)及「Management of Chemotherapy Extravasation: ESMO-EONS Clinical Practice Guidelines」(Perez Fidalgo 2012)中所描述採取預防措施防止外滲。在恩諾單抗維多汀外滲之情況下，應暫停組合藥物，直至與醫學監測者/試驗委託者協商及進一步討論。 (iii)恩諾單抗維多汀之劑量修改The infusion site should be closely monitored for redness, swelling, pain, and infection at all times during and after administration. Patients should be advised to promptly report redness or discomfort during or after administration. Administer chemotherapy according to institutional guidelines and take precautions to prevent extravasation as described in institutional standards and as described in “Chemotherapy and Biotherapy Guidelines and Recommendations for Practice” (Polovich 2014) and “Management of Chemotherapy Extravasation: ESMO-EONS Clinical Practice Guidelines” (Perez Fidalgo 2012). In the event of extravasation of enrofloxacin, the combination medication should be withheld until consultation and further discussion with the Medical Monitor/Trial Sponsor. (iii)Dose Modifications for Enrofloxacin
視毒性之類型及嚴重度而定，允許患者內劑量降低1或2個劑量含量(參見表8)。需要劑量降低的患者可重新遞增1個劑量含量(亦即，降低至0.75 mg/kg的患者僅可重新遞增至1 mg/kg)，其限制條件為毒性不需要中止研究藥物且已恢復至基線或≤1級。若毒性重現，則不允許重新增加。出現≥2級角膜AE的患者不允許再遞增劑量。Patients were allowed to have dose reductions of 1 or 2 dose levels depending on the type and severity of toxicity (see Table 8). Patients who required a dose reduction could be re-titrated by 1 dose level (i.e., patients who were reduced to 0.75 mg/kg could only be re-titrated to 1 mg/kg), provided that the toxicity did not require discontinuation of study drug and had recovered to baseline or ≤ Grade 1. If toxicity recurred, no re-titration was permitted. No further dose escalations were permitted for patients who experienced a Grade ≥ 2 corneal AE.
針對恩諾單抗維多汀相關毒性之劑量修改建議呈現於表11及表12中。表11針對恩諾單抗維多汀相關血液毒性的建議劑量修改
在醫學監測者及現場研究者的判斷下，允許因其他恩諾單抗維多汀相關毒性而降低或中斷患者內劑量。根據每位患者的情況，可能允許降低毒性劑量，包括DLT。DLT評估期為第一治療週期。在DLT評估期經歷DLT之患者不應接受進一步治療，除非在充分管控毒性的情況下展現出臨床益處且經醫學監測者批准。後續劑量含量由醫學監測者與現場研究者討論確定；考慮觀測到的AE之類型及嚴重度以供決策參考。At the discretion of the medical monitor and site investigator, intra-patient dose reduction or interruption is permitted due to other enrofloxacin-related toxicities. Dose reduction for toxicities, including DLT, may be permitted based on each patient's circumstances. The DLT evaluation period is the first treatment cycle. Patients who experience a DLT during the DLT evaluation period should not receive further treatment unless clinical benefit is demonstrated with adequate management of toxicity and approved by the medical monitor. Subsequent dose levels are determined by discussion between the medical monitor and site investigator; the type and severity of observed AEs are considered for decision-making.
若醫學監測者及現場研究者判定需要中斷恩諾單抗維多汀之劑量，則亦必須中斷派姆單抗之所有第1天劑量且該中斷可持續至多3週(1個週期)。If the Medical Monitor and Site Investigator determine that an interruption in the dose of enrofloxacin is necessary, all Day 1 doses of pembrolizumab must also be interrupted and the interruption may last up to 3 weeks (1 cycle).
若患者毒性不另外需要永久中止，則在醫學監測者批准下，對於先前未降低劑量且對治療有反應之患者，可中斷劑量超過3週。在劑量延遲期間，患者可能未接受其他研究性藥物、放射治療(除症狀性及非惡化性非目標骨病灶的姑息性放射治療之外)，或全身抗贅瘤療法。若在第1天給藥後出現需要劑量延遲的毒性，且在第8天給藥(直至第10天)之前未消退，則跳過而非延遲第8天恩諾單抗維多汀投與。若患者由於隨後消退之毒性而降低劑量，則患者可由醫學監測者及現場研究者酌情處理在初始劑量下恢復治療。若存在劑量中斷，則不調整反應評估之時程且仍自第1週期第1天計算。If patient toxicity does not otherwise require permanent discontinuation, dose interruptions of more than 3 weeks may be made with approval of the medical monitor for patients who have not previously had their dose reduced and who have responded to treatment. During the dose delay period, patients may not receive other investigational medications, radiation therapy (except palliative radiation therapy for symptomatic and non-malignant non-target bone lesions), or systemic antineoplastic therapy. If toxicity requiring dose delay occurs after the Day 1 dose and does not resolve before the Day 8 dose (until Day 10), the Day 8 dose of enrofloxacin will be skipped rather than delayed. If a patient has a dose reduction due to a toxicity that subsequently resolves, the patient may resume treatment at the original dose at the discretion of the medical monitor and site investigator. If there is a dose interruption, the schedule of response assessments will not be adjusted and will still be calculated from Day 1 of Cycle 1.
在與治療相關的AE以外的情況(諸如與研究療法無關的醫療/手術事件或物流原因)下，允許劑量中斷(恩諾單抗維多汀或派姆單抗)。除非與試驗委託者另外討論，否則參與者應在排定中斷之3週內恢復研究療法。中斷之原因應記載於患者之研究記錄中。Dose interruptions (enrofloxacin or pembrolizumab) are permitted for reasons other than treatment-related AEs (e.g., medical/surgical events unrelated to study therapy or logistical reasons). Participants should resume study therapy within 3 weeks of the scheduled interruption unless discussed otherwise with the trial sponsor. The reason for the interruption should be documented in the patient's study record.
關於輸注反應的管控建議，參見章節6.1.6.4(i)。關於高血糖症的管控建議，參見章節6.1.6.4(iv)。關於皮疹的管控建議，參見章節6.1.6.4(v)。For management recommendations for infusion reactions, see section 6.1.6.4(i). For management recommendations for hyperglycemia, see section 6.1.6.4(iv). For management recommendations for rash, see section 6.1.6.4(v).
在EV+派姆單抗組中，經歷僅可歸因於派姆單抗之不可接受的毒性的患者可永久中止派姆單抗且繼續接受恩諾單抗維多汀單藥療法，直至放射照相上確認疾病惡化、不可接受的毒性、研究者決定、撤回同意書、開始後續抗癌療法、妊娠或試驗委託者終止研究。EV+派姆單抗組中經歷僅可歸因於恩諾單抗維多汀之毒性的患者可永久中止恩諾單抗維多汀且繼續接受派姆單抗單藥療法(至多35個週期)，直至疾病惡化、不可接受的毒性、研究者決定、撤回同意書、開始後續抗癌療法、妊娠或試驗委託者終止研究。In the EV+pembrolizumab group, patients who experienced unacceptable toxicity attributable solely to pembrolizumab could permanently discontinue pembrolizumab and continue to receive enrofloxacin monotherapy until radiographically confirmed disease worsening, unacceptable toxicity, investigator decision, withdrawal of consent, initiation of subsequent anticancer therapy, pregnancy, or study termination by trial sponsors. Patients in the EV+pembrolizumab group who experienced toxicity attributable solely to enrofloxacin could permanently discontinue enrofloxacin and continue to receive pembrolizumab monotherapy (up to 35 cycles) until disease worsening, unacceptable toxicity, investigator decision, withdrawal of consent, initiation of subsequent anticancer therapy, pregnancy, or study termination by trial sponsors.
EV單藥組中經歷僅歸因於恩諾單抗維多汀之不可接受毒性的患者應中止使用研究藥物。Patients in the EV monotherapy group who experience unacceptable toxicity attributable solely to enrofloxacin should discontinue study medication.
中止恩諾單抗維多汀治療且繼續派姆單抗治療之患者應返回診所進行第8天及第15天訪視(用於安全性實驗室評估)。對於永久中止恩諾單抗維多汀治療之患者，不會收集第8天的生命徵象。 (a)與肝臟安全相關之治療中止建議Patients who discontinue enrofloxacin and continue pembrolizumab should return to the clinic for Day 8 and Day 15 visits (for safety laboratory assessments). For patients who permanently discontinue enrofloxacin, Day 8 vital signs will not be collected.(a) Treatment discontinuation recommendations related to liver safety
在沒有解釋LFT增加(諸如病毒性肝炎、先前存在的肝病或急性肝病，或暴露於與肝臟損傷相關的其他藥劑)的情況下，可中止患者的研究治療。研究者可判定，繼續研究治療不符合患者的最佳利益。Patients may be discontinued from study treatment without an explanation for an increase in LFTs (e.g., viral hepatitis, preexisting liver disease or acute liver disease, or exposure to other agents associated with liver damage). The investigator may determine that continuing study treatment is not in the best interest of the patient.
若出現以下情況，則應考慮中止治療： • ALT或天冬胺酸轉胺酶(AST)＞8×正常值上限(ULN) • ALT或AST＞5×ULN，超過2週 • ALT或AST＞3×ULN且總膽紅素＞2×ULN或國際標準化比值(INR)＞1.5 (若INR測試適用/經評估) • ALT或AST＞3×ULN，出現暗示肝臟損傷(例如右上腹疼痛或觸痛)及/或嗜酸性球增多症(＞5%)的症狀Discontinuation of treatment should be considered if:• ALT or aspartate aminotransferase (AST) > 8 x upper limit of normal (ULN)• ALT or AST > 5 x ULN for > 2 weeks• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or international normalized ratio (INR) > 1.5 (if INR testing is applicable/assessed)• ALT or AST > 3 x ULN with symptoms suggestive of liver damage (e.g. right upper quadrant pain or tenderness) and/or eosinophilia (> 5%)
此等治療中止建議係基於FDA行業指南(Drug-Induced Liver Injury: Premarketing Clinical Evaluation，2009年7月)。該等建議為對研究者的基本指導，其基於藥物開發中積累的臨床經驗，而非特指恩諾單抗維多汀的臨床經驗。These treatment discontinuation recommendations are based on FDA guidance for industry (Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009). These recommendations are general guidance to researchers based on clinical experience accumulated during drug development, not specific to clinical experience with enrofloxacin.
關於針對ALT、AST或膽紅素為2級或更高之患者的肝臟安全監測及評估準則建議，參見章節6.1.12。 iv)描述-派姆單抗See section 6.1.12 for recommended liver safety monitoring and assessment guidelines for patients with grade 2 or higher ALT, AST, or bilirubin. iv)Description-Pembrolizumab
派姆單抗為阻斷PD-1與其配位體PD-L1及PD-L2之間的相互作用的人源化單株抗體。派姆單抗為IgG4 κ Ig，大致分子量為149 kDa。Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2. Pembrolizumab is an IgG4 κ Ig with an approximate molecular weight of 149 kDa.
派姆單抗注射液為無菌、不含防腐劑、透明至略微乳白色、無色至略微黃色的溶液，需要稀釋以供IV輸注。各小瓶含有含100 mg派姆單抗之4 mL溶液。各1 mL溶液含有25 mg派姆單抗，且調配於L-組胺酸(1.55 mg)、聚山梨醇酯80 (0.2 mg)、蔗糖(70 mg)及注射用水(美國藥典(USP))中。 v)劑量及投藥Pembrolizumab injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution that requires dilution for IV infusion. Each vial contains 4 mL of solution containing 100 mg of pembrolizumab. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and water for injection (United States Pharmacopeia (USP)). v)Dosage and Administration
對於EV+派姆單抗組，在各3週治療週期之第1天在所有程序及評估完成後，且在恩諾單抗維多汀投與完成後約30分鐘，使用IV輸注投與派姆單抗。For the EV+pembrolizumab group, pembrolizumab was administered using IV infusion on Day 1 of each 3-week treatment cycle after all procedures and assessments were completed and approximately 30 minutes after the completion of enrofloxacin administration.
使用約30分鐘IV輸注以200 mg之劑量投與派姆單抗。Pembrolizumab was administered as a 200 mg dose using an IV infusion over approximately 30 minutes.
投與派姆單抗至多總共35個週期。 vi)與派姆單抗相關之免疫介導不良事件的劑量修改及毒性管控Administer pembrolizumab for a maximum of 35 total cycles. vi)Dose modification and toxicity management for pembrolizumab-related immune-mediated adverse events
與派姆單抗暴露相關之AE可代表免疫學病原。此等imAE可在派姆單抗治療第一次給藥之後不久或最後一次給藥之後數個月發生，且可同時影響多於1個身體系統。因此，早期識別及開始治療對於減少併發症至關重要。基於現有臨床研究資料，大部分imAE係可逆的，且可利用中斷派姆單抗、投與皮質類固醇及/或其他支持性照護來管控。對於疑似imAE，確保充分評估以確認病原或排除其他病因。可包括額外程序或測試(諸如支氣管鏡檢、內視鏡檢、皮膚生檢)作為評估之部分。基於imAE之嚴重度，停止或永久中止派姆單抗且投與皮質類固醇。與派姆單抗相關之imAE的劑量修改及毒性管控指南提供於表13中。 表13.與派姆單抗相關之免疫介導AE的劑量修改及毒性管控指南。
派姆單抗可導致嚴重或危及生命的輸注反應，包括嚴重超敏反應或過敏反應。病徵及症狀通常在藥物輸注期間或不久之後出現，且一般在輸注完成24小時內完全消退。關於派姆單抗相關輸注反應的劑量修改及治療指南提供於表14中。 表14派姆單抗輸注反應劑量修改及治療指南
適當的復蘇設備應在床邊提供，且在藥物投與時段期間容易找到醫師。關於其他資訊，請在可以ctep.cancer.gov訪問的網站參考美國國家癌症研究所不良事件通用術語準則(NCI CTCAE) 4.03版。 NSAID=非類固醇消炎藥；PO=經口vii.劑量中斷Appropriate resuscitation equipment should be available at the bedside and easily accessible to the physician during the drug administration period. For additional information, refer to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03, which can be accessed at ctep.cancer.gov. NSAID = nonsteroidal anti-inflammatory drug; PO = oralvii.Dose interruption
若醫學監測者及現場研究者判定需要中斷派姆單抗之劑量，則亦必須中斷其他藥物(恩諾單抗維多汀及/或化學療法)之所有第1天劑量且該中斷可持續至多3週(1個週期)。viii.派姆單抗之其他允許劑量中斷If the Medical Monitor and Site Investigator determine that an interruption in the dose of pembrolizumab is necessary, all Day 1 doses of the other medications (enrofloxacin and/or chemotherapy) must also be interrupted and the interruption may last up to 3 weeks (1 cycle).viii.Other Permitted Dose Interruptions of Pembrolizumab
在與治療相關的AE以外的情況(諸如與研究療法無關的醫療/手術事件或物流原因)下，可允許劑量中斷(恩諾單抗維多汀或派姆單抗)。除非與試驗委託者另外討論，否則參與者應在排定中斷之3週內恢復研究療法。中斷之原因應記載於患者之研究記錄中。6.1.6.3伴隨療法Dose interruptions (enrofloxacin or pembrolizumab) may be permitted for circumstances other than treatment-related AEs (e.g., medical/surgical events unrelated to study therapy or logistical reasons). Participants should resume study therapy within 3 weeks of the scheduled interruption unless discussed otherwise with the trial sponsor. The reason for the interruption should be documented in the patient's study record.6.1.6.3Concomitant Therapy
自第1天(給藥前)至安全報告期(EOT訪視或最後一次研究治療後30天，以較晚者為準)記錄所有伴隨藥物治療及血液產品。應自知情同意書籤署時起記錄針對研究方案相關AE所給與的任何伴隨藥物治療。 (i)必需的伴隨療法All concomitant medications and blood products were recorded from Day 1 (pre-dose) through the safety reporting period (EOT visit or 30 days after the last study treatment, whichever is later). Any concomitant medications given for protocol-related AEs should be recorded from the time of informed consent signing.(i) Required concomitant therapies
不存在必需的伴隨療法。 (ii)允許的伴隨療法There is no required concomitant therapy.(ii) Permitted concomitant therapy
在研究治療期間，在局部晚期/轉移性情況下允許對未惡化之非目標骨病灶進行姑息性放射治療，且其不視為後續抗癌療法(參見章節6.1.6.3(iii)中關於目標病灶之指導)。Palliative radiation therapy to non-target bone lesions that have not progressed is permitted in the locally advanced/metastatic setting during the study treatment period and is not considered as subsequent anticancer therapy (see Section 6.1.6.3(iii) for guidance regarding target lesions).
允許使用止吐藥。允許使用胰島素作為SOC之部分。允許根據章節6.1.6.4對IRR進行前驅用藥；然而，可能未在第1週期第1天的研究治療之前進行預防IRR的預防性前驅用藥。Antiemetics are permitted. Insulin is permitted as part of the SOC. Prophylactic medication for IRRs is permitted per Section 6.1.6.4; however, prophylactic prophylactic medication to prevent IRRs may not be administered prior to study treatment on Day 1 of Cycle 1.
對於正接受伴隨恩諾單抗維多汀服用的強CYP3A4抑制劑或P-醣蛋白(P-gp)抑制劑的患者，應密切監測其不良反應。Patients receiving strong CYP3A4 inhibitors or P-glycoprotein (P-gp) inhibitors concomitantly with enrofloxacin should be closely monitored for adverse reactions.
允許用疫苗進行常規預防；然而，在研究期間患者可能未用減毒活疫苗治療。Routine prophylaxis with vaccines was allowed; however, patients could not be treated with live attenuated vaccines during the study period.
以下適用於EV+派姆單抗組：經醫學監測者批准，可以≤10 mg/天之劑量使用伴隨的長期普賴松(或等效物)以管控預存病狀。在與醫學監測者討論之後，根據醫學上指示，允許在有限的持續時間內使用較高劑量之普賴松(或等效物)治療研究期間出現的急性病狀。在不存在活動性自體免疫性疾病的情況下，允許吸入或局部類固醇的長期使用。The following applies to the EV+pembrolizumab group: Concomitant long-term use of levofloxacin (or equivalent) at a dose of ≤10 mg/day may be used to manage pre-existing conditions with approval of the medical monitor. Higher doses of levofloxacin (or equivalent) are permitted for limited duration as medically indicated after discussion with the medical monitor for acute conditions that arise during the study. Long-term use of inhaled or topical steroids is permitted in the absence of active autoimmune disease.
對於EV單藥組，可按臨床上指示使用類固醇。 (iii)禁止的伴隨療法For the EV monotherapy group, steroids may be used as clinically indicated.(iii) Prohibited concomitant therapy
在進行中的試驗期間不允許排除準則中專門禁止的藥品或疫苗接種。若在試驗期間存在特別禁止之任何藥品或疫苗接種之臨床適應症，則可能需要中止試驗療法或疫苗接種。研究者應與醫學監測者討論與此相關的任何問題。關於任何支持性療法或疫苗接種之最終決定取決於研究者及/或參與者之主治醫師。然而，繼續使參與者接受研究治療之決定需要研究者、試驗委託者及參與者共同的同意。Exclusions from medications or vaccinations that are specifically prohibited in the guidelines are not permitted during an ongoing trial. If a clinical indication exists for any medication or vaccination that is specifically prohibited during the trial, it may be necessary to discontinue the trial therapy or vaccination. The investigator should discuss any questions regarding this with the medical monitor. The final decision regarding any supportive therapy or vaccination rests with the investigator and/or the participant's attending physician. However, the decision to continue a participant on study treatment requires the mutual agreement of the investigator, the trial sponsor, and the participant.
下文列出在研究過程期間用於伴隨療法或疫苗接種之特定限制： • 抗腫瘤全身性化學治療或生物療法。 • 此方案中未指定之免疫療法。 • 此方案中未指定之化學療法。 • 除派姆單抗或恩諾單抗維多汀外之研究性藥劑。 • 放射療法(注意：在研究者判斷下允許局部晚期/轉移性情況下對有症狀的非目標骨病灶進行放射療法。) • 在第一劑量之研究治療之前30天內及在參與研究時的活疫苗。活疫苗之實例包括(但不限於)以下：麻疹、流行性腮腺炎、風疹、水痘/帶狀疱疹、黃熱病、狂犬病、BCG及傷寒疫苗。用於注射之季節性流感疫苗一般為滅活病毒疫苗且予以允許；然而，鼻內流感疫苗(例如FluMist)為減毒活疫苗且不予允許。 • 吡格列酮。Specific restrictions on concomitant therapy or vaccinations used during the study are listed below:• Antineoplastic systemic chemotherapy or biologic therapy.• Immunotherapy not specified in the protocol.• Chemotherapy not specified in the protocol.• Investigational agents other than pembrolizumab or enrofloxacin.• Radiation therapy (Note: Radiation therapy to symptomatic non-target bone lesions is permitted at the discretion of the investigator in locally advanced/metastatic settings.)• Live vaccines within 30 days prior to the first dose of study treatment and at the time of study entry. Examples of live vaccines include (but are not limited to) the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccines. Seasonal influenza vaccines for injection are generally killed virus vaccines and are permitted; however, intranasal influenza vaccines (such as FluMist) are live attenuated vaccines and are not permitted.• Pioglitazone.
應自研究中移除在研究者之評估中需要使用前述治療中之任一者進行臨床管控的參與者。6.1.6.4不良反應的管控(i)輸注反應之管控-恩諾單抗維多汀Participants who, in the investigator’s assessment, require clinical management with any of the above treatments should be removed from the study.6.1.6.4Management of Adverse Reactions (i) Management of Infusion Reactions - Enromax Vedotin
IRR可發生在研究治療輸注期間。輸注應在配備適當設備及人員之場所投與，以便在過敏反應發生時對其進行管控。根據機構標準，應在整個研究中給與符合最佳患者照護之所有支持性措施。支持性措施可包括投與針對IRR之藥物。IRRs can occur during infusions of study treatment. Infusions should be administered in a setting with appropriate equipment and personnel to manage allergic reactions if they occur. All supportive measures consistent with optimal patient care should be administered throughout the study, according to institutional standards. Supportive measures may include administration of medications for IRRs.
如下文所描述，允許對IRR進行前驅用藥；然而，可能未在第1週期第1天的研究治療之前進行預防IRR的預防性前驅用藥。可向已經歷IRR的患者進行前驅用藥以便隨後輸注。前驅用藥可包括在各恩諾單抗維多汀輸注之前約30至60分鐘或根據機構標準投與的止痛藥(例如乙醯胺苯酚或等效物)、抗組織胺(例如，苯海拉明鹽酸鹽)及皮質類固醇。若患者在前驅用藥的情況下經歷IRR，則在下一次計劃劑量之前，與醫學監測者討論繼續治療。As described below, prophylactic prophylactic medication for IRR is permitted; however, prophylactic prophylactic medication to prevent IRR may not be administered prior to study treatment on Day 1 of Cycle 1. Prophylactic medication may be administered to patients who have experienced an IRR for subsequent infusions. Prophylactic medication may include analgesics (e.g., acetaminophen or equivalent), antihistamines (e.g., diphenhydramine hydrochloride), and corticosteroids administered approximately 30 to 60 minutes prior to each enrofloxacin infusion or according to institutional standards. If a patient experiences an IRR while on prophylactic medication, discuss continuation of treatment with the medical monitor prior to the next scheduled dose.
若發生過敏反應，則應立即且永久中止研究治療投與。 (ii)輸注反應之管控-派姆單抗If an allergic reaction occurs, administration of study treatment should be discontinued immediately and permanently.(ii) Management of infusion reactions - pembrolizumab
關於輸注反應之管控，參見上述表13。 (iii)派姆單抗之支持性照護指南For management of infusion reactions, see Table 13 above.(iii) Supportive Care Guidelines for Pembrolizumab
參與者應接受治療研究者認為必需的適當支持性照護措施。章節6.1.6.2及表12中概述管控具有潛在免疫學病原之AE的建議支持性照護措施以及劑量修改指南。適當時，此等指南包括使用皮質類固醇之經口或IV治療以及額外消炎劑(若症狀未隨皮質類固醇之投與而改善)。應注意，可能需要若干療程之類固醇逐漸減少，因為類固醇劑量減少時症狀可能惡化。對於各病症，應嘗試排除可能需要額外支持性照護之其他原因，諸如轉移性疾病或細菌或病毒感染。當研究者確定事件與派姆單抗相關時，意欲應用治療指南。Participants should receive appropriate supportive care measures as determined by the treating investigator to be necessary. Recommended supportive care measures for the management of AEs with a potential immunological etiology and guidelines for dose modifications are outlined in Section 6.1.6.2 and Table 12. These guidelines include oral or IV treatment with corticosteroids and additional anti-inflammatory agents if symptoms do not improve with administration of corticosteroids, as appropriate. It should be noted that several courses of steroid taper may be required as symptoms may worsen when the steroid dose is reduced. For each condition, attempts should be made to exclude other causes that may require additional supportive care, such as metastatic disease or bacterial or viral infection. Treatment guidelines are intended to apply when the investigator determines that the event is related to pembrolizumab.
注意：若在事件評估之後，確定其與派姆單抗無關，則研究者不需要遵循治療指導。關於劑量修改及支持性照護的指南，參考章節6.1.6.2中之表12。NOTE: If, after evaluation of the event, it is determined to be unrelated to pembrolizumab, the investigator does not need to follow treatment instructions. For guidance on dose modifications and supportive care, refer to Table 12 in Section 6.1.6.2.
可能有必要執行諸如支氣管鏡檢、內視鏡檢或皮膚攝影之條件程序作為事件評估之部分。 (iv)高血糖症之管控It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin photography as part of the event evaluation.(iv) Management of Hyperglycemia
研究者應監測血糖含量，且若觀測到高血糖症之任何症狀，則建議研究者執行額外評估，包括對感染的徹底評估。另外，若使用類固醇治療任何其他病狀，則可能需要對血糖含量進行額外的監測。若觀測到血糖含量升高，則患者應根據當地SOC進行治療且可考慮轉診至內分泌科。Investigators should monitor blood glucose levels and are advised to perform additional evaluations, including a thorough evaluation for infection, if any symptoms of hyperglycemia are observed. Additionally, if steroids are used to treat any other condition, additional monitoring of blood glucose levels may be necessary. If elevated blood glucose levels are observed, patients should be treated according to the local SOC and referral to endocrinology may be considered.
患者，尤其是有糖尿病或高血糖症病史或正在發生的糖尿病或高血糖症的患者，若其葡萄糖含量變得難以控制或若其經歷了暗示高血糖症的症狀，諸如尿頻、口渴加劇、視力模糊、疲勞及頭痛，則應最好立即告知其醫師。Patients, especially those with a history of or developing diabetes or hyperglycemia, are advised to tell their doctor right away if their glucose levels become uncontrollable or if they experience symptoms suggestive of hyperglycemia, such as frequent urination, increased thirst, blurred vision, fatigue, and headaches.
基線時HbA1c升高(≥6.5%)進入研究之患者應在第1週期期間轉診至適當提供者進行葡萄糖管控。在各給藥之前應檢查血糖，且對於血糖＞250 mg/dL應停止給藥。一旦患者血糖改善至≤250 mg/dL且患者在臨床及代謝上穩定，則給藥可繼續。允許使用胰島素作為SOC之部分。視為與恩諾單抗維多汀相關的血糖＞500 mg/dL需要藥物中斷及對高血糖症進行全面評估以確定潛在診斷。一旦高血糖症/升高之血糖改善至≤250 mg/dL，則在諮詢醫學監測者後在密切監測下恢復給藥。若患者經歷新發作型糖尿病，則用代謝組、尿酮、HbA1c、C-肽評估患者，以在與CPI組合之情況下評估新發作型第1型糖尿病。 (v)與恩諾單抗維多汀相關之皮疹的管控Patients entering the study with elevated HbA1c (≥6.5%) at baseline should be referred to an appropriate provider for glucose management during Cycle 1. Blood glucose should be checked prior to each dosing and dosing should be withheld for blood glucose >250 mg/dL. Dosing may be continued once the patient's blood glucose improves to ≤250 mg/dL and the patient is clinically and metabolically stable. Insulin is permitted as part of the SOC. Blood glucose >500 mg/dL considered related to enrofloxacin requires medication interruption and a full evaluation for hyperglycemia to determine the underlying diagnosis. Once hyperglycemia/elevated blood glucose improves to ≤250 mg/dL, dosing is resumed under close monitoring in consultation with the medical monitor. If the patient experiences new-onset diabetes, evaluate the patient with a metabolic panel, urine ketones, HbA1c, and C-peptide to assess for new-onset type 1 diabetes in combination with a CPI.(v) Management of rash associated with enrofloxacin
恩諾單抗維多汀為針對連接素-4之抗體藥物結合物。連接素-4為高度表現於尿路上皮癌中之細胞黏附分子。低至中等含量之連接素-4亦表現於正常組織上，包括皮膚角質細胞、汗腺及毛囊；因此，皮膚反應為預期事件。因此，皮膚反應為在恩諾單抗維多汀之所有臨床研究中所關注之AE。Enrotumab vedotin is an antibody-drug conjugate that targets NEC-4. NEC-4 is a cell adhesion molecule that is highly expressed in urothelial carcinoma. Low to moderate levels of NEC-4 are also expressed in normal tissues, including skin keratinocytes, sweat glands, and hair follicles; therefore, skin reactions are expected events. Therefore, skin reactions are an AE of concern in all clinical studies of Enrotumab vedotin.
在15名接受恩諾單抗維多汀之患者中鑑別出嚴重皮膚不良反應的報告，其中一些患者出現了致命後果。此等反應主要在第一治療週期期間發生。此等病例中報告之AE包括史蒂芬斯-強森症候群(SJS) (5例)、水皰(3例)、大皰性皮炎(3例)、對稱藥物相關擦爛性及屈曲性紅斑(SDRIFE；2例)及剝脫性皮炎、剝脫性皮疹、表皮壞死、口咽起泡、口腔炎及中毒性表皮壞死溶解(TEN)各1例。Reports of severe dermatologic adverse reactions, some with fatal outcomes, were identified in 15 patients receiving enrofloxacin. These reactions occurred primarily during the first treatment cycle. AEs reported in these cases included Stevens-Johnson syndrome (SJS) (5 cases), blistering (3 cases), blistering dermatitis (3 cases), symmetrical drug-related excoriation and flexural erythema (SDRIFE; 2 cases), and 1 case each of exfoliative dermatitis, exfoliative rash, epidermal necrosis, oropharyngeal blistering, stomatitis, and toxic epidermal necrolysis (TEN).
在尿路上皮癌之恩諾單抗維多汀單藥療法研究中，重度皮膚不良反應之SAE報告於749名個體中之11名(1.5%)中且包括大皰性皮炎(0.4%)、藥疹(0.4%)、水皰(0.1%)、結膜炎(0.1%)、SJS (0.1%)、口腔炎(0.1%)及毒性皮疹(0.1%)。In the enrofloxacin monotherapy study in urothelial carcinoma, severe cutaneous adverse reactions (SAEs) were reported in 11 of 749 subjects (1.5%) and included blister dermatitis (0.4%), drug eruption (0.4%), eczema (0.1%), conjunctivitis (0.1%), SJS (0.1%), stomatitis (0.1%), and toxic rash (0.1%).
若個體具有皮膚反應、口腔黏膜及眼部異常(包括，黏膜炎或結膜炎)之病徵及症狀，則應建議該等個體立即聯絡研究者。自第一週期開始及整個治療中，密切監測個體之皮膚反應。對於輕度至中度皮膚反應，考慮適當治療，諸如臨床上指示之局部皮質類固醇及抗組織胺。對於惡化的2級皮疹或皮膚反應，考慮停止恩諾單抗維多汀。對於重度(3級)皮疹或皮膚反應或疑似SJS或TEN，停止恩諾單抗維多汀且考慮轉診接受專門照護。在具有確診之SJS或TEN或者4級或復發性3級皮膚反應(若存在)之患者中，中止恩諾單抗維多汀為永久中止。Subjects should be advised to contact the investigator immediately if they have signs and symptoms of skin reactions, oral mucosal, and ocular abnormalities (including mucositis or conjunctivitis). Monitor subjects closely for skin reactions beginning in Cycle 1 and throughout treatment. For mild to moderate skin reactions, consider appropriate treatment, such as topical corticosteroids and antihistamines as clinically indicated. For worsening Grade 2 rash or skin reactions, consider discontinuation of enrofloxacin. For severe (Grade 3) rash or skin reactions or suspected SJS or TEN, discontinue enrofloxacin and consider referral for specialized care. In patients with confirmed SJS or TEN or Grade 4 or recurrent Grade 3 skin reactions (if present), discontinue enrofloxacin permanently.
對於恩諾單抗維多汀組合療法，若確定皮疹或皮膚反應與研究藥物相關但研究者不能區分與個別研究藥物之相關性，則管控措施(亦即，停止或中止治療)應該應用於所有研究藥物。6.1.6.5治療順應性For enrofloxacin combination therapy, if a rash or skin reaction is determined to be related to the study drug but the investigator cannot distinguish the relationship to an individual study drug, control measures (i.e., withholding or discontinuing treatment) should be applied to all study drugs.6.1.6.5Treatment Compliance
研究藥物的投與由研究現場的人員執行且記錄於源文件及CRF中。6.1.6.6治療持續時間The administration of study drugs is performed by the personnel at the study site and recorded in the source documents and CRF.6.1.6.6Duration of treatment
EV+派姆單抗組中之患者可已接受治療超過根據RECIST v1.1之疾病惡化，其限制條件為其得到臨床益處，如以下所有者所定義： • 如研究者所評估，臨床症狀或功能狀態改善。 • 沒有可歸因於疾病惡化的WHO或ECOG體能狀態下降。 • 不存在明確疾病惡化之症狀或徵象(包括惡化的實驗室值)。 • 關鍵解剖部位(例如CNS、脊髓壓迫)不存在疾病惡化。6.1.7研究評估6.1.7.1篩選/基線評估Patients in the EV+pembrolizumab group could have received treatment beyond disease worsening according to RECIST v1.1, provided that they had clinical benefit as defined by the owner below: • Improvement in clinical symptoms or functional status as assessed by the investigator. • No decline in WHO or ECOG performance status attributable to disease worsening. • No symptoms or signs of clear disease worsening (including worsening laboratory values). • No disease worsening in critical anatomical sites (e.g., CNS, spinal cord compression).6.1.7Study Assessments6.1.7.1Screening/Baseline Assessments
只有符合章節6.1.5中所指定之所有納入及排除準則的患者才入選此研究。入選情況及日期記錄於CRF中。Only patients who meet all the inclusion and exclusion criteria specified in Section 6.1.5 will be included in this study. The inclusion status and date will be recorded in the CRF.
患者病史包括對重要的既往病史、當前狀況、先前惡性腫瘤的任何治療及對先前治療之反應以及任何伴隨藥物治療的全面回顧。6.1.7.2局部晚期或轉移性尿路上皮癌The patient history should include a comprehensive review of significant past medical history, current condition, any previous treatment for malignant tumors and response to previous treatments, and any concomitant medical therapy.6.1.7.2Locally Advanced or Metastatic Urothelial Carcinoma
所有患者在篩選時需要獲取新鮮腫瘤生檢組織、收集歸檔腫瘤試樣、全面眼部檢查、腦部掃描(使用釓造影劑之MRI較佳；參見章節6.1.13以獲得較佳成像方法)、骨掃描、用於基線腫瘤成像之胸部、腹部及骨盆CT (使用IV造影劑) (若造影劑禁忌，則請參閱當前的影像擷取指南[章節6.1.13]以獲得較佳掃描及造影選擇)、B型肝炎表面抗原及抗B型肝炎核心抗體的血清學、抗C型肝炎抗體的血清學、使用反射顯微鏡分析的尿樣分析、HbA1c及甲狀腺功能測試。在基線時需要INR/PT/PTT、妊娠測試(尿液或血清，適用於有生育潛力的女性)、體檢(包括體重)、收集身高、生命徵象、分類CBC、血清化學組、CrCl及ECOG體能狀態評估。對於患有NYHA III級心臟衰竭或有冠心病、心律不整或其他嚴重心臟病史的個體，需要在基線時進行ECHO。6.1.7.3反應/功效評估All patients require fresh tumor biopsy tissue, collection of archival tumor specimens, complete eye examination, brain scan (MRI with gadolinium contrast is preferred; see Section 6.1.13 for optimal imaging methods), bone scan, chest, abdomen, and pelvic CT for baseline tumor imaging (with IV contrast) (if contrast is contraindicated, refer to current image acquisition guidelines [Section 6.1.13] for optimal scan and imaging options), serology for hepatitis B surface antigen and anti-hepatitis B core antibody, serology for anti-hepatitis C antibody, urine analysis using reflectance microscopy, HbA1c, and thyroid function tests at screening. INR/PT/PTT, pregnancy test (urine or serum for females of childbearing potential), physical examination (including weight), collection of height, vital signs, differential CBC, serum chemistry panel, CrCl, and ECOG performance status assessment are required at baseline. ECHO is required at baseline for individuals with NYHA Class III heart failure or a history of coronary artery disease, arrhythmias, or other serious heart disease.6.1.7.3Response/Efficacy Assessments
在方案規定的時間點藉由胸部、腹部及骨盆CT (使用IV造影劑)評估疾病。患者必須在整個研究中使用相同成像方法評估以進行反應評估。若造影劑禁忌，則請參閱當前的影像擷取指南(章節6.1.13)以獲得較佳掃描及造影選擇。若患者在其他區域具有已知疾病或暗示疾病之新症狀，則應掃描該等區域。若基線時已知或在整個研究中臨床上指示不活動性腦轉移，則應在疾病評估時間點重複腦部掃描(在篩選時需要)。若基線時鑑別出骨轉移，或若已知或疑似骨轉移，則亦應在反應評估時間點重複骨掃描(在篩選時需要)。Assess disease by CT of the chest, abdomen, and pelvis (with IV contrast) at protocol-specified times. Patients must be evaluated throughout the study using the same imaging modality for response assessments. If contrast is contraindicated, refer to current image acquisition guidelines (Section 6.1.13) for optimal scan and imaging selection. If patients have known disease or new symptoms suggestive of disease in other areas, those areas should be scanned. If inactive brain metastases are known at baseline or clinically indicated throughout the study, brain scans should be repeated at disease assessment time points (as needed for screening). If bone metastases are identified at baseline, or if bone metastases are known or suspected, bone scans should also be repeated at response assessment time points (as needed for screening).
在CT/MRI掃描中偵測到之膀胱病灶可選擇為目標病灶，其限制條件為放射科醫師認為病灶適宜於在基線後時間點進行可再現量測，且病灶已在充分的膀胱擴張下量測。在整個研究治療過程中應使用相同的成像方式。Bladder lesions detected on CT/MRI scans may be selected as target lesions provided that the radiologist considers the lesion to be amenable to reproducible measurement at post-baseline time points and that the lesion has been measured with adequate bladder distension. The same imaging modality should be used throughout the study treatment.
若提供新獲得的腫瘤病灶之粗針或切除生檢，則應在生檢之後執行(或重複)基線成像以確保準確評估腫瘤反應(若特定病灶已選擇為目標病灶)。If a core needle or excisional biopsy of a newly acquired tumor lesion is provided, baseline imaging should be performed (or repeated) after the biopsy to ensure accurate assessment of tumor response (if a specific lesion has been selected as a target lesion).
根據RECIST 1.1版(Eisenhauer 2009) (表40)確認客觀反應，在第一次記錄反應後至少4週重複掃描(需要在4至5週進行掃描)，隨後應根據初始時程自第1週期第1天起每9週(±7天)執行後續反應評估，直至第一次給藥後1年，隨後每12週(±7天)進行。每當懷疑疾病惡化時，亦應執行腫瘤成像。Objective response was confirmed according to RECIST version 1.1 (Eisenhauer 2009) (Table 40), with scans repeated at least 4 weeks after the first documented response (scans were required at 4 to 5 weeks), and subsequent response assessments were performed every 9 weeks (±7 days) starting on Day 1 of Cycle 1 according to the initial schedule until 1 year after the first dose, and then every 12 weeks (±7 days) thereafter. Tumor imaging should also be performed whenever disease progression is suspected.
根據iRECIST指南(Seymour 2017) (章節6.1.15)在療法中具有iUPD的EV+派姆單抗組中之患者可繼續接受研究治療，直至由研究者在iUPD後4至9週利用後續掃描確認iCPD。對於EV單藥組中之患者，研究者基於根據RECIST 1.1版掃描之現場評估作出治療決定。Patients in the EV+pembrolizumab arm who had iUPD on therapy according to iRECIST guidelines (Seymour 2017) (Section 6.1.15) could continue on study treatment until iCPD was confirmed by the investigator using a follow-up scan 4 to 9 weeks after iUPD. For patients in the EV alone arm, the investigator made treatment decisions based on on-site assessment of scans according to RECIST version 1.1.
出於除放射照相上確認疾病惡化或撤回同意書之外的原因中止研究治療之患者根據自第1週期第1天計算之初始時程每9週(±7天)繼續接受反應評估(包括使用造影劑之CT掃描)，直至第一次給藥後1年，隨後每12週(±7天)接受反應評估。掃描一直進行到研究者確定患者根據iRECIST指南(或對於EV單藥組，RECIST 1.1版指南)具有放射學確認的疾病惡化、開始後續抗癌療法、死亡、研究結束或患者撤回同意書，以先發生者為準。抗腫瘤活性之確定係基於研究者確定的RECIST 1.1版所定義之確認的客觀反應評估。研究者基於根據iRECIST指南(或對於EV單藥組，RECIST 1.1版指南)掃描之現場評估作出治療決定。根據RECIST 1.1版或根據iRECIST指南(適當時)在各評估時確定臨床反應。在各評估時確定CR、PR、SD或PD之臨床反應。Patients who discontinued study treatment for reasons other than radiographically confirmed disease worsening or withdrawal of consent continued to receive response assessments (including CT scans with contrast) every 9 weeks (±7 days) according to an initial schedule calculated from Day 1 of Cycle 1 until 1 year after the first dose and every 12 weeks (±7 days) thereafter. Scans were performed until the investigator determined that the patient had radiographically confirmed disease worsening according to iRECIST guidelines (or RECIST version 1.1 guidelines for the EV monotherapy group), initiation of subsequent anticancer therapy, death, study end, or patient withdrawal of consent, whichever occurred first. Antitumor activity was determined based on a confirmed objective response assessment as defined by RECIST version 1.1 as determined by the investigator. Treatment decisions were made by the investigator based on on-site assessment of scans according to iRECIST guidelines (or RECIST version 1.1 guidelines for the EV monotherapy arm). Clinical response was determined at each assessment according to RECIST version 1.1 or according to iRECIST guidelines, as appropriate. Clinical response of CR, PR, SD, or PD was determined at each assessment.
另外，在非預定時間點獲得的影像(包括經由其他方式)亦應提交至BICR。In addition, images obtained at unscheduled times (including by other means) should also be submitted to BICR.
每12週(±7天)更新存活狀態及關於後續抗癌療法之資訊，直至死亡、撤回同意書或研究結束，以先發生者為準。Survival status and information on subsequent anticancer therapy were updated every 12 weeks (±7 days) until death, withdrawal of consent, or end of study, whichever occurred first.
患者的臨床資料必須可用於CRF源驗證。將腫瘤影像提交至獨立審查機構進行讀取及分析。6.1.7.4藥物動力學及免疫原性評估Patient clinical data must be available for CRF source verification. Tumor images will be submitted to an independent review agency for reading and analysis.6.1.7.4Pharmacokinetic and immunogenicity assessment
根據表14中提供之樣品收集時程，在整個研究期間收集用於PK及ATA的血液樣品。經驗證或合格的分析用於量測血清或血漿中之恩諾單抗維多汀ADC、TAb及MMAE的濃度。收集PK樣品且歸檔以便對伴隨藥物含量或其他恩諾單抗維多汀相關物質(諸如MMAE之循環代謝物)進行可能的分析。經驗證的分析用於確定血漿中恩諾單抗維多汀之ATA含量。收集派姆單抗之PK及ATA樣品且歸檔以便在EV+派姆單抗組中進行潛在後續分析。若中止恩諾單抗維多汀或派姆單抗輸注，則不再需要收集相應的研究樣品。若在某個時間點不再需要前瞻性PK血液樣品收集，則通知站點。6.1.7.5生物標記物研究Blood samples for PK and ATA were collected throughout the study according to the sample collection schedule provided in Table 14. Validated or qualified assays were used to measure the concentrations of enrofloxacin ADC, TAb, and MMAE in serum or plasma. PK samples were collected and archived for possible analysis of concomitant drug levels or other enrofloxacin-related substances (such as circulating metabolites of MMAE). Validated assays were used to determine the ATA levels of enrofloxacin in plasma. PK and ATA samples for pembrolizumab were collected and archived for potential subsequent analysis in the EV+pembrolizumab group. If enrofloxacin or pembrolizumab infusions were discontinued, the corresponding study samples no longer needed to be collected. If prospective PK blood sample collection was no longer required at a certain point in time, the site was notified.6.1.7.5Biomarker Research
維多汀ADC之另一作用機制可涉及誘導免疫原性細胞死亡，且因此改變腫瘤相關及周邊免疫細胞之數目及活化狀態(Cao 2018)。此等變化可增強派姆單抗之活性。Another mechanism of action of vedotin ADC may involve inducing immunogenic cell death and thereby altering the number and activation status of tumor-associated and peripheral immune cells (Cao 2018). These changes may enhance the activity of pembrolizumab.
在方案規定之時間點收集用於探索性生物標記物分析的樣品(參見表15)。不使用生物標記物評估進行患者選擇。Samples for exploratory biomarker analysis were collected at protocol-specified time points (see Table 15). Biomarker assessments were not used for patient selection.
分析方法可包括：免疫組織化學(IHC)、DNA及RNA之下一代定序(NGS)、T細胞受體β鏈定序、PCR、流式細胞分析技術及免疫分析。Analytical methods may include: immunohistochemistry (IHC), next generation sequencing (NGS) of DNA and RNA, T cell receptor β chain sequencing, PCR, flow cytometry, and immunoassay.
所有患者均應自歸檔組織樣品或新獲得的腫瘤病灶之粗針或切除生檢提供用於生物標記物分析的組織。需要福馬林固定之石蠟包埋的腫瘤組織塊。若可獲得，則需要在入選6個月內接受最近一次治療後收集的歸檔腫瘤組織。來自腫瘤組織(非骨部位)之粗針及切除生檢為較佳的。若可行，則可提交腫瘤病灶之新鮮基線粗針生檢。在臨床上需要生檢作為SOC之一部分的情況下，應使得組織可用於生物標記物評估。All patients should provide tissue for biomarker analysis from either archival tissue samples or freshly obtained core needle or excisional biopsies of tumor lesions. Formalin-fixed, paraffin-embedded blocks of tumor tissue are required. If available, archival tumor tissue collected after the last treatment within 6 months of enrollment is required. Core needle and excisional biopsies from tumor tissue (non-bone sites) are preferred. A fresh baseline core needle biopsy of the tumor lesion may be submitted if feasible. In cases where biopsies are clinically necessary as part of the SOC, tissue should be made available for biomarker assessment.
在用恩諾單抗維多汀治療之前及期間監測與反應、抗性或安全性觀測結果相關之探索性、預測性及預後生物標記物。腫瘤組織中之生物標記物評估可包括(但不限於)恩諾單抗維多汀及其代謝物之量測，以及腫瘤微環境(TME)之表徵及藥物效應。分析可包括(但不限於) IHC以及RNA及DNA之下一代定序。 表15.用於局部晚期或轉移性尿路上皮癌之藥物動力學、免疫原性及生物標記物樣品收集時間點
血液樣品中之生物標記物評估可包括(但不限於)免疫功能之標記物，包括免疫細胞亞群之豐度及表型、T細胞選殖性分析、細胞介素(例如發炎標記物或高血糖症相關標記物)之豐度及作為腫瘤反應或療法抗性之標記物的循環腫瘤DNA。此等評估與恩諾單抗維多汀單藥療法試驗中進行之類似評估進行比較，且可提供對與恩諾單抗維多汀誘導之腫瘤細胞死亡及免疫檢查點阻斷相關的周邊免疫系統之活化狀態的治療相關變化的深刻理解。(ii)腫瘤組織中之生物標記物Biomarker assessments in blood samples may include, but are not limited to, markers of immune function, including abundance and phenotype of immune cell subsets, T cell selectivity analysis, abundance of interleukins (e.g., inflammatory markers or hyperglycemia-related markers), and circulating tumor DNA as a marker of tumor response or resistance to therapy. These assessments are compared to similar assessments performed in the enrofloxacin monotherapy trials and may provide insights into treatment-related changes in the activation state of the peripheral immune system associated with enrofloxacin-induced tumor cell death and immune checkpoint blockade.(ii)Biomarkers in Tumor Tissue
為了理解腫瘤細胞及TME歸檔腫瘤切片中之反應、抗性及治療誘導之變化的可能標記物，需要最後一次全身療法或新鮮生檢後的腫瘤切片及視情況選用之新鮮治療期生檢。若進行非方案指定生檢作為標準照護之一部分，則需要視情況提交組織樣品。To understand possible markers of response, resistance, and treatment-induced changes in tumor cells and TME archived tumor sections, tumor sections after the last systemic therapy or fresh biopsies and, if appropriate, fresh on-treatment biopsies are required. If non-protocol-specified biopsies are performed as part of standard care, tissue samples need to be submitted as appropriate.
需要治療前新鮮腫瘤生檢組織，且應在接受研究治療之前≤6個月內但在最近先前全身療法完成後獲得。或者，若可獲得，則提供約20個＜6個月的生檢或切除之載片。將歸檔腫瘤生物標記物(參見下文)與新所獲得的治療前腫瘤組織進行比較使得能夠評估此等生物標記物之耐久性。Fresh, pre-treatment tumor biopsy tissue is required and should be obtained ≤6 months prior to receiving study treatment but after completion of the most recent prior systemic therapy. Alternatively, approximately 20 biopsies or resection slides <6 months old, if available. Comparison of archived tumor biomarkers (see below) with freshly obtained pre-treatment tumor tissue will allow assessment of the durability of these biomarkers.
與單獨的CPI相比，恩諾單抗維多汀與CPI之組合可預期增加腫瘤中之早期先天性抗腫瘤免疫反應以及後續適應性抗腫瘤免疫反應。為了表徵腫瘤免疫微環境中之治療相關變化且將其與患者結果相關聯，對於具有可及腫瘤之患者(在研究者看來)，需要在第1週期之第15天至第21天之間進行治療期生檢。在第2週期第1天給藥之前執行治療期生檢，且若可能，則應自與治療前生檢相同的病灶獲得新鮮生檢。The combination of enrofloxacin and CPI is expected to increase early innate anti-tumor immune responses in tumors as well as subsequent adaptive anti-tumor immune responses compared to CPI alone. In order to characterize treatment-related changes in the tumor immune microenvironment and correlate them with patient outcomes, on-treatment biopsies are required between Day 15 and Day 21 of Cycle 1 for patients with accessible tumors (in the investigator's opinion). On-treatment biopsies are performed prior to dosing on Day 1 of Cycle 2, and fresh biopsies should be obtained from the same lesions as pre-treatment biopsies, if possible.
歸檔及新獲得的腫瘤組織中之生物標記物評估可包括但不限於： • 連接素-4及PD-L1蛋白之腫瘤表現 • GE (例如連接素-4、PD-1及PD-L1、藥物運輸蛋白(諸如ABCB1/P-gp)、不同免疫亞群之特徵)及疾病亞型之標記物(例如TCGA亞型)之探索性分析 • 突變負荷及疾病相關基因體變化(例如纖維母細胞生長因子受體畸變) • 腫瘤及腫瘤免疫微環境之蛋白質標記物(例如CD68、CD8、FOXP3、CD163)6.1.7.6生物樣本庫Biomarker assessments in archived and newly acquired tumor tissues may include, but are not limited to: • Tumor expression of nectin-4 and PD-L1 proteins • Exploratory analysis of GE (e.g., nectin-4, PD-1, and PD-L1, drug transporters (such as ABCB1/P-gp), signatures of different immune subsets) and markers of disease subtypes (e.g., TCGA subtypes) • Mutational burden and disease-associated genomic alterations (e.g., fibroblast growth factor receptor aberrations) • Protein markers of tumors and the tumor immune microenvironment (e.g., CD68, CD8, FOXP3, CD163)6.1.7.6Biobanks
在美國，對於提供額外同意書的患者而言，去標識化、未使用的剩餘血液及/或組織由研究試驗委託者保留且用於將來的研究，包括(但不限於)評估新穎治療劑之目標、ADC敏感性及抗性機制的生物學及ADC的生物標記物鑑別。捐贈給將來研究用的血液、尿液及組織樣品保留至多25年的時段。若未提供額外同意書，則在研究完成之後破壞任何剩餘生物樣品。6.1.7.7患者報告結果(PRO)In the United States, for patients who provide additional consent, de-identified, unused, surplus blood and/or tissue is retained by the research trial sponsor and used for future research, including (but not limited to) evaluating the target of novel therapeutics, the biology of ADC sensitivity and resistance mechanisms, and biomarker identification of ADCs. Blood, urine, and tissue samples donated for future research are retained for a period of up to 25 years. If additional consent is not provided, any surplus biological samples are destroyed upon completion of the study.6.1.7.7Patient Reported Outcomes(PROs)
患者報告結果(PRO)評估包括EQ 5D-5L、EORTC QLQ-C30、BPI-SF及HRU評估(細節參見章節6.1.7.8(i)至6.1.7.8(iii))。在第1天給藥之前、前3個週期每週一次(在給藥之前2天內)及研究治療部分的剩餘時間每週期一次(在給藥之前2天內)完成PRO評估。在給藥訪視日，應在給藥之前完成評估。在各隨訪及各長期隨訪聯絡時進行PRO評估(參見表16)。 表16事件時程
評估由患者在家中使用電子裝置(較佳報告媒介)完成，該電子裝置在第一次臨床訪視時向各患者提供。該裝置有預設提示，讓患者在預先指定的時間點填寫其評估。站點需要經由線上入口網站監測患者對ePRO裝置的依從性。僅當使用電子裝置不可行時，評估才以紙質形式或由診所工作人員藉由電話(使用站點可用的經批准之腳本)進行報告。當使用紙質或訪談方法時，向患者提供關於在臨床訪視時、在給藥之前及在預定時間點填寫評估之說明。研究者或現場指定人員在收集時應審查評估資料之正確完成情況。研究者或現場指定人員及現場人員接受了如何為各患者提供使用PRO裝置(或紙質評估，僅當使用電子裝置不可行時)之支援的培訓。 (i)EORTC核心生活品質(QLQ-C-30)評估The assessment is completed by the patient at home using an electronic device (preferred reporting medium) that is provided to each patient at the first clinic visit. The device has preset prompts for the patient to complete their assessment at pre-specified time points. Sites are required to monitor patient compliance with the ePRO device via an online portal. Only when the use of an electronic device is not feasible will the assessment be reported in paper form or by clinic staff via telephone (using an approved script available to the site). When using paper or interview methods, the patient is provided with instructions for completing the assessment at the clinic visit, prior to dosing, and at pre-specified time points. The investigator or site designee should review the assessment data for correct completion at the time of collection. The investigator or site designee and site personnel were trained on how to provide support to each patient using the PRO device (or paper assessment only when the use of an electronic device was not feasible). (i)EORTCCore Quality of Life(QLQ-C-30)Assessment
開發EORTC核心生活品質(QLQ-C30)以量測與參與臨床試驗之多種癌症的患者相關的QoL態樣(Aaronson 1993)；(Sneeuw 1998)。核心工具之現行版本(QLQ-C30，第3版)描繪於圖4中，且為由以下組成之30項評估： • 5個功能域(身體、角色、認知、情感及社交)； • 3個症狀量表(疲乏、疼痛、噁心及嘔吐)； • 症狀(呼吸短促、食慾不振、睡眠障礙、便秘、腹瀉)及疾病之財務影響的單個項目；及 • 2個全域項目(健康、總體QoL)。The EORTC Core Quality of Life (QLQ-C30) was developed to measure QoL aspects relevant to patients with a variety of cancers participating in clinical trials (Aaronson 1993); (Sneeuw 1998). The current version of the core instrument (QLQ-C30, version 3) is depicted inFigure4 and is a 30-item assessment consisting of: • 5 domains of functioning (physical, role, cognitive, emotional, and social); • 3 symptom scales (fatigue, pain, nausea, and vomiting); • Single items for symptoms (shortness of breath, loss of appetite, sleep disturbances, constipation, diarrhea) and financial impact of illness; and • 2 global domain items (well-being, overall QoL).
各領域評分為0至100。對於整體健康狀況/QoL及功能域評分，評分愈高分別表示QoL及功能愈佳。對於症狀量表，評分愈高表示症狀愈明顯(參見圖4)。 (ii)EuroQol-5維Each domain is scored from 0 to 100. For the global health status/QoL and function domain scores, higher scores indicate better QoL and function, respectively. For the symptom scale, higher scores indicate more obvious symptoms (seeFigure4 ). (ii)EuroQol-5dimensions
EQ-5D為EuroQol小組開發的標準化工具，其用作健康結果的通用、基於偏好的量度。其適用於大範圍的健康狀況及治療且針對健康狀況提供簡單的描述性概況及單一指標值。EQ-5D為功能及健康的5項自我報告的量度，其評估健康的5個維度，包括活動能力、自理、日常活動、疼痛/不適及焦慮/憂鬱(參見圖5)。各維度包含3個層級(沒有問題、一些/中度問題、極大問題)。獨特的EQ-5D健康狀態係藉由組合5個維度中之各者的1個層級來定義。隨後基於來源於一般群體樣本之值，將對5個項目之回答轉化成加權健康狀態指數(效用評分) (Herdman 2011)。健康效用評分在0與1之間，其中0為死亡且1為完美健康。除效用評分之外，此評估亦記錄調查對象在帶垂直刻度(0至100)之視覺類比量表上自評分之健康狀況(參見圖5)。6.1.7.8安全評估The EQ-5D is a standardized instrument developed by the EuroQol group that is used as a universal, preference-based measure of health outcomes. It is applicable to a wide range of health conditions and treatments and provides a simple descriptive summary and a single index value for health conditions. The EQ-5D is a 5-item self-report measure of function and health that assesses 5 dimensions of health, including mobility, self-care, daily activities, pain/discomfort, and anxiety/depression (seeFigure5 ). Each dimension contains 3 levels (no problems, some/moderate problems, and extreme problems). A unique EQ-5D health state is defined by combining 1 level of each of the 5 dimensions. The responses to the five items were then converted into a weighted health status index (utility score) based on values from a general population sample (Herdman 2011). The health utility score ranges from 0 to 1, where 0 is death and 1 is perfect health. In addition to the utility score, this assessment also records the respondents’ self-rated health status on a visual analog scale with a vertical scale (0 to 100) (seeFigure5 ).6.1.7.8Safety Assessment
此研究過程中的安全評估由以下組成：AE (包括SAE)的監測及記錄、伴隨藥物治療的記錄，及方案指定之體檢結論的量測、心臟監測及實驗室測試。如章節6.1.3及6.1.8.3中所描述，藉由受限制的SMC持續監測安全性。Safety assessments during this study consisted of monitoring and recording of AEs (including SAEs), recording of concomitant medications, and protocol-specified measures of physical findings, cardiac monitoring, and laboratory tests. Safety was monitored continuously by a restricted SMC as described in Sections 6.1.3 and 6.1.8.3.
與膀胱癌疾病治療及研究之AE相關的所有非預定實驗室評估應在非預定訪視中擷取，且實驗室報告發送至中央實驗室供應商。 (i)不良事件(a)關於不良事件All unscheduled laboratory evaluations related to AEs related to bladder cancer treatment and research should be captured at unscheduled visits and laboratory reports sent to the central laboratory provider. (i)Adverse Events (a) About Adverse Events
不良事件Adverse Events
根據國際協調委員會(International Council for Harmonisation，ICH) E2A指南速報(Expedited Reporting)之定義及標準，以及美國聯邦法規(CFR) 21 312.32，研究性新藥(IND)安全報告，AE為投與藥品之患者或臨床研究個體中發生的任何不良醫學事件，其未必與此治療有因果關係。According to the definition and standards of the International Council for Harmonisation (ICH) E2A guideline Expedited Reporting and the US Code of Federal Regulations (CFR) 21 312.32, Investigational New Drug (IND) Safety Reporting, AE is any adverse medical event occurring in patients or clinical study subjects administered a medicinal product, which may not be causally related to this treatment.
當確定是否在AE及預存病狀CRF上記錄測試結果、醫學病狀或其他事件時，應考慮以下資訊： • 自知情同意書籤署時直至研究第1天的前一天，應僅記錄與研究方案相關的AE。方案相關的AE定義為由於方案指定程序而發生的不良醫學事件。 • 應記錄研究第1天給藥前存在的或正在發生的所有醫學病狀。 • 應記錄自研究第1天(給藥前)至安全報告期結束之所有AE (無論與研究藥物之關係如何)。與任何程序(例如生檢)相關而發生的併發症應記錄為AE，無論該程序是否為方案指定的。 • 在安全報告期期間發生的醫學病狀及AE (包括嚴重度、頻率或特徵)變化應予以記錄。 • 一般而言，異常實驗值不應記錄為AE，除非其與臨床徵象或症狀有關，需要干預，導致SAE，或導致研究終止或研究治療中斷/中止。當記錄由實驗室異常導致的AE時，應記錄所產生的醫學病狀而非異常本身(例如記錄「貧血」，而非「低血紅素」)。The following information should be considered when determining whether to record a test result, medical condition, or other event on the AE and Pre-Existing Condition CRF:• From the time of informed consent signing until the day before Study Day 1, only protocol-related AEs should be recorded. Protocol-related AEs are defined as adverse medical events that occur as a result of a protocol-specified procedure.• All medical conditions that were present or occurring prior to dosing on Study Day 1 should be recorded.• All AEs (regardless of relationship to study drug) should be recorded from Study Day 1 (pre-dose) through the end of the safety reporting period. Complications that occur in association with any procedure (e.g., biopsy) should be recorded as AEs, regardless of whether the procedure was protocol-specified.• Changes in medical conditions and AEs (including severity, frequency, or character) that occur during the safety reporting period should be recorded.• Generally, abnormal laboratory values should not be recorded as AEs unless they are associated with clinical signs or symptoms, require intervention, result in a SAE, or result in study termination or study treatment interruption/discontinuation. When recording an AE due to a laboratory abnormality, the resulting medical condition should be recorded rather than the abnormality itself (e.g., record “anemia” rather than “low hemoglobin”).
嚴重不良事件Serious adverse events
若AE滿足以下準則中之一者，則應將其歸類為SAE： • 致死性：AE導致死亡 • 危及生命：AE將患者置於直接的死亡風險中。此分類不適用於假設若更嚴重則會引起死亡之AE。 • 住院：AE導致住院或延長現有住院患者的住院。根據此準則，在簽署研究知情同意書或常規檢查之前計劃的選擇性醫療或外科手術或治療的住院不為SAE。入住姑息治療單位或臨終關懷機構不被視為住院。在臨床試驗期間未惡化之潛在癌症或研究目標疾病之治療性、診斷性或手術程序的預先計劃的住院不必記為SAE。 • 失能/無力：導致持續或顯著失能或實質性破壞患者進行正常生活功能之能力的AE。 • 先天性異常或出生缺陷：在懷孕之前或妊娠期間暴露於分子或研究治療劑療法之患者的孩子或胎兒出現的不良結果。 • 醫學上顯著：AE不滿足上述準則中之任一者，但可能危及患者且可能需要醫療或手術干預來預防上文所列之結果中之一者，或涉及疑似經由傳染媒介物藥品傳播。An AE should be classified as an SAE if it meets one of the following criteria:• Fatal: The AE resulted in death• Life-threatening: The AE placed the patient at immediate risk of death. This classification does not apply to AEs that would have resulted in death if they were more severe.• Hospitalization: The AE resulted in hospitalization or prolonged hospitalization of an existing patient. Hospitalizations for elective medical or surgical procedures or treatments planned prior to signing the study informed consent or routine workup are not SAEs based on this criterion. Admissions to palliative care units or hospice facilities are not considered hospitalizations. Preplanned hospitalizations for therapeutic, diagnostic, or surgical procedures for underlying cancers or study target diseases that do not worsen during the clinical trial do not need to be recorded as SAEs.• Disability/Incapacity: AEs that result in persistent or significant disability or that substantially impair the patient's ability to carry out normal life functions.• Congenital anomaly or birth defect: Adverse outcome in a child or fetus of a patient exposed to the molecule or investigational therapy before or during pregnancy.• Medically significant: AEs that do not meet any of the above criteria but are potentially hazardous to the patient and may require medical or surgical intervention to prevent one of the outcomes listed above, or involve suspected drug transmission via an infectious agent.
不良事件嚴重度Severity of adverse events
AE嚴重度應使用美國國家癌症研究所不良事件通用術語準則(NCI CTCAE) 4.03版分級。AE severity should be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
獨立地評估AE嚴重度及嚴重性。「嚴重度」表徵AE之強度。「嚴重性」為法規定義且充當試驗委託者界定法規報告義務的指導(參見上述SAE定義)。Independently assess the severity and severity of the AE. “Severity” characterizes the intensity of the AE. “Severity” is defined by regulation and serves as a guide for trial commissioners in defining regulatory reporting obligations (see SAE definition above).
不良事件與研究治療之關係Relationship of adverse events to study treatment
各AE與恩諾單抗維多汀及/或派姆單抗及/或卡鉑/順鉑/吉西他濱的關係應由研究者利用使用準則評估： • 相關：有證據表明藥物與AE之間存在因果關係，諸如： o 單次出現不常見且已知與藥物暴露強烈相關之事件(例如，血管性水腫、肝損傷、史蒂芬斯-強森症候群) o 一或多次出現通常不與藥物暴露相關但在暴露於藥物之群體中並不常見之事件(例如，肌腱斷裂) • 不相關：AE之另一原因似乎更合理(例如歸因於潛在疾病或在研究群體中普遍發生)，或AE發作及研究治療投與無法建立時間順序，或因果關係被視為生物學上不可行。 (b)促使報告及記錄不良事件的程序The relationship of each AE to enrofloxacin and/or pembrolizumab and/or carboplatin/cisplatin/gemcitabine should be assessed by the investigator using the following criteria:• Related: There is evidence of a causal relationship between the drug and the AE, such as:o A single occurrence of an uncommon event known to be strongly related to drug exposure (e.g., angioedema, liver injury, Stevens-Johnson syndrome)o One or more occurrences of events not usually related to drug exposure but uncommon in the population exposed to the drug (e.g., tendon rupture)• Unrelated: Another cause of the AE seems more plausible (e.g., due to the underlying disease or common in the study population), or a temporal sequence between the onset of the AE and administration of study treatment cannot be established, or a causal relationship is considered biologically implausible.(b) Procedures to facilitate reporting and recording of adverse events
適當時，研究者及研究人員藉由將所有AE及SAE記錄於CRF及/或SAE表格上來報告所有AE及SAE，不論其是否在患者問卷調查期間促成、在體檢、實驗室試驗期間發現及/或藉由其他方式發現。Investigators and study personnel reported all AEs and SAEs by recording them on the CRF and/or SAE forms, as appropriate, regardless of whether they were prompted during the patient questionnaire, discovered during physical examination, laboratory testing, and/or discovered by other means.
促使報告不良事件Promoting reporting of adverse events
每次研究訪視時應使用開放式或非導引式問卷調查方法來促使報告AE。Open-ended or unguided questionnaires should be used at each study visit to prompt reporting of AEs.
記錄不良事件Record adverse events
以下資訊應記錄於AE及預存病狀CRF上： • 包括發生及消退日期在內的說明 • 其是否符合SAE準則 • 嚴重度 • 與研究治療的關係或其他因果關係 • 結果The following information should be recorded on the AE and pre-existing condition CRF:• Description including dates of onset and resolution• Whether it meets the SAE criteria• Severity• Relationship to study treatment or other causal relationship• Outcome
診斷相對於徵象或症狀Diagnosis versus signs or symptoms
一般而言，相對於列出個別症狀，較佳使用統一診斷。僅當徵象及/或症狀的各分量為醫學上確認的診斷分量(如標準醫學教科書所證明)時，才應將症狀分類納入診斷。若徵象或症狀之任何態樣不符合經典的診斷模式，則個別症狀作為各別AE報告。In general, it is preferable to use a unified diagnosis rather than listing individual symptoms. Symptoms should be categorized into a diagnosis only if the individual components of a sign and/or symptom are medically recognized diagnostic components (as evidenced by standard medical textbooks). If any aspect of a sign or symptom does not fit the classical diagnostic pattern, the individual symptoms should be reported as separate AEs.
此研究的重要例外為與研究藥物輸注相關的不良反應。對於IRR，記錄NCI CTCAE術語「輸注相關反應」以及總體嚴重度(根據NCI CTCAE)。另外，反應的各徵象或症狀作為個別AE記錄。若既定輸注相關事件出現多種徵象或症狀，則應分別記錄各徵象或症狀之嚴重度。An important exception for this study is adverse reactions related to the infusion of the study drug. For IRRs, record the NCI CTCAE term "infusion-related reaction" along with the overall severity (according to the NCI CTCAE). In addition, each sign or symptom of the reaction is recorded as an individual AE. If multiple signs or symptoms occur for a given infusion-related event, the severity of each sign or symptom should be recorded separately.
記錄嚴重不良事件Recording of serious adverse events
對於SAE而言，將事件記錄於CRF與SAE表格上。For SAEs, record the event on both the CRF and the SAE form.
當記錄SAE時，應考慮以下內容： • 死亡為事件的結果。導致死亡的事件應記錄且報告於SAE表格與CRF。 • 對於住院、手術或診斷程序而言，導致進行手術或診斷程序的病痛應記錄為SAE，而非程序自身。程序應作為回應於病痛而採取的行動的一部分記於敍述內容中。When recording an SAE, the following should be considered:• Death is the outcome of the event. Events leading to death should be recorded and reported on the SAE form and CRF.• For hospitalizations, surgeries, or diagnostic procedures, the illness leading to the surgery or diagnostic procedure should be recorded as an SAE, not the procedure itself. The procedure should be recorded in the narrative as part of the actions taken in response to the illness.
潛在癌症惡化Potential cancer progression
由於潛在惡性腫瘤之惡化以功效變數形式評估，因此其不應報告為AE或SAE。疾病惡化之放射照相跡象(例如「腫瘤惡化」或「轉移」)不應報告為AE或SAE (此等資料在功效評估中擷取)。若不能確定症狀完全由於潛在惡性腫瘤之惡化或不符合所研究疾病之預期惡化模式，則疾病惡化之臨床症狀及徵象(例如「疲乏」、「呼吸困難」)可報告為AE或SAE；疾病惡化未報告為AE術語。另外，由潛在惡性腫瘤惡化引起的併發症應報告為AE或SAE。Because worsening of a potentially malignant tumor is assessed as an efficacy variable, it should not be reported as an AE or SAE. Radiographic signs of disease worsening (e.g., "tumor worsening" or "metastasis") should not be reported as an AE or SAE (these data are captured in the efficacy assessment). Clinical symptoms and signs of disease worsening (e.g., "fatigue," "dyspnea") may be reported as an AE or SAE if it cannot be determined that the symptoms are entirely due to worsening of a potentially malignant tumor or do not fit the expected pattern of worsening of the disease under study; disease worsening is not reported as an AE term. In addition, complications caused by worsening of a potentially malignant tumor should be reported as an AE or SAE.
死亡為事件的結果。導致死亡的事件應記錄且報告於SAE表格與CRF。Death is the outcome of an event. Events resulting in death should be recorded and reported on the SAE form and CRF.
妊娠Pregnancy
藥物安全注意事項：對於自研究藥物第一次給與時直至研究藥物最後一次給與之後的6個月發生的所有妊娠，包括男性研究患者伴侶發生的任何妊娠，均完成妊娠報告表格。若估算的懷孕日期在男性患者第一次給與研究藥物之後，則報告男性患者伴侶發生的妊娠。在得知妊娠後48小時內將電子郵件或傳真發送至藥物安全部門(參見SAE報告表中指定之電子郵件或傳真號碼)。全程監測所有妊娠；應報告所有圍產期及新生兒結果。嬰兒應隨訪最少8週。Drug Safety Notes: Complete the Pregnancy Reporting Form for all pregnancies occurring from the time of the first dose of study drug until 6 months after the last dose of study drug, including any pregnancies occurring in partners of male study patients. Report pregnancies occurring in partners of male patients if the estimated date of conception is after the first dose of study drug in male patients. Email or fax to Drug Safety Department within 48 hours of learning of pregnancy (see email or fax number specified in SAE Reporting Form). Monitor all pregnancies throughout; all perinatal and neonatal outcomes should be reported. Infants should be followed for a minimum of 8 weeks.
CRF資料的收集：在研究藥物最後一次給與的30天內發生的所有妊娠(如上文所述)亦記錄於AE及預存病狀CRF上。Collection of CRF Data: All pregnancies occurring within 30 days of the last dose of study drug (as described above) were also recorded on the AE and Pre-Existing Conditions CRF.
不論意外、治療或自發引起的流產應報告為SAE。由以上「嚴重」準則定義的先天性異常或出生缺陷應報告為SAE。Abortions, whether accidental, treated, or spontaneous, should be reported as SAEs. Congenital anomalies or birth defects defined by the “serious” criteria above should be reported as SAEs.
角膜不良事件Corneal adverse events
角膜潰瘍或角膜炎AE≥2級應在其各別NCI CTCAE類別內分級。1級角膜潰瘍或角膜炎AE應根據「眼病-其他，詳細說明(Eye disorders - Other, specify)」準則分級。其他角膜AE應根據「眼病-其他，詳細說明」準則記錄且分級。Corneal ulcer or keratitis AEs ≥ Grade 2 should be graded within their respective NCI CTCAE categories. Grade 1 corneal ulcer or keratitis AEs should be graded according to the Eye disorders - Other, specify criteria. Other corneal AEs should be recorded and graded according to the Eye disorders - Other, specify criteria.
糖尿病及高血糖症Diabetes and hyperglycemia
糖尿病之分級應基於NCI CTCAE v4.03葡萄糖不耐事件術語。高血糖症之分級應基於NCI CTCAE v4.03高血糖症事件術語。The grading of diabetes mellitus should be based on the NCI CTCAE v4.03 Glucose Intolerance Event Terminology. The grading of hyperglycemia should be based on the NCI CTCAE v4.03 Hyperglycemia Event Terminology.
可能的肝源不良事件Possible adverse events of hepatic origin
若AE伴有LFT值(例如AST、ALT、膽紅素等)增加或懷疑歸因於肝功能異常，則參見章節6.1.12以瞭解肝臟異常監測及評估建議的詳細資訊。關於與肝安全有關的治療中止建議，參見6.1.6.2(iii)(a)。If the AE is associated with an increase in LFT values (e.g., AST, ALT, bilirubin, etc.) or is suspected to be due to liver function abnormalities, refer to section 6.1.12 for details on recommendations for monitoring and evaluation of liver abnormalities. For recommendations on treatment discontinuation related to liver safety, refer to 6.1.6.2(iii)(a).
應謹慎地監測肝源AE伴有LFT異常的患者。 (c)不良事件及嚴重不良事件報告期Patients with hepatic AEs and abnormal LFTs should be carefully monitored.(c) Adverse events and serious adverse events reporting period
追蹤SAE直至顯著變化返回至基線，事件穩定(恢復/消退)或不再被研究者視為臨床上顯著，或患者死亡或撤回同意書。貫穿安全報告期追蹤所有非SAE。研究者盡一切努力追蹤所有非嚴重AE患者之結果。可追蹤某些非嚴重AESI，直至消退、返回至基線或研究結束，以較晚者為準。符合任何嚴重準則之AE的報告時間框描述於以下章節(d) (「嚴重不良事件需要立即報告」)中。SAEs are tracked until a significant change returns to baseline, the event stabilizes (recovers/resolves) or is no longer considered clinically significant by the investigator, or the patient dies or withdraws consent. All non-SAEs are tracked throughout the safety reporting period. The investigator makes every effort to track outcomes for all patients with non-serious AEs. Certain non-serious AESIs may be tracked until resolution, return to baseline, or end of study, whichever is later. The reporting timeframe for AEs that meet any severity criteria is described in section (d) below (“Serious Adverse Events Require Immediate Reporting”).
所有AE及SAE (除與派姆單抗相關之SAE外)之安全報告期係自研究第1天(給藥前)至EOT訪視或最後一次研究治療後30天，以較晚者為準。與派姆單抗相關之SAE的報告期係自研究第1天(給藥前)至EOT訪視或最後一次研究治療後90天，以較晚者為準，或若參與者開始新的抗癌療法則為研究治療停止之後30天。自知情同意書籤署時記錄與研究方案相關的所有AE。安全報告期之後發生且研究者認為與研究治療相關的所有SAE亦應報告給試驗委託者。研究者盡一切努力追蹤所有非嚴重AE患者之結果。 (d)嚴重不良事件需要立即報告The safety reporting period for all AEs and SAEs (except SAEs related to pembrolizumab) is from Study Day 1 (pre-dose) to the EOT visit or 30 days after the last study treatment, whichever is later. The reporting period for SAEs related to pembrolizumab is from Study Day 1 (pre-dose) to the EOT visit or 90 days after the last study treatment, whichever is later, or 30 days after the cessation of study treatment if the participant starts a new anticancer regimen. All AEs related to the study protocol are recorded from the time of informed consent signing. All SAEs occurring after the safety reporting period and considered by the investigator to be related to the study treatment should also be reported to the trial sponsor. The investigator makes every effort to track the outcomes of all patients with non-serious AEs.(d) Serious adverse events require prompt reporting
在觀測或瞭解到SAE的24小時內，研究者應將事件報告給試驗委託者，不論事件與研究治療方案的關係如何。Within 24 hours of observing or becoming aware of a SAE, the investigator should report the event to the trial sponsor, regardless of the relationship of the event to the study treatment regimen.
對於初始SAE報告而言，應將可獲得的病例細節記錄於SAE表格上。最少應包括以下內容： • 患者編號 • 事件發生日期 • 事件描述 • 研究者之因果關係評估 • 研究治療(若已知)For initial SAE reports, available case details should be recorded on the SAE form. At a minimum, the following should be included:• Patient ID• Date of event• Description of event• Investigator’s causality assessment• Study treatment (if known)
完成的SAE表格及SAE傳真封面在24小時內藉由電子郵件或傳真發送至試驗委託者藥物安全部門。The completed SAE form and SAE fax cover are sent to the trial sponsor's drug safety department via email or fax within 24 hours.
一旦相關隨訪資訊變得可用，則將相關隨訪資訊提交至試驗委託者。 (e)特別受關注之不良事件Once relevant follow-up information becomes available, relevant follow-up information will be submitted to the trial sponsor.(e) Adverse events of special concern
所選AE亦稱為AESI，且必須報告給試驗委託者。Selected AEs are also called AESIs and must be reported to the trial sponsor.
恩諾單抗維多汀Ennotumab Vedotin
可追蹤某些非嚴重AESI (包括收集伴隨藥物治療)直至消退、返回至基線或患者退出研究，以較晚者為準。Certain non-serious AESIs may be followed (including collection of concomitant medication treatment) until resolution, return to baseline, or patient withdrawal from the study, whichever is later.
出於此目的，與恩諾單抗維多汀或恩諾單抗維多汀組合派姆單抗相關之AESI包括以下列出的事件(*表示事件必須≥2級或引起劑量修改之任何級別以被視為AESI)： • 皮疹 • 周邊神經病變 • 角膜事件 • 高血糖症 • IRR • imAE o 肺炎* o 腹瀉*或結腸炎* o 肝炎或AST/ALT或總膽紅素升高* o 內分泌病* (定義為垂體炎、腎上腺機能不全、甲狀腺低能症、甲狀腺高能症) o 腎炎或急性腎衰竭 o 心肌炎 o 胰臟炎 o 重症肌無力或症候群 o 血管炎 o 硬化性膽管炎 o 與免疫介導作用機制一致的研究者確認的imAE，其需要用全身皮質類固醇、其他免疫抑制劑或內分泌療法治療，且無明確替代病原。 (f)需要立即報告的特別受關注之不良事件For this purpose, AESIs associated with enrofloxacin or the combination of enrofloxacin and pembrolizumab include the events listed below (* indicates an event must be ≥ Grade 2 or any grade that resulted in a dose modification to be considered an AESI): • Rash• Peripheral neuropathy• Corneal events• Hyperglycemia• IRR• imAEso Pneumonitis*o Diarrhea* or colitis*o Hepatitis or elevated AST/ALT or total bilirubin*o Endocrinopathy* (defined as hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism)o Nephritis or acute renal failureo Myocarditiso Pancreatitiso Myasthenia gravis or syndromeo Vasculitiso Sclerosing cholangitiso Investigator-confirmed imAEs consistent with an immune-mediated mechanism of action requiring treatment with systemic corticosteroids, other immunosuppressants, or endocrine therapy, with no clear alternative etiology.(f) Adverse events of special concern requiring immediate reporting
對於自簽署同意書開始直至治療配置之時段，若任何患者發生的任何下列AESI或下列AESI的後續情況導致患者自試驗排除或為方案指定干預之結果(包括但不限於清除或中止通常療法、飲食或程序)，則必須在24小時內報告給試驗委託者。For the period from the signing of the consent form until treatment disposition, any patient who experiences any of the following AESIs or the sequelae of any of the following AESIs that results in the patient being excluded from the trial or undergoing a protocol-specified intervention (including but not limited to removal or discontinuation of usual therapy, diet, or procedures) must be reported to the trial sponsor within 24 hours.
對於在第1週期第1天開始直至最後一次給與研究藥物之後30天的時段，任何下列AESI或AESI之後續情況(無論是否與試驗委託者之產品相關)必須在24小時內藉由電子媒介或以紙質形式報告給試驗委託者。電子報告程序可見於EDC資料登錄指南。For the period beginning on Day 1 of Cycle 1 and ending 30 days after the last dose of study drug, any of the following AESIs or subsequent occurrences of AESIs (regardless of whether they are related to the sponsor’s product) must be reported to the sponsor electronically or in paper form within 24 hours. The electronic reporting procedures can be found in the EDC Data Entry Guide.
用於此目的之AESI包括： • 試驗委託者之產品過量(對於恩諾單抗維多汀：如所定義，在恩諾單抗維多汀過量＞10%之情況下，一旦發現過量，站點應立即通知試驗委託者。應密切監測患者之不良反應。應根據機構標準進行支持性照護(恩諾單抗維多汀)；且對於派姆單抗：如所定義，派姆單抗過量定義為≥1000 mg (5倍劑量)派姆單抗。沒有特定資訊可用於治療派姆單抗過量。在發生過量之情況下，一旦發現過量，站點應立即通知試驗委託者。應密切觀測患者之毒性徵象。若臨床上指示，則應提供適當支持性治療(派姆單抗))，該過量與臨床症狀或異常實驗室結果無關。 • 未另外藉由如章節6.1.6.2(iii)(a)中所定義之潛在肝臟病狀解釋的LFT增加。肝臟安全監測及評估之額外建議可見於章節6.1.12。 (f)生命徵象AESIs for this purpose include: • Overdose of the trial sponsor's product (for enrofloxacin: As defined, in the case of an enrofloxacin overdose >10%, the site should notify the trial sponsor immediately upon discovery of the overdose. Patients should be closely monitored for adverse reactions. Supportive care should be provided according to institutional standards (enrofloxacin); and for pembrolizumab: As defined, an overdose of pembrolizumab is defined as ≥1000 mg (5x dose) of pembrolizumab. No specific information is available for the treatment of pembrolizumab overdose. In the event of an overdose, sites should notify the trial sponsor immediately upon detection of the overdose. Patients should be closely monitored for signs of toxicity. Appropriate supportive treatment (pembrolizumab) should be provided if clinically indicated) for overdose not associated with clinical symptoms or abnormal laboratory results. • Increased LFTs not otherwise explained by underlying hepatic pathology as defined in Section 6.1.6.2(iii)(a). Additional recommendations for hepatic safety monitoring and assessments can be found in Section 6.1.12. (f) Vital Signs
執行生命徵象量測，包括心率(bpm)、舒張壓及收縮壓(mmHg)以及體溫。記錄生命徵象值，且與臨床上顯著的異常生命徵象相關的任何診斷記錄為AE或預存病狀。 (ii)臨床實驗室測試Vital sign measurements were performed, including heart rate (bpm), diastolic and systolic blood pressure (mmHg), and temperature. Vital sign values were recorded, and any diagnosis associated with clinically significant abnormal vital signs was recorded as an AE or pre-existing condition. (ii)Clinical Laboratory Tests
取樣用於當地實驗室。Samples were taken for use in local laboratories.
當地實驗室測試包括用於研究合格性、評估安全性及制定臨床決策之機構標準測試。為了確定是否繼續給藥或是否需要劑量修改，研究藥物投與之前，必須審查所有當地實驗室測試結果。Local laboratory tests include institutional standard tests used for study eligibility, assessing safety, and making clinical decisions. All local laboratory test results must be reviewed prior to study drug administration to determine whether to continue dosing or if a dose modification is needed.
以下實驗室評估由當地實驗室進行，以評估在研究過程期間排定時間點(參見表17)之安全性： • 血清化學組包括以下測試：白蛋白、鹼性磷酸酶、ALT、AST、碳酸氫鹽、血尿素氮、鈣、肌酐、氯離子、乳酸去氫酶、磷、鉀、鈉、總膽紅素、澱粉酶、脂肪酶、尿酸及GFR。 o 在給藥之前驗證血糖＜250 mg/dL (參見章節6.1.6.4(iv))。糖尿病患者必須在臨床中進行測試，且在給藥前血糖必須＜250 mg/dL。允許使用胰島素作為SOC之部分。 • 分類CBC包括以下測試：分五種部分的白血球計數(嗜中性白血球、淋巴球、單核球、嗜酸性白血球及嗜鹼性白血球)、血小板計數、血紅素及血容比。 • 根據機構標準確定的基線時CrCl。 • 甲狀腺功能測試，包括： o 三碘甲狀腺素或游離三碘甲狀腺素 o 游離甲狀腺素 o 甲狀腺刺激素 • 標準尿樣分析(使用反射顯微鏡) • INR/PT/PTT • B型肝炎表面抗原及抗B型肝炎核心抗體的血清學。 • 抗C型肝炎抗體的血清學。若為陽性，則後續進行聚合酶鏈反應/病毒負荷測試。 • 針對有生育潛力女性的血清或尿液β人類絨毛膜激性腺素妊娠測試。 • HbA1c。若HbA1c升高(≥6.5%)，則在第1週期期間將患者轉診至適當提供者以進行葡萄糖管控。 (iii)包括體重在內的體檢The following laboratory assessments were performed by local laboratories to assess safety at scheduled times during the study (see Table 17): • Serum chemistry panel including the following tests: albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea nitrogen, calcium, creatinine, chloride ion, lactate dehydrogenase, phosphorus, potassium, sodium, total bilirubin, amylase, lipase, uric acid, and GFR. o Verify blood glucose <250 mg/dL prior to dosing (see Section 6.1.6.4(iv)). Patients with diabetes must be tested in the clinic and blood glucose must be <250 mg/dL prior to dosing. Insulin is permitted as part of the SOC. • CBC with differential including the following tests: WBC count with five parts (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), platelet count, hemoglobin, and hematocrit. • CrCl at baseline determined according to institutional standards. • Thyroid function tests including: o Triiodothyronine or free triiodothyronine o Free thyroxine o Thyroid stimulating hormone • Standard urine analysis (using a reflective microscope) • INR/PT/PTT • Serology for hepatitis B surface antigen and anti-hepatitis B core antibody. • Serology for anti-hepatitis C antibody. If positive, follow up with polymerase chain reaction/viral load test. • Serum or urine beta human chorionic gonadotropin pregnancy test for females of childbearing potential. • HbA1c. If HbA1c is elevated (≥6.5%), refer the patient to an appropriate provider for glucose management during Cycle 1. (iii)Physical examination including weight
體檢應包括評估以下身體部分/系統：皮膚、腹部、肢體、頭部、心臟、肺、頸部及神經。僅在基線訪視時收集身高。在指定時間點(參見表17)，且另外在適用時根據機構標準收集體重，但在EOT之後訪視時不需要收集體重。 (iv)ECOG體能狀態The physical examination should include assessment of the following body parts/systems: skin, abdomen, extremities, head, heart, lungs, neck, and nerves. Height is collected only at the baseline visit. Weight is collected at designated time points (see Table 17) and additionally when applicable according to institutional standards, but does not need to be collected at post-EOT visits. (iv)ECOGperformance status
在方案指定時間點評估ECOG體能狀態(參見表17)。 表17體能狀態量表轉換
心臟監測Heart monitoring
在基線及EOT訪視時進行ECG。若臨床上指示，則應進行額外的ECG。患者以仰臥姿勢維持至少5分鐘之後，執行常規12導程ECG。根據此方案之修正案6及早期修正案進行之所有ECG在中央執行。根據此方案之修正案7進行之所有ECG在當地執行。若可能，則應在獲得PK及生物標記物樣品之前執行ECG評估。對於患有NYHA III級心臟衰竭(參見章節6.1.11)或有冠心病、心律不整或其他嚴重心臟病史的個體，需要在基線時進行經胸ECHO。若臨床上指示，則將來測試應使用相同模式。 (v)全面眼部檢查Perform ECGs at baseline and at the EOT visit. Additional ECGs should be obtained if clinically indicated. A routine 12-lead ECG is performed after the patient has been in the supine position for at least 5 minutes. All ECGs performed under Amendment 6 and earlier amendments to this protocol are performed centrally. All ECGs performed under Amendment 7 to this protocol are performed locally. ECG assessments should be performed before obtaining PK and biomarker samples, if possible. Transthoracic ECHO is indicated at baseline for individuals with NYHA Class III heart failure (see Section 6.1.11) or a history of coronary artery disease, arrhythmias, or other serious cardiac disease. Future testing should use the same modality if clinically indicated. (v)Comprehensive ocular examination
患者在篩選時由合格的驗光師或眼科醫師執行全面眼部檢查，包括(但不限於)視力、裂隙燈、壓力測定檢查及擴張眼底檢查。後續眼部檢查如臨床上指示進行。在研究期間經歷角膜AE的患者需要進行EOT裂隙燈檢查。EOT裂隙燈檢查(僅在研究期間經歷角膜AE的患者需要)必須距最後一次給藥至少4週執行。6.1.7.9治療後評估(i)隨訪評估Patients underwent a comprehensive eye examination at screening by a qualified optometrist or ophthalmologist, including (but not limited to) visual acuity, slit-lamp, tonometry, and dilated fundus examination. Subsequent eye examinations were performed as clinically indicated. Patients who experienced a corneal AE during the study period were required to undergo an EOT slit-lamp examination. The EOT slit-lamp examination (required only for patients who experienced a corneal AE during the study period) must be performed at least 4 weeks after the last dose of medication.6.1.7.9Post-Treatment Evaluations (i)Follow-up Evaluations
中止研究治療之患者在EOT後每9週(±1週)接受體檢、ECOG評估及反應評估直至第一次給藥後1年，隨後每12週(±1週)進行。每週期完成PRO評估(QLQ-C-30、EQ-5D-5L、BPI-SF、HRU)一次。掃描一直進行到研究治療時或之後放射學確認疾病惡化(對於EV+派姆單抗組，根據iRECIST指南由研究者確定；或對於EV單藥組，根據RECIST 1.1版)、開始後續抗癌療法、患者死亡、研究結束或撤回同意書，以先發生者為準。在研究治療期間，對未惡化之非目標骨病灶的姑息性放射治療(只要目標病灶不在輻射範圍內)不視為後續抗癌療法；然而，對任何目標病灶之放射治療均為後續抗癌療法。 (ii)長期隨訪評估Patients who discontinued study treatment underwent physical examination, ECOG assessment, and response assessment every 9 weeks (±1 week) after EOT until 1 year after the first dose, and then every 12 weeks (±1 week). PRO assessments (QLQ-C-30, EQ-5D-5L, BPI-SF, HRU) were completed once every cycle. Scanning was performed until the time of study treatment or radiologically confirmed disease progression (determined by the investigator according to iRECIST guidelines for the EV+pembrolizumab group; or according to RECIST version 1.1 for the EV monotherapy group), the initiation of subsequent anticancer therapy, patient death, study completion, or withdrawal of consent, whichever occurred first. During the study treatment period, palliative radiation therapy to non-target bone lesions that did not progress (as long as the target lesions were not within the radiation field) was not considered as subsequent anticancer therapy; however, radiation therapy to any target lesions was considered as subsequent anticancer therapy. (ii)Long-term Follow-up Evaluation
在研究治療時或之後放射學確認PD及研究治療中止後，每12週(±1週)聯絡患者以獲得關於後續抗癌療法及存活狀態之資訊。長期隨訪持續，直至患者死亡、研究結束或撤回同意書，以先發生者為準。During or after radiological confirmation of PD and discontinuation of study treatment, patients were contacted every 12 weeks (±1 week) to obtain information about subsequent anticancer therapy and survival status. Long-term follow-up continued until the patient's death, study completion, or withdrawal of consent, whichever occurred first.
在開始後續抗癌療法或在研究治療時或之後根據RECIST 1.1版(EV單藥組)或根據iRECIST (EV+派姆單抗組)放射學確認疾病惡化後，根據機構指南經由成像對患者進行隨訪，但頻率不低於每12週一次，直至記錄到PFS2或患者開始另一抗癌治療，以先發生者為準。所有後續抗癌療法(包括PFS2惡化日期)均記錄在CRF上。另外，EOT後每12週聯絡患者一次，以瞭解後續療法時或之後的存活狀態及臨床惡化狀態。Patients were followed by imaging according to institutional guidelines, but no less frequently than every 12 weeks, after initiation of subsequent anticancer therapy or radiologically confirmed disease worsening according to RECIST version 1.1 (EV monotherapy group) or according to iRECIST (EV + pembrolizumab group) during or after study treatment, until PFS2 was documented or the patient started another anticancer treatment, whichever occurred first. All subsequent anticancer therapies (including the date of PFS2 deterioration) were recorded on the CRF. In addition, patients were contacted every 12 weeks after EOT to understand survival status and clinical deterioration status during or after subsequent therapy.
在PFS2之後，患者進入存活隨訪期，且每12週(±1週)隨訪一次存活狀態直至死亡、研究結束或撤回同意書，以先發生者為準。After PFS2, patients entered the survival follow-up period and were followed up for survival status every 12 weeks (±1 week) until death, study termination, or withdrawal of consent, whichever occurred first.
每週期完成PRO評估(QLQ-C-30、EQ-5D-5L、BPI-SF、HRU)一次。6.1.7.10量測的適當性Complete PRO assessments (QLQ-C-30, EQ-5D-5L, BPI-SF, HRU) once per cycle.6.1.7.10Appropriateness of measurement
此試驗中使用的安全措施視為評估研究藥物之潛在不良作用的標準程序。The safety measures used in this study are considered standard procedures for evaluating potential adverse effects of study drugs.
抗腫瘤活性之確定係基於RECIST 1.1版(Eisenhauer 2009) (表40)所定義之確認的客觀反應評估，且研究者之治療決定對於EV+派姆單抗組係基於iRECIST指南(Seymour 2017) (章節6.1.15)；或對於EV單藥組係根據RECIST 1.1版。RECIST準則在此類型贅瘤的腫瘤學實務中被視為標準，且此方案中的評估時間間隔適於疾病管控。iRECIST指南為用作此研究之探索性準則的新公開準則。此等指南考慮到免疫治療劑(諸如派姆單抗)可引起免疫細胞浸潤，導致惡性病灶之尺寸暫時增加或不可偵測的病灶變得可偵測。指南在許多方面與RECIST 1.1版相同，但經調適以考慮腫瘤負荷增加或新病灶出現並不反映真實腫瘤惡化的情況。Antitumor activity was determined based on confirmed objective response assessments as defined by RECIST version 1.1 (Eisenhauer 2009) (Table 40), and investigator treatment decisions were based on iRECIST guidelines (Seymour 2017) (Section 6.1.15) for the EV+pembrolizumab arm; or RECIST version 1.1 for the EV alone arm. RECIST guidelines are considered standard in oncology practice for this type of tumor, and the assessment intervals in this protocol were appropriate for disease control. iRECIST guidelines are new published guidelines used as exploratory guidelines for this study. These guidelines take into account that immunotherapeutic agents (such as pembrolizumab) can induce immune cell infiltration, resulting in a temporary increase in the size of malignant lesions or undetectable lesions becoming detectable. The guidelines are identical to RECIST version 1.1 in many respects but have been adapted to take into account situations where an increase in tumor burden or the appearance of new lesions does not reflect true tumor progression.
通常評估生物製劑之免疫原性；因此，執行標準測試以偵測針對恩諾單抗維多汀之特異性抗體的可能存在。Biologics are routinely evaluated for immunogenicity; therefore, standard testing is performed to detect the possible presence of antibodies specific to enrofloxacin.
PK評估亦常見於臨床研究中以有助於表徵劑量暴露反應關係。PK assessments are also commonly used in clinical studies to help characterize dose-exposure-response relationships.
周邊血液樣品中的探究性生物標記物量測能夠與PK評估建立相關性且常見於臨床研究中。類似常見的是，對治療前腫瘤組織執行評估。周邊血液與腫瘤生物標記物樣品利用常用的標準測試加以評估。6.1.8資料分析方法6.1.8.1樣本大小的確定Measurement of exploratory biomarkers in peripheral blood samples can be correlated with PK assessments and is common in clinical studies. Similarly, assessments are performed on pre-treatment tumor tissue. Peripheral blood and tumor biomarker samples are assessed using commonly used standard assays.6.1.8Data Analysis Methods6.1.8.1Determination of Sample Size
將約150名患者以1:1之比隨機分組以接受恩諾單抗維多汀單藥療法(EV單藥組)或恩諾單抗維多汀組合派姆單抗(EV+派姆單抗組)。Approximately 150 patients were randomized in a 1:1 ratio to receive either enroku vedotin monotherapy (EV monotherapy group) or enroku vedotin combined with pembrolizumab (EV+pembrolizumab group).
樣本大小並非基於正式假設檢定之檢定力計算，而是基於藉由95% CI表徵的ORR之估計的精確度而選擇。未執行2個組之間的正式統計比較。The sample size was not chosen based on power calculations for formal hypothesis testing but rather on the precision of the estimate of the ORR as represented by the 95% CI. No formal statistical comparisons between the 2 groups were performed.
對於每組75名患者之樣本大小，假定ORR在50%與70%之間，雙邊95% CI概述於下表18中。 表18雙邊95% CI之概述
總共約150名患者入選研究。6.1.8.2研究終點定義(i)客觀反應率(ORR)A total of approximately 150 patients were enrolled in the study.6.1.8.2Study Endpoint Definitions (i)Objective Response Rate(ORR)
主要終點為藉由BICR評估的ORR。研究者評估的ORR為次要終點。The primary endpoint was ORR assessed by BICR. Investigator-assessed ORR was a secondary endpoint.
ORR定義為根據RECIST 1.1版(Eisenhauer 2009) (表40)具有確認的CR或PR的患者比例。未經歷至少2次(初始反應及確認性掃描)基線後反應評估的患者視為無反應者。ORR was defined as the proportion of patients with a confirmed CR or PR according to RECIST version 1.1 (Eisenhauer 2009) (Table 40). Patients who did not undergo at least 2 post-baseline response assessments (initial response and confirmatory scan) were considered non-responders.
對於利用派姆單抗之組，分析了概述基於iRECIST指南具有確認的CR或PR之患者比例的ORR獨立終點。 (ii)反應持續時間(DOR)For the pembrolizumab group, the independent endpoint of ORR, which summarizes the proportion of patients with a confirmed CR or PR based on iRECIST guidelines, was analyzed. (ii)Duration of response(DOR)
根據RECIST 1.1版之DOR定義為自第一次記錄客觀反應(隨後得到確認)至第一次記錄客觀腫瘤惡化或至因任何原因所致之死亡(以先發生者為準)的時間。DOR according to RECIST version 1.1 was defined as the time from the first documented objective response (subsequently confirmed) to the first documented objective tumor worsening or to death from any cause, whichever occurred first.
BICR及研究者評估的DOR為次要終點。BICR and investigator-assessed DOR were secondary endpoints.
僅計算達成確認的CR或PR之患者的DOR。DOR was calculated only for patients who achieved a confirmed CR or PR.
如下所述審查DOR資料： • 不具有PD且在分析時仍處於研究中的患者在記錄不存在PD的最後一次疾病評估日接受審查； • 在記錄PD之前開始除研究治療之外的抗癌療法的患者在新療法開始之前的最後一次疾病評估日接受審查； • 在記錄PD之前自研究移除的患者在記錄不存在PD的最後一次疾病評估日接受審查。DOR data were reviewed as follows:• Patients without PD who remained on study at the time of analysis were reviewed on the last disease assessment date when the absence of PD was documented;• Patients who started anticancer therapy other than study treatment before documenting PD were reviewed on the last disease assessment date before starting the new therapy;• Patients who were removed from the study before documenting PD were reviewed on the last disease assessment date when the absence of PD was documented.
對於利用派姆單抗之組，基於iRECIST指南分析DOR之獨立終點，其中基於iRECIST指南之DOR (iDOR)定義為自第一次記錄研究者評估的客觀反應(隨後得到確認)至第一次記錄客觀腫瘤惡化(隨後得到確認)或至因任何原因所致之死亡(以先發生者為準)的時間。 (iii)疾病控制率(DCR)For the pembrolizumab group, the independent endpoint of DOR was analyzed based on the iRECIST guidelines, where DOR based on the iRECIST guidelines (iDOR) was defined as the time from the first documented investigator-assessed objective response (subsequently confirmed) to the first documented objective tumor progression (subsequently confirmed) or death from any cause, whichever occurred first. (iii)Disease Control Rate(DCR)
DCR定義為根據RECIST 1.1版(Eisenhauer 2009) (參見表40)具有CR、PR或SD之患者比例。DCR was defined as the proportion of patients with CR, PR or SD according to RECIST version 1.1 (Eisenhauer 2009) (see Table 40).
BICR及研究者評估的DCR為次要終點。BICR and investigator-assessed DCR were secondary endpoints.
對於利用派姆單抗之組，基於iRECIST指南分析DCR之獨立終點，其中iDCR定義為基於iRECIST指南之CR (iCR)+基於iRECIST指南之部分反應(iPR)+基於iRECIST指南之穩定疾病(iSD)。 (iv)研究療法之無惡化存活期(PFS)For the pembrolizumab group, the independent endpoint of DCR was analyzed based on the iRECIST guidelines, where iDCR was defined as CR based on the iRECIST guidelines (iCR) + partial response based on the iRECIST guidelines (iPR) + stable disease based on the iRECIST guidelines (iSD). (iv)Progression-free survival(PFS) of the study treatment
PFS定義為自研究治療開始至根據RECIST 1.1版第一次記錄研究療法時或之後的客觀腫瘤惡化或至因任何原因所致之死亡(以先發生者為準)的時間。PFS was defined as the time from the start of study treatment to objective tumor progression on or after the first recorded study treatment according to RECIST version 1.1 or to death from any cause, whichever occurred first.
BICR及研究者評估的PFS為次要終點。BICR and investigator-assessed PFS were secondary endpoints.
章節9.2.2中關於DOR概述的審查規則同樣適用於PFS。第一次給藥後未評估腫瘤反應的患者在第1天審查其事件時間。The same review rules outlined for DOR in Section 9.2.2 apply to PFS. Patients who were not evaluable for tumor response after the first dose had their event time reviewed on Day 1.
對於利用派姆單抗之組，基於iRECIST指南分析PFS之獨立終點，其中iPFS定義為自研究治療開始至符合惡化準則之第一日期(亦即iUPD日期) (其限制條件為iCPD在下一次評估時得到確認)或至因任何原因所致之死亡(以先發生者為準)的時間。 (v)總存活期For the pembrolizumab group, the independent endpoint of PFS was analyzed based on the iRECIST guidelines, where iPFS was defined as the time from the start of study treatment to the first date that met the progression criteria (i.e., the iUPD date) (with the restriction that the iCPD was confirmed at the next assessment) or to death due to any cause, whichever occurred first. (v)Overall survival
OS定義為自研究治療開始至因任何原因所致之死亡日期的時間。OS為次要終點。6.1.8.3統計及分析計劃OS was defined as the time from the start of study treatment to the date of death due to any cause. OS was a secondary endpoint.6.1.8.3Statistical and Analysis Plan
下文所呈現之統計及分析計劃對統計分析計劃(statistical analytical plan，SAP)中所詳述的更完整計劃進行了概述。僅當改變方案的主要特徵時，改變方案中所描述的資料分析方法才需要修正方案。SAP在資料庫鎖定之前完成。對最終SAP中所描述之方法的任何改變在臨床研究報告中描述且證明。 (i)一般考慮因素The statistical and analysis plan presented below summarizes the more complete plan detailed in the statistical analytical plan (SAP). Changes to the data analysis methods described in the protocol require revisions to the protocol only if they change major features of the protocol. The SAP is completed before the database is locked. Any changes to the methods described in the final SAP are described and justified in the clinical study report. (i)General Considerations
根據RECIST 1.1版藉由BICR以及研究者評估概述疾病反應。另外，根據iRECIST指南(Seymour 2017) (章節6.1.15)，藉由研究者評估概述EV+派姆單抗組之疾病反應。Disease response was summarized by BICR and investigator assessment according to RECIST version 1.1. In addition, disease response in the EV+pembrolizumab group was summarized by investigator assessment according to the iRECIST guidelines (Seymour 2017) (Section 6.1.15).
一般而言，所呈現的描述性統計資料包括連續變數的觀測次數、平均值、標準差、中值、最小值及最大值，以及分類變數之每個類別的數目及(非遺漏)百分比。In general, descriptive statistics presented include the number of observations, mean, standard deviation, median, minimum and maximum values for continuous variables, and the number and (non-missing) percentage of each category for categorical variables.
除非另外說明，計算雙側95%水平的CI。Unless otherwise stated, two-sided CIs at the 95% level were calculated.
除非另外說明，計算雙側95%水平的CI。Unless otherwise stated, two-sided CIs at the 95% level were calculated.
適用時，使用克洛珀-皮爾森方法(Clopper 1934)，針對反應率(例如，ORR、DCR、pCRR及pDSR)計算雙側95%精確CI。Two-sided 95% exact CIs were calculated for response rates (eg, ORR, DCR, pCRR, and pDSR) using the Clopper-Pearson method (Clopper 1934), when applicable.
對於事件發生時間終點，使用卡本-麥爾(Kaplan Meier)方法估計中值存活時間；相關的95% CI根據互補對數-對數轉換計算(Collett 1994)。For time-to-event endpoints, median survival was estimated with the use of the Kaplan-Meier method; associated 95% CIs were calculated based on the complementary log-log transformation (Collett 1994).
隨機Random分組Grouping及盲and Blind法Law
此為開放標記研究。This is an open label study.
基於以下分層因子，將約150名患者以1:1之比隨機分入EV單藥組或EV+派姆單抗組：不存在或存在肝轉移，及ECOG體能狀態(0相對於1/2)。Approximately 150 patients were randomized in a 1:1 ratio to EV alone or EV + pembrolizumab based on the following stratification factors: absence or presence of liver metastases, and ECOG performance status (0 vs. 1/2).
EV單藥組包括約75名患者。The EV monotherapy group included approximately 75 patients.
EV+派姆單抗組包括約75名患者。The EV+pembrolizumab group included approximately 75 patients.
資料變換及推導Data transformation and derivation
除非計劃分析章節另外說明，否則基於2個日期(例如開始日期及結束日期)的時間變數將按照(結束日期-開始日期+1) (天)計算。Unless otherwise stated in the Planning Analysis section, time variables based on 2 dates (such as start date and end date) are calculated as (end date - start date + 1) (days).
除非在分析計劃中另外規定，否則所有分析中使用之基線值係在第一次給與研究藥物之前的最新非遺漏量測。Unless otherwise specified in the analysis plan, the baseline value used in all analyses was the most recent non-missed measurement prior to the first dose of study drug.
分析集Analysis Set
安全性分析集包括接受任何量之研究藥物(恩諾單抗維多汀或組合藥劑)的所有患者。安全性分析集用於所有安全性分析。The safety analysis set included all patients who received any amount of study drug (enrofloxacin or combination). The safety analysis set was used for all safety analyses.
全分析集(FAS)包括參與研究且接受任何量之研究藥物(恩諾單抗維多汀或組合藥劑)的所有患者。FAS用於分析功效終點。The full analysis set (FAS) included all patients who participated in the study and received any amount of study drug (enrofloxacin or combination). The FAS was used to analyze efficacy endpoints.
可評估有效性之分析集包括FAS中具有至少2個基線後反應評估或出於任何原因之中止治療的所有患者。可評估有效性之分析集用於功效終點之額外分析。The evaluable analysis set included all patients in the FAS who had at least 2 post-baseline response assessments or who discontinued treatment for any reason. The evaluable analysis set was used for additional analyses of efficacy endpoints.
PK分析集包括接受恩諾單抗維多汀的所有患者，自該等患者收集至少1個血液樣品且分析其中的恩諾單抗維多汀、MMAE或TAb濃度。對於所有恩諾單抗維多汀、MMAE及TAb濃度，給藥及樣品收集時間的相應記錄亦須可供利用。PK分析集用於PK參數之分析。The PK analysis set includes all patients who received enroku vedotin and from whom at least one blood sample was collected and analyzed for enroku vedotin, MMAE or TAb concentrations. For all enroku vedotin, MMAE and TAb concentrations, corresponding records of dosing and sample collection times must also be available. The PK analysis set is used for the analysis of PK parameters.
患者的其他分析集可在SAP中定義。Additional analysis sets of patients can be defined in SAP.
子組之檢查Subgroup inspection
作為探索性分析，可對所選終點進行子組分析。As an exploratory analysis, subgroup analyses can be performed on selected endpoints.
子組可包括以下： • 年齡(＜65、≥65歲) • 性別(女性、男性) • ECOG體能狀態(0、1-2) • 貝爾蒙特(Bellmunt)風險評分(0-1、≥2) • 內臟轉移相對於僅淋巴結轉移疾病 • 基線時肝轉移(是、否) • PD-L1表現(CPS ＜10、≥10)Subgroups may include the following:• Age (<65, ≥65 years)• Sex (female, male)• ECOG performance status (0, 1-2)• Bellmunt risk score (0-1, ≥2)• Visceral versus lymph node-only disease• Liver metastases at baseline (yes, no)• PD-L1 expression (CPS <10, ≥10)
分析時序Analysis time series
主要分析基於確認的ORR進行。The primary analysis was based on confirmed ORR.
可定義其他截止日期且可發生相應資料庫鎖定以允許更精確地估算事件發生時間終點。 (ii)患者安置Other cut-off dates may be defined and corresponding database locks may occur to allow for more precise estimates of the time-to-event endpoints. (ii)Patient placement
按安置將研究患者的核算列成表格，且概述各分析集中的患者數目。對於所有參與患者，概述中止研究治療之患者及退出研究之患者，以及中止或退出之原因。 (iii)患者特徵Tabulate the count of study patients by placement and summarize the number of patients in each analysis set. For all participating patients, summarize those who discontinued study treatment and those who withdrew from the study, along with the reasons for discontinuation or withdrawal. (iii)Patient characteristics
按安置將研究患者的人口統計資料核算列成表格，且概述各分析集中的患者數目。對於所有參與患者，概述中止研究治療之患者及退出研究之患者，以及中止或退出之原因。 (iv)功效分析Tabulate the demographics of the study patients by placement and summarize the number of patients in each analysis set. For all participating patients, summarize those who discontinued study treatment and those who withdrew from the study, along with the reasons for discontinuation or withdrawal. (iv)Efficacy Analysis
使用如章節9.4.1.7所定義之FAS分析功效終點之主要分析。功效終點之補充分析可使用可評估有效性之分析集呈現。The primary analysis of efficacy endpoints is performed using the FAS as defined in Section 9.4.1.7. Supplementary analyses of efficacy endpoints can be presented using an analysis set that assesses validity.
使用如章節6.1.7.11所定義之FAS分析功效終點之主要分析。功效終點之補充分析可使用可評估有效性之分析集呈現。The primary analysis of efficacy endpoints is analyzed using the FAS as defined in Section 6.1.7.11. Supplementary analyses of efficacy endpoints can be presented using an analysis set that assesses validity.
主要終點為藉由BICR評估的ORR。使用克洛珀-皮爾森方法按組為FAS群體提供藉由BICR評估的觀測ORR及95% CI。The primary endpoint was ORR assessed by BICR. The observed ORR and 95% CI assessed by BICR were provided for the FAS population by group using the Clopper-Pearson method.
概述對次要終點、研究者評估的ORR、藉由BICR評估的DCR及研究者評估的DCR的分析，且使用克洛珀-皮爾森方法(Clopper 1934)計算其精確雙邊95% CI。Analyses of the secondary endpoints, investigator-assessed ORR, DCR assessed by BICR, and investigator-assessed DCR were summarized, and their exact two-sided 95% CIs were calculated using the Clopper-Pearson method (Clopper 1934).
其他次要終點，諸如藉由BICR評估的DOR、研究者評估的DOR、藉由BICR評估的PFS、研究者評估的PFS、OS為事件發生時間終點，且使用卡本-麥爾方法對其進行分析且提供卡本-麥爾圖。審查演算法的詳情提供於SAP中。Other secondary endpoints such as DOR assessed by BICR, DOR assessed by investigator, PFS assessed by BICR, PFS assessed by investigator, OS were time-to-event endpoints and were analyzed using the Karben-Meier method and Karben-Meier plots were provided. Details of the review algorithm are provided in SAP.
根據iRECIST指南(Seymour 2017) (章節6.1.15)藉由研究者評估的EV+派姆單抗組之ORR、DCR、DOR及PFS與上文所描述類似地執行。ORR, DCR, DOR, and PFS in the EV+pembrolizumab group assessed by investigators were performed similarly to those described above according to the iRECIST guidelines (Seymour 2017) (Section 6.1.15).
未執行2個組之間的正式統計比較。 (v)藥物動力學及ATA分析No formal statistical comparisons between the 2 groups were performed. (v)Pharmacokinetic andATAanalysis
在各PK取樣時間點，以描述性統計概述恩諾單抗維多汀ADC、MMAE及TAb濃度。PK參數，包括(但不限於) AUC、Cmax及Tmax，藉由非隔室分析估計且藉由描述性統計資料概述。可探究PK與藥效學終點、安全性或功效之間的關係。At each PK sampling time point, the concentrations of enrofloxacin ADC, MMAE, and TAb were summarized with descriptive statistics. PK parameters, including (but not limited to) AUC, Cmax, and Tmax, were estimated by non-compartmental analysis and summarized with descriptive statistics. The relationship between PK and pharmacodynamic endpoints, safety, or efficacy can be explored.
使用安全性分析集，按訪視來概述ATA的發生率。 (vi)患者報告結果分析The safety analysis set was used to summarize the incidence of ATA by visit. (vi)Patient-reported outcome analyses
概述各評估之完成及順應率。對FAS群體執行PRO分析。若計劃任何額外分析，則其詳述於補充SAP中。 (vii)生物標記物分析Summarize the completion and compliance rates of each assessment. Perform PRO analysis on the FAS population. If any additional analyses are planned, they are detailed in the supplemental SAP. (vii)Biomarker Analysis
探究生物標記物參數(例如，治療前值、相對於治療前之絕對及相對變化)與功效、安全性及PK參數之關係。概括了確定為感興趣的關係及相關資料。分別描述此等分析之細節。 (viii)安全性分析Explore the relationship between biomarker parameters (e.g., pre-treatment values, absolute and relative changes from pre-treatment) and efficacy, safety, and PK parameters. Summarize the relationships identified as of interest and the relevant data. Describe the details of each of these analyses. (viii)Safety Analysis
安全性分析集用於概述所有安全性終點。 (a)暴露程度The safety analysis set is used to summarize all safety endpoints.(a) Exposure
概述治療持續時間、週期數、總劑量及劑量強度。劑量修改亦以類似方式概述。細節提供於SAP中。 (b)不良事件Summarize duration of treatment, number of cycles, total dose, and dose intensity. Dose modifications are similarly summarized. Details are provided in the SAP.(b) Adverse events
AE綜述將以下的發生率列成表格：所有AE、TEAE、治療相關的AE、3級及更高級AE、SAE、治療相關的SAE、死亡，及引起研究治療中止的AE。若AE在研究治療之後新發生或惡化，則將其定義為治療引發。The AE summary tabulated the incidence of the following: all AEs, TEAEs, treatment-related AEs, grade 3 and higher AEs, SAEs, treatment-related SAEs, deaths, and AEs leading to discontinuation of study treatment. AEs were defined as treatment-emergent if they occurred newly or worsened after study treatment.
AE係藉由監管活動醫學詞典(MedDRA)、較佳術語、嚴重度及與研究藥物之關係列出及概述。在1名患者中多次出現具有相同較佳術語之相同AE的情況下，對AE計數為發生一次。AE之發生率按較佳術語製成表。導致研究藥物過早中止的AE以相同方式概述及列出。 (c)死亡及嚴重不良事件AEs were listed and summarized by Medical Dictionary for Regulatory Activities (MedDRA), preferred term, severity, and relationship to study drug. In case of multiple occurrences of the same AE with the same preferred term in one patient, the AE was counted as one occurrence. The incidence of AEs was tabulated by preferred term. AEs leading to premature discontinuation of study drug were summarized and listed in the same manner.(c) Deaths and serious adverse events
SAE以與所有AE相同之方式列出及概述。列出具有致命結果之事件。 (d)臨床實驗室結果SAEs are listed and summarized in the same manner as all AEs. Events with fatal outcomes are listed.(d) Clinical laboratory results
實驗室值(例如化學、血液學及使用反射顯微鏡分析之尿樣分析)可按訪視以圖形方式呈現。可根據需要按預定訪視將概述統計資料製成表。根據NCI CTCAE 4.03版列舉實驗室值及級別，且當值處於正常參考範圍外時加以標記。 (e)其他安全性分析Laboratory values (e.g., chemistry, hematology, and urine analysis using reflectance microscopy) may be presented graphically by visit. Summary statistics may be tabulated as needed by scheduled visit. Laboratory values and grades are presented according to NCI CTCAE version 4.03, and values are noted when they are outside the normal reference range. (e)Other Safety Analyses
生命徵象Vital signs
在適當時可將概述統計資料及相對於基線及/或給藥前至給藥後的變化製成表。Summary statistics and changes from baseline and/or pre-dose to post-dose may be tabulated when appropriate.
ECOGECOG狀態condition
概述各訪視時之ECOG狀態。可將基線至最佳及最差基線後評分變化製成表。Summarize ECOG status at each visit. Changes in scores from baseline to best and worst baseline can be tabulated.
ECGECG
可針對排定及非排定的各ECG來概述ECG狀態(正常、臨床上顯著的異常或臨床上不顯著的異常)，且可將相對於基線的變化製成表。6.1.9研究結果The ECG status (normal, clinically significant abnormal, or clinically insignificant abnormal) can be summarized for each scheduled and unscheduled ECG, and the change from baseline can be tabulated.6.1.9Study Results
此實例中所描述的恩諾單抗維多汀組合派姆單抗作為不能接受基於順鉑之化學療法的不可切除性局部晚期或轉移性尿路上皮癌(la/mUC)之患者之一線治療的1b/2期研究於2021年10月11日完成入選，其中151名個體入選。研究之EV+派姆單抗組中接受任何量之研究藥物的個體數目為76。研究之EV單藥組中接受任何量之研究藥物的個體數目為73。包括經EV+派姆治療之劑量遞增/群組A (於2019年1月28日完成入選，45名個體入選且45名個體接受任何量之研究藥物)的結果作為如所指示之各種分析的比較。The Phase 1b/2 study of enrofloxacin in combination with pembrolizumab as first-line treatment for patients with unresectable locally advanced or metastatic urothelial carcinoma (la/mUC) who were unable to receive cisplatin-based chemotherapy described in this example completed enrollment on October 11, 2021, with 151 subjects enrolled. The number of subjects in the EV+pembrolizumab arm of the study who received any amount of study drug was 76. The number of subjects in the EV monotherapy arm of the study who received any amount of study drug was 73. Results from Dose Escalation/Cohort A treated with EV+pembro (enrollment completed on January 28, 2019, with 45 subjects enrolled and 45 subjects receiving any amount of study drug) were included as comparisons for various analyses as indicated.
關於安置，如表19中所示，進行性疾病為治療中止之最多說明的原因，其中25名個體在研究之EV+派姆單抗組中繼續治療且8名個體在研究之EV單藥組中繼續治療。 表19
關於人口統計資料，如表20中所示，人口統計資料及基線疾病特徵代表具有高度未滿足的醫療需求的不適合1L順鉑的LA或mUC群體。 表20
關於基線特徵，如表21中所示，研究群體為男性占主導、患有多種共生病症、具有已知不良預後因子之老年群體，代表先前研究中不適合順鉑的群體。 表21
關於基線疾病特徵，如表22中所示，研究群體代表其他臨床試驗中不適合順鉑的群體，且具有已知不良預後因子(例如腎損傷、上泌尿道疾病、包括肝轉移在內的內臟疾病)。 表22
關於順鉑不適合性之原因，如表23中所示，不適合順鉑的群體明確定義。腎機能不全為順鉑不適合性的最常見原因，其次為聽力損失。 表23
根據盲態中央獨立評估(BICR) (根據RECIST 1.1)，群組K EV+派姆單抗組之總反應率(ORR)為64.5% (95% CI：52.7%，75.1%)，完全反應(CR)為10.5%，如表24中所示。根據研究者評估之ORR與BICR評估一致。在群組K EV+派姆單抗組中，研究者與BICR之間的一致性為86.7%。 表24
表25顯示包括前述表24中呈現之資料的群組K EV+派姆單抗組及群組K EV單藥療法組之並列比較，以說明兩個組之間的差異。如上所指示，群組K EV+派姆單抗組之ORR為64.5% (95% CI：52.7%，75.1%)，完全反應(CR)為10.5%。相比之下，群組K EV單藥療法組之ORR為45.2% (95% CI：33.5%，57.3%)，完全反應(CR)為4.1%。 表25
觀測到目標病灶之顯著腫瘤減少，其中根據盲態中央獨立評估，97.1%的可評估群組K EV+派姆個體具有腫瘤減少(參見圖6)。Significant tumor reduction of target lesions was observed, with 97.1% of evaluable KEV+pembutaline individuals having tumor reduction based on blinded central independent review (seeFigure6 ).
根據BICR，目標病灶直徑總和隨時間推移相對於基線之變化百分比顯示於圖7中。在第一次評估(第9週+/-1週)時觀測到85.7%反應(參見圖7)。中值反應時間為2.07個月(範圍：1.1至6.6)。中值反應時間為2.07個月(範圍：1.1至6.6) (參見圖7)。The percentage change in the sum of target lesion diameters over time from baseline according to BICR is shown inFigure7. An 85.7% response was observed at the first assessment (week 9 +/- 1 week) (seeFigure7 ). The median duration of response was 2.07 months (range: 1.1 to 6.6). The median duration of response was 2.07 months (range: 1.1 to 6.6) (seeFigure7 ).
在群組K EV+派姆單抗組中之患者的ORR子組分析中，如圖8中所示，ORR在所有預定子組之間一致。不管基線時PD-L1表現狀態如何，均觀測到反應。如上文所指出，群組K EV+派姆單抗組之ORR為64.5% (95% CI：52.7%，75.1%)。在具有肝轉移之患者中觀測到53.8%確認的ORR。另外，所有子組之ORR點估計＞50%。In the ORR subgroup analysis of patients in the cohort K EV + pembrolizumab group,as shown in Figure8 , the ORR was consistent across all pre-specified subgroups. Responses were observed regardless of PD-L1 expression status at baseline. As noted above, the ORR in the cohort K EV + pembrolizumab group was 64.5% (95% CI: 52.7%, 75.1%). A 53.8% confirmed ORR was observed in patients with liver metastases. In addition, the ORR point estimates for all subgroups were >50%.
在群組K EV單藥療法組中之患者的ORR子組分析中，如圖9中所示，ORR在所有預定子組之間一致。不管基線時PD-L1表現狀態如何，均觀測到反應。如上文所指出，群組K EV單藥療法組之ORR為45.2% (95% CI：33.5%，57.3%)。在具有肝轉移之患者中觀測到53.8%確認的ORR。In the ORR subgroup analysis of patients in the group K EV monotherapy group,as shown in Figure9 , the ORR was consistent across all predetermined subgroups. Responses were observed regardless of PD-L1 expression status at baseline. As noted above, the ORR in the group K EV monotherapy group was 45.2% (95% CI: 33.5%, 57.3%). A 53.8% confirmed ORR was observed in patients with liver metastases.
圖10顯示基線時連接素-4表現之H評分及藉由BICR評估的最佳總反應。在94.6%的具有足夠測試用組織之個體的腫瘤組織中偵測到連接素-4。不管基線時連接素-4表現如何，均觀測到活性。Figure10 shows the H score for nectin-4 expression at baseline and the best overall response assessed by BICR. Nexin-4 was detected in tumor tissue in 94.6% of individuals with adequate tissue for testing. Activity was observed regardless of baseline nectin-4 expression.
圖11顯示按藉由BICR評估的最佳總反應，基線時連接素-4表現之H評分。無證據支持連接素-4與研究治療之間的表現-反應關係(參見圖11及表26)。在具有低連接素-4表現之患者中觀測到反應。 表26
根據盲態中央獨立評估，群組K EV+派姆單抗組之中值DOR未達到(參見圖12及表27)。分別84.2%及65.4%之反應者具有DOR≥6個月及DOR≥12個月(參見圖12及表27)。 表27
根據盲態中央獨立評估，群組K EV+派姆單抗組之中值PFS未達到(參見圖13及表28)。6個月時PFS為73.8%，且12個月時PFS為55.1% (參見圖13及表28)。 表28
根據此研究階段之盲態中央獨立評估，群組K EV+派姆單抗組之中值OS為22.3個月(95% CI 19.09，-)，6個月OS為88.2%且12個月OS為80.7% (參見圖14及表29)。 表29
使用治療持續時間作為暴露彙總參數，如表30中所示，中值治療持續時間為9.03個月，中值週期數為11 (1，29)。群組K EV+派姆單抗組中EV之相對劑量強度為77.23%。 表30
群組K具有比劑量遞增/群組A更長的中值EV治療暴露，如表31中所示。 表31
關於治療引發之不良事件的總體概述，安全概況一致、可管控且可耐受，如表32中所示。 表32
≥20%個體中發生之最常見的治療相關的TEAE (所有級別)顯示於表33中。群組K EV+派姆單抗組組合中最常見的TEAE包括疲乏、周邊感覺神經病變及禿髮。 表33
關於在大於或等於5%個體中發生的大於或等於3級的治療相關的TEAE，貧血、紅斑丘疹、脂肪酶升高及泌尿道感染最常見，如表34中所示。 表34
在大於或等於3%之個體中發生的嚴重不良事件(SAE)顯示於表35中。 表35
表36顯示導致死亡的TEAE。導致死亡的TEAE很大程度上因疾病惡化、預存共生病症及/或高齡而混淆。 表36
劑量修飾之概述顯示於表37中。不管劑量修改如何，群組間EV+P組合之相對劑量強度一致。 表37
EV特別受關注之不良事件(AESI)顯示於表38中。 表38
派姆單抗特別受關注之不良事件(AEOSI)顯示於表39中。EV+派姆單抗組合組中之派姆單抗AEOSI與派姆單抗單藥療法中觀測到的AEOSI大體上一致。 表39
皮膚反應Skin reactions((AESIAESI)/)/嚴重皮膚反應Severe skin reactions((AEOSIAEOSI))
皮膚反應為恩諾單抗維多汀治療及派姆單抗治療之預期重疊毒性。與派姆單抗單藥療法(KEYTRUDA USPI)相比，群組K之恩諾單抗維多汀加派姆單抗組(27.6%)中更頻繁地觀測到派姆單抗AEOSI「嚴重皮膚反應」。與群組K之恩諾單抗維多汀單藥療法組(52.1%)相比，恩諾單抗維多汀加派姆單抗組(69.7%)中更頻繁地觀測到恩諾單抗維多汀AESI「嚴重皮膚反應」。Skin reactions are an expected overlapping toxicity of enrofloxacin and pembrolizumab treatment. Pembrolizumab AEOSI "severe skin reactions" were observed more frequently in the enrofloxacin plus pembrolizumab group (27.6%) in cohort K compared with pembrolizumab monotherapy (KEYTRUDA USPI). Enrofloxacin AESI "severe skin reactions" were observed more frequently in the enrofloxacin plus pembrolizumab group (69.7%) compared with the enrofloxacin monotherapy group (52.1%) in cohort K.
臨床結果概述Overview of Clinical Results
功效effect
恩諾單抗維多汀(EV)與派姆單抗組合療法為不適合順鉑的患者提供了臨床上有意義的治療選項。對於不適合順鉑的患者，當前可用選項為：(1)對基於鉑之化學療法(4-6個週期)後疾病控制的患者，吉西他濱/卡鉑後接阿維魯單抗維持，(2)吉西他濱/卡鉑，及(3)對於PD-L1高表現者或不管PD-L1狀態如何不適合鉑的患者，CPI單藥療法。不管連接素-4及PD-L1表現量如何，EV與派姆單抗組合療法均展現高度益處，反應快速且持久。舉例而言，對於群組K EV+派姆單抗組，觀測到64.5%之高ORR，活性無關於連接素-4及PD-L1表現量。另外，當與吉西他濱/卡鉑之歷史資料相比時，反應速率較有利。EV與派姆單抗組合療法在患者子組(亦即，PD-L1表現/肝轉移/上泌尿道疾病等)間展現持續顯著功效。觀測到臨床上有意義的總反應率。ORR估計值超過歷史基準(亦即，吉西他濱/卡鉑)之估計值。在群組K中，6個月時之DOR率為84.2%且大部分反應者繼續對研究治療起反應。觀測到快速反應時間，在第一次評估(約第9週)時發現大部分反應(85.7%)。在此研究中，DOR、PFS及OS鼓舞人心。此外，EV與派姆單抗組合療法與其個別組分相比展現更大活性。The combination of enrofloxacin vedotin (EV) and pembrolizumab provides a clinically meaningful treatment option for patients who are ineligible for cisplatin. For patients who are ineligible for cisplatin, currently available options are: (1) gemcitabine/carboplatin followed by avelumab maintenance for patients with disease control after platinum-based chemotherapy (4-6 cycles), (2) gemcitabine/carboplatin, and (3) CPI monotherapy for patients with high PD-L1 expression or who are ineligible for platinum regardless of PD-L1 status. The combination of EV and pembrolizumab demonstrated a high degree of benefit, with rapid and durable responses, regardless of nectin-4 and PD-L1 expression. For example, for the Cohort K EV+pembrolizumab group, a high ORR of 64.5% was observed, with activity independent of nectin-4 and PD-L1 expression. In addition, the response rate was favorable when compared to historical data for gemcitabine/carboplatin. The EV plus pembrolizumab combination therapy demonstrated sustained significant efficacy across patient subgroups (i.e., PD-L1 expression/liver metastases/upper urinary tract disease, etc.). Clinically significant overall response rates were observed. ORR estimates exceeded estimates for historical benchmarks (i.e., gemcitabine/carboplatin). In Cohort K, the DOR rate at 6 months was 84.2% and the majority of responders continued to respond to study treatment. Rapid response times were observed, with the majority of responses (85.7%) observed at the first assessment (approximately week 9). DOR, PFS, and OS were encouraging in this study. In addition, the combination of EV and pembrolizumab demonstrated greater activity compared to its individual components.
安全性safety
EV與派姆單抗組合療法之安全概況在主要為患有多種共生病症的老年、虛弱群體中可管控且可耐受。EV與派姆單抗組合療法之安全概況保持與EV單藥療法及派姆單藥療法之概況大體上一致。所關注之不良事件與先前針對恩諾單抗維多汀及派姆單抗單藥療法報導的不良事件一致。劑量中止率表明EV與派姆單抗組合係可耐受的。劑量降低率表明EV與派姆單抗組合係可管控的。EV+派姆中之EV AESI (例如周邊神經病變、高血糖症、眼部病症及輸注反應)與EV單藥療法一致。未觀測到新的安全性問題。除嚴重皮膚反應之外，EV+派姆中觀測到的派姆單抗AEOSI與派姆單抗單藥療法中觀測到的AEOSI一致。AEOSI一般為可管控的。未觀測到新的安全性問題。皮膚反應/嚴重皮膚反應為恩諾單抗維多汀及派姆單抗療法之預期重疊毒性。治療相關死亡發生於老年、虛弱患者且因共生病症而混淆。6.1.10術語縮寫及描述清單The safety profile of the EV plus pembrolizumab combination was manageable and tolerable in a predominantly elderly, frail population with multiple comorbidities. The safety profile of the EV plus pembrolizumab combination remained generally consistent with that of EV monotherapy and pembrolizumab monotherapy. Adverse events of concern were consistent with those previously reported for enrofloxacin and pembrolizumab monotherapy. The dose discontinuation rate indicated that the EV plus pembrolizumab combination was tolerable. The dose reduction rate indicated that the EV plus pembrolizumab combination was manageable. EV AESIs in EV+pembrolizumab (e.g., peripheral neuropathy, hyperglycemia, ocular disorders, and infusion reactions) were consistent with EV monotherapy. No new safety issues were observed. With the exception of severe skin reactions, AEOSIs observed with EV+pembrolizumab were consistent with AEOSIs observed with pembrolizumab monotherapy. AEOSIs were generally manageable. No new safety issues were observed. Skin reactions/severe skin reactions were expected overlapping toxicities with enrofloxacin and pembrolizumab therapy. Treatment-related deaths occurred in elderly, debilitated patients and were confounded by comorbidities.6.1.10List of abbreviations and descriptions
ACS 美國癌症協會ACS American Cancer Society
ADC 抗體-藥物結合物ADC Antibody-drug conjugate
AE 不良事件AE Adverse Event
AESI 特別受關注之不良事件AESI Adverse Event of Special Interest
ALT 丙胺酸轉胺酶ALT Alanine transaminase
ANC 絕對嗜中性白血球計數ANC Absolute neutrophil count
aPTT 活化部分凝血活酶時間aPTT activated partial thromboplastin time
ASCO 美國臨床腫瘤學會ASCO American Society of Clinical Oncology
AST 天冬胺酸轉胺酶AST Aspartate aminotransferase
ASTRO 美國放射腫瘤學會ASTRO American Society of Radiation Oncology
ATA 抗治療抗體ATA Anti-therapy antibody
AUA 美國泌尿協會AUA American Urological Association
AUC 曲線下面積AUC Area Under the Curve
BCG 卡介苗(Bacillus Calmette-Guérin)BCG
BICR 盲態中央獨立評估BICR Blind Independent Central Review
BPI-SF 簡要疼痛量表簡表BPI-SF Brief Pain Inventory-Short Form
BSA 體表面積BSA Body surface area
卡鉑 順式-二胺(環丁烷1,1二羧酸)鉑Platinum Cis-diamine (cyclobutane 1,1-dicarboxylic acid) platinum
CBC 全血球計數CBC Complete blood count
cCR 臨床完全反應cCR Clinical complete response
CFR 美國聯邦法規CFR U.S. Federal Regulations
CI 信賴區間CI Trust Interval
順鉑 順式-二胺二氯鉑(II)Cis-Platum Cis-Diaminedichloroplatinum(II)
CNS 中樞神經系統CNS Central nervous system
CPI 檢查點抑制劑CPI Checkpoint Inhibitor
CR 完全反應CR Complete Response
CrCl 肌酐清除率CrCl Creatinine clearance
CRF 病例報告表CRF Case Report Form
CPS 綜合陽性評分CPS Comprehensive Positive Score
CT 電腦斷層攝影CT Computerized tomography
CTLA-4 細胞毒性T淋巴球相關蛋白質CTLA-4 Cytotoxic T lymphocyte-associated protein
DE 可評估DLTDE Can evaluate DLT
DCR 疾病控制率DCR Disease Control Rate
DFS 無疾病存活期DFS Disease Free Survival
DLT 劑量限制性毒性DLT Dose-limiting toxicity
DOR 反應持續時間DOR Duration of response
ECD 胞外域ECD Extracellular domain
ECG 心電圖ECG
ECHO 經胸心臟超音波檢查ECHO Transthoracic echocardiography
ECOG 美國東岸癌症臨床研究合作組織ECOG Eastern Coast Collaborative on Cancer
eCRF 電子病例報告表eCRF Electronic Case Report Form
EFS 無事件存活期EFS Event Free Survival
ELISA 酶聯結免疫吸附分析ELISA Enzyme-linked immunosorbent assay
EORTC 歐洲癌症研究及治療組織EORTC European Organisation for Research and Treatment of Cancer
EOT 治療結束EOT End of treatment
EQ-5D-5L EuroQOl-5維EQ-5D-5L EuroQOl-5D
EV 恩諾單抗維多汀EV Ennotumab Vedotin
EV單藥 恩諾單抗維多汀單藥療法EV monotherapy Ennotumab vedotin monotherapy
EV+派姆 恩諾單抗維多汀組合派姆單抗EV+Pembrolizumab Ennotumab Vedotin combined with Pembrolizumab
FAS 全分析集FAS Full Analysis Set
GE 基因表現GE Gene Expression
GFR 腎小球濾過率GFR Glomerular filtration rate
HbA1c 血紅素A1cHbA1c
HIV 人類免疫缺乏病毒HIV Human immunodeficiency virus
HRU 醫療資源利用HRU Health Resource Utilization
ICH 國際協調委員會ICH International Council for Harmonization
iCPD 基於iRECIST指南確認之進行性疾病iCPD Progressive disease confirmed based on iRECIST guidelines
IEC 獨立倫理委員會IEC Independent Ethics Committee
Ig 免疫球蛋白Ig Immunoglobulin
IHC 免疫組織化學IHC Immunohistochemistry
imAE 免疫介導之不良事件imAE Immune-mediated adverse events
IND 研究中新藥IND Investigational New Drug
INR 國際標準化比值INR International Normalized Ratio
IRB 機構審查委員會IRB Institutional Review Board
iRECIST 基於免疫之治療劑的經修改之RECIST 1.1iRECIST Modified RECIST 1.1 for immune-based therapies
IRR 輸注相關反應IRR Infusion Related Reaction
iUPD 未確認進行性疾病(基於iRECIST指南)iUPD Unconfirmed progressive disease (based on iRECIST guidelines)
IV 靜脈內IV
la/mUC 局部晚期或轉移性尿路上皮癌la/mUC Locally advanced or metastatic urothelial carcinoma
LFT 肝功能測試LFT Liver function test
M-CAVI 甲胺喋呤/卡鉑/長春鹼M-CAVI Methotrexate/Carboplatin/Vinblastine
MDRD 腎病膳食改良MDRD Modification of Diet in Kidney Disease
MMAE 單甲基奧瑞他汀EMMAE Monomethyl auristatin E
MRI 磁共振造影MRI Magnetic resonance imaging
MTD 最大耐受劑量MTD Maximum tolerated dose
MVAC 甲胺喋呤、長春鹼、小紅莓及順鉑MVAC Methotrexate, vinblastine, cranberries, and cisplatin
NAC 前輔助化學療法NAC Pre-adjuvant chemotherapy
NCI CTCAE 美國國家癌症研究所不良事件通用術語準則NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
NGS 下一代定序NGS Next Generation Sequencing
NMIBC 非肌肉侵襲性膀胱癌NMIBC Non-muscle invasive bladder cancer
NYHA 紐約心臟協會NYHA New York Heart Association
ORR 客觀反應率ORR Objective Response Rate
OS 總存活期OS
PBMC 周邊血液單核細胞PBMC Peripheral blood mononuclear cells
pCR 病理性完全反應pCR Pathological complete response
pCRR 病理完全反應率pCRR Pathological complete response rate
PD 進行性疾病PD Progressive disease
PD-1 計劃性細胞死亡1PD-1 Planned cell death 1
PD-L1 計劃性死亡配位體1PD-L1 Planned death ligand 1
PD-L2 計劃性死亡配位體2PD-L2 Planned death ligand 2
pDS 病理性降期pDS Pathological downstaging
pDSR 病理降期率pDSR Pathological downstaging rate
派姆 派姆單抗Pembrolizumab
PFS 無惡化存活期PFS Progression-free survival
PFS2 後續療法之無惡化存活期PFS2 Progression-free survival after follow-up therapy
PK 藥物動力學PK Pharmacokinetics
PLND 骨盆淋巴結擴清術PLND Pelvic lymph node dissection
PR 部分反應PR Partial response
PRO 患者報告結果PRO Patient Reported Outcomes
PSA 前列腺特異性抗原PSA Prostate-specific antigen
PT 凝血酶原時間PT Prothrombin time
PTT 部分凝血活酶時間PTT Partial thromboplastin time
QLQ-C30 核心QoL評估QLQ-C30 Core QoL Assessment
QoL 生活品質QoL Quality of life
Q2W 每2週Q2W Every 2 weeks
Q3W 每3週Q3W Every 3 weeks
RC 根治性膀胱切除術RC Radical cystectomy
RECIST 實體腫瘤反應評估準則版本RECIST Response Evaluation Criteria in Solid Tumors version
SAE 嚴重不良事件SAE Serious Adverse Event
SAP 統計分析計劃SAP Statistical Analysis Program
SD 穩定疾病SD Stable disease
SDRIFE 對稱藥物相關擦爛性及屈曲性紅斑SDRIFE Symmetrical drug-related abrasive and flexural erythema
SJS 史蒂芬斯-強森症候群SJS Stevens-Johnson syndrome
SMC 安全性監測委員會SMC Safety Monitoring Committee
SOC 標準照護SOC Standard of Care
SUO 泌尿腫瘤學會SUO Society of Urological Oncology
TAb 總抗體TAb Total Antibody
T1DM 第1型糖尿病T1DM Type 1 diabetes
TEAE 治療引發之不良事件TEAE Treatment Emergent Adverse Event
TEN 中毒性表皮壞死溶解TEN Toxic epidermal necrolysis
TME 腫瘤微環境TME Tumor Microenvironment
ULN 正常值上限ULN Upper limit of normal
USP 美國藥典 表40 RECIST準則概述(1.1版)
若後續疾病評估(初始反應之後的至少4-5週)仍顯示反應(CR或PR)，則反應(CR或PR)視為經確認。在初始反應之後出現SD的情況下，若SD之後出現PR或CR，則其視為經確認。舉例而言，若患者在第9週出現PR，在第14週出現SD，且在第18週出現PR，則此PR將視為經確認。A response (CR or PR) is considered confirmed if subsequent disease assessments (at least 4-5 weeks after the initial response) still show a response (CR or PR). In the case of SD after an initial response, it is considered confirmed if the SD is followed by a PR or CR. For example, if a patient has a PR at Week 9, SD at Week 14, and a PR at Week 18, the PR will be considered confirmed.
基線病灶鑑別：當在基線時存在超過一個可量測病灶時，代表所有受累器官的至多總共最多五個病灶(且每個器官最多兩個病灶)的所有病灶鑑別為目標病灶，且在基線時記錄及量測。目標病灶基於其大小進行選擇(具有最長直徑之病灶)，代表所有受累，但另外應為適宜於可再現重複量測之彼等病灶(不應選擇骨病灶為目標病灶)。有時，最大病灶可能不適宜於可再現量測，在此情況下，選擇可再現量測之第二大病灶。在CT/MRI掃描中偵測到之膀胱病灶選擇為目標病灶，其限制條件為放射科醫師認為病灶適宜於在基線後時間點進行可再現量測，且病灶在充分的膀胱擴張下量測。在整個研究治療過程中使用相同的成像方式。* 定義為可量測且可鑑別為目標病灶之病理性淋巴結必須滿足藉由CT或MRI掃描得到之短軸為≥15 mm的準則。所有其他病理性淋巴結(短軸≥10 mm但＜15 mm之彼等淋巴結)視為非目標病灶。短軸＜10 mm之淋巴結視為非病理性且不對其進行記錄或追蹤。包括病理性淋巴結之所有其他病灶(或疾病部位)鑑別為非目標病灶，且亦在基線時對其進行記錄。6.1.11紐約心臟協會分類Baseline Lesion Identification : When more than one measurable lesion was present at baseline, all lesions representing all organs involved up to a total of up to five lesions (and a maximum of two lesions per organ) were identified as target lesions and recorded and measured at baseline. Target lesions were selected based on their size (lesion with the longest diameter), representing all involvement, but otherwise should be those lesions that were amenable to reproducible repeated measurements (bone lesions should not be selected as target lesions). Sometimes, the largest lesion may not be amenable to reproducible measurement, in which case the second largest lesion that was reproducibly measured was selected. Bladder lesions detected on CT/MRI scans were selected as target lesions, with the proviso that the radiologist considered the lesion amenable to reproducible measurement at a post-baseline time point and that the lesion was measured with adequate bladder distension. The same imaging modality was used throughout the study treatment. * Pathological lymph nodes, defined as measurable and identifiable as target lesions, must meet the criterion of ≥15 mm on the short axis as determined by CT or MRI scanning. All other pathological lymph nodes (those with a short axis ≥10 mm but <15 mm) were considered non-target lesions. Lymph nodes with a short axis <10 mm were considered non-pathological and were not recorded or tracked. All other lesions (or disease sites), including pathological lymph nodes, were identified as non-target lesions and were also recorded at baseline.6.1.11New York Heart Association Classification
心臟病患者體能活動處方的功能及治療分類Functions and treatment categories of physical activity prescriptions for patients with heart disease
I級：活動不受限制的患者；其日常活動中不受症狀的困擾。Class I: Patients whose activities are not restricted; their daily activities are not disturbed by symptoms.
II級：活動受到輕微、輕度限制的患者；其在休息時或在輕度施力時感到舒適。Class II: Patients with minimal to mild restriction of activity; they are comfortable at rest or with mild exertion.
III級：活動明顯受限的患者；其僅在休息時感到舒適。Class III: Patients with marked limitation of activity; they are comfortable only at rest.
IV級：應完全休息、侷限於床或椅子的患者；任何體能活動帶來不適且在休息時出現症狀。Class IV: Patients who should be at complete rest, confined to bed or chair; any physical activity causes discomfort and symptoms occur at rest.
線上來源：http://www.heart.org/HEARTORG/Conditions/ HeartFailure/AboutHeartFailure/Classes-of-Heart-Failure_UCM_306328_Article.jsp6.1.12肝臟安全監測及評估Online source: http://www.heart.org/HEARTORG/Conditions/ HeartFailure/AboutHeartFailure/Classes-of-Heart-Failure_UCM_306328_Article.jsp6.1.12Liver safety monitoring and assessment
以下建議來自2009年7月頒佈、標題為「藥物誘導肝臟損傷：上市前臨床評估(Drug-Induced Liver Injury: Premarketing Clinical Evaluation)」的美國食品及藥物管理局(FDA)行業指南。The following recommendations are from a U.S. Food and Drug Administration (FDA) guidance for industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation,” issued in July 2009.
血清轉胺酶增加至＞3×正常值上限(ULN)或膽紅素＞2×ULN的任何患者應經歷肝酶(至少包括丙胺酸轉胺酶(ALT)、天冬胺酸轉胺酶(AST)、鹼性磷酸酶(ALP)及總膽紅素)的詳細測試。為了確認異常，應在告知測試結果的72小時內重複進行測試。Any patient with an increase in serum transaminases to >3× upper limit of normal (ULN) or bilirubin >2×ULN should undergo detailed testing of liver enzymes (including at least alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and total bilirubin). To confirm an abnormality, the test should be repeated within 72 hours of the test result.
肝臟異常的描述：Description of liver abnormalities:
經確認的肝臟異常表徵為中度及重度：Confirmed liver abnormalities were moderate and severe:
中度：• ALT或AST＞3×ULN或總膽紅素＞2×ULNModerate: • ALT or AST > 3×ULNor total bilirubin > 2×ULN
重度： • ALT或AST＞3×ULN且總膽紅素＞2×ULN (*參見哈依定律(Hy's Law)定義) • ALT或AST＞8×ULN • ALT或AST＞5×ULN，超過2週 • ALT或AST＞3×ULN且國際標準化比值(INR)＞1.5 (若INR測試適用/經評估) • ALT或AST＞3×ULN，出現暗示肝臟損傷(例如右上腹疼痛或觸痛)及/或嗜酸性球增多症(＞5%)的症狀Severe : • ALT or AST > 3 x ULNand total bilirubin > 2 x ULN (*See Hy's Law definition) • ALT or AST > 8 x ULN • ALT or AST > 5 x ULN for more than 2 weeks • ALT or AST > 3 x ULN and INR > 1.5 (if INR testing is available/assessed) • ALT or AST > 3 x ULN with symptoms suggestive of liver damage (e.g. right upper quadrant pain or tenderness) and/or eosinophilia (> 5%)
研究者可確定，除如上文所描述之外的異常肝功能結果可視為中度或重度異常且需要額外監測及隨訪。The Investigator may determine that abnormal liver function results other than those described above may be considered moderate or severe abnormalities and require additional monitoring and follow-up.
*哈依定律定義：由肝細胞損傷引起的藥物誘導黃疸，無顯著阻塞性成分，不良結果的比率高，死亡(或移植)率為10%至50%。哈依定律的2個「要求」為：1)藥物可導致肝細胞型損傷的證據，通常顯示為轉胺酶升幅增加更高：3×ULN (「2×ULN升幅在經治療及未治療之患者中太常見而無法區分」)。2)膽紅素增加(至少2×ULN)伴轉胺酶並行升高至少3×ULN且無證據證明肝內或肝外膽紅素阻塞(ALP升高)或吉爾伯氏症候群(Temple等人, Pharmacoepidemiol Drug Saf (2006);15(4): 241-3.)。*Hay's Law is defined as drug-induced jaundice caused by hepatocellular injury with no significant obstructive component and a high rate of adverse outcomes, with mortality (or transplantation) rates ranging from 10% to 50%. The two "requirements" of Hay's Law are: 1) Evidence of drug-induced hepatocellular injury, usually shown by an increase in transaminase levels greater than 3×ULN ("2×ULN increases are too common to be distinguished between treated and untreated patients"). 2) Increased bilirubin (at least 2×ULN) with concurrent elevations in transaminase levels of at least 3×ULN and no evidence of intrahepatic or extrahepatic bilirubin obstruction (elevated ALP) or Gilbert's syndrome (Temple et al., Pharmacoepidemiol Drug Saf (2006);15(4): 241-3.).
隨訪程序Visiting Program
經確認之中度及重度肝功能異常應藉由獲得適當專家會診、詳細相關病史、體檢及實驗室測試來充分表徵。具有經確認異常肝功能測試的患者應如下文所描述進行隨訪。Confirmed moderate and severe liver function abnormalities should be fully characterized by obtaining appropriate specialist consultation, detailed relevant history, physical examination, and laboratory testing. Patients with confirmed abnormal liver function tests should be followed up as described below.
確認的中度異常肝功能測試(LFT)應每週重複執行2至3次，接著若異常出現穩定或研究藥物中止且患者無症狀，則每週一次或以更低頻率重複執行。Confirmed moderately abnormal liver function tests (LFTs) should be repeated 2 to 3 times weekly, then once weekly or less frequently if the abnormality stabilizes or study drug is discontinued and the patient is asymptomatic.
在不存在另一病因的情況下，如上文所定義之重度肝功能異常可視為重要醫學事件且可報告為SAE。應聯絡試驗委託者且告知觀測到可能歸因於研究藥物的重度肝功能異常的所有患者。Severe liver function abnormalities, as defined above, are considered medically important events and reportable as SAEs in the absence of another etiology. The trial sponsor should be contacted and all patients informed of observed severe liver function abnormalities that may be attributable to the study drug.
為了進一步評估實驗室的異常肝結果，建議研究者： • 獲得更詳細的症狀及先前或並行疾病史。應注意可能導致繼發性肝異常之疾病及病狀，諸如低血壓事件及失代償性心臟疾病。非酒精性脂肪變性肝炎見於肥胖高脂蛋白症及/或糖尿病患者中，且可能與波動的轉胺酶含量相關。 • 獲得伴隨藥物使用(包括非處方藥品、補充及替代藥品)、飲酒、娛樂性藥物使用及特殊膳食史 • 獲得環境化學劑之暴露史。 • 基於患者的病史，其他測試可為適當的，包括： o 急性病毒性肝炎(A、B、C、D、E或其他傳染原)， o 評估膽道疾病的超音波成像或其他成像， o 其他實驗室測試，包括國際標準化比值(INR)、直接膽紅素。 • 考慮胃腸病學或肝病學會診。To further evaluate abnormal liver results from the laboratory, the investigator is advised to:• Obtain a more detailed history of symptoms and prior or concurrent illness. Diseases and conditions that may cause secondary liver abnormalities should be noted, such as hypotensive events and decompensated heart disease. Nonalcoholic steatohepatitis has been seen in obese patients with hyperlipoproteinemia and/or diabetes and may be associated with fluctuating transaminase levels.• Obtain a history of concomitant medication use (including over-the-counter, complementary and alternative medicines), alcohol use, recreational drug use, and special diets• Obtain a history of exposure to environmental chemicals.• Based on the patient’s history, other testing may be appropriate, including:o Acute viral hepatitis (A, B, C, D, E, or other infectious agents),o Ultrasound or other imaging to evaluate for bile duct disease,o Other laboratory tests, including international normalized ratio (INR), direct bilirubin.• Consider a gastroenterology or hepatology consult.
進行由研究者確定的其他測試以進一步評估可能的病因。關於與肝安全有關的治療中止建議，參見章節6.1.6.2(iii)(a)。6.1.13影像擷取指南Perform additional testing as determined by the investigator to further evaluate possible etiologies. See Section 6.1.6.2(iii)(a) for recommendations on treatment discontinuation related to hepatic safety.6.1.13Image Acquisition Guidelines
胸部-腹部-骨盆掃描(按以下優先順序降序)：1.使用IV造影劑的胸部-腹部-骨盆CT 2.不使用IV造影劑之胸部CT以及使用IV釓造影劑之腹部-骨盆MRI (若碘造影劑在醫學上為禁忌的) 3.不使用IV造影劑之胸部CT以及不使用IV釓造影劑之腹部-骨盆MRI (若碘造影劑及釓造影劑在醫學上為禁忌的) 4.使用IV釓造影劑之胸部-腹部及骨盆MRI 5. 不使用IV造影劑之胸部-腹部-骨盆CT (推薦口服造影劑) (若患者對碘造影劑及MRI掃描具有禁忌)Chest-abdomen-pelvis scan(in descending order of priority): 1. Chest-abdomen-pelvis CT with IV contrast 2. Chest CT without IV contrast and abdomen-pelvis MRI with IV gadolinium contrast (if iodine contrast is medically contraindicated) 3. Chest CT without IV contrast and abdomen-pelvis MRI without IV gadolinium contrast (if iodine contrast and gadolinium contrast are medically contraindicated) 4. Chest-abdomen and pelvic MRI with IV gadolinium contrast 5. Chest-abdomen-pelvis CT without IV contrast (oral contrast is recommended) (if the patient has contraindications to iodine contrast and MRI scans)
腦部掃描(若臨床上指示) (按優先順序降序)：1. 使用IV釓之腦部MRI 2. 使用IV造影劑之腦部CT (若釓及/或MRI為醫學上禁忌的) 3. 不使用IV釓之腦部MRI (若釓為醫學上禁忌的) 4. 不使用IV造影劑之腦部CT (若釓為醫學上禁忌的)Brain scan(if clinically indicated) (in descending order of priority): 1. Brain MRI with IV gadum 2. Brain CT with IV contrast (if gadum and/or MRI are medically contraindicated) 3. Brain MRI without IV gadum (if gadum is medically contraindicated) 4. Brain CT without IV contrast (if gadum is medically contraindicated)
CT口服造影劑1. 不透放射線的試劑(例如基於碘及鋇的試劑) 2. 可透過放射線的試劑(全乳、VoLumen®、水)CToral contrast agents 1. Radiopaque agents (e.g. iodine and barium based agents) 2. Radiolucent agents (whole milk, VoLumen®, water)
重要提示：成像方式、解剖覆蓋及擷取參數應在各患者之所有成像訪視中保持一致。6.1.14關於避孕之指南Important: Imaging modalities, anatomical coverage, and acquisition parameters should be consistent across all imaging visits for each patient.6.1.14Guidelines for Contraception
出於此指導之目的，若與患者偏好的生活方式一致，則完全禁慾為可接受的避孕形式。完全禁慾定義為自知情同意書之時間開始禁慾且在整個研究中繼續，直至全身性暴露結束(在研究藥物之最後一次劑量之後至少6個月)。For the purposes of this guidance, total abstinence is an acceptable form of contraception if it is consistent with the patient's preferred lifestyle. Total abstinence is defined as abstinence beginning at the time of informed consent and continuing throughout the study until the end of systemic exposure (at least 6 months after the last dose of study drug).
可接受之高效生育控制(預防懷孕)方法有生育潛力或其伴侶具有生育潛力且性活躍可能引起懷孕的患者可選擇以下任何兩種方法(請參見以下可接受之組合)： • 激素(不包括僅含孕激素的避孕藥；方法必須與抑制排卵相關)，除非禁忌 • 失敗率＜1%的子宮內避孕器 • 輸卵管結紮 • 輸精管結紮(自手術之日起至少90天，精液分析證明無精子症) • 障礙避孕法(具有或不具有殺精子劑之男性或女性保險套、具有或不具有殺精子劑之子宮頸帽、具有或不具有殺精子劑之隔膜) • 具有生育潛力之個人定義為已經歷初潮且未進行手術絕育(例如，子宮切除術、雙側輸卵管切除術、雙側卵巢切除術)或尚未完成停經之任何出生為女性的人。停經在臨床上定義為45歲以上出生為女性的人在不存在其他生物學、生理或藥理學病因之情況下閉經12個月。 • 障礙避孕法應僅與並非障礙避孕法之高效生育控制方法一起使用。單獨的障礙避孕法，包括雙重障礙避孕法，不被視為高效避孕措施(參見不可接受的避孕方法)。Acceptable Highly Effective Birth Control(Prevention of Pregnancy)Methods Patients of childbearing potential or whose partner is of childbearing potential and sexually active with the potential for pregnancy may choose any two of the following methods (see below for acceptable combinations): • Hormonal (excluding progestin-only contraceptives; method must be associated with inhibition of ovulation), unless contraindicated • Intrauterine contraceptive device with a failure rate of <1% • Tubal ligation • Vasectomy (at least 90 days from date of procedure with semen analysis demonstrating azoospermia) • Barrier method of contraception (male or female condom with or without spermicide, cervical cap with or without spermicide, diaphragm with or without spermicide) • An individual of childbearing potential is defined as any natal female who has experienced menarche and has not undergone surgical sterilization (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has not completed menopause. Menopause is clinically defined as the absence of menstruation for 12 months in a natal female over age 45 years in the absence of other biological, physiological, or pharmacological causes. • Barrier methods should only be used with highly effective birth control methods that are not barrier methods. Barrier methods alone, including double barrier methods, are not considered highly effective contraceptives (see Unacceptable Contraceptive Methods).
可接受的避孕方法組合包括激素方法及輸精管結紮、激素方法及障礙避孕法、子宮內避孕器及輸精管結紮、子宮內避孕器及障礙避孕法、輸卵管結紮及輸精管結紮以及輸卵管結紮及障礙避孕法。Acceptable combinations of contraceptive methods include hormonal methods and vasectomy, hormonal methods and barrier methods, intrauterine contraceptive devices and vasectomy, intrauterine contraceptive devices and barrier methods, tubal ligation and vasectomy, and tubal ligation and barrier methods.
可接受的防止二次暴露於精液的方法如下：選項1-男性保險套(具有或不具有殺精子劑)及子宮頸帽，及選項2-男性保險套(具有或不具有殺精子劑)及隔膜。出生為男性且與懷孕或哺乳者有性行為的個體必須使用選項1或2中的避孕用具。Acceptable methods of preventing secondary exposure to semen are as follows: Option 1 - male condom (with or without spermicide) and cervical cap, and Option 2 - male condom (with or without spermicide) and diaphragm. Individuals assigned male at birth who have sex with a pregnant or nursing woman must use a contraceptive from Option 1 or 2.
不可接受的避孕方法包括週期性禁慾、僅殺精子劑、無避孕法、僅含孕激素的避孕藥、性交中斷法、同時使用女性及男性保險套、週期避孕法及單獨使用障礙避孕法(包括雙重障礙避孕法)。6.1.15iRECIST：用於測試免疫治療劑之試驗的反應準則指南Unacceptable contraceptive methods include periodic abstinence, spermicides only, no contraceptive methods, progestin-only contraceptives, intercourse interruption, use of both female and male condoms, cyclical contraceptive methods, and single-use barrier contraceptive methods (including dual barrier contraceptive methods).6.1.15iRECIST: Response Criteria Guidelines for Trials Testing Immunotherapeutic Agents
亦使用基於免疫之治療劑之經修改RECIST 1.1 (iRECIST)指南(Seymour 2017)評估反應。免疫治療劑可引起免疫細胞浸潤，導致惡性病灶之尺寸暫時增加或不可偵測的病灶變得可偵測。準則在許多方面與實體腫瘤反應評估準則(RECIST) 1.1版一致，但經調適以考慮腫瘤負荷增加或新病灶出現並不反映真實腫瘤惡化的情況。Response to immune-based therapies is also assessed using modified RECIST 1.1 (iRECIST) guidelines (Seymour 2017). Immunotherapeutics can induce immune cell infiltration, resulting in a temporary increase in the size of malignant lesions or undetectable lesions becoming detectable. The criteria are consistent with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in many respects but have been adapted to take into account that increases in tumor burden or the appearance of new lesions do not reflect true tumor progression.
關鍵差異描述如下。使用iRECIST指南定義之所有反應名稱帶有字首。iRECIST時間點及最佳反應分別地記錄。Key differences are described below. All response names are prefixed with the iRECIST guidelines. iRECIST time points and best responses are recorded separately.
確認疾病惡化Confirm disease progression
不同於RECIST 1.1版，iRECIST指南需要確認惡化且使用術語iUPD (未確認免疫進行性疾病)及iCPD (經確認免疫進行性疾病)。出於此試驗之目的，應在iUPD後至少4週但不超過9週執行確認掃描。Unlike RECIST version 1.1, the iRECIST guidelines require confirmation of progression and use the terms iUPD (unconfirmed immune progressive disease) and iCPD (confirmed immune progressive disease). For the purposes of this trial, a confirmatory scan should be performed at least 4 weeks but no more than 9 weeks after iUPD.
若與上次評估相比，腫瘤負荷進一步增加由以下中之1或多者證明，則確認iCPD： • 腫瘤負荷持續增加(自iUPD)，其中目標、非目標疾病或新病灶符合RECIST 1.1版惡化定義(自最低點) • 目標疾病惡化加劇，總和絕對值增加至少5 mm • 非目標疾病持續明確惡化，腫瘤負荷增加 • 先前鑑別出的新病灶之尺寸增加(視為目標新病灶之病灶總和絕對值增加至少5 mm)或額外新病灶之尺寸增加。 • 先前未鑑別出惡化的病灶類型(目標及/或非目標及/或新病灶)符合RECIST 1.1版準則，包括出現額外新病灶iCPD is confirmed if a further increase in tumor burden compared to the last assessment is demonstrated by 1 or more of the following:• Sustained increase in tumor burden (from iUPD) with target, non-target disease, or new lesions meeting the definition of worsening according to RECIST version 1.1 (from nadir)• Worsening of target disease with a sum absolute increase of at least 5 mm• Sustained clear worsening of non-target disease with increased tumor burden• Increase in size of previously identified new lesions (considered as a sum absolute increase of target new lesions of at least 5 mm) or increase in size of additional new lesions.• The type of previously unidentified deteriorating lesions (target and/or non-target and/or new lesions) meets the RECIST version 1.1 criteria, including the appearance of additional new lesions
若下一次評估未確認i iUPD，則指定適當反應(若仍符合準則但不惡化則為iUPD，或與基線相比符合彼等準則，則為iSD [免疫穩定疾病]、iPR [免疫部分反應]或iCR [免疫完全反應])。關於更多細節，請參考iRECIST指南(Seymour 2017)。If the next assessment does not confirm iUPD, the appropriate response is assigned (iUPD if criteria are still met but not worsening, or iSD [immune stable disease], iPR [immune partial response], or iCR [immune complete response] if those criteria are met compared to baseline). For more details, refer to the iRECIST guidelines (Seymour 2017).
新病灶New lesions
新病灶應在出現時使用RECIST 1.1版準則進行評估及量測(最多5個病灶，每個部位不超過2個，長軸至少10 mm或對於淋巴結病灶短軸至少15 mm)，且記錄為新病灶-目標(NLT)及新病灶-非目標(NLNT)，使得可與基線目標及非目標病灶清楚地區分。New lesions should be assessed and measured using RECIST version 1.1 criteria when they appear (up to 5 lesions, no more than 2 per site, at least 10 mm in the long axis or at least 15 mm in the short axis for lymph node lesions) and recorded as new lesions-target (NLT) and new lesions-nontarget (NLNT) so that they can be clearly distinguished from baseline target and nontarget lesions.
新病灶可符合NLT或NLNT之準則以驅動iUPD (或iCPD)。然而，目標病灶之量測結果不應包括於基線時鑑別之原始目標病灶之量測總和中。實際上，此等量測結果在病例報告表中分別地收集。6.2實例2-不適合順鉑的先前未經治療之局部晚期或轉移性尿路上皮癌(la/mUC)之患者(Pt)中的恩諾單抗維多汀(EV)伴隨或不伴隨派姆單抗(P)；對群組K資料進行額外3個月隨訪6.2.1背景New lesions may meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, measurements of target lesions should not be included in the sum of measurements of the original target lesions identified at baseline. In practice, these measurements are collected separately in the case report form.6.2Example2-Enrotumab vedotin(EV) with or without concomitant pembrolizumab(P ) inpatients(Pt) withpreviously untreated locally advanced or metastatic urothelial carcinoma(la/mUC) who are not cisplatin-eligible; additional3-month follow-upof CohortKdata6.2.1Background
如上文所論述，儘管有可用的治療選項，但在一線情況下不適合順鉑的局部晚期或轉移性尿路上皮癌(la/mUC)之患者的需求仍亟待滿足。Gem-carbo (亦即，吉西他濱與卡鉑之組合)後接阿維魯單抗維持僅可供在基於鉑之化學療法後未惡化的患者使用。PD-1/L1抑制劑單藥療法僅可供選定患者使用。As discussed above, despite available treatment options, there remains an unmet need for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who are not cisplatin-eligible in the first-line setting. Gem-carbo (i.e., gemcitabine in combination with carboplatin) followed by avelumab maintenance is only available for patients who have not progressed after platinum-based chemotherapy. PD-1/L1 inhibitor monotherapy is only available for selected patients.
恩諾單抗維多汀(EV)+派姆單抗(P)組合在先前未經治療之la/mUC之患者中具有快速、持久反應(68%確認的ORR [95% CI：58.7至76.0]) (參見前述表24)及可管控的安全概況。The combination of enrofloxacin (EV) + pembrolizumab (P) resulted in rapid, durable responses (68% confirmed ORR [95% CI: 58.7 to 76.0]) (see Table 24 above) and a manageable safety profile in patients with previously untreated la/mUC.
在18個月之中值隨訪後，以下實例為實例1中所示的EV-103群組K之結果的更新(亦即，相對於實例1額外隨訪3個月)。6.2.2EV-103群組K-尿路上皮癌患者之開放標記、多群組、1b/2期研究部分。The following example is an update of the results for EV-103 Cohort K presented in Example 1 after a median follow-up of 18 months (i.e., an additional follow-up of 3 months relative to Example 1).6.2.2EV-103CohortK- Open-label, multi-cohort, Phase1b/2study portionin patients with urothelial carcinoma .
EV之給藥為在每3週週期之第1天及第8天1.25 mg/kg IV，且派姆單抗(P)之給藥為在該週期之第1天200 mg IV。主要終點為根據BICR按RECIST v1.1確認的ORR。關鍵次要終點為藉由研究者根據RECIST v1.1確認的ORR；藉由BICR及研究者評估的DOR、DCR、PFS；OS，；安全性/耐受性；及實驗室異常。EV was administered at 1.25 mg/kg IV on Day 1 and Day 8 of each 3-week cycle, and pembrolizumab (P) was administered at 200 mg IV on Day 1 of the cycle. The primary endpoint was ORR confirmed by BICR per RECIST v1.1. Key secondary endpoints were ORR confirmed by investigator per RECIST v1.1; DOR, DCR, PFS by BICR and investigator assessment; OS,; safety/tolerability; and laboratory abnormalities.
樣本大小係基於藉由95% CI表徵的ORR之估計的精確度。2個治療組之間未進行正式統計比較。The sample size was based on the precision of the estimate of ORR expressed by the 95% CI. No formal statistical comparison was performed between the 2 treatment groups.
分層因子為肝轉移(存在/不存在)及ECOG PS (0、1或2)。探索性終點為藥物動力學、抗治療抗體、包括基線PD-L1狀態及連接素-4表現之活性的生物標記物、藉由研究者評估的後續療法之無惡化存活期及患者報告結果。6.2.3方法Stratification factors were liver metastasis (presence/absence) and ECOG PS (0, 1, or 2). Exploratory endpoints were pharmacokinetics, anti-therapeutic antibodies, biomarkers of activity including baseline PD-L1 status and nectin-4 expression, progression-free survival with subsequent treatment assessed by investigators, and patient-reported outcomes.6.2.3Methods
將因不適合而未經治療的la/mUC患者以1:1隨機分入作為單藥療法之EV (1.25 mg/kg，第1天，第8天) (EV單藥)或其與P (200 mg，第1天)之組合，使用3週週期。主要終點為藉由盲態中央獨立評估(BICR)，根據RECIST v1.1的經確認客觀反應率(cORR)。次要終點包括反應持續時間(DOR)、疾病控制率(DCR)、無惡化存活期(PFS)、總存活期(OS)及安全性。治療組之間未計劃進行正式統計比較。6.2.4結果Patients with la/mUC who were unsuitable for treatment were randomized 1:1 to EV (1.25 mg/kg, day 1, day 8) as monotherapy (EV monotherapy) or in combination with P (200 mg, day 1) for 3 weeks. The primary endpoint was confirmed objective response rate (cORR) according to RECIST v1.1 by blinded central independent review (BICR). Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. No formal statistical comparisons between treatment groups were planned.6.2.4Results
此實例中所描述的恩諾單抗維多汀組合派姆單抗作為不能接受基於順鉑之化學療法的不可切除性局部晚期或轉移性尿路上皮癌(la/mUC)之患者之一線治療的1b/2期研究完成參與者入選，其中149名個體入選。研究之EV+派姆單抗組中接受任何量之研究藥物的個體數目為76。研究之EV單藥組中接受任何量之研究藥物的個體數目為73。Participants completed the Phase 1b/2 study of enrofloxacin vedotin in combination with pembrolizumab as first-line treatment for patients with unresectable locally advanced or metastatic urothelial carcinoma (la/mUC) who were unable to receive cisplatin-based chemotherapy described in this example, of which 149 subjects were enrolled. The number of subjects in the EV+pembrolizumab arm of the study who received any amount of study drug was 76. The number of subjects in the EV monotherapy arm of the study who received any amount of study drug was 73.
關於人口統計資料，如表41中所示，人口統計資料及基線疾病特徵代表不適合1L順鉑的LA/mUC群體。 表41
表42提供患者安置之概述。總共149名患者經治療(EV+派姆，N=77，及EV單藥，N=74，總共149名患者經治療)。EV+派姆單抗之中值隨訪時間(95% CI)為17.6 (16.03，20.37)個月。EV單藥之中值隨訪時間(95% CI)為18.2 (15.90，20.07)個月。 表42
根據BICR，EV+派姆單抗確認的ORR伴隨快速反應為64.5% (95% CI，52.7%，75.1%)，如表43中所示。對於EV+派姆單抗組，在第一次評估(第9週±1週)時觀測到42/49 (85.7%)反應。cORR在所有預定子組之間一致。此外，對於EV+派姆單抗組，在肝轉移患者中觀測到7/13 (53.8%) cORR。對於EV單藥組，所觀測到的活性與2L+la/mUC之先前結果一致。 表43
根據BICR，未達到EV+派姆單抗組之中值DOR (參見圖15及表44)。在12個月時，65.6%之反應者仍有反應。對於EV單藥組，中值DOR為13.2個月(6.14，-) (參見表44)。 表44
EV+派姆單抗組之疾病控制率(DCR)為86.6% (77.1，93.5) [資料未顯示]。對於EV單藥組，DCR為79.5% (68.4，88.0) [資料未顯示]。The disease control rate (DCR) of the EV+pembrolizumab group was 86.6% (77.1, 93.5) [data not shown]. For the EV alone group, the DCR was 79.5% (68.4, 88.0) [data not shown].
根據BICR，未達到EV+派姆單抗組之中值PFS (參見圖16及表45)。對於EV+派姆單抗組，6個月及12個月時之PFS率(95% CI)分別為73.8% (62.01，82.42)及54.5% (41.74，65.61) (參見圖16及表45)。對於EV單藥組，中值PFS為8.2 (6.05，15.28)個月(參見表45)。另外，對於EV單藥組，6個月及12個月時之PFS率分別為64.2% (51.09，74.69)及40.3% (26.62，53.60) [資料未顯示]。 表45
根據BICR，未達到EV+派姆單抗組之中值OS (參見圖17及表46)。對於EV+派姆單抗組，6個月及12個月時之OS率(95% CI)分別為88.2% (78.48，93.65)及81.5% (70.78，88.61) (參見圖17及表46)。對於EV單藥組，中值OS為21.7 (15.47，-) (參見表46)。此外，對於EV單藥組，6個月及12個月時之OS率分別為83.6% (72.87，90.31)及69.7% (57.68，78.87) [資料未顯示]。 表46
表47提供EV+派姆單抗及EV單藥治療組之治療相關不良事件(TRAE)。在EV+派姆單抗之情況下最常見的TRAE為疲乏、周邊感覺神經病變、紅斑丘疹及禿髮(參見表47)。對於EV+派姆單抗組，19名(25%)患者具有嚴重TRAE。對於EV單藥組，11名(15.1%)患者具有嚴重TRAE。對於EV+派姆單抗組，3名(3.9%)患者具有導致死亡的TRAE (局部肺炎、呼吸衰竭或敗血症)。對於EV單藥組，2名(2.7%)患者具有導致死亡的治療相關不良事件(多器官功能障礙或呼吸衰竭)。 表47
表48提供EV特別受關注之TRAE。大部分EV特別受關注之TRAE為低級的(參見表48)。在EV+派姆單抗之情況下更頻繁地觀測到皮膚反應。周邊神經病變仍為研究治療中止之最常見原因。 表48
派姆單抗特別受關注之TRAE與派姆單抗單藥療法之先前觀測結果一致，不同之處在於嚴重皮膚反應，其在此研究中以較高發生率報告(參見表49)。 表49
在18個月之中值隨訪時，EV+派姆單抗作為不適合順鉑的la/mUC患者之一線治療繼續顯示高cORR及快速且持久的反應。值得注意的是，尚未達到中值PFS及OS。另外，EV+派姆單抗組合之不良事件顯示可管控的安全概況，在延長治療暴露後未出現新的安全性問題。EV單藥療法結果與2L+la/mUC之先前結果大體上一致。總之，此實例中之資料顯示EV+派姆單抗組合療法用於在一線情況下治療不適合順鉑的la/mUC患者(存在亟待滿足的需求之患者群體)的功效、安全性及耐受性。At a median follow-up of 18 months, EV+pembrolizumab continued to show high cORR and rapid and durable responses as a first-line treatment for la/mUC patients who were not suitable for cisplatin. Notably, median PFS and OS have not yet been reached. In addition, adverse events of the EV+pembrolizumab combination showed a manageable safety profile, and no new safety issues emerged after extended treatment exposure. The results of EV monotherapy were generally consistent with previous results of 2L+la/mUC. In summary, the data in this example show the efficacy, safety, and tolerability of EV+pembrolizumab combination therapy for the treatment of la/mUC patients who are not suitable for cisplatin in the first-line setting, a patient group with unmet needs.
圖1A至圖1E描繪連接素-4蛋白的核苷酸及胺基酸序列(圖1A)、Ha22-2(2.4)6.1之重鏈(圖1B)及輕鏈(圖1C)的核苷酸及胺基酸序列，以及Ha22-2(2.4)6.1之重鏈(圖1D)及輕鏈(圖1E)的胺基酸序列。Figures1Ato1E depict the nucleotide and amino acid sequences of nectin-4 protein (Figure1A ), the nucleotide and amino acid sequences of the heavy chain (Figure1B ) and light chain (Figure1C ) of Ha22-2(2.4)6.1, and the amino acid sequences of the heavy chain (Figure1D ) and light chain (Figure1E ) of Ha22-2(2.4)6.1.
圖2描繪章節6.1所描述之臨床研究的總體研究設計。Figure2 depicts the overall study design of the clinical study described in Section 6.1.
圖3描繪臨床研究之研究階段，該臨床研究為不能接受基於順鉑之化學療法的不可切除性局部晚期或轉移性尿路上皮癌(la/mUC)之患者中恩諾單抗維多汀(enfortumab vedotin)組合派姆單抗作為一線治療的1b/2期研究，如章節6.1中所描述。Figure3 depicts the study stages of a Phase 1b/2 study of enfortumab vedotin in combination with pembrolizumab as first-line treatment in patients with unresectable locally advanced or metastatic urothelial carcinoma (la/mUC) who were unable to receive cisplatin-based chemotherapy, as described in Section 6.1.
圖4描繪歐洲癌症研究及治療組織(European Organization for the Research and Treatment，EORTC)核心生活品質(QLQ-C-30)評估(EORTC-QLQ-C-30，現行版本，第3版)，如章節6.1中所描述。Figure4 depicts the European Organization for the Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C-30) assessment (EORTC-QLQ-C-30, current version, version 3), as described in Section 6.1.
圖5描繪章節6.1中所描述之EuroQol-5維(EQ-5D-5L)。Figure5 depicts the EuroQol-5 dimensions (EQ-5D-5L) described in Section 6.1.
圖6描繪臨床研究中個別患者之腫瘤縮小(亦即，腫瘤尺寸(相對於基線之變化%))，如章節6.1中所描述。Figure6 depicts tumor reduction (i.e., tumor size (% change from baseline)) for individual patients in the clinical study, as described in Section 6.1.
圖7描繪臨床研究中根據盲態中央獨立評估(blinded independent central review)，目標病灶直徑總和隨時間推移(以月為單位)相對於基線之變化百分比，如章節6.1中所描述。Figure7 depicts the percentage change from baseline in the sum of target lesion diameters over time (in months) according to blinded independent central review in the clinical study, as described in Section 6.1.
圖8描繪在章節6.1中所描述之臨床研究中投與恩諾單抗維多汀與派姆單抗之組合之患者(亦即，EV+派姆(pembro)組)的ORR子組分析。Figure8 depicts a subgroup analysis of ORR in patients administered the combination of enrofloxacin and pembrolizumab (i.e., EV+pembro group) in the clinical study described in Section 6.1.
圖9描繪在章節6.1中所描述之臨床研究中投與恩諾單抗維多汀單藥療法之患者(亦即，EV單藥組)的ORR子組分析。Figure9 depicts a subgroup analysis of ORR in patients administered enrofloxacin monotherapy (i.e., EV monotherapy group) in the clinical study described in Section 6.1.
圖10描繪臨床研究中基線時連接素-4表現之H評分及根據盲態中央獨立評估之最佳反應，如章節6.1中所描述。Figure10 depicts the H-scores for nectin-4 expression at baseline and the best response according to blinded central independent assessment in the clinical study, as described in Section 6.1.
圖11描繪臨床研究中基線時連接素-4表現之H評分及根據盲態中央獨立評估之最佳總反應，如章節6.1中所描述。Figure11 depicts the H-score for nectin-4 expression at baseline in the clinical study and the best overall response as assessed by blinded central independent review, as described in Section 6.1.
圖12描繪章節6.1中所描述之臨床研究中根據盲態中央獨立評估之反應持續時間(DOR)。Figure12 depicts the duration of response (DOR) based on blinded central independent assessment in the clinical study described in Section 6.1.
圖13描繪章節6.1中所描述之臨床研究中根據盲態中央獨立評估之無惡化存活率。Figure13 depicts progression-free survival according to blinded central independent review in the clinical studies described in Section 6.1.
圖14描繪章節6.1所描述之臨床研究中的總存活率。Figure14 depicts the overall survival rates in the clinical studies described in Section 6.1.
圖15描繪章節6.2中所描述之臨床研究中根據盲態中央獨立評估之反應持續時間(DOR)。Figure15 depicts the duration of response (DOR) based on blinded central independent assessment in the clinical study described in Section 6.2.
圖16描繪章節6.2中所描述之臨床研究中根據盲態中央獨立評估之無惡化存活率。Figure16 depicts progression-free survival according to blinded central independent review in the clinical studies described in Section 6.2.
圖17描繪章節6.2所描述之臨床研究中的總存活率。Figure17 depicts the overall survival rates in the clinical studies described in Section 6.2.
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| US12257340B2 (en) | 2018-12-03 | 2025-03-25 | Agensys, Inc. | Pharmaceutical compositions comprising anti-191P4D12 antibody drug conjugates and methods of use thereof |
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| CN102131828B (en)* | 2007-06-18 | 2015-06-17 | 默沙东有限责任公司 | Antibody against human programmed death receptor PD-1 |
| US9907849B2 (en)* | 2014-07-18 | 2018-03-06 | Advaxis, Inc. | Combination of a PD-1 antagonist and a listeria-based vaccine for treating prostate cancer |
| CN111315782A (en)* | 2017-09-07 | 2020-06-19 | 蜻蜓疗法股份有限公司 | Proteins that bind to NKG2D, CD16 and tumor-associated antigens |
| CN111423512B (en)* | 2019-01-10 | 2024-01-05 | 北京比洋生物技术有限公司 | Multi-targeting fusion protein for blocking vascular endothelial cell growth and activating T cells and pharmaceutical composition comprising same |
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| Publication | Publication Date | Title |
|---|---|---|
| US20250064956A1 (en) | Methods for treating muscle invasive urothelial cancer or muscle invasive bladder cancer with antibody drug conjugates (adc) that bind to 191p4d12 proteins | |
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| US20230330251A1 (en) | Methods for treating cancers with antibody drug conjugates (adc) that bind to 191p4d12 proteins | |
| TW202417052A (en) | Methods for treating patients with locally advanced or metastatic urothelial cancer with antibody drug conjugates (adc) that bind 191p4d12 proteins in combination with pembrolizumab | |
| TW202515622A (en) | Methods for treating patients with locally advanced or metastatic urothelial cancer with antibody drug conjugates (adc) that bind 191p4d12 proteins in combination with pembrolizumab | |
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