本發明係關於用於治療個體之實體腫瘤，諸如非小細胞肺癌、頭頸癌、乳癌、食道癌、卵巢癌、皮膚癌、胰臟癌、膀胱癌、子宮頸癌及胃癌的方法及組合物，諸如藉由投與結合於α-vβ-6 (αvβ6)之抗體及抗體藥物結合物。The present invention relates to methods and compositions for treating a solid tumor in a subject, such as non-small cell lung cancer, head and neck cancer, breast cancer, esophageal cancer, ovarian cancer, skin cancer, pancreatic cancer, bladder cancer, cervical cancer, and gastric cancer, such as by administering antibodies and antibody-drug conjugates that bind to α-vβ-6 (αvβ6).
αvβ6 (亦稱為α-vβ-6)為結合細胞外基質蛋白，諸如纖維結合蛋白之細胞黏著受體。αvβ6由αv次單元及β6次單元構成，且在包括非小細胞肺癌(NSCLC)的多種癌症中上調。αvβ6 (also known as α-vβ-6) is a cell adhesion receptor that binds extracellular matrix proteins such as fibronectin. αvβ6 is composed of an αv subunit and a β6 subunit and is upregulated in many cancers including non-small cell lung cancer (NSCLC).
患有轉移性或不可切除性實體惡性腫瘤的個體(患有已復發或難以用所有標準照護療法治療之疾病或患有當前療法無法提供益處之疾病)，亦即已用盡所有標準照護治療之彼等個體，需要具有延緩新轉移性病變發展及/或控制或減少疾病負荷之潛力的新治療選擇方案。Individuals with metastatic or unresectable solid malignancies (who have disease that has relapsed or is refractory to all standard of care therapies or who have no benefit from current therapies) who have exhausted all standard of care therapies are in need of new treatment options with the potential to delay the development of new metastatic lesions and/or control or reduce disease burden.
本發明藉由提供高度特異性且有效的抗αvβ6抗體藥物結合物來滿足對改善實體腫瘤之治療的需要，該等實體腫瘤諸如非小細胞肺癌、頭頸癌、乳癌、食道癌、卵巢癌、皮膚癌、胰臟癌、膀胱癌、子宮頸癌及胃癌。The present invention addresses the need for improved treatment of solid tumors, such as non-small cell lung cancer, head and neck cancer, breast cancer, esophageal cancer, ovarian cancer, skin cancer, pancreatic cancer, bladder cancer, cervical cancer, and gastric cancer, by providing highly specific and potent anti-αvβ6 antibody-drug conjugates.
本文中所引用之所有參考文獻，包括專利申請案、專利公開案及科學文獻均以全文引用之方式併入本文中，如同各個別參考文獻特定地且個別地指示以引用之方式併入一般。All references, including patent applications, patent publications, and scientific literature cited herein are hereby incorporated by reference in their entirety to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
本文提供一種治療個體之實體腫瘤的方法，該方法包含向個體投與抗體藥物結合物，其結合於與單甲基奧瑞他汀(monomethyl auristatin)或其功能類似物或其功能衍生物結合之α-vβ-6 (αvβ6)或其抗原結合片段，其中抗體藥物結合物以在約0.7 mg/kg至約2.5 mg/kg個體體重之範圍內的劑量投與，且其中抗體藥物結合物之抗αvβ6抗體或抗原結合片段包含重鏈可變區及輕鏈可變區，其中重鏈可變區包含： (i) CDR-H1，其包含SEQ ID NO:1之胺基酸序列； (ii) CDR-H2，其包含SEQ ID NO:2之胺基酸序列；及 (iii) CDR-H3，其包含SEQ ID NO:3之胺基酸序列；且 其中輕鏈可變區包含： (i) CDR-L1，其包含SEQ ID NO:4之胺基酸序列； (ii) CDR-L2，其包含SEQ ID NO:5之胺基酸序列；及 (iii) CDR-L3，其包含SEQ ID NO:6之胺基酸序列。在一些實施例中，抗體藥物結合物之抗αvβ6抗體或其抗原結合片段包含有包含與SEQ ID NO:7之胺基酸序列至少85%一致之胺基酸序列的重鏈可變區及包含與SEQ ID NO:8之胺基酸序列至少85%一致之胺基酸序列的輕鏈可變區。在一些實施例中，抗體藥物結合物之抗αvβ6抗體或其抗原結合片段包含有包含SEQ ID NO:7之胺基酸序列的重鏈可變區及包含SEQ ID NO:8之胺基酸序列的輕鏈可變區。在一些實施例中，抗體藥物結合物之抗αvβ6抗體或其抗原結合片段包含有包含SEQ ID NO:9之胺基酸序列的重鏈及包含SEQ ID NO:10之胺基酸序列的輕鏈。在一些實施例中，單甲基奧瑞他汀為單甲基奧瑞他汀E (MMAE)。在一些實施例中，抗體藥物結合物之抗αvβ6抗體或其抗原結合片段為單株抗體或其單株抗原結合片段。在一些實施例中，抗體藥物結合物進一步包含在抗αvβ6抗體或其抗原結合片段與單甲基奧瑞他汀之間的連接子。在一些實施例中，連接子為可裂解肽連接子。在一些實施例中，可裂解肽連接子具有下式：-MC-vc-PAB-，其中： a) MC為：， b) vc 為二肽纈胺酸-瓜胺酸，及 c) PAB為：。在一些實施例中，連接子連接至藉由部分還原或完全還原抗αvβ6抗體或其抗原結合片段所獲得之抗αvβ6抗體的硫氫基殘基。在一些實施例中，連接子連接至單甲基奧瑞他汀E (MMAE)，其中抗體藥物結合物具有以下結構：其中p表示1至8之數值，S表示抗αvβ6抗體之硫氫基殘基，且Ab表示抗αvβ6抗體或其抗原結合片段。在一些實施例中，抗體藥物結合物群體中p的平均值為約4。在一些實施例中，劑量為約0.8 mg/kg、約1.0 mg/kg、約1.2 mg/kg、約1.25 mg/kg、約1.5 mg/kg、約1.8 mg/kg、約2.0或約2.4 mg/kg個體體重。在一些實施例中，劑量為0.8 mg/kg、1.0 mg/kg、1.2 mg/kg、1.25 mg/kg、1.5 mg/kg、1.8 mg/kg、2.0或2.4 mg/kg個體體重。在一些實施例中，劑量為1.8 mg/kg個體體重。在一些實施例中，劑量為1.25 mg/kg個體體重。在一些實施例中，劑量為1.5 mg/kg個體體重。在一些實施例中，個體體重為個體之理想體重(IBW)。在一些實施例中，個體體重為個體經調整之理想體重(AIBW)。在一些實施例中，抗體藥物結合物約每1週投與一次、約每2週投與一次、約每3週投與一次或約每3週投與兩次。在一些實施例中，抗體藥物結合物約每1週投與一次。在一些實施例中，抗體藥物結合物約每2週投與一次。在一些實施例中，抗體藥物結合物以約1.8 mg/kg個體體重之劑量每2週投與一次。在一些實施例中，抗體藥物結合物以1.5 mg/kg個體體重之劑量約每2週投與一次。在一些實施例中，抗體藥物結合物約每3週投與一次。在一些實施例中，抗體藥物結合物連續2週約每1週投與一次，接著為約1週休止期而不投與任何抗體藥物結合物，使得各週期時間為約21天(包括休止期)。在一些實施例中，在各21天週期之第1天及第8天投與抗體藥物結合物，而在第15天不投與。在一些實施例中，抗體藥物結合物連續2週約每1週投與一次，接著為約1週休止期而不投與任何抗體藥物結合物，使得各週期時間為約21天(包括休止期)，且抗體藥物結合物以1.25 mg/kg個體體重之劑量投與。在一些實施例中，抗體藥物結合物連續2週約每1週投與一次，接著為約1週休止期而不投與任何抗體藥物結合物，使得各週期時間為約21天(包括休止期)，且抗體藥物結合物以1.5 mg/kg個體體重之劑量投與。在一些實施例中，個體先前已用一或多種治療劑治療實體腫瘤且對治療不起反應、在治療之後復發或在治療期間經歷疾病進展，其中一或多種治療劑並非抗體藥物結合物。在一些實施例中，實體腫瘤為局部晚期或轉移性的。在一些實施例中，實體腫瘤係選自由以下組成之群：肺癌、頭頸癌、乳癌、食道癌、胃食道結合部癌、卵巢癌、腹膜癌或輸卵管癌、皮膚癌、胰臟癌、膀胱癌、子宮頸癌及胃癌。在一些實施例中，肺癌為非小細胞肺癌。在一些實施例中，非小細胞肺癌為鱗狀細胞癌。在一些實施例中，非小細胞肺癌為非鱗狀細胞癌。在一些實施例中，實體腫瘤為肺癌且肺癌不具有已知表皮生長因子受體(EGFR)或退行性淋巴瘤激酶(ALK)突變。在一些實施例中，實體腫瘤為肺癌且肺癌具有已知的表皮生長因子受體(EGFR)或退行性淋巴瘤激酶(ALK)突變。在一些實施例中，實體腫瘤為肺癌且個體接受先前基於鉑之療法及使用PD1/PD-L1抑制劑之先前療法。在一些實施例中，實體腫瘤為肺癌且個體未曾接受使用紫杉烷之先前療法。在一些實施例中，頭頸癌為頭頸部鱗狀細胞癌。在一些實施例中，實體腫瘤為頭頸癌且個體接受先前基於鉑之療法及使用PD1/PD-L1抑制劑之先前療法。在一些實施例中，乳癌為HER2陰性乳癌。在一些實施例中，實體腫瘤為乳癌且個體接受乳癌之1線或多線先前療法。在一些實施例中，1線或多線先前療法包括紫杉烷，其以單一藥劑形式或與不同藥劑組合投與。在一些實施例中，食道癌為食道鱗狀細胞癌。在一些實施例中，實體腫瘤為食道癌且個體接受先前基於鉑之化學療法。在一些實施例中，食道癌為食道腺癌。在一些實施例中，胃食道結合部癌為胃食道結合部腺癌。在一些實施例中，個體接受先前基於鉑之化學療法。在一些實施例中，卵巢癌為高級漿液性上皮卵巢癌。在一些實施例中，皮膚癌為皮膚鱗狀細胞癌。在一些實施例中，實體腫瘤為皮膚癌且個體接受使用PD1/PD-L1抑制劑之先前療法。在一些實施例中，胰臟癌為外分泌胰臟腺癌。在一些實施例中，實體腫瘤為晚期癌症。在一些實施例中，晚期癌症為3期或4期癌症。在一些實施例中，晚期癌症為轉移性癌症。在一些實施例中，抗體藥物結合物之投與途徑為靜脈內。在一些實施例中，至少約0.1%、至少約1%、至少約2%、至少約3%、至少約4%、至少約5%、至少約6%、至少約7%、至少約8%、至少約9%、至少約10%、至少約15%、至少約20%、至少約25%、至少約30%、至少約35%、至少約40%、至少約45%、至少約50%、至少約60%、至少約70%或至少約80%之癌細胞表現αvβ6。在一些實施例中，在投與抗體藥物結合物之後，個體中之一或多種治療效果相對於基線得到改善。在一些實施例中，一或多種治療效果係選自由以下組成之群：來源於癌症之腫瘤的尺寸、客觀反應率、反應持續時間、達至反應之時間、無進展存活期及總存活期。在一些實施例中，來源於癌症之腫瘤的尺寸相對於投與抗體藥物結合物之前的來源於癌症之腫瘤的尺寸減小至少約10%、至少約15%、至少約20%、至少約25%、至少約30%、至少約35%、至少約40%、至少約45%、至少約50%、至少約60%、至少約70%或至少約80%。在一些實施例中，客觀反應率為至少約20%、至少約25%、至少約30%、至少約35%、至少約40%、至少約45%、至少約50%、至少約60%、至少約70%或至少約80%。在一些實施例中，在投與抗體藥物結合物之後，個體展現出至少約1個月、至少約2個月、至少約3個月、至少約4個月、至少約5個月、至少約6個月、至少約7個月、至少約8個月、至少約9個月、至少約10個月、至少約11個月、至少約12個月、至少約十八個月、至少約兩年、至少約三年、至少約四年或至少約五年之無進展存活期。在一些實施例中，在投與抗體藥物結合物之後，個體展現出至少約1個月、至少約2個月、至少約3個月、至少約4個月、至少約5個月、至少約6個月、至少約7個月、至少約8個月、至少約9個月、至少約10個月、至少約11個月、至少約12個月、至少約十八個月、至少約兩年、至少約三年、至少約四年或至少約五年之總存活期。在一些實施例中，在投與抗體藥物結合物之後，對抗體藥物結合物之反應持續時間為至少約1個月、至少約2個月、至少約3個月、至少約4個月、至少約5個月、至少約6個月、至少約7個月、至少約8個月、至少約9個月、至少約10個月、至少約11個月、至少約12個月、至少約十八個月、至少約兩年、至少約三年、至少約四年或至少約五年。在一些實施例中，個體具有一或多種不良事件，且進一步投與額外治療劑以消除該一或多種不良事件或降低其嚴重程度。在一些實施例中，個體處於出現一或多種不良事件之風險下，且進一步投與額外治療劑以預防該一或多種不良事件或降低其嚴重程度。在一些實施例中，抗體藥物結合物以單一療法形式投與。在一些實施例中，該方法進一步包含向個體投與一或多種額外治療劑。在一些實施例中，一或多種額外治療劑為檢查點抑制劑。在一些實施例中，檢查點抑制劑為PD-1抑制劑或PD-L1抑制劑。在一些實施例中，PD-1抑制劑為抗PD-1抗體。在一些實施例中，抗PD-1抗體為帕博利珠單抗(pembrolizumab)或其生物類似物。在一些實施例中，帕博利珠單抗或其生物類似物以約200 mg之劑量投與。在一些實施例中，帕博利珠單抗或其生物類似物約每3週投與一次。在一些實施例中，帕博利珠單抗或其生物類似物以約400 mg之劑量投與。在一些實施例中，帕博利珠單抗或其生物類似物約每6週投與一次。在一些實施例中，帕博利珠單抗或其生物類似物之投與途徑為靜脈內。在一些實施例中，在治療之前，腫瘤包含一或多種表現PD-L1之細胞。在一些實施例中，個體患有表現PD-L1之腫瘤，其中TPS≥1%。在一些實施例中，個體患有表現PD-L1之腫瘤，其中TPS≥20%。在一些實施例中，個體患有表現PD-L1之腫瘤，其中TPS≥50%。在一些實施例中，個體患有表現PD-L1之腫瘤，其中CPS≥1。在一些實施例中，個體患有表現PD-L1之腫瘤，其中CPS≥20。在一些實施例中，一或多種額外治療劑為基於鉑之藥劑。在一些實施例中，基於鉑之藥劑為卡鉑或順鉑。在一些實施例中，在投與第一劑量之一或多種額外治療劑之前投與第一劑量之抗體藥物結合物。在一些實施例中，在投與第一劑量之一或多種額外治療劑之前至少1天、至少2天、至少3天、至少4天、至少5天、至少6天、至少7天、至少2週、至少3週、至少4週、至少2個月、至少3個月、至少4個月、至少5個月或至少6個月，投與第一劑量之抗體藥物結合物。在一些實施例中，個體為人類。在一些實施例中，抗體藥物結合物呈包含抗體藥物結合物及醫藥學上可接受之載劑的醫藥組合物形式。Provided herein is a method for treating a solid tumor in an individual, the method comprising administering to the individual an antibody-drug conjugate that binds to α-vβ-6 (αvβ6) or an antigen-binding fragment thereof bound to monomethyl auristatin or a functional analog or functional derivative thereof, wherein the antibody-drug conjugate is administered in an amount ranging from about 0.7 mg/kg to about 2.5 mg/kg of the individual's body weight, and wherein the anti-αvβ6 antibody or antigen-binding fragment of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:1; (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:2; and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: NO:3; and wherein the light chain variable region comprises: (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, the anti-αvβ6 antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-αvβ6 antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-αvβ6 antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:9 and a light chain comprising an amino acid sequence of SEQ ID NO:10. In some embodiments, the monomethyl auristatin is monomethyl auristatin E (MMAE). In some embodiments, the anti-αvβ6 antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof. In some embodiments, the antibody-drug conjugate further comprises a linker between the anti-αvβ6 antibody or antigen-binding fragment thereof and the monomethyl auristatin. In some embodiments, the linker is a cleavable peptide linker. In some embodiments, the cleavable peptide linker has the following formula: -MC-vc-PAB-, wherein: a) MC is: , b) vc is the dipeptide valine-citrulline, and c) PAB is: In some embodiments, the linker is linked to a sulfhydryl residue of an anti-αvβ6 antibody obtained by partial or complete reduction of the anti-αvβ6 antibody or an antigen-binding fragment thereof. In some embodiments, the linker is linked to monomethyl auristatin E (MMAE), wherein the antibody drug conjugate has the following structure: wherein p represents a number from 1 to 8, S represents a sulfhydryl residue of an anti-αvβ6 antibody, and Ab represents an anti-αvβ6 antibody or an antigen-binding fragment thereof. In some embodiments, the average value of p in the antibody drug conjugate population is about 4. In some embodiments, the dose is about 0.8 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 1.8 mg/kg, about 2.0, or about 2.4 mg/kg of individual body weight. In some embodiments, the dose is 0.8 mg/kg, 1.0 mg/kg, 1.2 mg/kg, 1.25 mg/kg, 1.5 mg/kg, 1.8 mg/kg, 2.0, or 2.4 mg/kg of individual body weight. In some embodiments, the dose is 1.8 mg/kg of individual body weight. In some embodiments, the dosage is 1.25 mg/kg of individual body weight. In some embodiments, the dosage is 1.5 mg/kg of individual body weight. In some embodiments, the individual body weight is the individual's ideal body weight (IBW). In some embodiments, the individual body weight is the individual's adjusted ideal body weight (AIBW). In some embodiments, the antibody-drug conjugate is administered once about every 1 week, once about every 2 weeks, once about every 3 weeks, or twice about every 3 weeks. In some embodiments, the antibody-drug conjugate is administered once about every 1 week. In some embodiments, the antibody-drug conjugate is administered once about every 2 weeks. In some embodiments, the antibody-drug conjugate is administered once every 2 weeks at a dosage of about 1.8 mg/kg of individual body weight. In some embodiments, the antibody drug conjugate is administered at a dose of 1.5 mg/kg of individual body weight about once every 2 weeks. In some embodiments, the antibody drug conjugate is administered about once every 3 weeks. In some embodiments, the antibody drug conjugate is administered about once every 1 week for 2 consecutive weeks, followed by a rest period of about 1 week without administering any antibody drug conjugate, so that each cycle time is about 21 days (including the rest period). In some embodiments, the antibody drug conjugate is administered on the 1st and 8th day of each 21-day cycle, and is not administered on the 15th day. In some embodiments, the antibody drug conjugate is administered about every 1 week for 2 consecutive weeks, followed by a rest period of about 1 week without administration of any antibody drug conjugate, such that each cycle time is about 21 days (including the rest period), and the antibody drug conjugate is administered at a dose of 1.25 mg/kg of individual body weight. In some embodiments, the antibody drug conjugate is administered about every 1 week for 2 consecutive weeks, followed by a rest period of about 1 week without administration of any antibody drug conjugate, such that each cycle time is about 21 days (including the rest period), and the antibody drug conjugate is administered at a dose of 1.5 mg/kg of individual body weight. In some embodiments, the individual has previously been treated with one or more therapeutic agents for a solid tumor and has failed to respond to treatment, relapsed after treatment, or experienced disease progression during treatment, wherein the one or more therapeutic agents are not an antibody drug conjugate. In some embodiments, the solid tumor is locally advanced or metastatic. In some embodiments, the solid tumor is selected from the group consisting of lung cancer, head and neck cancer, breast cancer, esophageal cancer, gastroesophageal junction cancer, ovarian cancer, peritoneal cancer or fallopian tube cancer, skin cancer, pancreatic cancer, bladder cancer, cervical cancer, and gastric cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is squamous cell carcinoma. In some embodiments, the non-small cell lung cancer is non-squamous cell carcinoma. In some embodiments, the solid tumor is lung cancer and the lung cancer does not have a known epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation. In some embodiments, the solid tumor is lung cancer and the lung cancer has a known epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation. In some embodiments, the solid tumor is lung cancer and the individual has received prior platinum-based therapy and prior therapy with a PD1/PD-L1 inhibitor. In some embodiments, the solid tumor is lung cancer and the individual has not received prior therapy with a taxane. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma. In some embodiments, the solid tumor is head and neck cancer and the individual receives prior platinum-based therapy and prior therapy with a PD1/PD-L1 inhibitor. In some embodiments, breast cancer is HER2-negative breast cancer. In some embodiments, the solid tumor is breast cancer and the individual receives 1 or more lines of prior therapy for breast cancer. In some embodiments, 1 or more lines of prior therapy include taxanes, which are administered as a single agent or in combination with different agents. In some embodiments, esophageal cancer is esophageal squamous cell carcinoma. In some embodiments, the solid tumor is esophageal cancer and the individual receives prior platinum-based chemotherapy. In some embodiments, esophageal cancer is esophageal adenocarcinoma. In some embodiments, gastroesophageal junction cancer is gastroesophageal junction adenocarcinoma. In some embodiments, the individual receives prior platinum-based chemotherapy. In some embodiments, the ovarian cancer is high-grade serous epithelial ovarian cancer. In some embodiments, the skin cancer is cutaneous squamous cell carcinoma. In some embodiments, the solid tumor is skin cancer and the individual receives prior therapy with a PD1/PD-L1 inhibitor. In some embodiments, the pancreatic cancer is exocrine pancreatic adenocarcinoma. In some embodiments, the solid tumor is an advanced cancer. In some embodiments, the advanced cancer is stage 3 or stage 4 cancer. In some embodiments, the advanced cancer is a metastatic cancer. In some embodiments, the route of administration of the antibody drug conjugate is intravenous. In some embodiments, at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the cancer cells express αvβ6. In some embodiments, following administration of the antibody drug conjugate, one or more therapeutic effects in the subject are improved relative to baseline. In some embodiments, the one or more therapeutic effects are selected from the group consisting of size of a tumor from a cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival. In some embodiments, the size of a cancer-derived tumor is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the cancer-derived tumor prior to administration of the antibody drug conjugate. In some embodiments, the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%. In some embodiments, following administration of the antibody drug conjugate, the subject exhibits a progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about two years, at least about three years, at least about four years, or at least about five years. In some embodiments, following administration of the antibody drug conjugate, the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about two years, at least about three years, at least about four years, or at least about five years. In some embodiments, after administration of the antibody drug conjugate, the duration of response to the antibody drug conjugate is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about two years, at least about three years, at least about four years, or at least about five years. In some embodiments, the subject has one or more adverse events, and the additional therapeutic agent is further administered to eliminate or reduce the severity of the one or more adverse events. In some embodiments, the subject is at risk for experiencing one or more adverse events, and the additional therapeutic agent is further administered to prevent or reduce the severity of the one or more adverse events. In some embodiments, the antibody drug conjugate is administered as a monotherapy. In some embodiments, the method further comprises administering one or more additional therapeutic agents to the individual. In some embodiments, the one or more additional therapeutic agents are checkpoint inhibitors. In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is pembrolizumab or a biosimilar thereof. In some embodiments, pembrolizumab or a biosimilar thereof is administered in an amount of about 200 mg. In some embodiments, pembrolizumab or a biosimilar thereof is administered about once every 3 weeks. In some embodiments, pembrolizumab or a biosimilar thereof is administered at a dose of about 400 mg. In some embodiments, pembrolizumab or a biosimilar thereof is administered approximately every 6 weeks. In some embodiments, the route of administration of pembrolizumab or a biosimilar thereof is intravenous. In some embodiments, prior to treatment, the tumor comprises one or more cells expressing PD-L1. In some embodiments, the individual has a tumor expressing PD-L1, wherein TPS ≥ 1%. In some embodiments, the individual has a tumor expressing PD-L1, wherein TPS ≥ 20%. In some embodiments, the individual has a tumor expressing PD-L1, wherein TPS ≥ 50%. In some embodiments, the individual has a tumor expressing PD-L1, wherein CPS ≥ 1. In some embodiments, the subject has a tumor expressing PD-L1, wherein the CPS is ≥ 20. In some embodiments, the one or more additional therapeutic agents are platinum-based agents. In some embodiments, the platinum-based agent is carboplatin or cisplatin. In some embodiments, the first dose of the antibody-drug conjugate is administered prior to the first dose of the one or more additional therapeutic agents. In some embodiments, the first dose of the antibody-drug conjugate is administered at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months prior to the administration of the first dose of one or more additional therapeutic agents. In some embodiments, the subject is a human. In some embodiments, the antibody-drug conjugate is in the form of a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.
本文亦提供一種套組，其包含： (a) 劑量在約0.7 mg/kg至約2.5 mg/kg範圍內的結合於αvβ6之抗體藥物結合物，其中抗體藥物結合物包含與單甲基奧瑞他汀或其功能類似物或其功能衍生物結合之抗αvβ6抗體或其抗原結合片段；及 (b) 使用根據本文所提供之實施例中之任一者之抗體藥物結合物的說明。Also provided herein is a kit comprising:(a) an antibody-drug conjugate that binds to αvβ6 in an amount ranging from about 0.7 mg/kg to about 2.5 mg/kg, wherein the antibody-drug conjugate comprises an anti-αvβ6 antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog or functional derivative thereof; and(b) instructions for using the antibody-drug conjugate according to any of the embodiments provided herein.
本文亦提供結合於αvβ6之抗體藥物結合物之用途，其用於製造供本文所提供之實施例中之任一者使用的藥劑，其中抗體藥物結合物包含與單甲基奧瑞他汀或其功能類似物或其功能衍生物結合之抗αvβ6抗體或其抗原結合片段。Also provided herein is the use of an antibody-drug conjugate that binds to αvβ6 for the manufacture of a medicament for use in any of the embodiments provided herein, wherein the antibody-drug conjugate comprises an anti-αvβ6 antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog or functional derivative thereof.
本文亦提供結合於αvβ6以用於本文所提供之實施例中之任一者的抗體藥物結合物，其中抗體藥物結合物包含與單甲基奧瑞他汀或其功能類似物或其功能衍生物結合之抗αvβ6抗體或其抗原結合片段。Also provided herein are antibody-drug conjugates that bind to αvβ6 for use in any of the embodiments provided herein, wherein the antibody-drug conjugate comprises an anti-αvβ6 antibody or an antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog or functional derivative thereof.
相關申請案之交互參考Cross-references to related applications
本申請案主張2022年11月3日申請之美國臨時申請案第63/422,098號及2023年4月5日申請之美國臨時申請案第63/457,205號之權益，其中之各者出於所有目的以全文引用之方式併入本文中。 序列表之參考This application claims the benefit of U.S. Provisional Application No. 63/422,098 filed on November 3, 2022 and U.S. Provisional Application No. 63/457,205 filed on April 5, 2023, each of which is incorporated herein by reference in its entirety for all purposes.Reference to Sequence Listing
本申請案包括在2023年10月6日創建之名為AVB6-00412PC_Sequence_Listing且含有11 Kb的檔案中之電子序列表，其特此以引用之方式併入。I.定義This application includes an electronic sequence listing in a file named AVB6-00412PC_Sequence_Listing, created on October 6, 2023, and containing 11 Kb, which is hereby incorporated by reference.I.Definitions
為了使本發明更易理解，首先定義某些術語。依本申請案中所用，除非本文中另外明確提供，否則以下術語中之各者應具有以下闡述之含義。額外的定義在整個申請案中均有闡述。In order to make the present invention easier to understand, some terms are first defined. As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meanings set forth below. Additional definitions are set forth throughout the application.
本文所用之術語「及/或」應視為兩種指定特徵或組分中之各者具有或不具有另一者之特定揭示內容。因此，諸如本文中「A及/或B」之片語中所用之術語「及/或」意欲包括「A及B」、「A或B」、「A」(單獨)及「B」(單獨)。同樣，如在諸如「A、B及/或C」之片語中所用之術語「及/或」意欲涵蓋以下態樣中之各者：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 herein should be construed as a specific disclosure that each of the two specified features or components has or does not have the other. Thus, the term "and/or" as used in phrases such as "A and/or B" herein is intended to include "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: 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).
應理解，本文所描述之本發明之態樣及實施例包括「包含」態樣及實施例、「由」態樣及實施例「組成」及「基本上由」態樣及實施例「組成」。It should be understood that aspects and embodiments of the present invention described herein include "comprising" aspects and embodiments, "consisting of" aspects and embodiments, and "consisting essentially of" aspects and embodiments.
除非另外定義，否則本文所用之所有技術及科學術語均具有與本發明所屬領域之一般技術者通常所理解相同之含義。舉例而言，the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 第2版, 2002, CRC Press；The Dictionary of Cell and Molecular Biology, 第3版, 1999, Academic Press；及the Oxford Dictionary of Biochemistry And Molecular Biology, 經修訂, 2000, Oxford University Press向此項技術者提供本發明中所用之許多術語的通用辭典。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd edition, 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd edition, 1999, Academic Press; and the Oxford Dictionary of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press provide such persons with general dictionaries of many of the terms used in the present invention.
單位、字首及符號以其國際單位制(Système International de Unites；SI)公認之形式表示。數值範圍包括界定該範圍之數字。本文所提供之標題並非本發明之各種態樣的限制，其可作為整體由說明書提及。因此，下文緊接著定義之術語藉由參考整個說明書來更充分地定義。Units, prefixes and symbols are expressed in the form recognized by the International System of Units (Système International de Unites; SI). Numerical ranges include the numbers defining the range. The headings provided herein are not limitations of the various aspects of the invention, which may be referred to as a whole by the specification. Therefore, the terms defined immediately below are more fully defined by reference to the entire specification.
術語「αvβ6」、「avb6」、「α-vβ-6」或「β6」在本文中可互換地使用，且除非另外規定，否則包括一般由細胞表現或表現在經αvβ6基因轉染的細胞上之人類αvβ6的任何變異體、同功異型物及物質同系物。The terms "αvβ6," "avb6," "α-vβ-6," or "β6" are used interchangeably herein and, unless otherwise specified, include any variants, isoforms, and homologs of human αvβ6 that are normally expressed by cells or expressed on cells transfected with the αvβ6 gene.
術語「免疫球蛋白」係指由兩對多肽鏈、一對輕(L)低分子量鏈及一對重(H)鏈組成的一類結構上相關糖蛋白，所有四對鏈藉由二硫鍵互連。已充分表徵免疫球蛋白之結構。參見例如Fundamental Immunology第7章(Paul, W.編, 第2版Raven Press, N .Y. (1989))。簡言之，各重鏈通常包含重鏈可變區(本文中縮寫為VH或VH)及重鏈恆定區(CH或CH)。重鏈恆定區通常包含三個域，CH1、CH2及CH3。重鏈一般經由所謂「鉸鏈區」中之二硫鍵互連。各輕鏈通常包含輕鏈可變區(本文中縮寫為VL或VL)及輕鏈恆定區(CL或CL)。輕鏈恆定區通常包含一個域，CL。CL可為κ (kappa)或λ (lambda)同型。術語「恆定域」與「恆定區」在本文中可互換使用。免疫球蛋白可來源於任何通常已知同型，包括但不限於IgA、分泌性IgA、IgG及IgM。IgG子類亦為熟習此項技術者所熟知，且包括但不限於人類IgG1、IgG2、IgG3及IgG4。「同型」係指由重鏈恆定區基因編碼之抗體類別或子類別(例如IgM或IgG1)。The term "immunoglobulin" refers to a class of structurally related glycoproteins composed of two pairs of polypeptide chains, a pair of light (L) low molecular weight chains and a pair of heavy (H) chains, all four pairs of chains interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Chapter 7 of Fundamental Immunology (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)). Briefly, each heavy chain generally comprises a heavy chain variable region (abbreviated herein asVH or VH) and a heavy chain constant region (CH or CH). The heavy chain constant region generally comprises three domains,CH1 ,CH2 , andCH3 . The heavy chains are generally interconnected by disulfide bonds in the so-called "hinge regions". Each light chain typically comprises a light chain variable region (abbreviated herein asVL or VL) and a light chain constant region (CL or CL). The light chain constant region typically comprises one domain,CL . CL may be of the κ (kappa) or λ (lambda) isotype. The terms "constant domain" and "constant region" are used interchangeably herein. Immunoglobulins may be derived from any commonly known isotype, including but not limited to IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those skilled in the art, and include but are not limited to human IgG1, IgG2, IgG3, and IgG4. "Isotype" refers to the antibody class or subclass (e.g., IgM or IgG1) encoded by the heavy chain constant region gene.
術語「可變區」或「可變域」係指涉及抗體結合至抗原的抗體重鏈或輕鏈域。天然抗體之重鏈及輕鏈的可變區(分別為VH及VL)可進一步細分成高變區(region of hypervariability) (或高變區(hypervariable region)，其可在序列及/或結構上限定環之形式中高變)，亦稱為互補決定區(CDR)，穿插有更保守的區，稱為框架區(FR)。與「高變區」或「HVR」同義之術語「互補決定區」及「CDR」在此項技術中已知係指抗體可變區內之非連續胺基酸序列，其賦予抗原特異性及/或結合親和力。一般而言，各重鏈可變區中存在三個CDR (CDR-H1、CDR-H2、CDR-H3)，且各輕鏈可變區中存在三個CDR (CDR-L1、CDR-L2、CDR-L3)。「構架區」及「FR」在此項技術中已知係指重鏈及輕鏈之可變區的非CDR部分。一般而言，各全長重鏈可變區中存在四個FR (FR-H1、FR-H2、FR-H3及FR-H4)，且各全長輕鏈可變區中存在四個FR (FR-L1、FR-L2、FR-L3及FR-L4)。在各VH及VL內，三個CDR及四個FR通常按以下次序自胺基端排列至羧基端：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4 (亦參見Chothia及LeskJ.Mot.Biol., 195, 901-917 (1987))。The term "variable region" or "variable domain" refers to the domain of an antibody heavy chain or light chain that is involved in binding the antibody to an antigen. The variable regions of the heavy and light chains of native antibodies (VH andVL , respectively) can be further subdivided into regions of hypervariability (or hypervariable regions, which are hypervariable in the form of sequence and/or structurally defined loops), also called complementary determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). The terms "complementary determining regions" and "CDRs," which are synonymous with "hypervariable regions" or "HVRs," are known in the art to refer to non-contiguous amino acid sequences within the variable regions of an antibody that confer antigen specificity and/or binding affinity. Generally, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-H2, CDR-H3), and three CDRs in each light chain variable region (CDR-L1, CDR-L2, CDR-L3). "Framework region" and "FR" are known in the art to refer to the non-CDR portions of the heavy and light chain variable regions. Generally, there are four FRs in each full-length heavy chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4), and there are four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4). Within eachVH andVL , the three CDRs and four FRs are typically arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and LeskJ.Mot.Biol ., 195, 901-917 (1987)).
在本發明之上下文中，術語「抗體」(Ab)係指免疫球蛋白分子、免疫球蛋白分子之片段或其中任一者之衍生物，其具有在典型生理條件下與抗原特異性結合之能力，具有較長時段之半衰期，諸如至少約30 min、至少約45 min、至少約一小時(h)、至少約兩小時、至少約四小時、至少約八小時、至少約12小時(h)、約24小時或更長、約48小時或更長、約三、四、五、六、七或更多天等，或任何其他相關功能上限定之時段(諸如足以誘導、促成、增強及/或調節與結合抗原之抗體相關聯之生理反應的時間及/或對於抗體補充效應活性而言足夠的時間)。免疫球蛋白分子之重鏈及輕鏈的可變區含有與抗原相互作用之結合域。抗體(Ab)之恆定區可介導免疫球蛋白與宿主組織或因子的結合，包括免疫系統之各種細胞(諸如效應細胞)及補體系統之組分(諸如C1q，補體活化之經典路徑中的第一組分)。抗體亦可為雙特異性抗體、雙功能抗體、多特異性抗體或類似分子。In the context of the present invention, the term "antibody" (Ab) refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule or a derivative thereof, which has the ability to specifically bind to an antigen under typical physiological conditions and has a half-life of a relatively long period, such as at least about 30 min, at least about 45 min, at least about one hour (h), at least about two hours, at least about four hours, at least about eight hours, at least about 12 hours (h), about 24 hours or longer, about 48 hours or longer, about three, four, five, six, seven or more days, etc., or any other relevant functionally defined time period (such as a time sufficient to induce, promote, enhance and/or regulate a physiological response associated with the antibody binding to the antigen and/or a time sufficient for the antibody to supplement the effector activity). The variable regions of the heavy and light chains of immunoglobulin molecules contain binding domains that interact with antigens. The constant regions of antibodies (Ab) mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system (such as C1q, the first component in the classical pathway of complement activation). Antibodies can also be bispecific antibodies, bifunctional antibodies, multispecific antibodies, or similar molecules.
依本文所用，術語「單株抗體」係指製備由小鼠B細胞融合體產生之用單個一級胺基酸序列以重組方式產生的抗體分子。單株抗體組合物對於特定抗原決定基顯示單一結合特異性及親和力。因此，術語「人類單株抗體」係指顯示單一結合特異性之抗體，其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。人類單株抗體可由融合瘤產生，該融合瘤包括融合至永生化細胞之自轉殖基因或轉殖染色體非人類動物(諸如轉殖基因小鼠)獲得的B細胞，其具有包含人類重鏈轉殖基因及人類輕鏈轉殖基因之基因體。As used herein, the term "monoclonal antibody" refers to an antibody molecule produced recombinantly from a single primary amino acid sequence prepared by mouse B cell fusion. Monoclonal antibody compositions display a single binding specificity and affinity for a particular antigenic determinant. Thus, the term "human monoclonal antibody" refers to an antibody that displays a single binding specificity and has variable and constant regions derived from human germline immunoglobulin sequences. Human monoclonal antibodies can be produced by a fusion tumor that includes a B cell obtained from a transgenic or transchromosomal non-human animal (such as a transgenic mouse) fused to an immortalized cell that has a genome comprising a human heavy chain transgene and a human light chain transgene.
術語「經分離抗體」係指實質上不含具有不同抗原特異性之其他抗體的抗體(例如特異性結合於αvβ6之經分離抗體實質上不含特異性地結合於除αvβ6之外的抗原之抗體)。然而，特異性結合於αvβ6之經分離抗體可與其他抗原，諸如來自不同物種之αvβ6分子具有交叉反應性。此外，經分離抗體可實質上不含其他細胞材料及/或化學物質。在一個實施例中，經分離抗體包括與另一藥劑(例如小分子藥物)連接之抗體結合物。在一些實施例中，經分離抗αvβ6抗體包括抗αvβ6抗體與小分子藥物(例如MMAE或MMAF)之結合物。The term "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to αvβ6 is substantially free of antibodies that specifically bind to antigens other than αvβ6). However, an isolated antibody that specifically binds to αvβ6 may have cross-reactivity with other antigens, such as αvβ6 molecules from different species. In addition, the isolated antibody may be substantially free of other cellular material and/or chemicals. In one embodiment, the isolated antibody includes an antibody conjugate linked to another agent, such as a small molecule drug. In some embodiments, the isolated anti-αvβ6 antibody includes a conjugate of an anti-αvβ6 antibody and a small molecule drug, such as MMAE or MMAF.
「人類抗體」(HuMAb)係指具有可變區之抗體，可變區中FR及CDR均來源於人類生殖系免疫球蛋白序列。另外，若該抗體含有恆定區，則該恆定區亦來源於人類生殖系免疫球蛋白序列。本發明之人類抗體可包括並非由人類生殖系免疫球蛋白序列編碼之胺基酸殘基(例如藉由活體外無規或位點特異性突變誘發或藉由活體內體細胞突變引入之突變)。然而，依本文所用，術語「人類抗體」並不意欲包括其中來源於另一哺乳動物物種(諸如小鼠)之生殖系之CDR序列已移植於人類構架序列上的抗體。術語「人類抗體」與「完全人類抗體」同義使用。"Human antibody" (HuMAb) refers to an antibody having a variable region in which both the FR and CDR are derived from human germline immunoglobulin sequences. In addition, if the antibody contains a constant region, the constant region is also derived from human germline immunoglobulin sequences. The human antibodies of the present invention may include amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations induced by random or site-specific mutagenesis in vitro or introduced by somatic cell mutagenesis in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species (such as mice) have been transplanted onto human framework sequences. The term "human antibody" is used synonymously with "fully human antibody."
依本文所用，術語「人源化抗體」係指經基因工程改造之非人類抗體，其含有經修飾以含有高水準之與人類可變域之序列同源性的人類抗體恆定域及非人類可變域。此可藉由將六個非人類抗體互補決定區(CDR) (其一起形成抗原結合位點)移植至同源人類接受體構架區(FR)上來達成(參見WO92/22653及EP0629240)。為了充分重建親本抗體之結合親和力及特異性，可能需要將親本抗體(亦即，非人類抗體)之框架殘基取代成人類框架區(回復突變)。結構同源性模型化可有助於鑑定出構架區中對於抗體結合特性而言重要的胺基酸殘基。因此，人源化抗體可包含非人類CDR序列(主要為人類框架區，其視情況包含非人類胺基酸序列之一或多個胺基酸回復突變)及完全人類恆定區。視情況，可應用不一定為回復突變的其他胺基酸修飾以獲得具有較佳特徵(諸如親和性及生物化學特性)的人源化抗體。As used herein, the term "humanized antibody" refers to a non-human antibody that has been genetically engineered and contains human antibody constant domains and non-human variable domains that have been modified to contain a high level of sequence homology with human variable domains. This can be achieved by transplanting six non-human antibody complementary determining regions (CDRs) (which together form an antigen binding site) onto homologous human acceptor framework regions (FRs) (see WO92/22653 and EP0629240). In order to fully reconstruct the binding affinity and specificity of the parent antibody, it may be necessary to replace the framework residues of the parent antibody (i.e., non-human antibody) with human framework regions (back mutations). Structural homology modeling can help identify amino acid residues in the framework region that are important for antibody binding properties. Therefore, a humanized antibody may comprise a non-human CDR sequence (mainly a human framework region, which may contain one or more amino acid return mutations in the non-human amino acid sequence as appropriate) and a completely human constant region. Optionally, other amino acid modifications, which may not necessarily be return mutations, may be applied to obtain a humanized antibody with better characteristics (such as affinity and biochemical properties).
依本文所用，術語「嵌合抗體」係指其中可變區來源於非人類物種(例如來源於嚙齒動物)且恆定區來源於不同物種(諸如人類)的抗體。嵌合抗體可藉由抗體工程改造產生。「抗體工程改造」為一般用於抗體之不同種類的修飾之術語，且其為熟習此項技術者熟知的方法。特定言之，嵌合抗體可藉由使用依Sambrook等人,1989, Molecular Cloning: A laboratory Manual, New York: Cold Spring Harbor Laboratory Press,第15章中所描述之標準DNA技術產生。因此，嵌合抗體可為經基因或酶工程改造之重組抗體。產生嵌合抗體為熟習此項技術者所瞭解，且因此根據本發明產生嵌合抗體可藉由本文所描述之外的其他方法進行。研發用於治療性應用之嵌合單株抗體以減小抗體免疫原性。其通常可含有對所關注抗原具有特異性之非人類(例如鼠類)可變區以及人類恆定抗體重鏈及輕鏈域。如在嵌合抗體之背景下所用之術語「可變區」或「可變域」係指包含免疫球蛋白之重鏈及輕鏈兩者之CDR及構架區的區域。As used herein, the term "chimeric antibody" refers to an antibody in which the variable region is derived from a non-human species (e.g., from a rodent) and the constant region is derived from a different species (e.g., human). Chimeric antibodies can be produced by antibody engineering. "Antibody engineering" is a term generally used for different types of modifications of antibodies, and it is a method well known to those skilled in the art. Specifically, chimeric antibodies can be produced by using standard DNA techniques described in Sambrook et al., 1989, Molecular Cloning: A laboratory Manual, New York: Cold Spring Harbor Laboratory Press, Chapter 15. Therefore, chimeric antibodies can be recombinant antibodies that have been genetically or enzymatically engineered. The production of chimeric antibodies is understood by those skilled in the art, and therefore the production of chimeric antibodies according to the present invention can be carried out by other methods than those described herein. Chimeric monoclonal antibodies are developed for therapeutic applications to reduce antibody immunogenicity. They typically contain non-human (e.g., mouse) variable regions specific for the antigen of interest and human constant antibody heavy and light chain domains. The term "variable region" or "variable domain" as used in the context of chimeric antibodies refers to the region containing the CDRs and framework regions of both the heavy and light chains of an immunoglobulin.
「抗抗原抗體」係指結合於抗原之抗體。舉例而言，抗αvβ6抗體為結合於抗原αvβ6之抗體。"Anti-antigen antibody" refers to an antibody that binds to an antigen. For example, an anti-αvβ6 antibody is an antibody that binds to the antigen αvβ6.
抗體之「抗原結合部分」或「抗原結合片段」係指抗體之保留特異性結合於整個抗體所結合之抗原之能力的一或多個片段。抗體片段(例如抗原結合片段)之實例包括但不限於Fv、Fab、Fab'、Fab'-SH、F(ab')2；雙功能抗體；線性抗體；單鏈抗體分子(例如scFv)；及由抗體片段形成之多特異性抗體。抗體之木瓜蛋白酶消化產生兩種一致的抗原結合片段，稱為「Fab」片段，各自具有單一抗原結合位點；以及殘餘「Fc」片段，名字反映其容易結晶之能力。胃蛋白酶治療產生具有兩個抗原組合位點且仍能夠使抗原交聯之F(ab')2片段。An "antigen-binding portion" or "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to the antigen bound by the entire antibody. Examples of antibody fragments (e.g., antigen-binding fragments) include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2 ; bifunctional antibodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site; and a residual "Fc" fragment, whose name reflects its ability to crystallize readily. Pepsin treatment produces a F(ab')2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen.
相對於參考多肽序列之「序列一致性百分比(%)」定義為在比對序列且必要時引入間隙以達成最大序列一致性百分比，且不將任何保守性取代視為序列一致性之一部分之後，候選序列中與參考多肽序列中之胺基酸殘基一致的胺基酸殘基之百分比。出於確定胺基酸序列一致性百分比之目的之比對可以此項技術內之各種方式，例如使用公開可獲得的電腦軟體，諸如BLAST、BLAST-2、SnapGene Align或ClustalW BioEdit軟體來達成。熟習此項技術者可確定適用於比對序列之參數，包括在所比較序列之全長內達成最大比對所需的任何算法。舉例而言，如下計算既定胺基酸序列A相對於、與或對照既定胺基酸序列B之序列一致性% (其可替代地表述為既定胺基酸序列A相對於、與或對照既定胺基酸序列B具有或包含一定的序列一致性%)： 100乘以分數X/Y 其中X為在A與B之程式比對中藉由序列評為一致匹配之胺基酸殘基數目，且其中Y為B中之胺基酸殘基之總數目。應瞭解，在胺基酸序列A之長度與胺基酸序列B之長度不相等之情況下，A相對於B之序列一致性%與B相對於A之序列一致性%不相等。"Percent sequence identity (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in a reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for the purpose of determining percent amino acid sequence identity can be achieved in a variety of ways within the art, for example, using publicly available computer software such as BLAST, BLAST-2, SnapGene Align, or ClustalW BioEdit software. One skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm necessary to achieve maximum alignment over the full length of the compared sequences. For example, the % sequence identity of a given amino acid sequence A relative to, with, or against a given amino acid sequence B (which can alternatively be expressed as the % sequence identity that a given amino acid sequence A has or contains relative to, with, or against a given amino acid sequence B) is calculated as follows:100 multiplied by the fraction X/Ywhere X is the number of amino acid residues scored as identical matches by the sequence in the program alignment of A and B, and where Y is the total number of amino acid residues in B. It should be understood that in the case where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % sequence identity of A relative to B is not equal to the % sequence identity of B relative to A.
依本文所用，在抗體與預定抗原結合之情形下，術語「結合(binding)」、「結合(binds)」或「特異性結合」通常為當藉由例如使用抗體作為配位體且使用抗原作為分析物的Octet HTX儀器中之生物層干涉術(BioLayer Interferometry，BLI)技術測定時，以對應於約10-6M或更小的KD之親和力的結合，例如10-7M或更小、諸如約10-8M或更小、諸如約10-9M或更小、約10-10M或更小、或約10-11M或甚至更小，且其中抗體以對應於一KD之親和力與預定抗原結合，該KD相比於與除預定抗原或緊密相關的抗原以外之非特異性抗原(例如BSA、酪蛋白)結合之KD低至少十倍，諸如低至少100倍、例如低至少1,000倍、諸如低至少10,000倍、例如低至少100,000倍。結合KD為更低之量係視抗體之KD而定，使得當抗體之KD極低時，結合於抗原之KD低於結合非特異性抗原之KD的量可為至少10,000倍(亦即，抗體為高度特異性的)。As used herein, the term "binding", "binds" or "specific binding" in the context of an antibody binding to a predetermined antigen generally refers to binding with an affinity corresponding to a K of about10-6 M or less, such as10-7 M or less, such as about10-8 M or less, such as about10-9 M or less, about10-10 M or less, or about10-11 M or even less, when measured, for example, by BioLayer Interferometry (BLI ) technology inanOctetHTX instrument using the antibody asaligand and the antigen as an analyte,and wherein the antibody binds to the predetermined antigen with an affinity corresponding to aK , the K TheKD for binding to a non-specific antigen other than the predetermined antigen or a closely related antigen (e.g., BSA, casein) is at least ten times lower, such as at least 100 times lower, such as at least 1,000 times lower, such as at least 10,000 times lower, such as at least 100,000 times lower. The amount by whichthe KDfor binding is lower depends on theKD of the antibody, such that when theKD of the antibody is very low, the amount by which theKD for binding to the antigen is lower than theKD for binding to the non-specific antigen may be at least 10,000 times (i.e., the antibody is highly specific).
依本文所用，術語「KD」(M)係指特定抗體-抗原相互作用之解離平衡常數。依本文所用，親和力與KD為反相關的，亦即愈高親和力意欲指愈低KD，且愈低親和力意欲指愈高KD。As used herein, the term "KD " (M) refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. As used herein, affinity andKD are inversely related, i.e., higher affinity is intended to mean lowerKD , and lower affinity is intended to mean higherKD .
術語「ADC」係指抗體藥物結合物，其在本發明之情形下係指抗αvβ6抗體，依本申請案中所描述其與藥物部分(例如MMAE或MMAF)偶合。The term "ADC" refers to antibody-drug conjugate, which in the context of the present invention refers to an anti-αvβ6 antibody, which is coupled to a drug moiety (e.g., MMAE or MMAF) as described in this application.
縮寫「vc」及「val-cit」係指二肽纈胺酸-瓜胺酸。The abbreviations "vc" and "val-cit" refer to the dipeptide valeric acid-citrulline.
縮寫VKG係指三肽連接子纈胺酸-離胺酸-甘胺酸。The abbreviation VKG refers to the tripeptide linker valine-lysine-glycine.
縮寫「PAB」係指自我分解型間隔子：The abbreviation "PAB" refers to a self-resolving spacer:
縮寫「MC」係指延伸子順丁烯二醯亞胺基己醯基：The abbreviation "MC" refers to the extender cis-butylene diamidohexanoyl:
縮寫「MP」係指延伸子順丁烯二醯亞胺基丙醯基：The abbreviation "MP" refers to the extender cis-butylenediimidopropionyl:
依本文所用，「PEG單元」為包含重複伸乙基-氧基次單元(PEG或PEG次單元)且可為多分散、單分散或離散(亦即，具有離散數目之伸乙基-氧基次單元)的有機部分。多分散PEG為尺寸及分子量之異質混合物，而單分散PEG通常自異質混合物純化且因此提供單鏈長度及分子量。較佳PEG單元包含離散PEG，即以逐步方式且不經由聚合方法合成之化合物。離散PEG提供具有限定及指定鏈長之單一分子。As used herein, a "PEG unit" is an organic moiety comprising repeating ethylene-oxy subunits (PEG or PEG subunits) and can be polydisperse, monodisperse or discrete (i.e., having a discrete number of ethylene-oxy subunits). Polydisperse PEGs are heterogeneous mixtures of size and molecular weight, whereas monodisperse PEGs are typically purified from a heterogeneous mixture and thus provide a single chain length and molecular weight. Preferred PEG units include discrete PEGs, i.e., compounds synthesized in a stepwise manner and not via polymerization methods. Discrete PEGs provide single molecules with defined and specified chain lengths.
本文所提供之PEG單元包含一或多個聚乙二醇鏈，各自包含一或多個彼此共價連接之伸乙基氧基次單元。聚乙二醇鏈可例如以直鏈、分支鏈或星形組態連接在一起。通常，在併入喜樹鹼結合物之前，至少一個聚乙二醇鏈在一端用經親電子基團取代的烷基部分衍生，以便共價連接至亞甲基胺基甲酸酯單元之胺基甲酸酯氮(亦即，代表R之實例)。通常，各聚乙二醇鏈中不涉及與連接子單元之其餘部分共價連接的末端伸乙基氧基次單元經PEG封端單元修飾，該PEG封端單元通常為視情況經取代之烷基，諸如-CH3、CH2CH3或CH2CH2CO2H。較佳PEG單元具有單一聚乙二醇鏈，該單一聚乙二醇鏈具有2至24個串聯共價連接且在一端處用PEG封端單元封端之-CH2CH2O-次單元。The PEG units provided herein comprise one or more polyethylene glycol chains, each comprising one or more ethyleneoxy subunits covalently linked to one another. The polyethylene glycol chains can be linked together, for example, in a straight chain, a branched chain, or a star configuration. Typically, prior to incorporation into the dendrobium alkaloid conjugate, at least one polyethylene glycol chain is derivatized at one end with an alkyl moiety substituted with an electrophilic group for covalent linkage to the carbamate nitrogen of a methylene carbamate unit (i.e., representing an example of R) . Typically, the terminal ethyleneoxy subunit of each polyethylene glycol chain that is not involved in covalent linkage to the remainder of the linker unit is modified with a PEG end-capping unit, which is typicallyan optionally substituted alkyl group, such as-CH3 ,CH2CH3 , orCH2CH2CO2H. Preferred PEG units have a single polyethylene glycol chain having 2 to 24 -CH2 CH2 O- subunits covalently linked in series and terminated at one end with a PEG end-capping unit.
「癌症」係指特徵為異常細胞在體內不受控生長之廣泛多種疾病群。「癌症」或「癌症組織」可包括腫瘤。不受調控的細胞分裂及生長導致惡性腫瘤形成，該等惡性腫瘤侵入鄰近組織且亦可經由淋巴系統或血流轉移至身體之遠端部分。轉移之後，遠端腫瘤可稱為「來源於」轉移前腫瘤。"Cancer" refers to a broad group of diseases characterized by the uncontrolled growth of abnormal cells in the body. "Cancer" or "cancer tissue" can include tumors. Unregulated cell division and growth leads to the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body via the lymphatic system or bloodstream. After metastasis, the distant tumor may be said to have "arrived from" the pre-metastatic tumor.
術語「抗體依賴性細胞毒性」或ADCC為一種誘導細胞死亡之機制，其取決於經抗體包覆之目標細胞與具有裂解活性之免疫細胞(亦稱為效應細胞)之相互作用。此類效應細胞包括自然殺手細胞、單核球/巨噬細胞及嗜中性白血球。效應細胞經由其抗原組合位點連接至與目標細胞結合之Ig之Fc效應子域。經抗體包覆之目標細胞之死亡由於效應細胞活性而發生。The term "antibody-dependent cytotoxicity" or ADCC is a mechanism of cell death induction that depends on the interaction of an antibody-coated target cell with immune cells with lytic activity (also called effector cells). Such effector cells include natural killer cells, monocytes/macrophages, and neutrophils. Effector cells are linked via their antigen binding sites to the Fc effector domain of Ig bound to the target cell. Death of the antibody-coated target cell occurs as a result of effector cell activity.
術語「抗體依賴性細胞吞噬作用」或ADCP係指藉由與Ig之Fc效應子域結合之吞噬免疫細胞(例如巨噬細胞、嗜中性白血球及樹突狀細胞)而使經抗體包覆之細胞完整或部分內化的過程。The term "antibody-dependent cellular phagocytosis" or ADCP refers to the process of complete or partial internalization of antibody-coated cells by phagocytic immune cells (e.g., macrophages, neutrophils, and dendritic cells) that bind to the Fc effector domain of Ig.
術語「補體依賴性細胞毒性」或CDC係指一種誘導細胞死亡之機制，其中目標結合抗體之Fc效應子域活化在目標細胞膜中之孔形成中達到頂點之一系列酶促反應。通常，抗原-抗體複合物(諸如經抗體包覆之目標細胞上之彼等抗原-抗體複合物)結合且活化補體組分Clq，該補體組分轉而活化引起目標細胞死亡之補體級聯。補體活化亦可藉由結合白血球上之補體受體(例如CR3)而引起促成ADCC之補體組分沉積於目標細胞表面上。The term "complement-dependent cytotoxicity" or CDC refers to a mechanism of cell death induction in which the Fc effector domain of a target-bound antibody activates a series of enzymatic reactions that culminate in pore formation in the target cell membrane. Typically, antigen-antibody complexes (such as those on antibody-coated target cells) bind and activate the complement component Clq, which in turn activates the complement cascade leading to target cell death. Complement activation can also result in deposition of complement components on the target cell surface that contribute to ADCC by binding to complement receptors (e.g., CR3) on leukocytes.
「細胞生長抑制作用」係指抑制細胞增殖。「細胞生長抑制劑」係指對細胞具有細胞生長抑制作用，由此抑制特定子集之細胞的生長及/或擴增之藥劑。細胞生長抑制劑可與抗體結合或與抗體組合投與。"Cytostatic effect" refers to the inhibition of cell proliferation. "Cytostatic agent" refers to an agent that has a cytostatic effect on cells, thereby inhibiting the growth and/or expansion of a specific subset of cells. Cytostatic agents can be conjugated to antibodies or administered in combination with antibodies.
個體之「治療」或「療法」係指對個體進行之任何類型之介入或過程，或向個體投與活性劑，目標為逆轉、緩解、改善、抑制、減緩或防止與疾病相關之症狀、併發症、病狀或生物化學標誌的發作、進展、發展、嚴重程度或復發。在一些實施例中，疾病為癌症。"Treatment" or "therapy" of a subject refers to any type of intervention or procedure performed on a subject, or the administration of an active agent to a subject, with the goal of reversing, alleviating, ameliorating, inhibiting, slowing down, or preventing the onset, progression, development, severity, or recurrence of symptoms, complications, pathologies, or biochemical markers associated with a disease. In some embodiments, the disease is cancer.
「個體」包括任何人類或非人類動物。術語「非人類動物」包括但不限於脊椎動物，諸如非人類靈長類動物、羊、狗以及嚙齒動物，諸如小鼠、大鼠及天竺鼠。在一些實施例中，個體為人類。術語「個體(subject)」及「患者」及「個體(individual)」在本文中可互換使用。"Subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject is a human. The terms "subject", "patient", and "individual" are used interchangeably herein.
藥物或治療劑之「有效量」或「治療有效量」或「治療有效劑量」為藥物在單獨或與另一治療劑組合使用時，保護個體避免疾病發作或促進疾病消退的任何量，疾病消退藉由以下證明：疾病症狀之嚴重程度降低、無疾病症狀期之頻率及持續時間增加或預防由疾病病痛引起之損傷或殘疾。治療劑促進疾病消退之能力可使用熟習此項技術者已知的多種方法評估，諸如在臨床試驗期間在人類個體中評估、在預測人體內之功效的動物模型系統中評估或藉由在活體外分析中分析藥劑活性評估。An "effective amount" or "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of the drug, when used alone or in combination with another therapeutic agent, that protects a subject from the onset of a disease or promotes regression of a disease, as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or prevention of damage or disability caused by the disease affliction. The ability of a therapeutic agent to promote regression of a disease can be assessed using a variety of methods known to those skilled in the art, such as in human subjects during clinical trials, in animal model systems that predict efficacy in humans, or by analyzing the activity of the agent in an in vitro assay.
藉助於治療腫瘤之實例，相對於未經治療個體(例如一或多個未經治療個體)而言，在經治療個體(例如一或多個經治療個體)中治療有效量之抗癌劑抑制細胞生長或腫瘤生長至少約10%、至少約20%、至少約30%、至少約40%、至少約50%、至少約60%、至少約70%或至少約80%、至少約90%、至少約95%、至少約96%、至少約97%、至少約98%或至少約99%。在一些實施例中，相對於未經治療個體(例如一或多個未經治療個體)而言，在經治療個體(例如一或多個經治療個體)中治療有效量之抗癌劑抑制細胞生長或腫瘤生長達100%。By way of example of treating a tumor, a therapeutically effective amount of an anticancer agent inhibits cell growth or tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% in a treated subject (e.g., one or more treated subjects) relative to an untreated subject (e.g., one or more untreated subjects). In some embodiments, a therapeutically effective amount of an anticancer agent inhibits cell growth or tumor growth by 100% in a treated subject (e.g., one or more treated subjects) relative to an untreated subject (e.g., one or more untreated subjects).
在本發明之其他實施例中，可觀測到腫瘤消退且持續至少約20天、至少約30天、至少約40天、至少約50天或至少約60天之時段。In other embodiments of the invention, tumor regression is observed and persists for a period of at least about 20 days, at least about 30 days, at least about 40 days, at least about 50 days, or at least about 60 days.
藥物(例如抗αvβ6抗體藥物結合物)之治療有效量包括「預防有效量」，其為當單獨或與抗癌劑組合向具有患有癌症之風險的個體(例如患有惡化前病狀的個體)或遭受癌症復發的個體投與時，抑制癌症之發展或復發的藥物之任何量。在一些實施例中，預防有效量完全地阻止癌症發展或復發。「抑制」癌症之發展或復發意謂降低癌症之發展或復發的可能性或完全地阻止癌症之發展或復發。A therapeutically effective amount of a drug (e.g., an anti-αvβ6 antibody-drug conjugate) includes a "prophylactically effective amount," which is any amount of a drug that, when administered alone or in combination with an anti-cancer agent to an individual at risk for cancer (e.g., an individual with a pre-malignant condition) or an individual suffering from a recurrence of cancer, inhibits the development or recurrence of cancer. In some embodiments, a prophylactically effective amount completely prevents the development or recurrence of cancer. "Inhibiting" the development or recurrence of cancer means reducing the likelihood of the development or recurrence of cancer or completely preventing the development or recurrence of cancer.
依本文所用，「次治療劑量(subtherapeutic dose)」意謂低於單獨投與用於治療過度增生性疾病(例如癌症)時治療化合物之常用或典型劑量的治療化合物(例如抗αvβ6抗體藥物結合物)之劑量。As used herein, a "subtherapeutic dose" means an amount of a therapeutic compound (e.g., an anti-αvβ6 antibody-drug conjugate) that is less than the usual or typical dose of the therapeutic compound administered alone for the treatment of a hyperproliferative disease (e.g., cancer).
「免疫相關反應模式」係指用藉由誘導癌症特異性免疫反應或藉由改良原生免疫過程而產生抗腫瘤作用之免疫治療劑治療的癌症患者中通常觀測到的臨床反應模式。此反應模式特徵為在腫瘤負荷之最初增加或新病變出現(其在傳統化學治療劑的評估中將歸類為疾病進展且將與藥物失效同義)之後的有益治療效果。因此，免疫治療劑之適當評估可能需要長期監測此等藥劑對目標疾病之作用。An "immune-related response pattern" refers to the clinical response pattern typically observed in cancer patients treated with immunotherapeutics that produce anti-tumor effects by inducing a cancer-specific immune response or by modifying native immune processes. This response pattern is characterized by a beneficial treatment effect that follows an initial increase in tumor burden or the appearance of new lesions, which in the evaluation of traditional chemotherapy would be classified as disease progression and would be synonymous with drug failure. Therefore, appropriate evaluation of immunotherapeutics may require long-term monitoring of the effects of these agents on the target disease.
舉例而言，「抗癌劑」促進個體內之癌症消退。在一些實施例中，治療有效量之藥物促進癌症消退至消除癌症之點。「促進癌症消退」意謂投與有效量的單獨或與抗癌劑組合的藥物，使得腫瘤生長或尺寸減小、腫瘤壞死、至少一種疾病症狀的嚴重程度降低、無疾病症狀期的頻率及持續時間增加，或預防由疾病病痛引起之損傷或殘疾。另外，關於治療之術語「有效」及「有效性」包括藥理學有效性及生理學安全性兩者。藥理學有效性係指藥物促進患者中之癌症消退之能力。生理學安全性係指由藥物投與引起的毒性水準或細胞、器官及/或生物體水準下之其他不良生理學作用(副作用)。For example, an "anticancer agent" promotes the regression of cancer in an individual. In some embodiments, a therapeutically effective amount of a drug promotes the regression of cancer to the point of eliminating the cancer. "Promoting cancer regression" means administering an effective amount of a drug, alone or in combination with an anticancer agent, such that tumor growth or size is reduced, tumor necrosis occurs, the severity of at least one disease symptom is reduced, the frequency and duration of disease-free periods are increased, or damage or disability caused by the disease is prevented. In addition, the terms "effective" and "effectiveness" with respect to treatment include both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a drug to promote the regression of cancer in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (side effects) at the cellular, organ and/or biological level caused by drug administration.
「持續反應」係指在停止治療之後，對減少腫瘤生長之持續作用。舉例而言，與投與階段開始時之尺寸相比，腫瘤尺寸可保持相同或更小。在一些實施例中，持續反應具有至少與治療持續時間相同或比治療持續時間長至少1.5倍、2.0倍、2.5倍或3倍之持續時間。A "sustained response" refers to a sustained effect on reducing tumor growth after treatment has stopped. For example, the tumor size can remain the same or smaller than the size at the beginning of the administration period. In some embodiments, a sustained response has a duration that is at least the same as the duration of treatment or at least 1.5 times, 2.0 times, 2.5 times, or 3 times longer than the duration of treatment.
依本文所用，「完全反應」或「CR」係指所有目標病變消失；「部分反應」或「PR」係指目標病變之最長直徑的總和(SLD)降低至少30%，以基線SLD作為參考；及「穩定疾病」或「SD」係指目標病變既未充分收縮至適合於PR，亦未充分增加至適合於PD，以自治療開始時之最小SLD作為參考。As used herein, "complete response" or "CR" means the disappearance of all target lesions; "partial response" or "PR" means a reduction of at least 30% in the sum of the longest diameters of target lesions (SLD), with the baseline SLD as a reference; and "stable disease" or "SD" means that the target lesions have neither shrunk sufficiently to be suitable for PR nor increased sufficiently to be suitable for PD, with the minimum SLD at the start of self-treatment as a reference.
依本文所用，「無進展存活期」或「PFS」係指治療期間及治療之後的時長，在此期間所治療之疾病(例如癌症)並未惡化。無進展存活期可包括患者經歷完全反應或部分反應之時間量，以及患者經歷穩定疾病之時間量。As used herein, "progression-free survival" or "PFS" refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not get worse. Progression-free survival can include the amount of time a patient experiences a complete response or a partial response, as well as the amount of time a patient experiences stable disease.
依本文所用，「總反應率」或「ORR」係指完全反應(CR)率與部分反應(PR)率之總和。As used herein, "overall response rate" or "ORR" refers to the sum of the complete response (CR) rate and the partial response (PR) rate.
依本文所用，「總存活期」或「OS」係指可能在特定持續時間之後存活之組中個體之百分比。As used herein, "overall survival" or "OS" refers to the percentage of individuals in a group who are likely to survive after a specified duration.
片語「醫藥學上可接受」指示物質或組合物必須與包含調配物之其他成分及/或正用其治療之哺乳動物化學上及/或毒理學上相容。The phrase "pharmaceutically acceptable" indicates that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated with it.
依本文所用，片語「醫藥學上可接受之鹽」係指本發明之化合物的醫藥學上可接受之有機或無機鹽。例示性鹽包括但不限於硫酸鹽、檸檬酸鹽、乙酸鹽、草酸鹽、氯化物、溴化物、碘化物、硝酸鹽、硫酸氫鹽、磷酸鹽、酸式磷酸鹽、異菸鹼酸鹽、乳酸鹽、水楊酸鹽、酸式檸檬酸鹽、酒石酸鹽、油酸鹽、丹寧酸鹽、泛酸鹽、酒石酸氫鹽、抗壞血酸鹽、丁二酸鹽、順丁烯二酸鹽、龍膽酸鹽、反丁烯二酸鹽、葡糖酸鹽、葡糖醛酸鹽、葡糖二酸鹽、甲酸鹽、苯甲酸鹽、麩胺酸鹽、甲烷磺酸鹽(「甲磺酸鹽」)、乙烷磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽、雙羥萘酸鹽(亦即，4,4'-亞甲基-雙-(2-羥基-3-萘甲酸))、鹼金屬(例如鈉及鉀)鹽、鹼土金屬(例如鎂)鹽及銨鹽。醫藥學上可接受之鹽可涉及包括另一分子，諸如乙酸根離子、丁二酸根離子或其他相對離子。相對離子可為使母化合物上之電荷穩定之任何有機或無機部分。此外，醫藥學上可接受之鹽在其結構中可具有超過一個帶電原子。多個帶電原子為醫藥學上可接受之鹽之一部分的情況可具有多個相對離子。因此，醫藥學上可接受之鹽可具有一或多個帶電原子及/或一或多個相對離子。As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compounds of the present invention. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbic acid, succinates, citric acid, gentianates, trans- Pharmaceutically acceptable salts may involve the inclusion of another molecule, such as acetate ions, succinate ions, or other counter ions. A counter ion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, a pharmaceutically acceptable salt can have more than one charged atom in its structure. Where multiple charged atoms are part of a pharmaceutically acceptable salt, there can be multiple counter ions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ions.
「投與(administering)」或「投與(administration)」係指使用熟習此項技術者已知之多種方法及遞送系統中之任一者向個體物理引入治療劑。抗αvβ6抗體藥物結合物之例示性投與途徑包括靜脈內、肌肉內、皮下、腹膜內、脊椎或其他非經腸投與途徑，例如藉由注射或輸注(例如靜脈內輸注)。依本文所用，片語「非經腸投與」意謂通常藉由注射進行之除經腸及局部投與之外的投與模式，且包括但不限於靜脈內、肌肉內、動脈內、鞘內、淋巴管內、病灶內、囊內、眶內、心內、皮內、腹膜內、經氣管、皮下、表皮下、關節內、囊下、蛛膜下、脊髓內、硬膜外及胸骨內注射及輸注，以及活體內電穿孔。治療劑可經由非非經腸途徑或經口投與。其他非非經腸途徑包括局部、表皮或經黏膜投與途徑，例如鼻內、經陰道、經直腸、舌下或局部。投與亦可例如進行一次、複數次及/或經一或多個延長之時段。"Administering" or "administration" refers to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Exemplary routes of administration of the anti-αvβ6 antibody-drug conjugate include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion (e.g., intravenous infusion). As used herein, the phrase "non-parenteral administration" means modes of administration other than enteral and topical administration, which are usually performed by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnical, intraspinal, epidural, and intrasternal injection and infusion, and in vivo electroporation. The therapeutic agent may be administered via a non-enteral route or orally. Other non-enteral routes include topical, epidermal, or transmucosal routes of administration, such as intranasal, vaginal, rectal, sublingual, or topical. Administration may also be performed, for example, once, multiple times, and/or over one or more extended periods of time.
在本文中可互換使用之術語「基線」或「基線值」可指療法(例如依本文所描述之抗αvβ6抗體藥物結合物)投與之前或在療法投與開始時的症狀之量測或表徵。可將基線值與參考值相比較以便確定本文所涵蓋之αvβ6相關疾病(例如癌症)之症狀的減輕或改善。在本文中可互換使用之術語「參考」或「參考值」可指在療法(例如依所描述之抗αvβ6抗體藥物結合物)投與之後的症狀之量測或表徵。在劑量方案或治療週期期間或在完成劑量方案或治療週期時可量測參考值一或多次。「參考值」可為絕對值；相對值；具有上限及/或下限之值；一系列值；平均值；中位值：均值；或相比於基線值之值。The terms "baseline" or "baseline value," as used interchangeably herein, may refer to a measurement or indicative of a symptom prior to administration of a therapy (e.g., an anti-αvβ6 antibody-drug conjugate as described herein) or at the start of administration of a therapy. A baseline value may be compared to a reference value in order to determine a reduction or improvement in a symptom of an αvβ6-related disease (e.g., cancer) contemplated herein. The terms "reference" or "reference value," as used interchangeably herein, may refer to a measurement or indicative of a symptom after administration of a therapy (e.g., an anti-αvβ6 antibody-drug conjugate as described). A reference value may be measured one or more times during a dosing regimen or treatment cycle or upon completion of a dosing regimen or treatment cycle. A "reference value" can be an absolute value; a relative value; a value with an upper and/or lower limit; a range of values; an average; a median: a mean; or a value compared to a baseline value.
類似地，「基線值」可為絕對值；相對值；具有上限及/或下限之值；一系列值；平均值；中位值：均值；或相比於參考值之值。參考值及/或基線值可自一名個體、自兩名不同個體或自一組個體(例如兩名、三名、四名、五名或更多名個體之組)獲得。Similarly, a "baseline value" can be an absolute value; a relative value; a value with an upper and/or lower limit; a range of values; an average value; a median value: a mean value; or a value compared to a reference value. A reference value and/or a baseline value can be obtained from one individual, from two different individuals, or from a group of individuals (e.g., a group of two, three, four, five or more individuals).
依本文所用，術語「單一療法」意謂抗αvβ6抗體藥物結合物為在治療週期期間向個體投與之唯一抗癌劑。然而，可向個體投與其他治療劑。舉例而言，向患有癌症之個體投與以治療與癌症相關之症狀但並非潛在的癌症本身(包括例如發炎、疼痛、體重減輕及一般不適)的抗炎劑或其他藥劑可在單一療法時段期間投與。As used herein, the term "monotherapy" means that the anti-αvβ6 antibody-drug conjugate is the only anti-cancer agent administered to a subject during a treatment cycle. However, other therapeutic agents may be administered to the subject. For example, an anti-inflammatory agent or other agent administered to a subject with cancer to treat symptoms associated with the cancer but not the underlying cancer itself (including, for example, inflammation, pain, weight loss, and general discomfort) may be administered during a single therapy session.
依本文所用，「不良事件」(AE)為與醫學治療之使用相關之任何不利且一般不希望或不合意的跡象(包括異常實驗室研究結果)、症狀或疾病。醫學治療可具有一或多個相關AE且各AE可具有相同或不同的嚴重程度水準。提及能夠「改變不良事件」之方法意謂降低與不同治療方案之使用相關之一或多個AE的發生率及/或嚴重程度的治療方案。As used herein, an "adverse event" (AE) is any unfavorable and generally undesirable or unwelcome sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment. A medical treatment may have one or more associated AEs and each AE may have the same or different levels of severity. Reference to a method that can "modify adverse events" means a treatment regimen that reduces the incidence and/or severity of one or more AEs associated with the use of a different treatment regimen.
依本文所用，「嚴重不良事件」或「SAE」為符合以下準則中之一者的不良事件： ● 為致死性或危及生命的(依嚴重不良事件之定義中所使用，「危及生命」係指其中患者在事件發生時具有死亡風險的事件；其並非指假設在更嚴重時可能引起死亡之事件。) ● 導致持續或顯著殘疾/失能 ● 構成先天性異常/出生缺陷 ● 為醫學上顯著的，亦即定義為危及患者或可能需要醫學或手術介入以防止上文所列之結果中之一者的事件。在決定AE是否為「醫學上顯著」時必須執行醫學及科學判斷 ● 需要住院病人住院或延長現有住院，不包括以下：1)潛在疾病之常規治療或監測，不與病狀之任何惡化相關；2)對預先存在病狀之選擇性或預規劃治療，該病狀與根據研究之適應症不相關且自對知情同意書進行簽名尚未惡化；及3)在患者之一般病狀沒有任何惡化的情況下的社會原因及暫時護理。As used herein, a "serious adverse event" or "SAE" is an adverse event that meets one of the following criteria:● Is fatal or life-threatening (As used in the definition of a serious adverse event, "life-threatening" refers to an event in which the patient is at risk of death at the time of the event; it does not refer to an event that, if assumed to be more severe, could result in death.)● Resulting in persistent or significant disability/disability● Constitutes a congenital anomaly/birth defect● Is medically significant, defined as an event that endangers the patient or may require medical or surgical intervention to prevent one of the outcomes listed above. Medical and scientific judgment must be exercised in determining whether an AE is “medically significant”● Inpatient hospitalization or prolongation of an existing hospitalization does not include the following: 1) routine treatment or monitoring of an underlying condition not associated with any worsening of the condition; 2) elective or preplanned treatment for a pre-existing condition that is unrelated to the indication for the study and has not worsened since the signing of the informed consent form; and 3) social reasons and respite care in the absence of any worsening of the patient’s general condition.
使用替代性連接詞(例如「或」)應理解為意謂替代方案中之一者、兩者或其任何組合。應理解，依本文所用，不定冠詞「一(a)」或「一(an)」係指任何所敍述或列舉之組分的「一或多者」。Use of alternative conjunctions such as "or" should be understood to mean one, both, or any combination of the alternatives. It should be understood that, as used herein, the indefinite article "a" or "an" refers to "one or more" of any stated or listed component.
術語「約」或「基本上包含」係指由一般熟習此項技術者確定，在特定值或組合物之可接受誤差範圍內之值或組合物，其將部分地取決於如何量測或確定值或組合物，亦即量測系統之侷限性。舉例而言，「約」或「基本上包含」可意謂按照此項技術中之實踐在1或大於1個標準差內。替代地，「約」或「基本上包含」可意謂至多20%之範圍。此外，尤其在生物系統或方法方面，該等術語可意謂值之至多一個數量級或至多5倍。當特定值或組合物提供於本申請案及申請專利範圍中時，除非另外陳述，否則「約」或「基本上包含」之含義應假設為在特定值或組合物之可接受的誤差範圍內。The term "about" or "substantially comprising" refers to a value or composition that is within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" or "substantially comprising" can mean within 1 or more than 1 standard deviation as practiced in the art. Alternatively, "about" or "substantially comprising" can mean a range of up to 20%. Furthermore, particularly with respect to biological systems or methods, the terms can mean up to an order of magnitude or up to 5 times of a value. When specific values or compositions are provided in this application and the claims, unless otherwise stated, the meaning of "about" or "substantially including" should be assumed to be within an acceptable error range for the specific value or composition.
本文中對「約」一值或參數之提及包括(且描述)本身係關於該值或參數之實施例。舉例而言，提及「約X」之描述涵蓋且描述「X」。References herein to "about" a value or parameter include (and describe) the embodiments that are per se related to that value or parameter. For example, descriptions referring to "about X" include and describe "X."
依本文所用，術語「綜合陽性評分」或「CPS」係指量測癌症(諸如來自癌症之腫瘤樣品)中之PD-L1表現的免疫組織化學方法。CPS為PD-L1染色細胞(腫瘤細胞、淋巴球、巨噬細胞)數目除以活腫瘤細胞之總數目乘以100。對於一些治療性治療，若CPS ≥ 1，則腫瘤樣品視為具有PD-L1表現。舉例而言，CPS ≥ 1為符合某些PD-1或PD-L1抑制劑療法之個體，諸如患有胃癌、子宮頸癌及頭頸部鱗狀細胞癌之個體所需。在一些情況下，CPS ≥ 10為符合某些PD-1或PD-L1抑制劑療法之個體，諸如患有尿道上皮癌(膀胱癌)、食道鱗狀細胞癌(ESCC)或三陰性乳癌而正用帕博利珠單抗治療之個體所需。As used herein, the term "combined positive score" or "CPS" refers to an immunohistochemical method that measures PD-L1 expression in cancer (e.g., a tumor sample from a cancer). CPS is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells multiplied by 100. For some therapeutic treatments, a tumor sample is considered to have PD-L1 expression if CPS ≥ 1. For example, CPS ≥ 1 is required for individuals eligible for certain PD-1 or PD-L1 inhibitor therapies, such as individuals with gastric cancer, cervical cancer, and head and neck squamous cell carcinoma. In some cases, a CPS ≥ 10 is required for individuals who are eligible for certain PD-1 or PD-L1 inhibitor therapies, such as individuals with urothelial carcinoma (bladder cancer), esophageal squamous cell carcinoma (ESCC), or triple-negative breast cancer who are being treated with pembrolizumab.
依本文所用，術語「腫瘤比例評分」或「TPS」係指量測癌症(諸如來自癌症之腫瘤樣品)中之PD-L1表現的免疫組織化學方法。TPS為在任何強度下顯示部分或完全膜染色之活腫瘤細胞的百分比。對於一些治療性治療，若TPS ≥ 1%，則腫瘤樣品視為具有PD-L1表現，且若TPS ≥ 50%，則腫瘤樣品視為具有高PD-L1表現。舉例而言，TPS ≥ 1%為符合某些PD-1或PD-L1抑制劑療法(例如帕博利珠單抗)之個體，諸如患有非小細胞肺癌之個體所需。在一些情況下，TPS ≥ 50%為符合某些PD-1或PD-L1抑制劑療法(例如測米匹單抗(cemiplimab))之個體所需。As used herein, the term "tumor proportion score" or "TPS" refers to an immunohistochemical method that measures PD-L1 expression in a cancer, such as a tumor sample from a cancer. The TPS is the percentage of live tumor cells that show partial or complete membrane staining at any intensity. For some therapeutic treatments, a tumor sample is considered to have PD-L1 expression if the TPS ≥ 1%, and a tumor sample is considered to have high PD-L1 expression if the TPS ≥ 50%. For example, a TPS ≥ 1% is required for individuals eligible for certain PD-1 or PD-L1 inhibitor therapies (e.g., pembrolizumab), such as individuals with non-small cell lung cancer. In some cases, a TPS ≥ 50% is required for individuals to be eligible for certain PD-1 or PD-L1 inhibitor therapies (e.g., cemiplimab).
依本文所用，術語「理想體重」或「IBW」係指與總體重不相關的尺寸描述詞。IBW為針對性別及身高以及視情況骨架尺寸進行校正之重量的估測值。IBW可例如使用式IBW=0.9H−88 (對於男性)及IBW=0.9H−92 (對於女性)計算，其中H=以cm為單位之身高。替代地，亦可例如使用下式計算IBW：IBW (男性)=50 kg + 2.3 kg×(身高-60吋)；IBW (女性)=45.5 kg + 2.3 kg×(身高-60吋)。As used herein, the term "ideal body weight" or "IBW" refers to a size descriptor that is not related to total body weight. IBW is an estimate of weight corrected for sex and height and, where appropriate, frame size. IBW can be calculated, for example, using the formula IBW = 0.9H-88 (for men) and IBW = 0.9H-92 (for women), where H = height in cm. Alternatively, IBW can be calculated, for example, using the following formula: IBW (male) = 50 kg + 2.3 kg × (height - 60 inches); IBW (female) = 45.5 kg + 2.3 kg × (height - 60 inches).
依本文所用，術語「經調整之理想體重」或「AIBW」係指考慮性別、總體重及身高之尺寸描述詞。舉例而言，可使用式AIBW=IBW+0.4(以kg為單位之體重−IBW)計算AIBW。As used herein, the term "adjusted ideal body weight" or "AIBW" refers to a size descriptor that takes into account gender, total weight, and height. For example, AIBW can be calculated using the formula AIBW = IBW + 0.4 (weight in kg - IBW).
依本文所描述，除非另有指示，否則任何濃度範圍、百分比範圍、比率範圍或整數範圍應理解為包括在所列舉範圍內之任何整數值及(在適當時)其分數(諸如整數之十分之一及百分之一)。As described herein, unless otherwise indicated, any concentration range, percentage range, ratio range or integer range should be understood to include any integer value and, where appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer) within the recited range.
在以下子章節中進一步詳細描述本發明之各種態樣。 II. 綜述Various aspects of the present invention are described in further detail in the following subsections.II. Overview
本發明提供特異性結合αvβ6之抗體。本發明部分地基於靶向αvβ6之抗體藥物結合物(包括vcMMAE抗體藥物結合物)在殺滅αvβ6+表現細胞方面尤其有效的發現。αvβ6已被證明在多種癌症中表現，包括非小細胞肺癌(NSCLC) (鱗狀及腺)、頭頸癌(包括頭頸部鱗狀癌瘤)、食道癌、乳癌(包括乳房侵襲性癌)、卵巢癌、膀胱癌(包括尿道上皮癌)、皮膚癌(鱗狀細胞癌或SCC)、腎癌(包括腎透明細胞、腎乳頭狀細胞及腎難染細胞(kidney chromophobe))、子宮頸癌、胃癌、前列腺癌(包括前列腺腺癌)、子宮內膜癌(包括子宮癌肉瘤及子宮體子宮內膜)、直腸腺癌、甲狀腺癌、結腸腺癌、胃腺癌及胰臟癌(包括胰臟腺癌)。本發明提供一種結合於αvβ6之抗αvβ6抗體藥物結合物，其用於治療非小細胞肺癌、頭頸癌(諸如頭頸部鱗狀癌瘤)、乳癌(諸如晚期HER2陰性乳癌)、食道癌(諸如食道鱗狀細胞癌)、卵巢癌(諸如高級漿液性上皮卵巢癌)、皮膚癌(諸如皮膚鱗狀細胞癌)、胰臟癌(諸如外分泌胰臟腺癌)、膀胱癌、子宮頸癌及胃癌。在一些實施例中，癌症為非小細胞肺癌。在一些實施例中，非小細胞肺癌為鱗狀細胞癌。在一些實施例中，非小細胞肺癌為非鱗狀細胞癌。在一些實施例中，癌症為頭頸癌(諸如頭頸部鱗狀癌瘤)。在一些實施例中，癌症為乳癌(諸如晚期HER2陰性乳癌)。在一些實施例中，癌症為食道癌(諸如食道鱗狀細胞癌)。在一些實施例中，癌症為卵巢癌(諸如高級漿液性上皮卵巢癌)。在一些實施例中，癌症為皮膚癌(諸如皮膚鱗狀細胞癌)。在一些實施例中，癌症為胰臟癌(諸如外分泌胰臟腺癌)。在一些實施例中，癌症為膀胱癌。在一些實施例中，癌症為子宮頸癌。在一些實施例中，癌症為胃癌。III.目標分子The present invention provides antibodies that specifically bind to αvβ6. The present invention is based, in part, on the discovery that antibody-drug conjugates targeting αvβ6, including vcMMAE antibody-drug conjugates, are particularly effective in killing αvβ6+ expressing cells. αvβ6 has been shown to be expressed in a variety of cancers, including non-small cell lung cancer (NSCLC) (squamous and glandular), head and neck cancer (including head and neck squamous carcinoma), esophageal cancer, breast cancer (including invasive breast carcinoma), ovarian cancer, bladder cancer (including urothelial carcinoma), skin cancer (squamous cell carcinoma or SCC), kidney cancer (including kidney chromophobe), cervical cancer, gastric cancer, prostate cancer (including prostate adenocarcinoma), endometrial cancer (including uterine carcinosarcoma and corpus endometrium), rectal adenocarcinoma, thyroid cancer, colon adenocarcinoma, gastric adenocarcinoma, and pancreatic cancer (including pancreatic adenocarcinoma). The present invention provides an anti-αvβ6 antibody-drug conjugate that binds to αvβ6 for use in treating non-small cell lung cancer, head and neck cancer (such as head and neck squamous carcinoma), breast cancer (such as advanced HER2-negative breast cancer), esophageal cancer (such as esophageal squamous cell carcinoma), ovarian cancer (such as high-grade serous epithelial ovarian cancer), skin cancer (such as cutaneous squamous cell carcinoma), pancreatic cancer (such as exocrine pancreatic adenocarcinoma), bladder cancer, cervical cancer, and gastric cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is squamous cell carcinoma. In some embodiments, the non-small cell lung cancer is non-squamous cell carcinoma. In some embodiments, the cancer is head and neck cancer (such as head and neck squamous carcinoma). In some embodiments, the cancer is breast cancer (such as advanced HER2 negative breast cancer). In some embodiments, the cancer is esophageal cancer (such as esophageal squamous cell carcinoma). In some embodiments, the cancer is ovarian cancer (such as high-grade serous epithelial ovarian cancer). In some embodiments, the cancer is skin cancer (such as cutaneous squamous cell carcinoma). In some embodiments, the cancer is pancreatic cancer (such as exocrine pancreatic adenocarcinoma). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is gastric cancer.III.Target Molecules
除非另有指示，否則αvβ6係指人類αvβ6。例示性β6人類序列經指定為GenBank寄存編號AAA36122。例示性αv人類序列經指定為NCBI NP_002201.1。 IV. 本發明之抗體Unless otherwise indicated, αvβ6 refers to human αvβ6. An exemplary β6 human sequence is designated as GenBank Accession No. AAA36122. An exemplary αv human sequence is designated as NCBI NP_002201.1.IV. Antibodies of the Invention
一般而言，本發明之抗αvβ6抗體結合αvβ6，例如人類αvβ6，且對惡性細胞(諸如非小細胞肺癌、頭頸癌(諸如頭頸部鱗狀癌瘤)、乳癌(諸如晚期HER2陰性乳癌)、食道癌(諸如食道鱗狀細胞癌)、卵巢癌(諸如高級漿液性上皮卵巢癌)、皮膚癌(皮膚鱗狀細胞癌)、胰臟癌(諸如外分泌胰臟腺癌)、膀胱癌、子宮頸癌及胃癌細胞)發揮細胞生長抑制及細胞毒性作用。本發明之抗αvβ6抗體較佳為單株的且可為多特異性、人類、人源化或嵌合抗體、單鏈抗體、Fab片段、F(ab')片段、由Fab表現庫產生之片段及以上中之任一者之αvβ6結合片段。在一些實施例中，本發明之抗αvβ6抗體特異性結合αvβ6。本發明之免疫球蛋白分子可為免疫球蛋白分子之任何類型(例如IgG、IgE、IgM、IgD、IgA及IgY)、類別(例如IgG1、IgG2、IgG3、IgG4、IgA1及IgA2)或子類別。In general, the anti-αvβ6 antibodies of the invention bind to αvβ6, e.g., human αvβ6, and exert cytostatic and cytotoxic effects on malignant cells (e.g., non-small cell lung cancer, head and neck cancer (e.g., head and neck squamous carcinoma), breast cancer (e.g., advanced HER2-negative breast cancer), esophageal cancer (e.g., esophageal squamous cell carcinoma), ovarian cancer (e.g., high-grade serous epithelial ovarian cancer), skin cancer (squamous cell carcinoma of the skin), pancreatic cancer (e.g., exocrine pancreatic adenocarcinoma), bladder cancer, cervical cancer, and gastric cancer cells). The anti-αvβ6 antibodies of the present invention are preferably monoclonal and may be multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab') fragments, fragments generated by a Fab repertoire, and αvβ6 binding fragments of any of the above. In some embodiments, the anti-αvβ6 antibodies of the present invention specifically bind to αvβ6. The immunoglobulin molecules of the present invention may be any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass of immunoglobulin molecules.
在本發明之某些實施例中，抗αvβ6抗體為依本文所描述之抗原結合片段，且包括但不限於Fab、Fab'及F(ab')2、Fd、單鏈Fv (scFv)、單鏈抗體、二硫化物連接的Fv (sdFv)及包含VL或VH域之片段。抗原結合片段(包括單鏈抗體)可包含單獨或與以下之全部或一部分組合的可變區：鉸鏈區、CH1、CH2、CH3及CL域。本發明中亦包括包含可變區與鉸鏈區、CH1、CH2、CH3及CL域之任何組合的抗原結合片段。在一些實施例中，抗αvβ6抗體或其抗原結合片段為人類、鼠類(例如小鼠及大鼠)、驢、綿羊、兔子、山羊、天竺鼠、駱駝、馬或雞。In certain embodiments of the invention, the anti-αvβ6 antibody is an antigen-binding fragment as described herein, and includes, but is not limited to, Fab, Fab' and F(ab')2 , Fd, single chain Fv (scFv), single chain antibodies, disulfide-linked Fv (sdFv), and fragments comprising aVL orVH domain. Antigen-binding fragments (including single chain antibodies) may comprise a variable region alone or in combination with all or part of the following: hinge region, CH1, CH2, CH3, and CL domain. Antigen-binding fragments comprising any combination of a variable region and a hinge region, CH1, CH2, CH3, and CL domain are also included in the invention. In some embodiments, the anti-αvβ6 antibody or antigen-binding fragment thereof is human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken.
本發明之抗αvβ6抗體可為單特異性、雙特異性、三特異性的或具有更高多特異性。多特異性抗體可對αvβ6之不同抗原決定基具有特異性，或可對αvβ6以及異源蛋白兩者具有特異性。參見例如PCT公開案WO 93/17715；WO 92/08802；WO 91/00360；WO 92/05793；Tutt, 等人, 1991, J. Immunol. 147:60 69；美國專利第4,474,893號；第4,714,681號；第4,925,648號；第5,573,920號；第5,601,819號；Kostelny等人, 1992, J. Immunol. 148:1547 1553。The anti-αvβ6 antibodies of the present invention may be monospecific, bispecific, trispecific, or have higher multispecificity. Multispecific antibodies may be specific for different antigenic determinants of αvβ6, or may be specific for both αvβ6 and a heterologous protein. See, e.g., PCT Publication Nos. WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., 1991, J. Immunol. 147:60-69; U.S. Patent Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et al., 1992, J. Immunol. 148:1547-1553.
可就本發明之抗αvβ6抗體所包含之特定CDR而言來描述或指定本發明之抗αvβ6抗體。既定CDR或FR之精確胺基酸序列邊界可使用多種熟知方案中之任一者來容易地確定，包括由以下所描述之彼等方案：Kabat等人, (1991), 「Sequences of Proteins of Immunological Interest」, 第5版Public Health Service, National Institutes of Health, Bethesda, MD, Bethesda, MD (「Kabat」編號方案)；Al-Lazikani等人, (1997) JMB 273,927-948 (「Chothia」編號方案)；MacCallum等人, J. Mol. Biol. 262:732-745 (1996), 「Antibody-antigen interactions: Contact analysis and binding site topography」, J. Mol. Biol. 262, 732-745. (「Contact」編號方案)；Lefranc MP等人, 「IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains」, Dev Comp Immunol, 2003年1月; 27(1):55-77 (「IMGT」編號方案)；Honegger A及Plückthun A, 「Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool」, J Mol Biol, 2001年6月8日; 309(3):657-70 (「Aho」編號方案)；及Martin等人, 「Modeling antibody hypervariable loops: a combined algorithm」, PNAS, 1989, 86(23):9268-9272, (「AbM」編號方案)。既定CDR之邊界可視用於鑑別之方案而變化。在一些實施例中，既定抗體或其區(例如其可變區)之「CDR」或「互補決定區」或個別指定CDR (例如CDR-H1、CDR-H2、CDR-H3)應理解為涵蓋依由任何前述方案所定義之CDR (或特定CDR)。舉例而言，在陳述特定CDR (例如CDR-H3)含有既定VH或VL區胺基酸序列中對應CDR之胺基酸序列時，應理解，此類CDR具有依由任何前述方案所定義的可變區內之對應CDR (例如CDR-H3)之序列。可指定用於鑑別一或多個特定CDR之方案，諸如由Kabat、Chothia、AbM或IMGT方法所定義之CDR。The anti-αvβ6 antibodies of the invention may be described or specified with respect to the particular CDRs that they comprise. The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al., (1991), "Sequences of Proteins of Immunological Interest", 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD, Bethesda, MD ("Kabat" numbering scheme); Al-Lazikani et al., (1997) JMB 273, 927-948 ("Chothia" numbering scheme); MacCallum et al., J. Mol. Biol. 262:732-745 (1996), "Antibody-antigen interactions: Contact analysis and binding site topography", J. Mol. Biol. 262, 732-745. ("Contact" numbering scheme); Lefranc MP et al., "IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains”, Dev Comp Immunol, 2003 Jan; 27(1):55-77 (“IMGT” numbering scheme); Honegger A and Plückthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool”, J Mol Biol, 2001 Jun 8; 309(3):657-70 (“Aho” numbering scheme); and Martin et al., “Modeling antibody hypervariable loops: a combined algorithm”, PNAS, 1989, 86(23):9268-9272, (“AbM” numbering scheme). The boundaries of a given CDR may vary depending on the scheme used for identification. In some embodiments, a "CDR" or "complementary determining region" or an individual designated CDR (e.g., CDR-H1, CDR-H2, CDR-H3) of a given antibody or region thereof (e.g., a variable region thereof) is understood to encompass CDRs (or specific CDRs) defined according to any of the aforementioned schemes. For example, when stating that a specific CDR (e.g., CDR-H3) contains the amino acid sequence of a corresponding CDR in a givenVH orVL region amino acid sequence, it is understood that such CDR has the sequence of a corresponding CDR (e.g., CDR-H3) in a variable region defined according to any of the aforementioned schemes. Schemes for identifying one or more specific CDRs may be specified, such as CDRs defined by the Kabat, Chothia, AbM, or IMGT methods.
本文所提供之CDR序列係根據依以下中所描述之Kabat編號方案：Kabat等人, (1991), 「Sequences of Proteins of Immunological Interest」, 第5版Public Health Service, National Institutes of Health, Bethesda, MD (「Kabat」編號方案)。The CDR sequences provided herein are according to the Kabat numbering scheme described in Kabat et al., (1991), "Sequences of Proteins of Immunological Interest", 5th Edition Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme).
在某些實施例中，本發明之抗αvβ6抗體包含WO 2021/113697中所描述之抗體的一或多個CDR。在某些實施例中，本發明之抗體包含人源化抗體抗αvβ6 h2A2 HCLG之一或多個CDR。參見WO 2021/113697。本發明涵蓋包含重鏈或輕鏈可變域之抗體或其衍生物，該可變域包含(a)一組三個CDR，其中該組CDR來自單株抗體h2A2 HCLG；及(b)一組四個構架區，其中該組構架區不同於單株抗體h2A2 HCLG中之構架區組，且其中該抗體或其衍生物結合於αvβ6。在一些實施例中，該抗體或其衍生物特異性結合於αvβ6。在某些實施例中，抗αvβ6抗體為h2A2 HCLG。In certain embodiments, the anti-αvβ6 antibodies of the present invention comprise one or more CDRs of an antibody described in WO 2021/113697. In certain embodiments, the antibodies of the present invention comprise one or more CDRs of the humanized antibody anti-αvβ6 h2A2 HCLG. See WO 2021/113697. The present invention encompasses antibodies or derivatives thereof comprising a heavy chain or light chain variable domain comprising (a) a set of three CDRs, wherein the set of CDRs is from a monoclonal antibody h2A2 HCLG; and (b) a set of four framework regions, wherein the set of framework regions is different from the set of framework regions in a monoclonal antibody h2A2 HCLG, and wherein the antibody or derivative thereof binds to αvβ6. In some embodiments, the antibody or derivative thereof specifically binds to αvβ6. In certain embodiments, the anti-αvβ6 antibody is h2A2 HCLG.
在一個態樣中，本文亦提供與結合於αvβ6之h2A2 HCLG競爭的抗αvβ6抗體。本文亦提供結合於與h2A2 HCLG相同之抗原決定基的抗αvβ6抗體。In one aspect, anti-αvβ6 antibodies that compete with h2A2 HCLG that binds to αvβ6 are also provided herein. Anti-αvβ6 antibodies that bind to the same antigenic determinant as h2A2 HCLG are also provided herein.
在一個態樣中，本文提供一種抗αvβ6抗體，其包含h2A2 HCLG之1、2、3、4、5或6個CDR序列。In one aspect, provided herein is an anti-αvβ6 antibody comprising 1, 2, 3, 4, 5 or 6 CDR sequences of h2A2 HCLG.
在一個態樣中，本文提供包含重鏈可變區及輕鏈可變區之抗αvβ6抗體，其中重鏈可變區包含：(i) CDR-H1，其包含SEQ ID NO:1之胺基酸序列，(ii) CDR-H2，其包含SEQ ID NO:2之胺基酸序列，及(iii) CDR-H3，其包含SEQ ID NO:3之胺基酸序列；及/或其中輕鏈可變區包含：(i) CDR-L1，其包含SEQ ID NO:4之胺基酸序列，(ii) CDR-L2，其包含SEQ ID NO:5之胺基酸序列，及(iii) CDR-L3，其包含SEQ ID NO:6之胺基酸序列。In one aspect, provided herein is an anti-αvβ6 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; and/or wherein the light chain variable region comprises: (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO:4, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO:5, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6.
本文所描述之抗αvβ6抗體可包含任何適合之構架可變域序列，其限制條件為抗體仍能夠結合αvβ6 (例如人類αvβ6)。依本文所用，重鏈構架區命名為「HC-FR1-FR4」且輕鏈構架區命名為「LC-FR1-FR4」。The anti-αvβ6 antibodies described herein can comprise any suitable framework variable domain sequence, provided that the antibody is still able to bind to αvβ6 (e.g., human αvβ6). As used herein, the heavy chain framework region is designated as "HC-FR1-FR4" and the light chain framework region is designated as "LC-FR1-FR4".
在本文所描述之抗αvβ6抗體之一些實施例中，重鏈可變域包含以下胺基酸序列： QFQLVQSGAEVKKPGASVKVSCKASGYSFTDYNVNWVRQAPGQGLEWIGVINPKYGTTRYNQKFKGRATLTVDKSTSTAYMELSSLRSEDTAVYYCTRGLNAWDYWGQGTLVTVSS (SEQ ID NO:7) ，且輕鏈可變域包含以下胺基酸序列：DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLEDGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCQNVLTTPYTFGQGTKLEIK (SEQ ID NO:8)。In some embodiments of the anti-αvβ6 antibodies described herein, the heavy chain variable domain comprises the following amino acid sequence:QFQLVQSGAEVKKPGASVKVSCKASGYSFTDYNVNWVRQAPGQGLEWIGVINPKYGTTRYNQKFKGRATLTVDKSTSTAYMELSSLRSEDTAVYYCTRGLNAWDYWGQGTLVTVSS (SEQ ID NO:7) and the light chain variable domain comprises the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLEDGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCQNVLTTPYTFGQGTKLEIK (SEQ ID NO:8).
在本文所描述之抗αvβ6抗體之一些實施例中，重鏈包含以下胺基酸序列： QFQLVQSGAEVKKPGASVKVSCKASGYSFTDYNVNWVRQAPGQGLEWIGVINPKYGTTRYNQKFKGRATLTVDKSTSTAYMELSSLRSEDTAVYYCTRGLNAWDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:9) ，且輕鏈包含以下胺基酸序列：DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLEDGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCQNVLTTPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:10)In some embodiments of the anti-αvβ6 antibodies described herein, the heavy chain comprises the following amino acid sequence:QFQLVQSGAEVKKPGASVKVSCKASGYSFTDYNVNWVRQAPGQGLEWIGVINPKYGTTRYNQKFKGRATLTVDKSTSTAYMELSSLRSEDTAVYYCTRGLNAWDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:9), and the light chain comprises the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLEDGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCQNVLTTPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:10)
在本文所描述之抗αvβ6抗體之一些實施例中，重鏈CDR序列包含以下： a) CDR-H1：DYNVN (SEQ ID NO:1)； b) CDR-H2：VINPKYGTTRYNQKFKG (SEQ ID NO:2)；及 c) CDR-H3：GLNAWDY (SEQ ID NO:3)。In some embodiments of the anti-αvβ6 antibodies described herein, the heavy chain CDR sequences include the following:a) CDR-H1: DYNVN (SEQ ID NO: 1);b) CDR-H2: VINPKYGTTRYNQKFKG (SEQ ID NO: 2); andc) CDR-H3: GLNAWDY (SEQ ID NO: 3).
在本文所描述之抗αvβ6抗體之一些實施例中，輕鏈CDR序列包含以下： a) CDR-L1：GASENIYGALN (SEQ ID NO:4)； b) CDR-L2：GATNLED (SEQ ID NO:5)；及 c) CDR-L3：QNVLTTPYT (SEQ ID NO:6)。In some embodiments of the anti-αvβ6 antibodies described herein, the light chain CDR sequences include the following:a) CDR-L1: GASENIYGALN (SEQ ID NO:4);b) CDR-L2: GATNLED (SEQ ID NO:5); andc) CDR-L3: QNVLTTPYT (SEQ ID NO:6).
在一個態樣中，本文提供一種抗αvβ6抗體，其包含有包含SEQ ID NO:7之胺基酸序列的重鏈可變域或包含有包含SEQ ID NO:8之胺基酸序列的輕鏈可變域。在一個態樣中，本文提供一種抗αvβ6抗體，其包含有包含SEQ ID NO:7之胺基酸序列的重鏈可變域且包含有包含SEQ ID NO:8之胺基酸序列的輕鏈可變域。In one aspect, provided herein is an anti-αvβ6 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 or a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8. In one aspect, provided herein is an anti-αvβ6 antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8.
在一些實施例中，本文提供一種抗αvβ6抗體，其包含有包含與SEQ ID NO:7之胺基酸序列具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之胺基酸序列的重鏈可變域。在某些實施例中，包含與SEQ ID NO:7之胺基酸序列具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之胺基酸序列的重鏈可變域相對於參考序列含有取代(例如保守取代)、插入或缺失，且仍能夠結合於αvβ6 (例如人類αvβ6)。在某些實施例中，SEQ ID NO:7中總共1至10個胺基酸已經取代、插入及/或缺失。在某些實施例中，取代、插入或缺失(例如1、2、3、4或5個胺基酸)發生在CDR外部之區中(亦即，FR中)。在一些實施例中，抗αvβ6抗體包含SEQ ID NO:7之重鏈可變域序列，包括該序列之轉譯後修飾。在一特定實施例中，重鏈可變域包含一個、兩個或三個選自以下之CDR：(a) CDR-H1，其包含SEQ ID NO:1之胺基酸序列；(b) CDR-H2，其包含SEQ ID NO:2之胺基酸序列；及(c) CDR-H3，其包含SEQ ID NO:3之胺基酸序列。In some embodiments, provided herein is an anti-αvβ6 antibody comprising a heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 7. In certain embodiments, the heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 7 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence and is still capable of binding to αvβ6 (e.g., human αvβ6). In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:7. In certain embodiments, the substitution, insertion or deletion (e.g., 1, 2, 3, 4 or 5 amino acids) occurs in a region outside of the CDRs (i.e., in the FRs). In some embodiments, the anti-αvβ6 antibody comprises the heavy chain variable domain sequence of SEQ ID NO:7, including post-translational modifications of that sequence. In a specific embodiment, the heavy chain variable domain comprises one, two or three CDRs selected from: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:1; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:2; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:3.
在一些實施例中，本文提供一種抗αvβ6抗體，其包含有包含與SEQ ID NO:8之胺基酸序列具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之胺基酸序列的輕鏈可變域。在某些實施例中，包含與SEQ ID NO:8之胺基酸序列具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之胺基酸序列的輕鏈可變域相對於參考序列含有取代(例如保守取代)、插入或缺失，且仍能夠結合於αvβ6 (例如人類αvβ6)。在某些實施例中，SEQ ID NO:8中總共1至10個胺基酸已經取代、插入及/或缺失。在某些實施例中，取代、插入或缺失(例如1、2、3、4或5個胺基酸)發生在CDR外部之區中(亦即，FR中)。在一些實施例中，抗αvβ6抗體包含SEQ ID NO:8之輕鏈可變域序列，包括該序列之轉譯後修飾。在一特定實施例中，輕鏈可變域包含一個、兩個或三個選自以下之CDR：(a) CDR-L1，其包含SEQ ID NO:4之胺基酸序列；(b) CDR-L2，其包含SEQ ID NO:5之胺基酸序列；及(c) CDR-L3，其包含SEQ ID NO:6之胺基酸序列。In some embodiments, provided herein is an anti-αvβ6 antibody comprising a light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 8. In certain embodiments, the light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 8 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence and is still capable of binding to αvβ6 (e.g., human αvβ6). In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:8. In certain embodiments, the substitution, insertion or deletion (e.g., 1, 2, 3, 4 or 5 amino acids) occurs in a region outside of the CDRs (i.e., in the FRs). In some embodiments, the anti-αvβ6 antibody comprises a light chain variable domain sequence of SEQ ID NO:8, including post-translational modifications of that sequence. In a specific embodiment, the light chain variable domain comprises one, two or three CDRs selected from: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6.
在一些實施例中，抗αvβ6抗體包含依上文所提供之任何實施例中之重鏈可變域及依上文所提供之任何實施例中之輕鏈可變域。在一個實施例中，抗體包含SEQ ID NO:7之重鏈可變域序列及SEQ ID NO:8之輕鏈可變域序列，包括彼等序列之轉譯後修飾。In some embodiments, the anti-αvβ6 antibody comprises a heavy chain variable domain according to any of the embodiments provided above and a light chain variable domain according to any of the embodiments provided above. In one embodiment, the antibody comprises a heavy chain variable domain sequence of SEQ ID NO: 7 and a light chain variable domain sequence of SEQ ID NO: 8, including post-translational modifications of those sequences.
在一些實施例中，抗αvβ6抗體藥物結合物之抗αvβ6抗體包含：i) 重鏈CDR1，其包含SEQ ID NO:1之胺基酸序列；重鏈CDR2，其包含SEQ ID NO:2之胺基酸序列；重鏈CDR3，其包含SEQ ID NO:3之胺基酸序列；以及ii)輕鏈CDR1，其包含SEQ ID NO:4之胺基酸序列；輕鏈CDR2，其包含SEQ ID NO:5之胺基酸序列；及輕鏈CDR3，其包含SEQ ID NO:6之胺基酸序列。In some embodiments, the anti-αvβ6 antibody of the anti-αvβ6 antibody-drug conjugate comprises: i) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:1; a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:2; a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:3; and ii) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:4; a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:5; and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:6.
在一些實施例中，抗αvβ6抗體藥物結合物之抗αvβ6抗體包含：i)與包含SEQ ID NO:7之胺基酸序列的重鏈可變區具有至少85%序列一致性之胺基酸序列，及ii)與包含SEQ ID NO:8之胺基酸序列的輕鏈可變區具有至少85%序列一致性之胺基酸序列。In some embodiments, the anti-αvβ6 antibody of the anti-αvβ6 antibody-drug conjugate comprises: i) an amino acid sequence having at least 85% sequence identity to a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7, and ii) an amino acid sequence having at least 85% sequence identity to a light chain variable region comprising the amino acid sequence of SEQ ID NO:8.
在一些實施例中，抗αvβ6抗體藥物結合物之抗αvβ6抗體為單株抗體。In some embodiments, the anti-αvβ6 antibody of the anti-αvβ6 antibody-drug conjugate is a monoclonal antibody.
在一些實施例中，抗αvβ6抗體藥物結合物之抗αvβ6抗體為依WO 2021/113697中所描述之h2A2 HCLG。In some embodiments, the anti-αvβ6 antibody of the anti-αvβ6 antibody-drug conjugate is h2A2 HCLG as described in WO 2021/113697.
本發明之抗αvβ6抗體亦可依據其與αvβ6 (例如人類αvβ6)之結合親和力來描述或指定。較佳結合親和力包括具有小於以下之解離常數或Kd的彼等結合親和力：5×10-2M、10-2M、5×10-3M、10-3M、5×10-4M、10-4M、5×10-5M、10-5M、5×10-6M、10-6M、5×10-7M、10-7M、5×10-8M、10-8M、5×10-9M、10-9M、5×10-10M、10-10M、5×10-11M、10-11M、5×10-12M、10-12M、5×10-13M、10-13M、5×10-14M、10-14M、5×10-15M或10-15M。The anti-αvβ6 antibodies of the invention may also be described or specified according to their binding affinity to αvβ6 (e.g., human αvβ6). Preferred binding affinities include those having a dissociation constant or Kd of less than 5×10-2 M,10-2 M, 5×10-3 M,10-3 M, 5×10-4 M, 10-4 M, 5×10-5 M,10-5 M, 5×10-6 M,10-6 M, 5×10-7 M,10-7 M, 5×10-8 M,10-8 M, 5×10-9 M,10-9 M, 5×10-10 M,10-10 M, 5×10-11 M,10-11 M, 5×10-12 M,10-12 M, 5×10-13 M,10-13 M, 5×10-14 M, 10-14 M, 5×10-15M, or10-15 M.
存在五種類別之免疫球蛋白：IgA、IgD、IgE、IgG及IgM，其分別具有命名為α、δ、ε、γ及μ之重鏈。γ及α類別進一步分成子類，例如人類表現以下子類：IgG1、IgG2、IgG3、IgG4、IgA1及IgA2。IgG1抗體可以多種稱為同種異型之多形態變異體形式存在(綜述於Jefferis及Lefranc 2009.mAbs第1卷, 第4期1-7中)，其中任一者均適用於本文中之一些實施例。人類群體中之常見同種異型變異體為由字母a、f、n、z或其組合命名之變異體。在本文中之任何實施例中，抗體可包含重鏈Fc區，該重鏈Fc區包含人類IgG Fc區。在其他實施例中，人類IgG Fc區包含人類IgG1。There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, which have heavy chains designated α, δ, ε, γ, and μ, respectively. The γ and α classes are further divided into subclasses, for example humans exhibit the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. IgG1 antibodies can exist in a variety of polymorphic variants called isotypes (reviewed in Jefferis and Lefranc 2009.mAbs Vol. 1, No. 4, 1-7), any of which are applicable to some embodiments herein. Common isotypic variants in the human population are those designated by the letters a, f, n, z, or a combination thereof. In any of the embodiments herein, the antibody may comprise a heavy chain Fc region comprising a human IgG Fc region. In other embodiments, the human IgG Fc region comprises human IgG1.
人源化抗體之重鏈及輕鏈可變區可連接至人類恆定區的至少一部分。恆定區之選擇可部分視是否需要抗體依賴性細胞介導之細胞毒性、抗體依賴性細胞吞噬作用及/或補體依賴性細胞毒性而定。舉例而言，人類同型IgG1及IgG3具有強補體依賴性細胞毒性，人類同型IgG2具有弱補體依賴性細胞毒性且人類IgG4缺乏補體依賴性細胞毒性。人類IgG1及IgG3亦較人類IgG2及IgG4誘導更強細胞介導之效應功能。輕鏈恆定區可為λ或κ。抗體可表現為含有兩個輕鏈及兩個重鏈之四聚體，表現為單獨重鏈、輕鏈，表現為Fab、Fab'、F(ab')2及Fv，或表現為單鏈抗體，其中重鏈及輕鏈可變域經由間隔子連接。The heavy and light chain variable regions of the humanized antibody can be linked to at least a portion of a human constant region. The choice of constant region can depend in part on whether antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and/or complement-dependent cytotoxicity is desired. For example, human isotypes IgG1 and IgG3 have strong complement-dependent cytotoxicity, human isotype IgG2 has weak complement-dependent cytotoxicity and human IgG4 lacks complement-dependent cytotoxicity. Human IgG1 and IgG3 also induce stronger cell-mediated effector functions than human IgG2 and IgG4. The light chain constant region can be λ or κ. The antibody can be expressed as a tetramer containing two light chains and two heavy chains, as a separate heavy chain, light chain, as Fab, Fab', F(ab')2 and Fv, or as a single chain antibody in which the heavy and light chain variable domains are linked by a spacer.
人類恆定區顯示在不同個體之間的同種異型變化及異種異型(isoallotypic)變化，亦即，在不同個體中在一或多個多形態位置處恆定區可不同。異種異型不同於同種異型之原因在於辨識異種異型之血清結合於一或多個其他同型之非多形態區。Human constant regions show both allotypic and isoallotypic variation between individuals, i.e., constant regions may differ in different individuals at one or more polymorphic positions. Isoallotypic isotypes differ from allotypes in that sera recognizing isoallotypic isotypes bind to non-polymorphic regions of one or more other isotypes.
在一定比例的或全部分子中，可缺失或衍生輕鏈及/或重鏈之胺基或羧基端處之一個或若干個胺基酸，諸如重鏈之C端離胺酸。取代可在恆定區中進行以減小或增大效應功能，諸如補體介導之細胞毒性或ADCC (參見例如Winter等人，美國專利第5,624,821號；Tso等人，美國專利第5,834,597號；及Lazar等人, Proc. Natl. Acad. Sci. USA 103:4005, 2006)，或以延長在人類中之半衰期(參見例如Hinton等人, J. Biol. Chem. 279:6213, 2004)。In a certain proportion or in the entire molecule, one or more amino acids at the amino or carboxyl terminus of the light chain and/or heavy chain, such as the C-terminal lysine of the heavy chain, may be deleted or derivatized. Substitutions may be made in the constant region to reduce or increase effector functions, such as complement-mediated cytotoxicity or ADCC (see, e.g., Winter et al., U.S. Pat. No. 5,624,821; Tso et al., U.S. Pat. No. 5,834,597; and Lazar et al., Proc. Natl. Acad. Sci. USA 103:4005, 2006), or to extend the half-life in humans (see, e.g., Hinton et al., J. Biol. Chem. 279:6213, 2004).
例示性取代包括在胺基酸位置234、235、237、239、267、298、299、326、330或332處引入由原生胺基酸取代成半胱胺酸殘基之胺基酸取代，較佳地人類IgG1同型中之S239C突變(US 20100158909)。額外半胱胺酸殘基之存在允許鏈間二硫鍵形成。此類鏈間二硫鍵形成可導致位阻，由此減小Fc區-FcyR結合相互作用之親和力。引入IgG恆定區之Fc區中或接近於IgG恆定區之Fc區之半胱胺酸殘基亦可充當用於與治療劑結合之位點(亦即，使用硫醇特異性試劑，諸如藥物之順丁烯二醯亞胺衍生物來偶合細胞毒素藥物)。治療劑之存在導致位阻，由此進一步減小Fc區-FcγR結合相互作用之親和力。位置234、235、236及/或237中之任一者處的其他取代減小Fcγ受體(尤其FcγRI受體)之親和力(參見例如US 6,624,821、US 5,624,821)。Exemplary substitutions include the introduction of amino acid substitutions at amino acid positions 234, 235, 237, 239, 267, 298, 299, 326, 330 or 332, preferably the S239C mutation in the human IgG1 isotype (US 20100158909). The presence of additional cysteine residues allows for the formation of interchain disulfide bonds. Such interchain disulfide bond formation can lead to steric hindrance, thereby reducing the affinity of the Fc region-FcyR binding interaction. Cysteine residues introduced into the Fc region of the IgG constant region or close to the Fc region of the IgG constant region can also serve as sites for binding to therapeutic agents (i.e., using thiol-specific reagents, such as cis-butylenediamide derivatives of drugs to couple cytotoxic drugs). The presence of the therapeutic agent causes steric hindrance, thereby further reducing the affinity of the Fc region-FcγR binding interaction. Other substitutions at any of positions 234, 235, 236 and/or 237 reduce the affinity of Fcγ receptors (especially FcγRI receptors) (see, e.g., US 6,624,821, US 5,624,821).
抗體之活體內半衰期亦可對其效應功能產生影響。可延長或縮短抗體之半衰期以改變其治療活性。FcRn為結構上類似於與β2-微球蛋白非共價締合之I類MHC抗原的受體。FcRn調節IgG之代謝及其在整個組織中之胞吞轉運(Ghetie及Ward, 2000, Annu. Rev. Immunol. 18:739- 766；Ghetie及Ward, 2002, Immunol. Res. 25:97-113)。IgG-FcRn相互作用發生在pH 6.0 (細胞內小泡之pH)而非pH 7.4 (血液之pH)下；此相互作用能夠使得IgG再循環回到循環(Ghetie及Ward, 2000, Ann. Rev. Immunol. 18:739-766；Ghetie及Ward, 2002, Immunol. Res. 25:97-113)。已定位人類IgG1上涉及FcRn結合之區(Shields等人, 2001, J. Biol. Chem. 276:6591-604)。人類IgG1之位置Pro238、Thr256、Thr307、Gln311、Asp312、Glu380、Glu382或Asn434處之丙胺酸取代增強FcRn結合(Shields等人, 2001, J. Biol. Chem. 276:6591-604)。具有此等取代之IgG1分子具有更長血清半衰期。因此，與未經修飾之IgG1相比此等經修飾IgG1分子可能夠在更長時段內進行其效應功能，且因此發揮其治療功效。用於增加與FcRn之結合的其他例示性取代包括位置250處之Gln及/或位置428處之Leu。EU編號用於恆定區中之所有位置。The in vivo half-life of an antibody can also affect its effector function. The half-life of an antibody can be prolonged or shortened to alter its therapeutic activity. FcRn is a receptor structurally similar to class I MHC antigens that non-covalently associate with β2-microglobulin. FcRn regulates IgG metabolism and its endocytic transport throughout tissues (Ghetie and Ward, 2000, Annu. Rev. Immunol. 18:739-766; Ghetie and Ward, 2002, Immunol. Res. 25:97-113). The IgG-FcRn interaction occurs at pH 6.0 (the pH of intracellular vesicles) but not at pH 7.4 (the pH of blood); this interaction enables IgG to be recycled back into the circulation (Ghetie and Ward, 2000, Ann. Rev. Immunol. 18:739-766; Ghetie and Ward, 2002, Immunol. Res. 25:97-113). The region on human IgG1 involved in FcRn binding has been mapped (Shields et al., 2001, J. Biol. Chem. 276:6591-604). Alanine substitutions at positions Pro238, Thr256, Thr307, Gln311, Asp312, Glu380, Glu382, or Asn434 of human IgG1 enhance FcRn binding (Shields et al., 2001, J. Biol. Chem. 276:6591-604). IgG1 molecules with such substitutions have longer serum half-lives. Therefore, these modified IgG1 molecules may be able to perform their effector functions over a longer period of time than unmodified IgG1, and thus exert their therapeutic efficacy. Other exemplary substitutions for increasing binding to FcRn include Gln at position 250 and/or Leu at position 428. EU numbering is used for all positions in the constant region.
共價附接至保守性Asn297之寡醣涉及IgG之Fc區結合FcyR之能力(Lund等人, 1996, J. Immunol. 157:4963-69；Wright及Morrison, 199 ', Trends Biotechnol. 15:26-31)。IgG上此糖型之工程改造可顯著提高IgG介導之ADCC。添加二等分N-乙醯基葡糖胺修飾(Umana等人, 1999, Nat. Biotechnol. 17:176-180；Davies等人, 2001, Biotech. Bioeng. 74:288-94)至此糖型或自此糖型移除海藻糖(Shields等人, 2002, J. Biol. Chem. 277:26733-40；Shinkawa等人, 2003, J. Biol. Chem. 278:6591-604；Niwa等人, 2004, Cancer Res. 64:2127-33)為提高IgG Fc與FcyR之間的結合由此增強Ig介導之ADCC活性的IgG Fc工程改造之兩個實例。Oligosaccharides covalently attached to the conserved Asn297 are involved in the ability of the Fc region of IgG to bind FcγR (Lund et al., 1996, J. Immunol. 157:4963-69; Wright and Morrison, 199 ', Trends Biotechnol. 15:26-31). Engineering of this glycoform on IgG can significantly enhance IgG-mediated ADCC. Adding a bisecting N-acetylglucosamine modification (Umana et al., 1999, Nat. Biotechnol. 17:176-180; Davies et al., 2001, Biotech. Bioeng. 74:288-94) to this glycoform or removing trehalose from this glycoform (Shields et al., 2002, J. Biol. Chem. 277:26733-40; Shinkawa et al., 2003, J. Biol. Chem. 278:6591-604; Niwa et al., 2004, Cancer Res. 64:2127-33) are two examples of IgG Fc engineering that improves the binding between IgG Fc and FcyRs, thereby enhancing Ig-mediated ADCC activity.
人類IgG1 Fc區之經溶劑暴露之胺基酸之系統性取代已產生具有改變的FcyR結合親和力之IgG變異體(Shields等人, 2001, J. Biol. Chem. 276:6591-604)。當與親本IgG1相比時，涉及在Thr256/Ser298、Ser298/Glu333、Ser298/Lys334或Ser298/Glu333 Lys334處取代成Ala的一部分此等變異體證實與FcyR之結合親和力及ADCC活性兩者均增加(Shields等人, 2001, J. Biol. Chem. 276:6591-604；Okazaki等人, 2004, J. Mol. Biol. 336:1239-49)。Systematic substitution of solvent-exposed amino acids in the Fc region of human IgG1 has generated IgG variants with altered FcγR binding affinity (Shields et al., 2001, J. Biol. Chem. 276:6591-604). These variants involving substitutions of Thr256/Ser298, Ser298/Glu333, Ser298/Lys334, or Ser298/Glu333 Lys334 to Ala demonstrated increased binding affinity to FcγRs and ADCC activity when compared to the parental IgG1 (Shields et al., 2001, J. Biol. Chem. 276:6591-604; Okazaki et al., 2004, J. Mol. Biol. 336:1239-49).
抗體之補體結合活性(Clq結合及CDC活性兩者)可藉由Lys326及Glu333處之取代提高(Idusogie等人, 2001, J. Immunol. 166:2571-2575)。人類IgG2主鏈上之相同取代可將與Clq不充分結合且嚴重缺乏補體活化活性之抗體同型轉化成可結合Clq且介導CDC之抗體同型(Idusogie等人, 2001, J. Immunol. 166:2571-75)。若干其他方法亦已應用於提高抗體之補體結合活性。舉例而言，將IgM之18-胺基酸羧基端尾片移植至IgG之羧基端極大增強其CDC活性。即使在通常不具有可偵測CDC活性之IgG4情況下亦觀測到此增強(Smith等人, 1995, J. Immunol. 154:2226-36)。此外，用Cys取代靠近IgG 1重鏈之羧基端處的Ser444誘導IgG 1之尾部與尾部二聚，相比於單體IgG1而言CDC活性增加200倍(Shopes等人, 1992, J. Immunol. 148:2918-22)。另外，具有Clq之特異性的雙特異性雙功能抗體構築體亦賦予CDC活性(Kontermann等人, 1997, Nat. Biotech. 15:629-31)。The complement binding activity (both Clq binding and CDC activity) of an antibody can be improved by substitutions at Lys326 and Glu333 (Idusogie et al., 2001, J. Immunol. 166:2571-2575). The same substitutions on the human IgG2 backbone can convert an antibody isotype that binds poorly to Clq and severely lacks complement activation activity into an antibody isotype that can bind Clq and mediate CDC (Idusogie et al., 2001, J. Immunol. 166:2571-75). Several other approaches have also been applied to improve the complement binding activity of antibodies. For example, grafting the 18-amino acid carboxyl-terminal tail of IgM to the carboxyl terminus of IgG greatly enhances its CDC activity. This enhancement was observed even in the case of IgG4, which normally does not have detectable CDC activity (Smith et al., 1995, J. Immunol. 154:2226-36). In addition, substitution of Ser444 near the carboxyl terminus of the IgG1 heavy chain with Cys induced tail-to-tail dimerization of IgG1, increasing CDC activity 200-fold compared to monomeric IgG1 (Shopes et al., 1992, J. Immunol. 148:2918-22). In addition, bispecific, bifunctional antibody constructs with the specificity of C1q also conferred CDC activity (Kontermann et al., 1997, Nat. Biotech. 15:629-31).
補體活性可藉由使重鏈之胺基酸殘基318、320及322中之至少一者突變成具有不同側鏈之殘基(諸如Ala)而降低。其他經烷基取代之非離子型殘基，諸如Gly、He、Leu或Val，或替代三個殘基中之任一者的諸如Phe、Tyr、Trp及Pro之此類芳族非極性殘基亦降低或消除Clq結合。Ser、Thr、Cys及Met可用於殘基320及322而非318處以降低或消除Clq結合活性。Complementation activity can be reduced by mutating at least one of the amino acid residues 318, 320, and 322 of the heavy chain to a residue with a different side chain, such as Ala. Other alkyl-substituted nonionic residues, such as Gly, He, Leu, or Val, or aromatic nonpolar residues such as Phe, Tyr, Trp, and Pro replacing any of the three residues also reduce or eliminate Clq binding. Ser, Thr, Cys, and Met can be used at residues 320 and 322 instead of 318 to reduce or eliminate Clq binding activity.
藉由極性殘基替代318 (Glu)殘基可調節而非消除Clq結合活性。用Ala置換殘基297 (Asn)使得移除裂解活性，但僅略微降低(約弱三倍)對Clq之親和力。此改變破壞醣基化位點及補體活化所需之碳水化合物之存在。此位點處之任何其他取代亦破壞醣基化位點。以下突變及其任何組合亦降低Clq結合：D270A、K322A、P329A及P31 IS (參見WO 06/036291)。L234A/L235A突變(或LALA突變)亦降低C1q結合以及FcyR結合。Replacing residue 318 (Glu) with a polar residue modulates, rather than eliminates, Clq binding activity. Replacing residue 297 (Asn) with Ala removes cleavage activity but only slightly reduces (approximately three times weaker) affinity for Clq. This change destroys the glycosylation site and the presence of carbohydrates required for complement activation. Any other substitution at this site also destroys the glycosylation site. The following mutations and any combination thereof also reduce Clq binding: D270A, K322A, P329A and P31 IS (see WO 06/036291). L234A/L235A mutations (or LALA mutations) also reduce Clq binding as well as FcγR binding.
提及人類恆定區時包括具有任何天然同種異型或天然同種異型中佔據多形態位置之殘基的任何排列之恆定區。此外，相對於天然人類恆定區可存在至多1、2、5或10個突變，諸如上文所指示之彼等突變以降低Fcγ受體結合或增加與FcRN之結合。Reference to human constant regions includes constant regions having any natural allotype or any arrangement of residues occupying polymorphic positions in natural allotypes. In addition, there may be up to 1, 2, 5 or 10 mutations relative to the natural human constant region, such as those indicated above to reduce Fcγ receptor binding or increase binding to FcRN.
抗體亦包括經修飾之衍生物，亦即藉由使任何類型之分子與抗體共價連接以使得共價連接不阻止抗體與αvβ6結合或對HD細胞發揮細胞生長抑制或細胞毒性作用。舉例而言，但不作為限制，抗體衍生物包括已經修飾之抗體，修飾例如藉由醣基化、乙醯化、聚乙二醇化(PEGylation)、磷酸化、醯胺化、由已知保護/阻斷基團進行之衍生化、蛋白水解裂解、與細胞配位體或其他蛋白連接等進行。許多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(tunicamycin)之代謝合成等。另外，衍生物可含有一或多個非典型胺基酸。V.重組抗體之表現Antibodies also include derivatives that have been modified, i.e., by covalently linking any type of molecule to the antibody such that the covalent link does not prevent the antibody from binding to αvβ6 or exerting a cytostatic or cytotoxic effect on HD cells. By way of example, and not limitation, antibody derivatives include antibodies that have been modified, for example, by glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization with known protecting/blocking groups, proteolytic cleavage, linkage to cellular ligands or other proteins, and the like. Any of a number of chemical modifications may be performed by known techniques, including but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, and the like. In addition, the derivatives may contain one or more atypical amino acids.V.Expression of recombinant antibodies
人源化抗體通常藉由重組表現產生。重組聚核苷酸構築體通常包括可操作地連接至抗體鏈之編碼序列的表現控制序列，包括天然相關或異源啟動子區。較佳地，表現控制序列為載體中能夠轉型或轉染真核宿主細胞之真核啟動子系統。一旦載體已併入至適當宿主中，宿主即維持在適合核苷酸序列之高表現量及交叉反應抗體的收集及純化之條件下。Humanized antibodies are usually produced by recombinant expression. The recombinant polynucleotide construct usually includes an expression control sequence, including a naturally associated or heterologous promoter region, operably linked to the coding sequence of the antibody chain. Preferably, the expression control sequence is a eukaryotic promoter system in a vector capable of transforming or transfecting a eukaryotic host cell. Once the vector has been incorporated into an appropriate host, the host is maintained under conditions suitable for high expression of the nucleotide sequence and collection and purification of cross-reactive antibodies.
哺乳動物細胞為用於表現編碼免疫球蛋白或其片段之核苷酸區段的較佳宿主。參見Winnacker, From Genes to Clones, (VCH Publishers, NY, 1987)。能夠分泌完整異源蛋白之多種適合宿主細胞株已在此項技術中研發，且包括CHO細胞株(例如DG44)、各種COS細胞株、希拉細胞(HeLa cell)、HEK293細胞、L細胞及非抗體產生骨髓瘤(包括Sp2/0及NS0)。較佳地，細胞為非人類的。此等細胞之表現載體可包括表現控制序列，諸如複製起點、啟動子、強化子(Queen等人, Immunol. Rev. 89:49 (1986))，及必需的加工資訊位點，諸如核糖體結合位點、RNA剪接位點、聚腺苷酸化位點及轉錄終止子序列。較佳表現控制序列為來源於內源基因、巨細胞病毒、SV40、腺病毒、牛乳突狀瘤病毒及其類似物之啟動子。參見Co等人, J. Immunol. 148:1149 (1992)。Mammalian cells are preferred hosts for expressing nucleotide segments encoding immunoglobulins or fragments thereof. See Winnacker, From Genes to Clones, (VCH Publishers, NY, 1987). A variety of suitable host cell lines capable of secreting intact heterologous proteins have been developed in this technology and include CHO cell lines (e.g., DG44), various COS cell lines, HeLa cells, HEK293 cells, L cells, and non-antibody-producing myelomas (including Sp2/0 and NS0). Preferably, the cells are non-human. The expression vectors for these cells may include expression control sequences such as origins of replication, promoters, enhancers (Queen et al., Immunol. Rev. 89:49 (1986)), and necessary processing information sites such as ribosome binding sites, RNA splicing sites, polyadenylation sites, and transcription terminator sequences. Preferred expression control sequences are promoters derived from endogenous genes, cytomegalovirus, SV40, adenovirus, bovine papilloma virus, and the like. See Co et al., J. Immunol. 148:1149 (1992).
一旦表現，抗體即可根據此項技術之標準程序純化，包括HPLC純化、管柱層析法、凝膠電泳及其類似者(一般參見Scopes, Protein Purification (Springer-Verlag, NY, 1982))。 VI. 核酸Once expressed, antibodies can be purified by standard procedures of the art, including HPLC purification, column chromatography, gel electrophoresis, and the like (see generally Scopes, Protein Purification (Springer-Verlag, NY, 1982)).VI. Nucleic Acids
本發明進一步提供編碼上文所描述之任何人源化重鏈及輕鏈之核酸。通常，核酸亦編碼與成熟重鏈及輕鏈融合之信號肽。核酸上之編碼序列可以可操作地與調節序列連接以確保編碼序列(諸如啟動子、強化子、核糖體結合位點、轉錄終止信號及其類似物)之表現。編碼重鏈及輕鏈之核酸可以分離形式出現或可選殖至一或多個載體中。核酸可藉由例如固態合成或重疊寡核苷酸之PCR來合成。編碼重鏈及輕鏈之核酸可在例如表現載體內接合為一個連續核酸，或可為分離的，例如各自選殖至其自身表現載體中。The present invention further provides nucleic acids encoding any of the humanized heavy and light chains described above. Typically, the nucleic acids also encode signal peptides fused to the mature heavy and light chains. The coding sequence on the nucleic acid can be operably linked to a regulatory sequence to ensure the expression of the coding sequence (such as a promoter, enhancer, ribosome binding site, transcription termination signal and the like). The nucleic acids encoding the heavy and light chains can appear in separate form or can be cloned into one or more vectors. The nucleic acids can be synthesized by, for example, solid state synthesis or PCR of overlapping oligonucleotides. The nucleic acids encoding the heavy and light chains can be joined into one continuous nucleic acid, for example, within an expression vector, or can be separate, for example, each cloned into its own expression vector.
在一些態樣中，本文亦提供編碼依本文所描述之抗αvβ6抗體或其抗原結合片段之核酸。本文進一步提供包含編碼依本文所描述之抗αvβ6抗體或其抗原結合片段之核酸的載體。本文進一步提供表現編碼依本文所描述之抗αvβ6抗體或其抗原結合片段之核酸的宿主細胞。本文進一步提供包含載體之宿主細胞，該等載體包含編碼依本文所描述之抗αvβ6抗體或其抗原結合片段的核酸。In some aspects, provided herein are nucleic acids encoding an anti-αvβ6 antibody or an antigen-binding fragment thereof as described herein. Further provided herein are vectors comprising nucleic acids encoding an anti-αvβ6 antibody or an antigen-binding fragment thereof as described herein. Further provided herein are host cells expressing nucleic acids encoding an anti-αvβ6 antibody or an antigen-binding fragment thereof as described herein. Further provided herein are host cells comprising vectors comprising nucleic acids encoding an anti-αvβ6 antibody or an antigen-binding fragment thereof as described herein.
本文所描述之抗αvβ6抗體可藉由熟知的重組技術使用熟知表現載體系統及宿主細胞來製備。在一個實施例中，依De la Cruz Edmunds等人, 2006,MolecularBiotechnology34; 179-190、EP216846、美國專利第5,981,216號、WO 87/04462、EP323997、美國專利第5,591,639號、美國專利第5,658,759號、EP338841、美國專利第5,879,936號及美國專利第5,891,693號中所揭示使用GS表現載體系統在CHO細胞中製備抗體。The anti-αvβ6 antibodies described herein can be prepared by well-known recombinant techniques using well-known expression vector systems and host cells. In one embodiment, the antibodies are prepared in CHO cells using a GS expression vector system as disclosed in De la Cruz Edmunds et al., 2006,MolecularBiotechnology 34; 179-190, EP216846, U.S. Pat. No. 5,981,216, WO 87/04462, EP323997, U.S. Pat. No. 5,591,639, U.S. Pat. No. 5,658,759, EP338841, U.S. Pat. No. 5,879,936, and U.S. Pat. No. 5,891,693.
本文所描述之單株抗αvβ6抗體可例如藉由首次由Kohler等人,Nature, 256, 495 (1975)所描述之融合瘤方法產生或可藉由重組DNA方法產生。單株抗體亦可使用例如Clackson等人,Nature, 352, 624-628 (1991)及Marks等人,JMol, Biol., 222(3):581-597 (1991)中所描述之技術來與噬菌體抗體庫分離。單株抗體可自任何適合之來源獲得。因此，例如，單株抗體可自融合瘤獲得，該等融合瘤由自經所關注的抗原(例如呈在表面上表現抗原之細胞或編碼所關注的抗原之核酸形式)免疫接種之小鼠獲得之鼠類脾臟B細胞製備。單株抗體亦可自來源於經免疫人類或非人類哺乳動物(諸如大鼠、狗、靈長類動物等)之表現抗體的細胞之融合瘤獲得。 VII. 抗體藥物結合物The monoclonal anti-αvβ6 antibodies described herein can be produced, for example, by the hybridoma method first described by Kohler et al.,Nature , 256, 495 (1975) or can be produced by recombinant DNA methods. Monoclonal antibodies can also be isolated from phage antibody libraries using techniques described, for example, in Clackson et al.,Nature , 352, 624-628 (1991) and Marks et al.,J Mol, Biol ., 222(3):581-597 (1991). Monoclonal antibodies can be obtained from any suitable source. Thus, for example, monoclonal antibodies can be obtained from hybridomas prepared from murine splenic B cells obtained from mice immunized with an antigen of interest (e.g., in the form of cells expressing the antigen on their surface or nucleic acid encoding the antigen of interest). Monoclonal antibodies can also be obtained from fusion tumors derived from antibody-expressing cells of immunized humans or non-human mammals (such as rats, dogs, primates, etc.). VII. Antibody-drug conjugates
抗αvβ6抗體可與細胞毒性或細胞生長抑制部分(包括其醫藥學上相容之鹽)結合以形成抗體藥物結合物(ADC)。用於與抗體結合之尤其適合之部分為細胞毒性劑(例如化學治療劑)、前藥轉換酶、放射性同位素或化合物、或毒素(此等部分統稱為治療劑)。舉例而言，抗αvβ6抗體可與細胞毒性劑(諸如化學治療劑)或毒素(例如細胞生長抑制劑或殺細胞劑，諸如相思子毒素(abrin)、蓖麻毒素A、綠膿桿菌外毒素或白喉毒素)結合。Anti-αvβ6 antibodies can be conjugated to cytotoxic or cytostatic moieties (including pharmaceutically compatible salts thereof) to form antibody-drug conjugates (ADCs). Particularly suitable moieties for conjugation to the antibody are cytotoxic agents (e.g., chemotherapeutic agents), prodrug converting enzymes, radioisotopes or compounds, or toxins (such moieties are collectively referred to as therapeutic agents). For example, anti-αvβ6 antibodies can be conjugated to cytotoxic agents (e.g., chemotherapeutic agents) or toxins (e.g., cytostatic or cytocidal agents such as abrin, ricin A, Pseudomonas aeruginosa exotoxin, or diphtheria toxin).
抗αvβ6抗體可與前藥轉化酶結合。前藥轉化酶可與抗體重組融合或使用已知方法與其化學結合。例示性前藥轉化酶為羧肽酶G2、β-葡糖醛酸酶、青黴素-V-醯胺酵素、青黴素-G-醯胺酵素、β-內醯胺酶、β-葡糖苷酶、硝基還原酶及羧肽酶A。The anti-αvβ6 antibody can be conjugated to a prodrug converting enzyme. The prodrug converting enzyme can be recombinantly fused to the antibody or chemically conjugated thereto using known methods. Exemplary prodrug converting enzymes are carboxypeptidase G2, β-glucuronidase, penicillin-V-amidase, penicillin-G-amidase, β-lactamase, β-glucosidase, nitroreductase, and carboxypeptidase A.
用於使治療劑與蛋白(且尤其與抗體)結合之技術為熟知的。(參見例如Monoclonal Antibodies And Cancer Therapy (Reisfeld等人編, Alan R. Liss, Inc., 1985)中之Arnon等人, 「Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy」；Controlled Drug Delivery (Robinson等人編, Marcel Dekker, Inc., 第2版. 1987)中之Hellstrom等人, 「Antibodies For Drug Delivery」；Monoclonal Antibodies '84: Biological And Clinical Applications (Pinchera等人編, 1985)中之Thorpe, 「Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review」；Monoclonal Antibodies For Cancer Detection And Therapy (Baldwin等人編, Academic Press, 1985)中之「Analysis, Results, and Future Prospective of the Therapeutic Use of Radiolabeled Antibody In Cancer Therapy」；及Thorpe等人, 1982, Immunol. Rev. 62:119-58。亦參見例如PCT公開案WO 89/12624)。Techniques for conjugating therapeutic agents to proteins, and in particular to antibodies, are well known. (See, e.g., Arnon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy" (Reisfeld et al., ed., Alan R. Liss, Inc., 1985); Hellstrom et al., "Antibodies For Drug Delivery", "Controlled Drug Delivery" (Robinson et al., ed., Marcel Dekker, Inc., 2nd ed. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review" in bodies '84: Biological And Clinical Applications (Pinchera et al., eds. 1985); "Analysis, Results, and Future Prospective of the Therapeutic Use of Radiolabeled Antibody In Cancer" in Monoclonal Antibodies For Cancer Detection And Therapy (Baldwin et al., eds. Academic Press, 1985) Therapy"; and Thorpe et al., 1982, Immunol. Rev. 62:119-58. See also, e.g., PCT Publication WO 89/12624).
除非治療劑裂解掉抗體(例如藉由水解、藉由抗體降解或藉由裂解劑)，否則治療劑可以降低其活性的方式結合。此類治療劑藉由可裂解連接子(其對在表現αvβ6之癌細胞之細胞內環境中的裂解敏感但對細胞外環境大體上不敏感)與抗體連接，使得結合物在其藉由表現αvβ6之癌細胞內化(例如在核內體中，或例如在溶酶體環境或小窩環境(caveolear environment)中藉助於pH敏感性或蛋白酶敏感性)時自抗體裂解。Unless the therapeutic agent cleaves the antibody (e.g., by hydrolysis, by antibody degradation, or by a cleaving agent), the therapeutic agent may be bound in a manner that reduces its activity. Such therapeutic agents are linked to the antibody by a cleavable linker that is sensitive to cleavage in the intracellular environment of a cancer cell expressing αvβ6 but is substantially insensitive to the extracellular environment, such that the conjugate is cleaved from the antibody when it is internalized by a cancer cell expressing αvβ6 (e.g., in an endosome, or, for example, in a lysosomal environment or caveolear environment by virtue of pH sensitivity or protease sensitivity).
通常，ADC包含治療劑與抗αvβ6抗體之間的連接子區。依上文所提及，通常連接子為可在細胞內條件下裂解，使得在細胞內環境中(例如在溶酶體或核內體或胞膜窖內)，連接子之裂解自抗體釋放治療劑。連接子可為例如藉由包括溶酶體或核內體蛋白酶之細胞內肽酶或蛋白酶裂解之肽基連接子。通常，肽基連接子為至少兩個胺基酸長或至少三個胺基酸長。裂解劑可包括組織蛋白酶B及D以及纖維蛋白溶酶(參見例如Dubowchik及Walker, 1999, Pharm. Therapeutics 83:67-123)。最典型的肽基連接子為可藉由存在於表現αvβ6之細胞中之酶裂解的肽基連接子。舉例而言，可使用可藉由在癌組織中高度表現之硫醇依賴性蛋白酶組織蛋白酶-B裂解之肽基連接子(例如包含Phe-Leu或Gly-Phe-Leu-Gly肽之連接子)。其他此類連接子描述於例如美國專利第6,214,345號中。在特定實施例中，可藉由細胞內蛋白酶裂解之肽基連接子包含Val-Cit連接子或Phe-Lys二肽(參見例如美國專利6,214,345，其描述用Val-Cit連接子合成小紅莓(doxorubicin))。使用細胞內蛋白水解釋放治療劑之一個優點為藥劑在結合時通常毒性減弱且結合物之血清穩定性通常較高。Typically, the ADC comprises a linker region between the therapeutic agent and the anti-αvβ6 antibody. As mentioned above, the linker is typically cleavable under intracellular conditions, such that cleavage of the linker releases the therapeutic agent from the antibody in the intracellular environment (e.g., in a lysosome or endosome or caveolae). The linker can be, for example, a peptidyl linker that is cleaved by an intracellular peptidase or protease, including a lysosomal or endosomal protease. Typically, the peptidyl linker is at least two amino acids long or at least three amino acids long. Cleaving agents can include cathepsins B and D and fibrolytic enzymes (see, e.g., Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123). The most typical peptidyl linker is a peptidyl linker that can be cleaved by an enzyme present in cells expressing αvβ6. For example, a peptidyl linker that can be cleaved by the thiol-dependent protease cathepsin-B, which is highly expressed in cancer tissues, can be used (e.g., a linker comprising a Phe-Leu or Gly-Phe-Leu-Gly peptide). Other such linkers are described, for example, in U.S. Patent No. 6,214,345. In a specific embodiment, the peptidyl linker that can be cleaved by an intracellular protease comprises a Val-Cit linker or a Phe-Lys dipeptide (see, for example, U.S. Patent No. 6,214,345, which describes the synthesis of doxorubicin using a Val-Cit linker). One advantage of using intracellular proteolytic release of therapeutic agents is that the toxicity of the agent is generally reduced when conjugated and the serum stability of the conjugate is generally improved.
可裂解連接子可為pH敏感的，亦即對在某些pH值下之水解敏感。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)。(參見例如美國專利第5,122,368號；第5,824,805號；第5,622,929號；Dubowchik及Walker, 1999, Pharm. Therapeutics 83:67-123；Neville等人, 1989, Biol. Chem. 264: 14653-14661)。此類連接子在中性pH條件下(諸如血液中之pH值條件下)相對穩定，但在低於pH 5.5或5.0 (近似溶體之pH)下不穩定。在某些實施例中，可水解連接子為硫醚連接子(諸如經由醯腙鍵連接至治療劑之硫醚(參見例如美國專利第5,622,929號))。The cleavable linker can be pH sensitive, that is, sensitive to hydrolysis at certain pH values. Typically, the pH sensitive linker can be hydrolyzed under acidic conditions. For example, an acid-labile linker that can be hydrolyzed in the lysosome (e.g., a hydrazone, a semicarbazone, a thiosemicarbazide, a cis-abibutamide, an orthoester, an acetal, a ketone, or the like) can be used. (See, e.g., U.S. Patent Nos. 5,122,368; 5,824,805; 5,622,929; Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123; Neville et al., 1989, Biol. Chem. 264: 14653-14661). Such linkers are relatively stable at neutral pH (such as the pH in blood), but are unstable below pH 5.5 or 5.0 (approximately the pH of the solution). In certain embodiments, the hydrolyzable linker is a thioether linker (such as a thioether linked to the therapeutic agent via an acylhydrazone bond (see, e.g., U.S. Patent No. 5,622,929)).
其他連接子可在還原條件下裂解(例如二硫化物連接子)。二硫化物連接子包括彼等可使用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形成之連接子。(參見例如Thorpe等人, 1987, Cancer Res. 47:5924-5931；Wawrzynczak等人, Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C. W. Vogel編, Oxford U. Press, 1987)。亦參見美國專利第4,880,935號)。Other linkers can be cleaved under reducing conditions (e.g., disulfide linkers). Disulfide linkers include 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. (See, e.g., Thorpe et al., 1987, Cancer Res. 47:5924-5931; Wawrzynczak et al., Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C. W. Vogel, ed., Oxford U. Press, 1987). See also U.S. Patent No. 4,880,935).
連接子亦可為丙二酸酯連接子(Johnson等人, 1995, Anticancer Res. 15:1387-93)、順丁烯二醯亞胺基苯甲醯基連接子(Lau等人, 1995, Bioorg-Med-Chem. 3(10):1299-1304)或3'-N-醯胺類似物(Lau等人, 1995, Bioorg-Med-Chem. 3(10):1305-12)。連接子亦可為丙二酸酯連接子(Johnson等人, 1995, Anticancer Res. 15:1387-93)、順丁烯二醯亞胺基苯甲醯基連接子(Lau等人, 1995, Bioorg-Med-Chem. 3(10):1299-1304)或3'-N-醯胺類似物(Lau等人, 1995, Bioorg-Med-Chem. 3(10):1305-12)。The linker may also be a malonate linker (Johnson et al., 1995, Anticancer Res. 15:1387-93), a cis-butylenediimidobenzyl linker (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1299-1304), or a 3'-N-amide analog (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1305-12). The linker may also be a malonate linker (Johnson et al., 1995, Anticancer Res. 15:1387-93), a cis-butylenediimidobenzyl linker (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1299-1304), or a 3'-N-amide analog (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1305-12).
連接子亦可為不可裂解連接子，諸如直接連接於治療劑(例如藥物)之順丁烯二醯亞胺基-伸烷基-或順丁烯二醯亞胺-芳基連接子。藉由抗體之降解來釋放活性藥物-連接子。The linker can also be a non-cleavable linker, such as a cis-imide-alkylene- or cis-imide-aryl linker that is directly linked to the therapeutic agent (e.g., drug). The active drug-linker is released by degradation of the antibody.
連接子可促進細胞內化。連接子當與治療劑結合時(亦即，在依本文所描述之ADC或ADC衍生物之連接子-治療劑部分的背景下)，可促進細胞內化。或者，連接子當與治療劑及抗αvβ6抗體兩者結合時(亦即，在依本文所描述之ADC的背景下)，可促進細胞內化。The linker can promote cellular internalization. The linker can promote cellular internalization when conjugated to a therapeutic agent (i.e., in the context of a linker-therapeutic agent portion of an ADC or ADC derivative as described herein). Alternatively, the linker can promote cellular internalization when conjugated to both a therapeutic agent and an anti-αvβ6 antibody (i.e., in the context of an ADC as described herein).
抗αvβ6抗體可經由抗體之雜原子而與連接子結合。此等雜原子可呈其天然狀態存在於抗體上或可經引入至抗體中。在一些態樣中，抗αvβ6抗體將經由離胺酸殘基之氮原子而與連接子結合。在其他態樣中，抗αvβ6抗體將經由半胱胺酸殘基之硫原子而與連接子結合。半胱胺酸殘基可為天然存在的或為經工程改造至抗體中之半胱胺酸殘基。經由離胺酸及半胱胺酸殘基使連接子及藥物-連接子與抗體結合之方法為此項技術中已知的。The anti-αvβ6 antibody may be conjugated to the linker via a heteroatom of the antibody. Such heteroatom may be present on the antibody in its natural state or may be introduced into the antibody. In some aspects, the anti-αvβ6 antibody will be conjugated to the linker via the nitrogen atom of a lysine residue. In other aspects, the anti-αvβ6 antibody will be conjugated to the linker via the sulfur atom of a cysteine residue. The cysteine residue may be naturally occurring or may be a cysteine residue engineered into the antibody. Methods for conjugating linkers and drug-linkers to antibodies via lysine and cysteine residues are known in the art.
例示性抗體藥物結合物包括基於奧瑞他汀之抗體藥物結合物(亦即，藥物組分為奧瑞他汀藥物)。奧瑞他汀結合微管蛋白已顯示干擾微管動力學以及細胞核及細胞分裂，且具有抗癌活性。通常，基於奧瑞他汀之抗體藥物結合物包含在奧瑞他汀藥物與抗αvβ6抗體之間的連接子。連接子可為例如可裂解連接子(例如肽基連接子、碳水化合物連接子)或不可裂解連接子(例如藉由抗體之降解釋放之連接子)。奧瑞他汀包括但不限於奧瑞他汀T、MMAF及MMAE。例示性奧瑞他汀之合成及結構描述於美國公開案第7,659,241號、第7,498,298號、第2009-0111756號、第2009-0018086號及第7,968,687號中，其各自以全文引用之方式併入本文中且用於所有目的。Exemplary antibody-drug conjugates include auristatin-based antibody-drug conjugates (i.e., the drug component is an auristatin drug). Auristatins binding to tubulin have been shown to interfere with microtubule dynamics as well as nuclear and cell division, and have anti-cancer activity. Typically, an auristatin-based antibody-drug conjugate comprises a linker between the auristatin drug and an anti-αvβ6 antibody. The linker may be, for example, a cleavable linker (e.g., a peptidyl linker, a carbohydrate linker) or a non-cleavable linker (e.g., a linker released by degradation of the antibody). Auristatins include, but are not limited to, auristatin T, MMAF, and MMAE. The synthesis and structure of exemplary auristatins are described in U.S. Patent Publication Nos. 7,659,241, 7,498,298, 2009-0111756, 2009-0018086, and 7,968,687, each of which is incorporated herein by reference in its entirety and for all purposes.
例示性基於奧瑞他汀之抗體藥物結合物包括依下文所示之vcMMAE (或1006)、vcMMAF及mcMMAF抗體藥物結合物，其中p表示載藥量，Ab為依本文所描述之抗αvβ6抗體且val-cit或「vc」表示纈胺酸-瓜胺酸二肽：或其醫藥學上可接受之鹽。藥物負載由p表示，p為每一抗體之藥物-連接子分子之數目。提及靶向αvβ6之抗體藥物結合物，下標p表示載藥量，且視上下文而定，可表示與個別抗體分子連接之藥物-連接子分子的分子數且因此為整數值，或可表示平均載藥量且因此可為整數值或非整數值，但通常為非整數值。平均載藥量表示群體中每一抗體之藥物-連接子分子之平均數量。通常而非始終，當吾人提及抗體(例如單株抗體)時，吾人係提及一群抗體分子。在包含一群抗體藥物結合物分子之組合物中，平均載藥量為重要的品質屬性，此係由於其確定可遞送至目標細胞之藥物的量。組合物中未結合抗體分子之百分比包括於平均載藥量值中。Exemplary auristatin-based antibody-drug conjugates include vcMMAE (or 1006), vcMMAF, and mcMMAF antibody-drug conjugates as shown below, wherein p represents the drug loading, Ab is an anti-αvβ6 antibody as described herein, and val-cit or "vc" represents a valsartan-citrulline dipeptide: or a pharmaceutically acceptable salt thereof. Drug loading is represented by p, which is the number of drug-linker molecules per antibody. In reference to an antibody-drug conjugate targeting αvβ6, the subscript p represents drug loading, and, depending on the context, may represent the number of molecules of drug-linker molecules linked to an individual antibody molecule and thus be an integer value, or may represent the average drug loading and thus may be an integer or non-integer value, but typically is a non-integer value. The average drug loading represents the average number of drug-linker molecules per antibody in the population. Typically, but not always, when we refer to an antibody (e.g., a monoclonal antibody), we are referring to a population of antibody molecules. In a composition comprising a population of antibody-drug conjugate molecules, the average drug loading is an important quality attribute because it determines the amount of drug that can be delivered to the target cell. The percentage of unbound antibody molecules in the composition was included in the average drug loading value.
在本發明之較佳態樣中，當參考包含抗體藥物結合物化合物群體之組合物時，平均載藥量(藥物相對於抗體比率(DAR))為約1至約16，較佳為約2至約14，更佳為約2至約10。在一實施例中，DAR為約2至約5。在另一實施例中，DAR為約4。在另一實施例中，DAR為4。在另一實施例中，DAR為約6至約10。在另一實施例中，DAR為約8。在另一實施例中，DAR為8。製劑中每抗體之藥物平均數目可藉由諸如質譜法、HIC、ELISA分析及HPLC之習知方式來表徵。在一些態樣中，抗αvβ6抗體經由抗體之半胱胺酸殘基而與藥物-連接子連接。在一些態樣中，半胱胺酸殘基為經工程改造至抗體中之殘基。在其他態樣中，半胱胺酸殘基為鏈間二硫化物半胱胺酸殘基。In preferred aspects of the invention, when referring to a composition comprising a population of antibody-drug conjugate compounds, the average drug loading (drug to antibody ratio (DAR)) is about 1 to about 16, preferably about 2 to about 14, and more preferably about 2 to about 10. In one embodiment, the DAR is about 2 to about 5. In another embodiment, the DAR is about 4. In another embodiment, the DAR is 4. In another embodiment, the DAR is about 6 to about 10. In another embodiment, the DAR is about 8. In another embodiment, the DAR is 8. The average number of drugs per antibody in the formulation can be characterized by known methods such as mass spectrometry, HIC, ELISA analysis, and HPLC. In some aspects, the anti-αvβ6 antibody is linked to the drug-linker via a cysteine residue of the antibody. In some aspects, the cysteine residue is a residue engineered into the antibody. In other aspects, the cysteine residue is an interchain disulfide cysteine residue.
在一些實施例中，與非聚乙二醇化對照相比較，將聚乙二醇聚合物作為側鏈併入至可裂解β-葡萄糖苷酸MMAE藥物-連接子中提供在異種移植模型中具有減小的血漿清除率及增大的抗腫瘤活性之抗體藥物結合物。因此，用於與本發明之抗體連接之特別有利的藥物-連接子為如下式V：或其醫藥學上可接受之鹽。In some embodiments, incorporation of a polyethylene glycol polymer as a side chain into a cleavable β-glucuronide MMAE drug-linker provides an antibody drug conjugate with reduced plasma clearance and increased anti-tumor activity in a xenograft model compared to a non-PEGylated control. Thus, a particularly advantageous drug-linker for conjugation to an antibody of the invention is the following Formula V: or a pharmaceutically acceptable salt thereof.
對於此類藥物-連接子之較佳立體化學展示於下式Va中：或其醫藥學上可接受之鹽，其中對於式V及Va，Z表示具有能夠與抗體上之官能基反應以形成針對其之共價連接的反應性位點之有機部分，n在8至36之範圍內且最佳在8至14之範圍內(最佳12)，R21為用於聚乙二醇部分之封端單元，較佳為-CH3或-CH2CH2CO2H。The preferred stereochemistry for this type of drug-linker is shown below in Formula Va: or a pharmaceutically acceptable salt thereof, wherein for Formula V and Va, Z represents an organic moiety having a reactive site capable of reacting with a functional group on the antibody to form a covalently linked site thereof, n is in the range of 8 to 36 and is preferably in the range of 8 to 14 (most preferably 12), and R21 is a capping unit for a polyethylene glycol moiety, preferably -CH3 or -CH2 CH2 CO2 H.
較佳Z部分為含順丁烯二醯亞胺基之部分。尤其較佳之Z部分展示於以下藥物-連接子中：或其醫藥學上可接受之鹽。Preferred Z moieties are those containing a cis-butenediimido group. Particularly preferred Z moieties are shown in the following drug-linkers: or a pharmaceutically acceptable salt thereof.
對於此類藥物-連接子之較佳立體化學在下方展示：或其醫藥學上可接受之鹽，其中對於式VI、VIa、VII及VIIa，n在8至36之範圍內且最佳在8至14之範圍內(最佳12)，RPR為氫或保護基，例如酸不穩定保護基，例如BOC，R21為用於聚乙二醇部分之封端單元，較佳為-CH3或-CH2CH2CO2H。The preferred stereochemistry for this class of drug-linkers is shown below: or a pharmaceutically acceptable salt thereof, wherein for Formulae VI, VIa, VII and VIIa, n is in the range of 8 to 36 and preferably in the range of 8 to 14 (most preferably 12), RPR is hydrogen or a protecting group, such as an acid-labile protecting group, such as BOC, and R21 is a capping unit for the polyethylene glycol moiety, preferably -CH3 or -CH2 CH2 CO2 H.
依上所指出，RPR可為氫或保護基。依本文所用之保護基係指選擇性阻斷(暫時或永久地)多官能化合物中之反應性位點之基團。保護基在其滿足以下條件時為適合之保護基：能夠在實現分子中之別處之所需化學轉變所需的反應條件下及在需要時純化新形成之分子期間，防止或避免非所需副反應或保護基之過早損失，且可在不有害影響新形成之分子之結構或立體化學完整性的條件下進行移除。適合之胺保護基包括酸不穩定氮保護基，包括由Isidro-Llobel等人「Amino acid-protecting groups」 Chem. Rev. (2009) 109: 2455-2504提供之彼等保護基。通常，酸不穩定氮保護基將一級或二級胺基轉變成其對應胺基甲酸酯且包括含胺基甲酸三級丁酯、胺基甲酸烯丙酯及胺基甲酸苯甲酯。As noted above, RPR can be hydrogen or a protecting group. As used herein, a protecting group refers to a group that selectively blocks (temporarily or permanently) a reactive site in a multifunctional compound. A protecting group is suitable when it satisfies the following conditions: it is capable of preventing or avoiding undesirable side reactions or premature loss of the protecting group under the reaction conditions required to achieve the desired chemical transformation elsewhere in the molecule and during purification of the newly formed molecule when necessary, and can be removed under conditions that do not adversely affect the structural or stereochemical integrity of the newly formed molecule. Suitable amine protecting groups include acid-labile nitrogen protecting groups, including those provided by Isidro-Llobel et al. "Amino acid-protecting groups" Chem. Rev. (2009) 109: 2455-2504. Typically, acid-labile nitrogen protecting groups convert primary or secondary amine groups to their corresponding carbamates and include tertiary butyl carbamate, allyl carbamate, and benzyl carbamate.
依上所指出，R21為用於聚乙二醇部分之封端單元。依熟習此項技術者將瞭解，聚乙二醇單元可藉由多種有機部分(通常相對無反應性之彼等有機部分)經末端封端。烷基及經取代烷基為較佳的。As noted above,R21 is a capping unit for the polyethylene glycol moiety. As will be appreciated by those skilled in the art, the polyethylene glycol unit can be terminally capped with a variety of organic moieties, typically those that are relatively unreactive. Alkyl and substituted alkyl groups are preferred.
對於MMAE聚乙二醇化ADC，諸如本文例示之ADC，尤其較佳之平均載藥量為約8。在例示性實施例中，將藥物-連接子與經還原之鏈間二硫化物的半胱胺酸殘基結合。在一些態樣中，對於抗體藥物結合物化合物之群體中之個別抗體分子的實際載藥量為1至10 (或6至10或6至8)，主導藥物負載為8。舉例而言，若除鏈間二硫化物之外，使藥物-連接子與引入之半胱胺酸殘基(諸如位置239處引入之半胱胺酸殘基，根據EU索引)結合，則可達成較高載藥量。For MMAE-PEGylated ADCs, such as those exemplified herein, a particularly preferred average drug loading is about 8. In exemplary embodiments, the drug-linker is conjugated to a cysteine residue of a reduced interchain disulfide. In some aspects, the actual drug loading for individual antibody molecules in a population of antibody-drug conjugate compounds is 1 to 10 (or 6 to 10 or 6 to 8), with a predominant drug loading of 8. For example, higher drug loading can be achieved if the drug-linker is conjugated to an introduced cysteine residue (such as the introduced cysteine residue at position 239, according to the EU index) in addition to the interchain disulfide.
例示性ADC包括以下：或其醫藥學上可接受之鹽，其中n在8至36之範圍內且最佳在8至14之範圍內(最佳12)，RPR為氫或保護基，例如酸不穩定保護基，例如BOC，R21為用於聚乙二醇部分之封端單元，較佳為-CH3或-CH2CH2CO2H，Ab表示抗αVβ6抗體且p在指個別抗體分子時表示在1至16，較佳1至14、6至12、6至10或8至10之範圍內的整數或在指抗體分子群體時表示約4或約6至約14，較佳約8之平均載藥量。Exemplary ADCs include the following: or a pharmaceutically acceptable salt thereof, wherein n is in the range of 8 to 36 and preferably in the range of 8 to 14 (optimally 12), RPR is hydrogen or a protecting group, for example, an acid-labile protecting group, such as BOC, R21 is a capping unit for the polyethylene glycol portion, preferably -CH3 or -CH2 CH2 CO2 H, Ab represents an anti-αVβ6 antibody and p represents an integer in the range of 1 to 16, preferably 1 to 14, 6 to 12, 6 to 10 or 8 to 10 when referring to an individual antibody molecule or represents an average drug loading of about 4 or about 6 to about 14, preferably about 8 when referring to a group of antibody molecules.
依上所指出，藥物連接子之PEG (聚乙二醇)部分可在8至36之範圍內，然而已發現12個環氧乙烷單元之PEG為尤其較佳的。已發現較長PEG鏈可產生較慢清除率而較短PEG鏈可產生減弱之活性。因此，上述所有實施例中之下標n較佳為8至14、8至12、10至12或10至14且最佳為12。As noted above, the PEG (polyethylene glycol) portion of the drug linker can range from 8 to 36, however, PEG with 12 ethylene oxide units has been found to be particularly preferred. Longer PEG chains have been found to result in slower clearance rates and shorter PEG chains have been found to result in reduced activity. Thus, in all of the above embodiments, the subscript n is preferably 8 to 14, 8 to 12, 10 to 12, or 10 to 14 and most preferably 12.
多分散PEG、單分散PEG及離散PEG可用於製備本發明之聚乙二醇化抗體藥物結合物。多分散PEG為尺寸及分子量之異質混合物，而單分散PEG通常自異質混合物純化且因此提供單鏈長度及分子量。較佳PEG單元為離散PEG，即以逐步方式且不經由聚合方法合成之化合物。離散PEG提供具有限定及指定鏈長之單一分子。如同下標「p」，當提及抗體藥物結合物之群體時，下標「n」之值可為平均數值且可為整數或非整數數值。Polydisperse PEG, monodisperse PEG and discrete PEG can be used to prepare the PEGylated antibody-drug conjugates of the present invention. Polydisperse PEG is a heterogeneous mixture of size and molecular weight, while monodisperse PEG is usually purified from a heterogeneous mixture and thus provides a single chain length and molecular weight. The preferred PEG unit is discrete PEG, i.e., a compound synthesized in a stepwise manner and not via a polymerization process. Discrete PEG provides a single molecule with a defined and specified chain length. As with the subscript "p", when referring to a population of antibody-drug conjugates, the value of the subscript "n" can be an average value and can be an integer or non-integer value.
在較佳實施例中，抗體與藥物-連接子之共價連接係經由抗體之硫氫基官能基與藥物連接子之順丁烯二醯亞胺官能基相互作用以形成經硫取代之丁二醯亞胺來實現。硫氫基官能基可以配位體之天然狀態，例如以天然存在之殘基(鏈間二硫化物殘基)形式存在於配位體單元上，或可經由化學修飾、或藉由生物工程改造或兩者之組合引入至配位體中。應理解，經抗體取代之丁二醯亞胺可以一或多種水解形式存在。舉例而言，在較佳實施例中，ADC包含丁二醯亞胺部分，該部分在結合於抗體時由以下之結構表示：或包含其對應酸-醯胺部分，該部分在結合於抗體時由以下之結構表示：。 波浪線指示與藥物-連接子之其餘部分的連接。In preferred embodiments, the covalent attachment of the antibody to the drug-linker is achieved via the interaction of the sulfhydryl functional group of the antibody with the cis-butylenediimide functional group of the drug linker to form a sulfur-substituted succinimide. The sulfhydryl functional group may be present on the ligand unit in the native state of the ligand, e.g., as a naturally occurring residue (interchain disulfide residue), or may be introduced into the ligand via chemical modification, or by bioengineering, or a combination of both. It is understood that the antibody-substituted succinimide may exist in one or more hydrolyzed forms. For example, in preferred embodiments, the ADC comprises a succinimide moiety that, when bound to the antibody, is represented by the following structure: or comprises a corresponding acid-amide portion thereof, which, when bound to an antibody, is represented by the following structure: The wavy line indicates the connection to the rest of the drug-linker.
在一些實施例中，本發明之抗αvβ6抗體經由MDpr-PEG(12)-gluc連接子與單甲基奧瑞他汀E結合，形成具有以下結構之抗體藥物結合物：或其醫藥學上可接受之鹽，其中n在8至36之範圍內且最佳在8至14之範圍內(最佳12)，RPR為氫或保護基，例如酸不穩定保護基，例如BOC，R21為用於聚乙二醇部分之封端單元，較佳為-CH3或-CH2CH2CO2H，Ab表示抗αVβ6抗體且p在指個別抗體分子時表示在1至16，較佳1至14、6至12、6至10或8至10之範圍內的整數或在指抗體分子群體時表示約4或約6至約14，較佳約8之平均載藥量。In some embodiments, the anti-αvβ6 antibody of the present invention is conjugated to monomethyl auristatin E via a MDpr-PEG(12)-gluc linker to form an antibody-drug conjugate having the following structure: or a pharmaceutically acceptable salt thereof, wherein n is in the range of 8 to 36 and preferably in the range of 8 to 14 (optimally 12), RPR is hydrogen or a protecting group, for example, an acid-labile protecting group, such as BOC, R21 is a capping unit for the polyethylene glycol portion, preferably -CH3 or -CH2 CH2 CO2 H, Ab represents an anti-αVβ6 antibody and p represents an integer in the range of 1 to 16, preferably 1 to 14, 6 to 12, 6 to 10 or 8 to 10 when referring to an individual antibody molecule or represents an average drug loading of about 4 or about 6 to about 14, preferably about 8 when referring to a group of antibody molecules.
例示性抗體藥物結合物亦包括基於喜樹鹼之抗體藥物結合物(亦即，藥物組分為喜樹鹼藥物)。喜樹鹼為已顯示具有抗癌活性之拓樸異構酶抑制劑。通常基於喜樹鹼之抗體藥物結合物包含在喜樹鹼藥物與抗αvβ6抗體之間的連接子。連接子可為例如可裂解連接子(例如肽基連接子、碳水化合物連接子)或不可裂解連接子(例如藉由抗體之降解釋放之連接子)。例示性喜樹鹼藥物-連接子之合成及結構描述於PCT/US19/025968 (2019年4月5日申請)中，其以全文引用之方式併入本文中且用於所有目的。Exemplary antibody-drug conjugates also include camptothecin-based antibody-drug conjugates (i.e., the drug component is a camptothecin drug). Camptothecins are topoisomerase inhibitors that have been shown to have anti-cancer activity. Typically, camptothecin-based antibody-drug conjugates include a linker between the camptothecin drug and the anti-αvβ6 antibody. The linker can be, for example, a cleavable linker (e.g., a peptidyl linker, a carbohydrate linker) or a non-cleavable linker (e.g., a linker that is released by degradation of the antibody). The synthesis and structure of exemplary camptothecin drug-linkers are described in PCT/US19/025968 (filed on April 5, 2019), which is incorporated herein by reference in its entirety and for all purposes.
例示性抗αvβ6抗體藥物結合物包括如下喜樹鹼抗體藥物結合物，其中p表示載藥量及Ab表示抗αvβ6抗體：Exemplary anti-αvβ6 antibody-drug conjugates include the following cathepsin-based antibody-drug conjugates, where p represents the drug loading and Ab represents the anti-αvβ6 antibody:
在一些實施例中，喜樹鹼ADC具有式(IC)：或其醫藥學上可接受之鹽； 其中 Ab為抗αvβ6抗體； y為1、2、3或4，或為1或4；且 z為2至12之整數，或為2、4、8或12； 且p為1至16。In some embodiments, the camptotherine ADC has formula (IC): or a pharmaceutically acceptable salt thereof; wherein Ab is an anti-αvβ6 antibody; y is 1, 2, 3 or 4, or is 1 or 4; and z is an integer from 2 to 12, or is 2, 4, 8 or 12; and p is 1 to 16.
在此等實施例之一些態樣中，p為2、3、4、5、6、7、8、9或10。在一些態樣中，p為2、4或8。In some aspects of these embodiments, p is 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some aspects, p is 2, 4, or 8.
在一些實施例中，喜樹鹼ADC具有下式：或其醫藥學上可接受之鹽； 其中p為2、4或8，較佳地p為8。In some embodiments, the camptotherine ADC has the formula: or a pharmaceutically acceptable salt thereof; wherein p is 2, 4 or 8, preferably p is 8.
在一些實施例中，喜樹鹼ADC具有下式：或其醫藥學上可接受之鹽； 其中p為2、4或8，較佳地p為8。In some embodiments, the camptotherine ADC has the formula: or a pharmaceutically acceptable salt thereof; wherein p is 2, 4 or 8, preferably p is 8.
在一些實施例中，喜樹鹼藥物-連接子具有下式：或其醫藥學上可接受之鹽； 其中 y為1、2、3或4，或為1或4；且 z為2至12之整數，或為2、4、8或12。In some embodiments, the camptothecin drug-linker has the formula: or a pharmaceutically acceptable salt thereof; wherein y is 1, 2, 3 or 4, or is 1 or 4; and z is an integer from 2 to 12, or is 2, 4, 8 or 12.
在一些實施例中，喜樹鹼藥物-連接子具有下式：MP-PEG8-VKG-喜樹鹼In some embodiments, the camptothecin drug-linker has the formula: MP-PEG8-VKG-Camphor alkaloids
在一些實施例中，喜樹鹼藥物-連接子具有下式：MP-PEG4-VKG-喜樹鹼In some embodiments, the camptothecin drug-linker has the formula: MP-PEG4-VKG-Camphor alkaloids
在一些實施例中，喜樹鹼藥物-連接子具有下式：MP-PEG12-VKG-喜樹鹼In some embodiments, the camptothecin drug-linker has the formula: MP-PEG12-VKG-Camphor alkaloids
其他例示性抗體藥物結合物包括類美登素(maytansinoid)抗體藥物結合物(亦即藥物組分為類美登素藥物)及苯并二氮呯抗體藥物結合物(亦即藥物組分為苯并二氮呯(例如吡咯并[l,4]苯并二氮呯二聚體(PBD二聚體)、吲哚啉并苯并二氮呯二聚體及㗁唑啶并苯并二氮呯二聚體))。Other exemplary antibody-drug conjugates include maytansinoid antibody-drug conjugates (i.e., the drug component is a maytansinoid drug) and benzodiazepine antibody-drug conjugates (i.e., the drug component is a benzodiazepine (e.g., pyrrolo[1,4]benzodiazepine dimer (PBD dimer), indolinonebenzodiazepine dimer, and oxazolidinonebenzodiazepine dimer)).
在一些實施例中，用於本發明之PBD二聚體由式I表示。PBD二聚體之較佳立體化學依式Ia中所示：或醫藥學上之鹽、溶劑合物或該鹽之溶劑合物；其中下標n為1或3。In some embodiments, the PBD dimer used in the present invention is represented by Formula I. The preferred stereochemistry of the PBD dimer is as shown in Formula Ia: or a pharmaceutical salt, a solvent complex, or a solvent complex of the salt; wherein the subscript n is 1 or 3.
式(I)及(Ia)之溶劑合物通常由在一個或兩個PBD單體之亞胺官能基中添加水或醇溶劑以形成甲醇胺及/或甲醇胺醚而形成。舉例而言，在N10-C11位置處，可存在亞胺(N=C)、甲醇胺(NH-CH(OH))或甲醇胺醚(NH-CH(Ome))，由以下式I'及Ia'表示：其中，以下中之任一者： (a) R10為H，且R11為OH或ORA，其中RA為飽和C1-4烷基(較佳甲基)；或 (b) R10及R11於氮與碳原子之間形成與其結合的氮-碳雙鍵；或 I R10之一為H，且R11為OH或ORA，其中RA為飽和C1-4烷基(較佳甲基)；且R10及R11中之另一者在氮與碳原子之間形成與其結合的氮-碳雙鍵。Solvates of formula (I) and (Ia) are generally formed by adding water or an alcohol solvent to the imine functional groups of one or both PBD monomers to form carbinolamine and/or carbinolamine ether. For example, at the N10-C11 positions, imine (N=C), carbinolamine (NH-CH(OH)) or carbinolamine ether (NH-CH(Ome)) may be present, represented by the following formulas I' and Ia': wherein any one of the following: (a) R10 is H,and R11 is OH or ORA , whereinRA is a saturated C1-4alkyl group (preferably methyl); or (b) R10 and R11 form a nitrogen-carbon double bond between the nitrogen and carbon atom to which they are bound; or one of R10 is H,and R11 is OH or ORA , whereinRA is a saturated C1-4alkyl group (preferably methyl); and the other of R10 and R11 forms a nitrogen-carbon double bond between the nitrogen and carbon atom to which they are bound.
式I或la之PBD二聚體(或醫藥學上之鹽、溶劑合物或其鹽之溶劑合物)通常經由連接子單元LU與抗體連接。連接子單元用以在目標位點(例如癌細胞內部)釋放式I或la之PBD二聚體(或醫藥學上之鹽、溶劑合物或其鹽之溶劑合物)。用於本發明之PBD藥物-連接子化合物下方藉由式II表示(依Ila所示之較佳立體化學)，其中LU為連接子單元。連接子單元可為例如可裂解肽連接子單元(例如包含纈胺酸-丙胺酸肽之連接子)或可裂解二硫化物連接子單元：或醫藥學上之鹽、溶劑合物或該鹽之溶劑合物；其中下標n為1或3。The PBD dimer of formula I or la (or a pharmaceutical salt, a solvent complex or a solvent complex of a salt thereof) is usually linked to the antibody via a linker unit LU. The linker unit is used to release the PBD dimer of formula I or la (or a pharmaceutical salt, a solvent complex or a solvent complex of a salt thereof) at a target site (e.g., inside a cancer cell). The PBD drug-linker compound used in the present invention is represented below by formula II (preferred stereochemistry as shown in Ila), wherein LU is a linker unit. The linker unit may be, for example, a cleavable peptide linker unit (e.g., a linker comprising a valine-alanine peptide) or a cleavable disulfide linker unit: or a pharmaceutical salt, a solvent complex, or a solvent complex of the salt; wherein the subscript n is 1 or 3.
用於本發明之較佳PBD藥物-連接子化合物由下式III表示：或醫藥學上之鹽、溶劑合物或該鹽之溶劑合物；其中下標n為1或3且下標m為2至5之整數。Preferred PBD drug-linker compounds for use in the present invention are represented by the following Formula III: or a pharmaceutical salt, a solvent complex, or a solvent complex of the salt; wherein the subscript n is 1 or 3 and the subscript m is an integer from 2 to 5.
PBD藥物-連接子與抗αvβ6抗體結合以產生靶向αvβ6之抗體藥物結合物。舉例而言，抗體可與式II或式III之藥物-連接子結合。例示性靶向αvβ6之抗體藥物結合物係示於下式IV、IVa及IVb中：或醫藥學上之鹽、溶劑合物或該鹽之溶劑合物；其中下標n為1或3；下標m為2至5之整數；且下標p為1至4。The PBD drug-linker is conjugated to an anti-αvβ6 antibody to generate an antibody-drug conjugate targeting αvβ6. For example, the antibody can be conjugated to a drug-linker of Formula II or Formula III. Exemplary antibody-drug conjugates targeting αvβ6 are shown in the following Formulas IV, IVa, and IVb: or a pharmaceutical salt, a solvent complex, or a solvent complex of the salt; wherein subscript n is 1 or 3; subscript m is an integer from 2 to 5; and subscript p is 1 to 4.
對於與抗αvβ6抗體結合有用之類別的細胞毒性劑包括例如抗微管蛋白劑、DNA小溝結合劑、DNA複製抑制劑、化學療法增感劑或類似物。其他例示性類別的細胞毒性劑包括蒽環黴素(anthracycline)、奧瑞他汀、喜樹鹼、倍癌黴素(duocarmycin)、依託泊苷(etoposide)、類美登素及長春花生物鹼(vinca alkaloid)。一些例示性細胞毒性劑包括奧瑞他汀(例如奧瑞他汀T、奧瑞他汀E、AFP、單甲基奧瑞他汀F (MMAF)、親脂性單甲基奧瑞他汀F、單甲基奧瑞他汀E (MMAE))、DNA小溝結合劑(例如烯二炔及萊希普辛(lexitropsin))、倍癌黴素、紫杉烷(例如太平洋紫杉醇(paclitaxel)及多西他賽(docetaxel))、長春花生物鹼、菸鹼醯胺磷酸核糖基轉移酶抑制劑(nicotinamide phosphoribosyltranferase inhibitor，NAMPTi)、特吡萊辛M (tubulysin M)、小紅莓、嗎啉基-小紅莓及氰基嗎啉基-小紅莓。Useful classes of cytotoxic agents for binding to anti-αvβ6 antibodies include, for example, anti-tubulin agents, DNA minor groove binding agents, DNA replication inhibitors, chemotherapy sensitizers, or the like. Other exemplary classes of cytotoxic agents include anthracyclines, auristatins, camptothecins, duocarmycins, etoposides, maytansines, and vinca alkaloids. Some exemplary cytotoxic agents include auristatins (e.g., auristatin T, auristatin E, AFP, monomethyl auristatin F (MMAF), lipophilic monomethyl auristatin F, monomethyl auristatin E (MMAE)), DNA groove binders (e.g., enediynes and lexitropsin), duocarcins, taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids, nicotinamide phosphoribosyltranferase inhibitor (NAMPTi), tubulysin M, raspberries, morpholino-raspberries, and cyanomorpholino-raspberries.
細胞毒性劑可為化學治療劑，諸如小紅莓、太平洋紫杉醇、美法侖(melphalan)、長春花生物鹼、甲胺喋呤、絲裂黴素C (mitomycin C)或依託泊苷。藥劑亦可為CC-1065類似物、卡奇黴素(calicheamicin)、美登素、海兔毒素10 (dolastatin 10)之類似物、根黴毒素(rhizoxin)或沙海葵毒素(palytoxin)。The cytotoxic agent may be a chemotherapeutic agent such as paclitaxel, melphalan, vinca alkaloids, methotrexate, mitomycin C, or etoposide. The agent may also be a CC-1065 analog, calicheamicin, maytansine, an analog of dolastatin 10, rhizoxin, or palytoxin.
細胞毒性劑亦可為奧瑞他汀。奧瑞他汀可為奧瑞他汀E衍生物，其為例如奧瑞他汀E與酮酸之間形成的酯。舉例而言，奧瑞他汀E可與對乙醯基苯甲酸或苯甲醯基戊酸反應以分別產生AEB及AEVB。其他典型的奧瑞他汀包括奧瑞他汀T、AFP、MMAF及MMAE。各種奧瑞他汀之合成及結構描述於例如US 2005-0238649及US2006-0074008中。The cytotoxic agent may also be an auristatin. Auristatin may be an auristatin E derivative, such as an ester formed between auristatin E and a keto acid. For example, auristatin E may react with p-acetylbenzoic acid or benzoylvaleric acid to produce AEB and AEVB, respectively. Other typical auristatins include auristatin T, AFP, MMAF and MMAE. The synthesis and structure of various auristatins are described in, for example, US 2005-0238649 and US2006-0074008.
細胞毒性劑可為DNA小溝結合劑。(參見例如美國專利第6,130,237號)。舉例而言，小溝結合劑可為CBI化合物或烯二炔(例如卡奇黴素)。The cytotoxic agent may be a DNA groove binding agent. (See, e.g., U.S. Patent No. 6,130,237). For example, the groove binding agent may be a CBI compound or an enediyne (e.g., kacinomycin).
細胞毒性劑或細胞生長抑制劑可為抗微管蛋白劑。抗微管蛋白劑之實例包括紫杉烷(例如Taxol®(太平洋紫杉醇)、Taxotere®(多西他賽))、T67 (Tularik)、長春花生物鹼(例如長春新鹼(vincristine)、長春鹼(vinblastine)、長春地辛(vindesine)及長春瑞濱(vinorelbine))及奧瑞他汀(例如奧瑞他汀E、AFP、MMAF、MMAE、AEB、AEVB)。例示性奧瑞他汀以式III-XIII示於下文中。其他適合之抗微管蛋白劑包括例如漿果赤黴素(baccatin)衍生物、紫杉烷類似物(例如埃坡黴素(epothilone) A及B)、諾考達唑(nocodazole)、秋水仙鹼(colchicine)及秋水醯胺(colcimid)、雌氮芥(estramustine)、克瑞普托非森(cryptophysin)、西馬多丁(cemadotin)、類美登素、風車子抑素(combretastatin)、迪斯德莫來(discodermolide)及軟珊瑚醇(eleuthrobin)。The cytotoxic agent or cell growth inhibitory agent may be an anti-tubulin agent. Examples of anti-tubulin agents include taxanes (e.g.,Taxol® (paclitaxel),Taxotere® (docetaxel)), T67 (Tularik), vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), and auristatins (e.g., auristatin E, AFP, MMAF, MMAE, AEB, AEVB). Exemplary auristatins are shown below as Formula III-XIII. Other suitable anti-tubulin agents include, for example, baccatin derivatives, taxane analogs (e.g., epothilone A and B), nocodazole, colchicine and colcimid, estramustine, cryptophysin, cemadotin, maytansine, combretastatin, discodermolide, and eleuthrobin.
細胞毒性劑可為類美登素，另一組抗微管蛋白劑(例如DM1、DM2、DM3、DM4)。舉例而言，類美登素可為美登素或含有諸如DM-1或DM-4之藥物連接子的美登素(ImmunoGen公司；亦參見Chari等人, 1992, Cancer Res.)。 VIII. 治療應用The cytotoxic agent may be a maytansinoid, another group of anti-tubulin agents (e.g., DM1, DM2, DM3, DM4). For example, a maytansinoid may be maytansine or maytansine containing a drug linker such as DM-1 or DM-4 (ImmunoGen; see also Chari et al., 1992, Cancer Res.).VIII. Therapeutic Applications
本發明之抗αvβ6抗體單獨或以其抗αvβ6抗體藥物結合物形式可用於治療癌症。一些此類癌症顯示在蛋白(例如藉由免疫分析，諸如藉由使用例示性抗體中之一者)或mRNA水準量測之可偵測的αvβ6含量。一些此類癌症相對於相同類型之非癌性組織(較佳來自同一患者)顯示升高的αvβ6含量。儘管可治療較高或較低含量，但在癌細胞上適合於治療之例示性αvβ6含量為每細胞5000至500,000個αvβ6分子。視情況，在進行治療之前量測癌症中之αvβ6含量。The anti-αvβ6 antibodies of the invention, alone or in the form of their anti-αvβ6 antibody-drug conjugates, can be used to treat cancer. Some such cancers display detectable levels of αvβ6 as measured at the protein level (e.g., by an immunoassay, such as by using one of the exemplary antibodies) or at the mRNA level. Some such cancers display elevated levels of αvβ6 relative to noncancerous tissue of the same type, preferably from the same patient. Exemplary levels of αvβ6 on cancer cells that are suitable for treatment are 5000 to 500,000 αvβ6 molecules per cell, although higher or lower levels can be treated. Optionally, the level of αvβ6 in the cancer is measured prior to initiating treatment.
與αvβ6表現相關聯且適合於治療之癌症的實例包括非小細胞肺癌(NSCLC) (鱗狀及腺)、頭頸癌(包括頭頸部鱗狀癌瘤)、食道癌、乳癌(包括乳房侵襲性癌)、卵巢癌、膀胱癌(包括尿道上皮癌)、皮膚癌(鱗狀細胞癌或SCC)、腎癌(包括腎透明細胞、腎乳頭狀細胞及腎難染細胞)、子宮頸癌、胃癌、前列腺癌(包括前列腺腺癌)、子宮內膜癌(包括子宮癌肉瘤及子宮體子宮內膜)、直腸腺癌、甲狀腺癌、結腸腺癌、胃腺癌及胰臟癌(包括胰臟腺癌)。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療NSCLC之方法。在一些實施例中，NSCLC為鱗狀細胞癌。在一些實施例中，NSCLC為非鱗狀細胞癌。在一些實施例中，NSCLC為腺癌。在一些實施例中，NSCLC不具有賦予審批通過之靶向療法合格性的已知突變/變化(例如表皮生長因子受體(EGFR)、退行性淋巴瘤激酶(ALK)等)。在一些實施例中，NSCLC具有一或多種賦予審批通過之靶向療法合格性的已知突變/變化(例如表皮生長因子受體(EGFR)、退行性淋巴瘤激酶(ALK)等)。在一些實施例中，NSCLC具有已知的EGFR突變。在一些實施例中，NSCLC具有已知的ALK突變。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療頭頸癌之方法。在一些實施例中，頭頸癌為鱗狀細胞癌。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療皮膚癌之方法。在一些實施例中，皮膚癌為皮膚鱗狀細胞癌。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療食道癌之方法。在一些實施例中，食道癌為食道鱗狀細胞癌。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療乳癌之方法。在一些實施例中，乳癌為HER2陰性乳癌。在一些實施例中，乳癌為乳房侵襲性癌。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療卵巢癌之方法。在一些實施例中，卵巢癌為高級漿液性上皮卵巢癌。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療原發性腹膜癌之方法。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療輸卵管癌之方法。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療膀胱癌之方法。在一些實施例中，膀胱癌為尿道上皮癌。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療子宮頸癌之方法。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療胃癌(gastric cancer)之方法。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療前列腺癌之方法。在一些實施例中，前列腺癌為前列腺腺癌。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療腎癌之方法。在一些實施例中，腎癌為腎透明細胞癌。在一些實施例中，腎癌為腎乳頭狀細胞癌。在一些實施例中，腎癌為腎難染細胞癌。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療子宮內膜癌之方法。在一些實施例中，子宮內膜癌為子宮癌肉瘤。在一些實施例中，子宮內膜癌為子宮體子宮內膜癌。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療直腸腺癌之方法。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療甲狀腺癌之方法。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療結腸腺癌之方法。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療胃癌(stomach cancer)之方法。在一些實施例中，胃癌為胃腺癌。在一些實施例中，本發明之抗體或抗體藥物結合物用於治療胰臟癌之方法。在一些實施例中，胰臟癌為外分泌胰臟腺癌。治療可應用於患有任何此等類別之局部晚期腫瘤的患者。治療可應用於患有任何此等類別之原發性或轉移性腫瘤的患者。治療亦可應用於患有任何此等類型之腫瘤的患者，該等患者難以用習知的治療進行治療或在對此類治療起反應之後復發。在一些實施例中，個體已接受1線或多線先前療法以治療任何此等類別之腫瘤。在一些實施例中，個體先前已用基於鉑之療法治療任何此等類別之腫瘤。在一些實施例中，個體先前已用PD-1/PD-L1抑制劑治療任何此等類別之腫瘤。在一些實施例中，個體先前已用紫杉烷治療任何此等類別之腫瘤。在一些實施例中，個體先前未用紫杉烷治療任何此等類別之腫瘤。在一些實施例中，個體先前已用磷酸肌醇3-激酶(PI3K)抑制劑治療任何此等類別之腫瘤。在一些實施例中，個體先前已用聚ADP核糖聚合酶(PARP)抑制劑治療任何此等類別之腫瘤。在一些實施例中，個體先前已用貝伐珠單抗(bevacizumab)治療任何此等類別之腫瘤。在一些實施例中，個體先前已用CDK4/6抑制劑治療任何此等類別之腫瘤。在一些實施例中，個體先前已用激素導向之療法治療任何此等類別之腫瘤。治療可應用於患有不可切除的任何此等類別之腫瘤的患者。在一些實施例中，在第一劑量之本發明抗體或抗體藥物結合物之前3年內，個體不具有另一惡性腫瘤之病史。在一些實施例中，在第一劑量之本發明之抗體或抗體藥物結合物時，個體不具有來自先前診斷之惡性腫瘤的殘餘疾病之任何跡象。在一些實施例中，個體未患有已知的中樞神經系統癌轉移。在一些實施例中，個體未患有癌性腦膜炎。在一些實施例中，個體先前未接受用含MMAE之藥劑或靶向整合素β-6之藥劑治療。Examples of cancers associated with αvβ6 expression and suitable for treatment include non-small cell lung cancer (NSCLC) (squamous and glandular), head and neck cancer (including head and neck squamous carcinoma), esophageal cancer, breast cancer (including invasive breast carcinoma), ovarian cancer, bladder cancer (including urothelial carcinoma), skin cancer (squamous cell carcinoma or SCC), kidney cancer (including kidney clear cell, kidney papillary cell and kidney refractory cell), cervical cancer, gastric cancer, prostate cancer (including prostate adenocarcinoma), endometrial cancer (including uterine carcinosarcoma and corpus endometrium), rectal adenocarcinoma, thyroid cancer, colon adenocarcinoma, gastric adenocarcinoma, and pancreatic cancer (including pancreatic adenocarcinoma). In some embodiments, the antibody or antibody drug conjugate of the present invention is used in a method for treating NSCLC. In some embodiments, NSCLC is squamous cell carcinoma. In some embodiments, NSCLC is non-squamous cell carcinoma. In some embodiments, NSCLC is adenocarcinoma. In some embodiments, NSCLC does not have a known mutation/variation that qualifies for approved targeted therapy (e.g., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), etc.). In some embodiments, NSCLC has one or more known mutations/variations that qualify for approved targeted therapy (e.g., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), etc.). In some embodiments, NSCLC has a known EGFR mutation. In some embodiments, the NSCLC has a known ALK mutation. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method of treating head and neck cancer. In some embodiments, the head and neck cancer is squamous cell carcinoma. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method of treating skin cancer. In some embodiments, the skin cancer is cutaneous squamous cell carcinoma. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method of treating esophageal cancer. In some embodiments, esophageal cancer is esophageal squamous cell carcinoma. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method of treating breast cancer. In some embodiments, the breast cancer is HER2-negative breast cancer. In some embodiments, breast cancer is invasive breast cancer. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating ovarian cancer. In some embodiments, ovarian cancer is high-grade serous epithelial ovarian cancer. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating primary peritoneal cancer. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating fallopian tube cancer. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating bladder cancer. In some embodiments, bladder cancer is urothelial carcinoma. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating cervical cancer. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating gastric cancer. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating prostate cancer. In some embodiments, prostate cancer is prostate adenocarcinoma. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating kidney cancer. In some embodiments, kidney cancer is kidney clear cell carcinoma. In some embodiments, kidney cancer is kidney papillary cell carcinoma. In some embodiments, kidney cancer is kidney refractory cell carcinoma. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating endometrial cancer. In some embodiments, endometrial cancer is carcinosarcoma. In some embodiments, the endometrial cancer is corpus endometrial cancer. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating rectal adenocarcinoma. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating thyroid cancer. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating colon adenocarcinoma. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating stomach cancer. In some embodiments, stomach cancer is gastric adenocarcinoma. In some embodiments, the antibody or antibody-drug conjugate of the present invention is used in a method for treating pancreatic cancer. In some embodiments, pancreatic cancer is exocrine pancreatic adenocarcinoma. Treatment may be applied to patients with locally advanced tumors of any of these categories. Treatment may be applied to patients with primary or metastatic tumors of any of these categories. Treatment may also be applied to patients with any of these types of tumors who are refractory to known treatments or who have relapsed after responding to such treatments. In some embodiments, the individual has received 1 or more lines of prior therapy to treat any of these categories of tumors. In some embodiments, the individual has previously been treated with a platinum-based therapy for any of these categories of tumors. In some embodiments, the individual has previously been treated with a PD-1/PD-L1 inhibitor for any of these categories of tumors. In some embodiments, the individual has previously been treated with a taxane for any of these classes of tumors. In some embodiments, the individual has not previously been treated with a taxane for any of these classes of tumors. In some embodiments, the individual has previously been treated with a phosphoinositide 3-kinase (PI3K) inhibitor for any of these classes of tumors. In some embodiments, the individual has previously been treated with a poly ADP ribose polymerase (PARP) inhibitor for any of these classes of tumors. In some embodiments, the individual has previously been treated with bevacizumab for any of these classes of tumors. In some embodiments, the individual has previously been treated with a CDK4/6 inhibitor for any of these classes of tumors. In some embodiments, the individual has previously been treated with hormone-directed therapy for any of these categories of tumors. Treatment may be applied to patients with unresectable tumors of any of these categories. In some embodiments, the individual does not have a history of another malignant tumor within 3 years prior to the first dose of the antibody or antibody drug conjugate of the invention. In some embodiments, at the time of the first dose of the antibody or antibody drug conjugate of the invention, the individual does not have any signs of residual disease from a previously diagnosed malignant tumor. In some embodiments, the individual does not have known metastases of central nervous system cancer. In some embodiments, the individual does not have carcinomatous meningitis. In some embodiments, the subject has not been previously treated with an agent containing MMAE or an agent that targets integrin beta-6.
本發明之抗αvβ6抗體(諸如人源化抗體)單獨或以其結合物形式以有效方案投與，該有效方案意謂延遲癌症之發作、降低癌症之嚴重程度、抑制癌症之進一步惡化及/或改善癌症之至少一種病徵或症狀的劑量、投與途徑及投與頻率。若患者已罹患癌症，則方案可稱作治療上有效之方案。若患者相對於一般群體處於升高之癌症風險下，但尚未經歷症狀，則方案可稱作預防上有效之方案。在一些情況下，可在個別患者中相對於同一患者之歷史對照或過去經歷觀測到治療性或預防性功效。在其他情況下，可在臨床前或臨床試驗中在經治療患者群體中相對於未經治療患者之對照群體證明治療性或預防性功效。The anti-αvβ6 antibodies (such as humanized antibodies) of the present invention are administered alone or in the form of their conjugates in an effective regimen, which means a dose, route of administration, and frequency of administration that delays the onset of cancer, reduces the severity of cancer, inhibits further deterioration of cancer, and/or improves at least one sign or symptom of cancer. If the patient already has cancer, the regimen can be referred to as a therapeutically effective regimen. If the patient is at an elevated risk of cancer relative to the general population, but has not yet experienced symptoms, the regimen can be referred to as a preventively effective regimen. In some cases, therapeutic or preventive efficacy can be observed in individual patients relative to historical controls or past experience of the same patient. In other cases, therapeutic or preventive efficacy may be demonstrated preclinically or in clinical trials in a population of treated patients compared to a control population of untreated patients.
本文所描述之抗αvβ6單株抗體或抗體藥物結合物的例示性劑量為0.1 mg/kg至50 mg/kg個體體重，更通常1 mg/kg至30 mg/kg、1 mg/kg至20 mg/kg、1 mg/kg至15 mg/kg、1 mg/kg至12 mg/kg、或1 mg/kg至10 mg/kg 1、或2 mg/kg至30 mg/kg、2 mg/kg至20 mg/kg、2 mg/kg至15 mg/kg、2 mg/kg至12 mg/kg、或2 mg/kg至10 mg/kg、或3 mg/kg至30 mg/kg、3 mg/kg至20 mg/kg、3 mg/kg至15 mg/kg、3 mg/kg至12 mg/kg或3 mg/kg至10 mg/kg。在一些實施例中，個體體重為個體之理想體重(IBW)。在一些實施例中，個體體重為個體經調整之理想體重(AIBW)。單株抗體或其抗體藥物結合物之例示性劑量為1 mg/kg至7.5 mg/kg或2 mg/kg至7.5 mg/kg或3 mg/kg至7.5 mg/kg個體體重，或0.1-20、或0.5-5 mg/kg體重(例如0.5、1、2、3、4、5、6、7、8、9或10 mg/kg)或10-1500或200-1500 mg作為固定劑量。在一些實施例中，劑量為0.8 mg/kg。在一些實施例中，劑量為1.0 mg/kg。在一些實施例中，劑量為1.2 mg/kg。在一些實施例中，劑量為1.25 mg/kg。在一些實施例中，劑量為1.5 mg/kg。在一些實施例中，劑量為1.8 mg/kg。在一些實施例中，劑量為2.4 mg/kg。在一些方法中，向患者投與至少0.8 mg/kg、至少1.0 mg/kg、至少1.2 mg/kg、至少1.25 mg/kg、至少1.5 mg/kg、至少1.8 mg/kg或至少2.4 mg/kg之劑量，每週或更久投與一次。在一些方法中，向患者投與至少0.8 mg/kg、至少1.0 mg/kg、至少1.2 mg/kg、至少1.25 mg/kg、至少1.5 mg/kg、至少1.8 mg/kg或至少2.4 mg/kg之劑量，每週投與一次。在一些方法中，向患者投與至少1.5 mg/kg或至少1.8 mg/kg之劑量，每兩週或更久投與一次。在一些方法中，向患者投與至少1.2 mg/kg或至少1.25 mg/kg之劑量，每三週投與兩次。在一些方法中，向患者投與1.25 mg/kg之劑量，每三週投與兩次。在一些方法中，向患者投與1.5 mg/kg之劑量，每三週投與兩次。在一些方法中，向患者投與1.8 mg/kg之劑量，每兩週投與一次。在一些方法中，向患者投與1.5 mg/kg之劑量，每兩週投與一次。在一些方法中，向患者投與至少1.5 mg/kg、至少2 mg/kg或至少3 mg/kg之劑量，每三週或更久投與一次。除其他因素之外，劑量視投與頻率、患者之病狀及對先前治療(若存在)之反應而定，無論該治療為預防性或治療性且無論病症為急性或慢性的。Exemplary dosages of the anti-αvβ6 monoclonal antibodies or antibody drug conjugates described herein are 0.1 mg/kg to 50 mg/kg of individual body weight, more typically 1 mg/kg to 30 mg/kg, 1 mg/kg to 20 mg/kg, 1 mg/kg to 15 mg/kg, 1 mg/kg to 12 mg/kg, or 1 mg/kg to 10 mg/kg 1, or 2 mg/kg to 30 mg/kg, 2 mg/kg to 20 mg/kg, 2 mg/kg to 15 mg/kg, 2 mg/kg to 12 mg/kg, or 2 mg/kg to 10 mg/kg, or 3 mg/kg to 30 mg/kg, 3 mg/kg to 20 mg/kg, 3 mg/kg to 15 mg/kg, 3 mg/kg to 12 mg/kg, or 3 mg/kg to 10 mg/kg. In some embodiments, the individual's body weight is the individual's ideal body weight (IBW). In some embodiments, the individual weight is the individual's adjusted ideal body weight (AIBW). Exemplary dosages of monoclonal antibodies or their antibody-drug conjugates are 1 mg/kg to 7.5 mg/kg, or 2 mg/kg to 7.5 mg/kg, or 3 mg/kg to 7.5 mg/kg of individual body weight, or 0.1-20, or 0.5-5 mg/kg of body weight (e.g., 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg/kg), or 10-1500 or 200-1500 mg as a fixed dose. In some embodiments, the dosage is 0.8 mg/kg. In some embodiments, the dosage is 1.0 mg/kg. In some embodiments, the dosage is 1.2 mg/kg. In some embodiments, the dosage is 1.25 mg/kg. In some embodiments, the dose is 1.5 mg/kg. In some embodiments, the dose is 1.8 mg/kg. In some embodiments, the dose is 2.4 mg/kg. In some methods, a dose of at least 0.8 mg/kg, at least 1.0 mg/kg, at least 1.2 mg/kg, at least 1.25 mg/kg, at least 1.5 mg/kg, at least 1.8 mg/kg, or at least 2.4 mg/kg is administered to a patient once a week or more. In some methods, a dose of at least 0.8 mg/kg, at least 1.0 mg/kg, at least 1.2 mg/kg, at least 1.25 mg/kg, at least 1.5 mg/kg, at least 1.8 mg/kg, or at least 2.4 mg/kg is administered to a patient once a week. In some methods, the patient is administered a dose of at least 1.5 mg/kg or at least 1.8 mg/kg once every two weeks or more. In some methods, the patient is administered a dose of at least 1.2 mg/kg or at least 1.25 mg/kg twice every three weeks. In some methods, the patient is administered a dose of 1.25 mg/kg twice every three weeks. In some methods, the patient is administered a dose of 1.5 mg/kg twice every three weeks. In some methods, the patient is administered a dose of 1.8 mg/kg once every two weeks. In some methods, the patient is administered a dose of 1.5 mg/kg once every two weeks. In some methods, a dose of at least 1.5 mg/kg, at least 2 mg/kg, or at least 3 mg/kg is administered to the patient once every three weeks or more. The dose depends on, among other factors, the frequency of administration, the patient's condition, and response to prior treatment (if any), whether the treatment is preventive or therapeutic and whether the condition is acute or chronic.
投與可為非經腸、靜脈內、經口、皮下、動脈內、顱內、鞘內、腹膜內、局部、鼻內或肌肉內。投與亦可直接定位至腫瘤中。藉由靜脈內或皮下投與而投與至全身循環中為較佳的。靜脈內投與可例如藉由在諸如30-90 min之時段內輸注或藉由單次推注注射來進行。在一些實施例中，本發明之抗體或抗體藥物結合物藉由靜脈內輸注投與。Administration can be parenteral, intravenous, oral, subcutaneous, intraarterial, intracranial, intrathecal, intraperitoneal, topical, intranasal or intramuscular. Administration can also be directly localized into the tumor. Administration into the systemic circulation by intravenous or subcutaneous administration is preferred. Intravenous administration can be performed, for example, by infusion over a period of time such as 30-90 min or by a single bolus injection. In some embodiments, the antibodies or antibody drug conjugates of the present invention are administered by intravenous infusion.
除其他因素之外，投與頻率視循環中之抗體或結合物之半衰期、患者之病狀及投與途徑而定。隨患者病狀之變化或所治療之癌症的進展，本文所描述之抗αvβ6抗體或抗體藥物結合物的投與頻率可為每日一次、每週一次、每兩週一次、每三週兩次、每三週一次、每月一次、每季度一次或以不規律間隔。在一些實施例中，投與頻率為約每週一次。在一些實施例中，每週投與係在21天週期之約第1天、第8天及第15天。在一些實施例中，投與頻率為約每兩週一次。在一些實施例中，投與頻率為約每三週兩次。在一些實施例中，投與頻率係在21天週期之約第1天及第8天。在一些實施例中，投與頻率為約每三週一次。在一些實施例中，投與頻率為每週一次。在一些實施例中，每週投與係在21天週期之第1天、第8天及第15天。在一些實施例中，投與頻率為每兩週一次。在一些實施例中，投與頻率係在21天週期之第1天及第8天。在一些實施例中，投與頻率為每三週兩次。在一些實施例中，投與頻率為每三週一次。對於皮下投與，例示性給藥頻率為每日至每月，但是更頻繁或較不頻繁的給藥亦為可能的。在連續治療過程內，靜脈內投與之例示性頻率在一週兩次與每季一次之間，但更頻繁或較不頻繁的給藥亦為可能的。在連續治療過程內，靜脈內投與之其他例示性頻率為每週或每四週三週之間，但更頻繁或較不頻繁的給藥亦為可能的。在連續治療過程內，靜脈內投與之其他示例性頻率為每兩週一次或每三週一次，但更頻繁或較不頻繁的給藥亦為可能的。在一些實施例中，劑量係基於個體體重投與。在一些實施例中，個體體重為個體之理想體重(IBW)。在一些實施例中，個體體重為個體經調整之理想體重(AIBW)。在一些實施例中，劑量為0.7 mg/kg且約每1週投與一次。在一些實施例中，劑量為0.7 mg/kg且約每2週投與一次。在一些實施例中，劑量為0.7 mg/kg且約每3週投與兩次。在一些實施例中，劑量為0.7 mg/kg且約每3週投與一次。在一些實施例中，劑量為0.8 mg/kg且約每1週投與一次。在一些實施例中，劑量為0.8 mg/kg且約每2週投與一次。在一些實施例中，劑量為0.8 mg/kg且約每3週投與兩次。在一些實施例中，劑量為0.8 mg/kg且約每3週投與一次。在一些實施例中，劑量為0.9 mg/kg且約每1週投與一次。在一些實施例中，劑量為0.9 mg/kg且約每2週投與一次。在一些實施例中，劑量為0.9 mg/kg且約每3週投與兩次。在一些實施例中，劑量為0.9 mg/kg且約每3週投與一次。在一些實施例中，劑量為1.0 mg/kg且約每1週投與一次。在一些實施例中，劑量為1.0 mg/kg且約每2週投與一次。在一些實施例中，劑量為1.0 mg/kg且約每3週投與兩次。在一些實施例中，劑量為1.0 mg/kg且約每3週投與一次。在一些實施例中，劑量為1.1 mg/kg且約每1週投與一次。在一些實施例中，劑量為1.1 mg/kg且約每2週投與一次。在一些實施例中，劑量為1.1 mg/kg且約每3週投與兩次。在一些實施例中，劑量為1.1 mg/kg且約每3週投與一次。在一些實施例中，劑量為1.2 mg/kg且約每1週投與一次。在一些實施例中，劑量為1.2 mg/kg且約每2週投與一次。在一些實施例中，劑量為1.2 mg/kg且約每3週投與兩次。在一些實施例中，劑量為1.2 mg/kg且約每3週投與一次。在一些實施例中，劑量為1.25 mg/kg且約每1週投與一次。在一些實施例中，劑量為1.25 mg/kg且約每2週投與一次。在一些實施例中，劑量為1.25 mg/kg且約每3週投與兩次。在一些實施例中，劑量為1.25 mg/kg且約每3週投與一次。在一些實施例中，劑量為1.3 mg/kg且約每1週投與一次。在一些實施例中，劑量為1.3 mg/kg且約每2週投與一次。在一些實施例中，劑量為1.3 mg/kg且約每3週投與兩次。在一些實施例中，劑量為1.3 mg/kg且約每3週投與一次。在一些實施例中，劑量為1.4 mg/kg且約每1週投與一次。在一些實施例中，劑量為1.4 mg/kg且約每2週投與一次。在一些實施例中，劑量為1.4 mg/kg且約每3週投與兩次。在一些實施例中，劑量為1.4 mg/kg且約每3週投與一次。在一些實施例中，劑量為1.5 mg/kg且約每1週投與一次。在一些實施例中，劑量為1.5 mg/kg且約每2週投與一次。在一些實施例中，劑量為1.5 mg/kg且約每3週投與兩次。在一些實施例中，劑量為1.5 mg/kg且約每3週投與一次。在一些實施例中，劑量為1.6 mg/kg且約每1週投與一次。在一些實施例中，劑量為1.6 mg/kg且約每2週投與一次。在一些實施例中，劑量為1.6 mg/kg且約每3週投與兩次。在一些實施例中，劑量為1.6 mg/kg且約每3週投與一次。在一些實施例中，劑量為1.7 mg/kg且約每1週投與一次。在一些實施例中，劑量為1.7 mg/kg且約每2週投與一次。在一些實施例中，劑量為1.7 mg/kg且約每3週投與兩次。在一些實施例中，劑量為1.7 mg/kg且約每3週投與一次。在一些實施例中，劑量為1.8 mg/kg且約每1週投與一次。在一些實施例中，劑量為1.8 mg/kg且約每2週投與一次。在一些實施例中，劑量為1.8 mg/kg且約每3週投與兩次。在一些實施例中，劑量為1.8 mg/kg且約每3週投與一次。在一些實施例中，劑量為1.9 mg/kg且約每1週投與一次。在一些實施例中，劑量為1.9 mg/kg且約每2週投與一次。在一些實施例中，劑量為1.9 mg/kg且約每3週投與兩次。在一些實施例中，劑量為1.9 mg/kg且約每3週投與一次。在一些實施例中，劑量為2.0 mg/kg且約每1週投與一次。在一些實施例中，劑量為2.0 mg/kg且約每2週投與一次。在一些實施例中，劑量為2.0 mg/kg且約每3週投與兩次。在一些實施例中，劑量為2.0 mg/kg且約每3週投與一次。在一些實施例中，劑量為2.1 mg/kg且約每1週投與一次。在一些實施例中，劑量為2.1 mg/kg且約每2週投與一次。在一些實施例中，劑量為2.1 mg/kg且約每3週投與兩次。在一些實施例中，劑量為2.1 mg/kg且約每3週投與一次。在一些實施例中，劑量為2.2 mg/kg且約每1週投與一次。在一些實施例中，劑量為2.2 mg/kg且約每2週投與一次。在一些實施例中，劑量為2.2 mg/kg且約每3週投與兩次。在一些實施例中，劑量為2.2 mg/kg且約每3週投與一次。在一些實施例中，劑量為2.3 mg/kg且約每1週投與一次。在一些實施例中，劑量為2.3 mg/kg且約每2週投與一次。在一些實施例中，劑量為2.3 mg/kg且約每3週投與兩次。在一些實施例中，劑量為2.3 mg/kg且約每3週投與一次。在一些實施例中，劑量為2.4 mg/kg且約每1週投與一次。在一些實施例中，劑量為2.4 mg/kg且約每2週投與一次。在一些實施例中，劑量為2.4 mg/kg且約每3週投與兩次。在一些實施例中，劑量為2.4 mg/kg且約每3週投與一次。在一些實施例中，劑量為2.5 mg/kg且約每1週投與一次。在一些實施例中，劑量為2.5 mg/kg且約每2週投與一次。在一些實施例中，劑量為2.5 mg/kg且約每3週投與兩次。在一些實施例中，劑量為2.5 mg/kg且約每3週投與一次。The frequency of administration depends on, among other factors, the half-life of the antibody or conjugate in circulation, the condition of the patient, and the route of administration. As the condition of the patient changes or the cancer being treated progresses, the anti-αvβ6 antibody or antibody drug conjugate described herein may be administered daily, weekly, biweekly, twice every three weeks, once every three weeks, monthly, quarterly, or at irregular intervals. In some embodiments, the frequency of administration is about once a week. In some embodiments, weekly administration is on about day 1, day 8, and day 15 of a 21 day cycle. In some embodiments, the frequency of administration is about once every two weeks. In some embodiments, the frequency of administration is about twice every three weeks. In some embodiments, the frequency of administration is about day 1 and day 8 of a 21 day cycle. In some embodiments, the frequency of administration is about once every three weeks. In some embodiments, the frequency of administration is once a week. In some embodiments, weekly administration is on day 1, day 8, and day 15 of a 21 day cycle. In some embodiments, the frequency of administration is once every two weeks. In some embodiments, the frequency of administration is on day 1 and day 8 of a 21 day cycle. In some embodiments, the frequency of administration is twice every three weeks. In some embodiments, the frequency of administration is once every three weeks. For subcutaneous administration, exemplary dosing frequencies are daily to monthly, but more or less frequent dosing is also possible. During continuous treatment, exemplary frequencies of intravenous administration are between twice a week and once a quarter, but more or less frequent dosing is also possible. During continuous treatment, other exemplary frequencies of intravenous administration are weekly or between every four to three weeks, but more or less frequent dosing is also possible. During continuous treatment, other exemplary frequencies of intravenous administration are once every two weeks or once every three weeks, but more or less frequent dosing is also possible. In some embodiments, the dosage is administered based on the individual's weight. In some embodiments, the individual's weight is the individual's ideal body weight (IBW). In some embodiments, the individual's weight is the individual's adjusted ideal body weight (AIBW). In some embodiments, the dosage is 0.7 mg/kg and is administered approximately once every 1 week. In some embodiments, the dosage is 0.7 mg/kg and is administered approximately once every 2 weeks. In some embodiments, the dosage is 0.7 mg/kg and is administered twice approximately every 3 weeks. In some embodiments, the dosage is 0.7 mg/kg and is administered approximately once every 3 weeks. In some embodiments, the dosage is 0.8 mg/kg and is administered approximately once every 1 week. In some embodiments, the dosage is 0.8 mg/kg and is administered approximately once every 2 weeks. In some embodiments, the dose is 0.8 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 0.8 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 0.9 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 0.9 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 0.9 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 0.9 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.0 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.0 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.0 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 1.0 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.1 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.1 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.1 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 1.1 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.2 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.2 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.2 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 1.2 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.25 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.25 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.25 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 1.25 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.3 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.3 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.3 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 1.3 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.4 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.4 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.4 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 1.4 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.5 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.5 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.5 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 1.5 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.6 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.6 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.6 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 1.6 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.7 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.7 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.7 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 1.7 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.8 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.8 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.8 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 1.8 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 1.9 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 1.9 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 1.9 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 1.9 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 2.0 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 2.0 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 2.0 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 2.0 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 2.1 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 2.1 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 2.1 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 2.1 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 2.2 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 2.2 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 2.2 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 2.2 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 2.3 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 2.3 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 2.3 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 2.3 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 2.4 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 2.4 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 2.4 mg/kg and is administered twice about every 3 weeks. In some embodiments, the dose is 2.4 mg/kg and is administered once about every 3 weeks. In some embodiments, the dose is 2.5 mg/kg and is administered once about every 1 week. In some embodiments, the dose is 2.5 mg/kg and is administered once about every 2 weeks. In some embodiments, the dose is 2.5 mg/kg and is administered approximately twice every 3 weeks. In some embodiments, the dose is 2.5 mg/kg and is administered approximately once every 3 weeks.
投與劑量的次數視癌症性質(例如是否呈現急性或慢性症狀)及病症對治療之反應而定。對於急性病症或慢性病症之急性惡化，1個與10個劑量之間常常為足夠的。有時候，視情況呈分開形式的單一推注劑量對於急性病症或慢性病症之急性惡化而言為足夠的。針對急性病症或急性惡化之復發，治療可重複。對於慢性病症，抗體可以常規間隔投與，例如每週一次、每兩週一次、每月一次、每季度一次、每六個月一次，持續至少1、5或10年，或患者一生。The number of doses administered depends on the nature of the cancer (e.g., whether it presents acutely or chronically) and the response of the condition to treatment. For acute conditions or acute exacerbations of chronic conditions, between 1 and 10 doses are often sufficient. Sometimes, a single bolus dose in divided form, as appropriate, is sufficient for acute conditions or acute exacerbations of chronic conditions. Treatment may be repeated for recurrences of acute conditions or acute exacerbations. For chronic conditions, the antibody may be administered at regular intervals, such as once a week, once every two weeks, once a month, once a quarter, once every six months, for at least 1, 5, or 10 years, or for the patient's lifetime.
用於非經腸投與之醫藥組合物較佳係無菌的且實質上等張且在GMP條件下製造。醫藥組合物可呈單位劑型(亦即，用於單次投與之劑量)提供。醫藥組合物可使用一或多種生理學上可接受之載劑、稀釋劑、賦形劑或助劑來調配。調配視所選投與途徑而定。對於注射，抗體可在水溶液中調配，較佳在生理相容的緩衝液中，諸如漢克氏溶液(Hank's solution)、林格氏溶液(Ringer's solution)，或生理鹽水或乙酸鹽緩衝液(以減少注射部位處之不適)。溶液可含有調配劑，諸如懸浮劑、穩定劑及/或分散劑。替代地，抗體可呈凍乾形式，在使用之前用適合媒劑，例如無菌無熱原質水復原。液體調配物中之抗體濃度可為例如1-100 mg/ml，諸如10 mg/ml。Pharmaceutical compositions for parenteral administration are preferably sterile and substantially isotonic and manufactured under GMP conditions. Pharmaceutical compositions may be provided in unit dosage form (i.e., a dose for a single administration). Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers, diluents, excipients, or adjuvants. The formulation depends on the selected route of administration. For injection, the antibody may be formulated in an aqueous solution, preferably in a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or saline or acetate buffer (to reduce discomfort at the injection site). The solution may contain a formulating agent, such as a suspending agent, a stabilizing agent and/or a dispersing agent. Alternatively, the antibody may be in lyophilized form and reconstituted with a suitable medium, such as sterile pyrogen-free water, before use. The antibody concentration in the liquid formulation may be, for example, 1-100 mg/ml, such as 10 mg/ml.
用本文所描述之抗αvβ6抗體或抗體藥物結合物的治療可與一或多種額外治療組合，諸如化學療法、放射、幹細胞治療、手術、有效針對所治療病症之其他治療。可與如本文所描述之針對αvβ6之抗體及抗體藥物結合物一起投與的有用類別之其他藥劑包括例如針對癌細胞上表現之其他受體的抗體、抗微管蛋白劑(例如奧瑞他汀)、DNA小溝結合劑、DNA複製抑制劑、烷基化劑(例如鉑錯合物，諸如順鉑、單(鉑)、雙(鉑)及三核鉑錯合物及卡鉑)、蒽環黴素、抗生素、抗葉酸劑、抗代謝物、化學治療增感劑、倍癌黴素、依託泊苷、氟化嘧啶、離子載體、萊希普辛、亞硝基脲、順氯氨鉑(platinol)、預成型化合物、嘌呤抗代謝物、嘌呤黴素、放射增感劑、類固醇、紫杉烷、拓樸異構酶抑制劑、長春花生物鹼及其類似物。在一些實施例中，一或多種額外治療為投與檢查點抑制劑。額外治療劑為PD-1抑制劑或PD-L1抑制劑。在一些實施例中，PD-1抑制劑為抗PD-1抗體。在一些實施例中，抗PD-1抗體為AMP-224、CT-011、測米匹單抗、卡瑞利珠單抗(camrelizumab)、信迪利單抗(sintilimab)、替雷利珠單抗(tislelizumab)、TSR-042、PDR001、特瑞普利單抗(toripalimab)、BGB-A317、納武利尤單抗(nivolumab) (亦稱為ONO-4538、BMS-936558或MDX1106)、帕博利珠單抗(亦稱為MK-3475、SCH 900475或藍布洛利珠單抗(lambrolizumab))、薩善利單抗(sasanlimab) (亦稱為PF-06801591)、多塔利單抗(dostarlimab)或任何此等抗體之生物類似物。在一些實施例中，PD-L1抑制劑為抗PD-L1抗體。在一些實施例中，抗PD-L1抗體為MEDI4736 (亦稱為德瓦魯單抗(durvalumab)或IMFINZI®)、BMS-936559 (亦稱為MDX-1105-01)、阿特利珠單抗(atezolizumab) (亦稱為MPDL3280A及Tecentriq®)、阿維魯單抗(avelumab) (亦稱為BAVENCIO®)或任何此等抗體之生物類似物。在一個實施例中，抗PD-1抗體為納武利尤單抗。納武利尤單抗為人類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抗體為帕博利珠單抗。帕博利珠單抗為人源化單株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。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，抗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Fcγ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抗體為測米匹單抗。在另一實施例中，抗PD-1抗體為卡瑞利珠單抗。在另一實施例中，抗PD-1抗體為信迪利單抗。在一些實施例中，抗PD-1抗體為替雷利珠單抗。在某些實施例中，抗PD-1抗體為TSR-042。在又另一實施例中，抗PD-1抗體為PDR001。在又另一實施例中，抗PD-1抗體為特瑞普利單抗。在又另一實施例中，抗PD-1抗體為薩善利單抗。在又另一實施例中，抗PD-1抗體為多塔利單抗。在一些實施例中，抗PD-L1抗體為MEDI4736 (亦稱為德瓦魯單抗或IMFINZI®)、BMS-936559 (亦稱為MDX-1105-01)、阿特利珠單抗(亦稱為MPDL3280A及Tecentriq®)或阿維魯單抗(亦稱為BAVENCIO®)。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。在又另一實施例中，PD-L1抑制劑為阿特利珠單抗。在另一實施例中，PD-L1抑制劑為阿維魯單抗。Treatment with the anti-αvβ6 antibodies or antibody-drug conjugates described herein can be combined with one or more additional therapies, such as chemotherapy, radiation, stem cell therapy, surgery, other treatments effective for the condition being treated. Useful classes of other agents that can be administered with the antibodies and antibody-drug conjugates directed against αvβ6 as described herein include, for example, antibodies directed against other receptors expressed on cancer cells, anti-tubulin agents (e.g., auristatins), DNA minor groove binding agents, DNA replication inhibitors, alkylating agents (e.g., platinum complexes, such as cis-platinum, mono(platinum), di(platinum) and trinuclear platinum complexes and carboplatins). Platinum), anthracyclines, antibiotics, antifolates, antimetabolites, chemotherapeutic sensitizers, duocarcin, etoposide, fluorinated pyrimidines, ion carriers, lecithin, nitrosoureas, platinol, preformed compounds, purine antimetabolites, puromycins, radiosensitizers, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids, and the like. In some embodiments, one or more additional therapies are administered a checkpoint inhibitor. The additional therapeutic agent is a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is AMP-224, CT-011, sepilumab, camrelizumab, sintilimab, tislelizumab, TSR-042, PDR001, toripalimab, BGB-A317, nivolumab (also known as ONO-4538, BMS-936558, or MDX1106), pembrolizumab (also known as MK-3475, SCH 900475, or lambrolizumab), sasanlimab (also known as PF-06801591), dostarlimab, or a biosimilar of any of these antibodies. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is MEDI4736 (also known as durvalumab or IMFINZI®), BMS-936559 (also known as MDX-1105-01), atezolizumab (also known as MPDL3280A andTecentriq® ), avelumab (also known as BAVENCIO®), or a biosimilar of any of these antibodies. 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. In yet another embodiment, the anti-PD-1 antibody is the fusion protein AMP-224. In another embodiment, the anti-PD-1 antibody is BGB-A317. BGB-A317 is a monoclonal antibody in which the ability to bind to Fcγ receptor I is specifically engineered, and it has the characteristics of uniquely binding to PD-1 with high affinity and good target specificity. In one embodiment, the PD-1 antibody is semapilizumab. In another embodiment, the anti-PD-1 antibody is carrelizumab. In another embodiment, the anti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1 antibody is tislelizumab. In certain embodiments, the anti-PD-1 antibody is TSR-042. In yet another embodiment, the anti-PD-1 antibody is PDR001. In yet another embodiment, the anti-PD-1 antibody is toripalimab. In yet another embodiment, the anti-PD-1 antibody is saxanthlimab. In yet another embodiment, the anti-PD-1 antibody is dotalimumab. In some embodiments, the anti-PD-L1 antibody is MEDI4736 (also known as durvalumab or IMFINZI®), BMS-936559 (also known as MDX-1105-01), atelizumab (also known as MPDL3280A andTecentriq® ) or avelumab (also known as BAVENCIO®). In one embodiment, the anti-PD-L1 antibody is MEDI4736 (durvalumab). In another embodiment, the anti-PD-L1 antibody is BMS-936559. In yet another embodiment, the PD-L1 inhibitor is atelizumab. In another embodiment, the PD-L1 inhibitor is avelumab.
在一些實施例中，一或多種額外治療與本文所描述之抗αvβ6抗體或抗體藥物結合物同時投與。在一些實施例中，一或多種額外治療及本文所描述之抗αvβ6抗體或抗體藥物結合物依序投與。在一些實施例中，同時意謂本文所描述之抗αvβ6抗體或抗體藥物結合物與一或多種額外治療相隔小於一小時，諸如相隔小於約30分鐘、相隔小於約15分鐘、相隔小於約10分鐘或相隔小於約5分鐘向個體投與。在一些實施例中，依序投與意謂本文所描述之抗αvβ6抗體或抗體藥物結合物及一或多種額外治療相隔至少1小時、相隔至少2小時、相隔至少3小時、相隔至少4小時、相隔至少5小時、相隔至少6小時、相隔至少7小時、相隔至少8小時、相隔至少9小時、相隔至少10小時、相隔至少11小時、相隔至少12小時、相隔至少13小時、相隔至少14小時、相隔至少15小時、相隔至少16小時、相隔至少17小時、相隔至少18小時、相隔至少19小時、相隔至少20小時、相隔至少21小時、相隔至少22小時、相隔至少23小時、相隔至少24小時、相隔至少2天、相隔至少3天、相隔至少4天、相隔至少5天、相隔至少5天、相隔至少7天、相隔至少2週、相隔至少3週、相隔至少4週、相隔至少6週、相隔至少2個月、相隔至少3個月、相隔至少4個月、相隔至少5個月或相隔至少6個月投與。In some embodiments, one or more additional therapies are administered concurrently with an anti-αvβ6 antibody or antibody drug conjugate described herein. In some embodiments, one or more additional therapies and an anti-αvβ6 antibody or antibody drug conjugate described herein are administered sequentially. In some embodiments, concurrently means that an anti-αvβ6 antibody or antibody drug conjugate described herein and the one or more additional therapies are administered to a subject less than an hour apart, such as less than about 30 minutes apart, less than about 15 minutes apart, less than about 10 minutes apart, or less than about 5 minutes apart. In some embodiments, sequential administration means that the anti-αvβ6 antibody or antibody drug conjugate described herein and the one or more additional therapies are administered at least 1 hour apart, at least 2 hours apart, at least 3 hours apart, at least 4 hours apart, at least 5 hours apart, at least 6 hours apart, at least 7 hours apart, at least 8 hours apart, at least 9 hours apart, at least 10 hours apart, at least 11 hours apart, at least 12 hours apart, at least 13 hours apart, at least 14 hours apart, at least 15 hours apart, at least 16 hours apart, at least 17 hours apart, at least 18 hours apart, at least 19 hours apart, at least 20 hours apart, at least 21 hours apart, at least 22 hours apart, at least 23 hours apart, at least 24 hours apart, at least 25 hours apart, at least 26 hours apart, at least 27 hours apart, at least 28 hours apart, at least 29 hours apart, at least 30 hours apart, at least 31 hours apart, at least 32 hours apart, at least 33 hours apart, at least 34 hours apart, at least 35 hours apart, at least 36 hours apart, at least 37 hours apart, at least 38 hours apart, at least 39 hours apart, at least 40 hours apart, at least 41 hours apart, at least 42 hours apart, at least 43 hours apart, at least 44 hours apart, at least 45 hours apart, at least 46 hours apart, at least 47 hours apart, at least 48 hours apart, at least 49 hours apart, At least 17 hours apart, at least 18 hours apart, at least 19 hours apart, at least 20 hours apart, at least 21 hours apart, at least 22 hours apart, at least 23 hours apart, at least 24 hours apart, at least 2 days apart, at least 3 days apart, at least 4 days apart, at least 5 days apart, at least 5 days apart, at least 7 days apart, at least 2 weeks apart, at least 3 weeks apart, at least 4 weeks apart, at least 6 weeks apart, at least 2 months apart, at least 3 months apart, at least 4 months apart, at least 5 months apart, or at least 6 months apart.
在一些實施例中，一或多種額外治療為投與化學治療劑。在一些實施例中，一或多種額外治療為投與基於鉑之藥劑。在一些實施例中，基於鉑之藥劑為卡鉑或順鉑。在一些實施例中，基於鉑之藥劑為卡鉑。在一些實施例中，基於鉑之藥劑為順鉑。In some embodiments, one or more additional treatments are administration of a chemotherapeutic agent. In some embodiments, one or more additional treatments are administration of a platinum-based agent. In some embodiments, the platinum-based agent is carboplatinum or cisplatinum. In some embodiments, the platinum-based agent is carboplatinum. In some embodiments, the platinum-based agent is cisplatin.
在一些實施例中，一或多種額外治療為投與基於鉑之藥劑及檢查點抑制劑。在一些實施例中，基於鉑之藥劑為卡鉑或順鉑。在一些實施例中，基於鉑之藥劑為卡鉑。在一些實施例中，基於鉑之藥劑為順鉑。在一些實施例中，檢查點抑制劑為帕博利珠單抗或其生物類似物。在一些實施例中，檢查點抑制劑為帕博利珠單抗。In some embodiments, one or more additional treatments are administration of a platinum-based agent and a checkpoint inhibitor. In some embodiments, the platinum-based agent is carboplatin or cis-platinum. In some embodiments, the platinum-based agent is carboplatin. In some embodiments, the platinum-based agent is cis-platinum. In some embodiments, the checkpoint inhibitor is pembrolizumab or a biosimilar thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab.
在一些實施例中，一或多種額外治療為投與帕博利珠單抗或其生物類似物。在一些實施例中，帕博利珠單抗或其生物類似物以約200 mg之劑量投與。在一些實施例中，帕博利珠單抗或其生物類似物以200 mg之劑量投與。在一些實施例中，帕博利珠單抗或其生物類似物以約400 mg之劑量投與。在一些實施例中，帕博利珠單抗或其生物類似物以400 mg之劑量投與。在一些實施例中，帕博利珠單抗或其生物類似物約每3週投與一次。在一些實施例中，帕博利珠單抗或其生物類似物每3週投與一次。在一些實施例中，帕博利珠單抗或其生物類似物約每6週投與一次。在一些實施例中，帕博利珠單抗或其生物類似物每6週投與一次。在一些實施例中，帕博利珠單抗或其生物類似物以約200 mg之劑量約每3週投與一次。在一些實施例中，帕博利珠單抗或其生物類似物以200 mg之劑量每3週投與一次。在一些實施例中，帕博利珠單抗或其生物類似物以約400 mg之劑量約每6週投與一次。在一些實施例中，帕博利珠單抗或其生物類似物以400 mg之劑量每6週投與一次。在一些實施例中，帕博利珠單抗或其生物類似物之投與途徑為靜脈內。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少1天、至少2天、至少3天、至少4天、至少5天、至少6天、至少7天、至少2週、至少3週、至少4週、至少2個月、至少3個月、至少4個月、至少5個月或至少6個月，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少1天，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少2天，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少3天，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少4天，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少5天，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少6天，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少7天，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少1週，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少2週，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少3週，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少4週，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少2個月，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少3個月，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少4個月，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少5個月，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。在一些實施例中，在投與第一劑量之帕博利珠單抗或其生物類似物之前至少6個月，向個體投與第一劑量之抗αvβ6抗體或抗體藥物結合物。In some embodiments, one or more additional treatments are administration of pembrolizumab or a biosimilar thereof. In some embodiments, pembrolizumab or a biosimilar thereof is administered in an amount of about 200 mg. In some embodiments, pembrolizumab or a biosimilar thereof is administered in an amount of 200 mg. In some embodiments, pembrolizumab or a biosimilar thereof is administered in an amount of about 400 mg. In some embodiments, pembrolizumab or a biosimilar thereof is administered in an amount of 400 mg. In some embodiments, pembrolizumab or a biosimilar thereof is administered approximately once every 3 weeks. In some embodiments, pembrolizumab or a biosimilar thereof is administered once every 3 weeks. In some embodiments, pembrolizumab or a biosimilar thereof is administered approximately once every 6 weeks. In some embodiments, pembrolizumab or a biosimilar thereof is administered once every 6 weeks. In some embodiments, pembrolizumab or a biosimilar thereof is administered once every 3 weeks at a dose of about 200 mg. In some embodiments, pembrolizumab or a biosimilar thereof is administered once every 3 weeks at a dose of 200 mg. In some embodiments, pembrolizumab or a biosimilar thereof is administered once every 6 weeks at a dose of about 400 mg. In some embodiments, pembrolizumab or a biosimilar thereof is administered once every 6 weeks at a dose of 400 mg. In some embodiments, the route of administration of pembrolizumab or a biosimilar thereof is intravenous. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject prior to the administration of the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months prior to the administration of the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 1 day prior to the administration of the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 2 days prior to the administration of the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 3 days prior to the administration of the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 4 days prior to the administration of the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 5 days prior to the administration of the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 6 days prior to the administration of the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 7 days prior to the administration of the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 1 week prior to the administration of the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 2 weeks prior to the administration of the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 3 weeks prior to the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 4 weeks prior to the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 2 months prior to the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 3 months prior to the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 4 months prior to the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 5 months prior to the first dose of pembrolizumab or a biosimilar thereof. In some embodiments, the first dose of the anti-αvβ6 antibody or antibody drug conjugate is administered to the subject at least 6 months prior to the first dose of pembrolizumab or a biosimilar thereof.
視情況與上文所描述之其他藥劑或方案中之任一者組合，用抗αvβ6抗體或抗體藥物結合物之治療可增加患者的中值無進展存活期或總存活期時間，該等患者患有實體腫瘤(例如非小細胞肺癌(NSCLC) (鱗狀及腺)、頭頸癌(包括頭頸部鱗狀癌瘤)、食道癌(包括食道鱗狀細胞癌)、乳癌(包括乳房侵襲性癌)、HER2-乳癌、卵巢癌(包括高級漿液性卵巢癌(HGSOC)、膀胱癌(包括尿道上皮癌)、皮膚癌(包括鱗狀細胞癌或SCC)、腎癌(包括腎透明細胞、腎乳頭狀細胞及腎難染細胞)、子宮頸癌、胃癌、前列腺癌(包括前列腺腺癌)、子宮內膜癌(包括子宮癌肉瘤及子宮體子宮內膜)、直腸腺癌、甲狀腺癌、結腸腺癌、胃腺癌及胰臟癌(包括胰臟腺癌))，尤其在具有復發性或難治性時，與相同治療(例如化學療法)但無單獨或呈結合物形式之抗αvβ6抗體相比較，增加至少30%或40%，但較佳50%、60%至70%或甚至100%或更長。另外或替代地，與相同治療(例如化學療法)但無單獨或呈結合物形式之抗αvβ6抗體相比較，包括單獨或呈結合物形式之抗αvβ6抗體的治療(例如標準化學療法)可增加患有腫瘤之患者的完全反應率、部分反應率或客觀反應率(完全+部分)至少30%或40%，但較佳50%、60%至70%或甚至100%。Treatment with an anti-αvβ6 antibody or antibody-drug conjugate, optionally in combination with any of the other agents or regimens described above, may increase the median progression-free survival or overall survival time in patients with solid tumors such as non-small cell lung cancer (NSCLC) (squamous and glandular), head and neck cancer (including head and neck squamous carcinoma), esophageal cancer (including esophageal squamous cell carcinoma), breast cancer (including invasive breast cancer), HER2- breast cancer, ovarian cancer (including high-grade serous ovarian cancer (HGSOC), bladder cancer (including urothelial carcinoma), skin cancer (including squamous cell carcinoma or SCC), kidney cancer (including kidney clear cell, kidney papillary cell and kidney refractory cell), cervical cancer, gastric cancer, prostate cancer (including prostate adenocarcinoma), endometrial cancer (including uterine carcinosarcoma and corpus endometrium), rectal adenocarcinoma, thyroid cancer, colon adenocarcinoma, gastric adenocarcinoma and pancreatic cancer (including pancreatic adenocarcinoma)), especially in recurrent In some embodiments, the invention relates to a method for treating a tumor that is refractory to or refractory to an anti-αvβ6 antibody, wherein the increase is at least 30% or 40%, but preferably 50%, 60% to 70%, or even 100% or longer compared to the same treatment (e.g., chemotherapy) but without the anti-αvβ6 antibody, alone or in the form of a conjugate. Additionally or alternatively, a treatment (e.g., standard chemotherapy) comprising an anti-αvβ6 antibody, alone or in the form of a conjugate, may increase the complete response rate, partial response rate, or objective response rate (complete + partial) in patients with the tumor by at least 30% or 40%, but preferably 50%, 60% to 70%, or even 100%, compared to the same treatment (e.g., chemotherapy) but without the anti-αvβ6 antibody, alone or in the form of a conjugate.
在一個態樣中，一種用本文所描述之抗αvβ6抗體或抗體藥物結合物治療實體腫瘤的方法使得在投與本文所描述之抗體或抗體藥物結合物之後，個體中之一或多種治療效果相對於基線得到改善。在一些實施例中，一或多種治療效果為來源於癌症之腫瘤的尺寸、客觀反應率、反應持續時間、達至反應之時間、無進展存活期、總存活期或其任何組合。在一個實施例中，一或多種治療效果為來源於癌症之腫瘤的尺寸。在一個實施例中，一或多種治療效果為腫瘤尺寸減小。在一個實施例中，一或多種治療效果為穩定疾病。在一個實施例中，一或多種治療效果為部分反應。在一個實施例中，一或多種治療效果為完全反應。在一個實施例中，一或多種治療效果為客觀反應率。在一個實施例中，一或多種治療效果為反應持續時間。在一個實施例中，一或多種治療效果為達至反應之時間。在一個實施例中，一或多種治療效果為無進展存活期。在一個實施例中，一或多種治療效果為總存活期。在一個實施例中，一或多種治療效果為癌症消退。In one aspect, a method of treating a solid tumor with an anti-αvβ6 antibody or antibody-drug conjugate described herein results in an improvement in one or more therapeutic effects in the subject relative to baseline following administration of the antibody or antibody-drug conjugate described herein. In some embodiments, the one or more therapeutic effects are size of a tumor derived from a cancer, objective response rate, duration of response, time to response, progression-free survival, overall survival, or any combination thereof. In one embodiment, the one or more therapeutic effects are size of a tumor derived from a cancer. In one embodiment, the one or more therapeutic effects are a decrease in tumor size. In one embodiment, the one or more therapeutic effects are stable disease. In one embodiment, one or more therapeutic effects are partial response. In one embodiment, one or more therapeutic effects are complete response. In one embodiment, one or more therapeutic effects are objective response rate. In one embodiment, one or more therapeutic effects are duration of response. In one embodiment, one or more therapeutic effects are time to achieve response. In one embodiment, one or more therapeutic effects are progression-free survival. In one embodiment, one or more therapeutic effects are overall survival. In one embodiment, one or more therapeutic effects are cancer regression.
在本文所提供之方法或用途或使用產物的一個實施例中，對用本文所描述之抗αvβ6抗體或抗體藥物結合物治療的反應可包括以下準則(RECIST準則1.1)：
在本文所提供之方法或用途或使用產物的一個實施例中，用本文所描述之抗αvβ6抗體或抗體藥物結合物治療的有效性係藉由量測客觀反應率來評估。在一些實施例中，客觀反應率為腫瘤尺寸降低預定義量且持續最小時段之患者的比例。在一些實施例中，客觀反應率係基於RECIST v1.1。在一個實施例中，客觀反應率為至少約20%、至少約25%、至少約30%、至少約35%、至少約40%、至少約45%、至少約50%、至少約60%、至少約70%或至少約80%。在一個實施例中，客觀反應率為至少約20%-80%。在一個實施例中，客觀反應率為至少約30%-80%。在一個實施例中，客觀反應率為至少約40%-80%。在一個實施例中，客觀反應率為至少約50%-80%。在一個實施例中，客觀反應率為至少約60%-80%。在一個實施例中，客觀反應率為至少約70%-80%。在一個實施例中，客觀反應率為至少約80%。在一個實施例中，客觀反應率為至少約85%。在一個實施例中，客觀反應率為至少約90%。在一個實施例中，客觀反應率為至少約95%。在一個實施例中，客觀反應率為至少約98%。在一個實施例中，客觀反應率為至少約99%。在一個實施例中，客觀反應率為至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少60%、至少70%或至少80%。在一個實施例中，客觀反應率為至少20%-80%。在一個實施例中，客觀反應率為至少30%-80%。在一個實施例中，客觀反應率為至少40%-80%。在一個實施例中，客觀反應率為至少50%-80%。在一個實施例中，客觀反應率為至少60%-80%。在一個實施例中，客觀反應率為至少70%-80%。在一個實施例中，客觀反應率為至少80%。在一個實施例中，客觀反應率為至少85%。在一個實施例中，客觀反應率為至少90%。在一個實施例中，客觀反應率為至少95%。在一個實施例中，客觀反應率為至少98%。在一個實施例中，客觀反應率為至少99%。在一個實施例中，客觀反應率為100%。In one embodiment of the methods or uses or products of use provided herein, the effectiveness of treatment with an anti-αvβ6 antibody or antibody drug conjugate described herein is assessed by measuring the objective response rate. In some embodiments, the objective response rate is the proportion of patients whose tumor size is reduced by a predetermined amount and for a minimum period of time. In some embodiments, the objective response rate is based on RECIST v1.1. In one embodiment, the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%. In one embodiment, the objective response rate is at least about 20%-80%. In one embodiment, the objective response rate is at least about 30%-80%. In one embodiment, the objective response rate is at least about 40%-80%. In one embodiment, the objective response rate is at least about 50%-80%. In one embodiment, the objective response rate is at least about 60%-80%. In one embodiment, the objective response rate is at least about 70%-80%. In one embodiment, the objective response rate is at least about 80%. In one embodiment, the objective response rate is at least about 85%. In one embodiment, the objective response rate is at least about 90%. In one embodiment, the objective response rate is at least about 95%. In one embodiment, the objective response rate is at least about 98%. In one embodiment, the objective response rate is at least about 99%. In one embodiment, the objective response rate is at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70% or at least 80%. In one embodiment, the objective response rate is at least 20%-80%. In one embodiment, the objective response rate is at least 30%-80%. In one embodiment, the objective response rate is at least 40%-80%. In one embodiment, the objective response rate is at least 50%-80%. In one embodiment, the objective response rate is at least 60%-80%. In one embodiment, the objective response rate is at least 70%-80%. In one embodiment, the objective response rate is at least 80%. In one embodiment, the objective response rate is at least 85%. In one embodiment, the objective response rate is at least 90%. In one embodiment, the objective response rate is at least 95%. In one embodiment, the objective response rate is at least 98%. In one embodiment, the objective response rate is at least 99%. In one embodiment, the objective response rate is 100%.
在本文所提供之方法或用途或使用產物的一個實施例中，對用本文所描述之抗αvβ6抗體或抗體藥物結合物治療之反應係藉由量測來源於癌症之腫瘤的尺寸來評估。在一個實施例中，來源於癌症之腫瘤的尺寸相對於投與本文所描述之抗體或抗體藥物結合物之前的來源於癌症之腫瘤的尺寸減小至少約10%、至少約15%、至少約20%、至少約25%、至少約30%、至少約35%、至少約40%、至少約45%、至少約50%、至少約60%、至少約70%或至少約80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少約10%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少約20%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少約30%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少約40%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少約50%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少約60%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少約70%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少約80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少約85%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少約90%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少約95%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少約98%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少約99%。在一個實施例中，來源於癌症之腫瘤的尺寸相對於投與本文所描述之抗體或抗體藥物結合物之前的來源於癌症之腫瘤的尺寸減小至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少60%、至少70%或至少80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少10%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少20%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少30%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少40%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少50%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少60%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少70%-80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少80%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少85%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少90%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少95%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少98%。在一個實施例中，來源於癌症之腫瘤的尺寸減小至少99%。在一個實施例中，來源於癌症之腫瘤的尺寸減小100%。在一個實施例中，來源於癌症之腫瘤的尺寸係藉由磁共振成像(MRI)來量測。在一個實施例中，來源於癌症之腫瘤的尺寸係藉由電腦斷層攝影術(CT)來量測。在一個實施例中，來源於癌症之腫瘤的尺寸係藉由正電子發射斷層攝影術(PET)來量測。在一個實施例中，來源於癌症之腫瘤的尺寸係藉由超音波來量測。In one embodiment of the methods or uses or products of use provided herein, the response to treatment with an anti-αvβ6 antibody or antibody-drug conjugate described herein is assessed by measuring the size of a tumor originating from a cancer. In one embodiment, the size of a tumor originating from a cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor originating from the cancer prior to administration of the antibody or antibody-drug conjugate described herein. In one embodiment, the size of a tumor originating from a cancer is reduced by at least about 10%-80%. In one embodiment, the size of a tumor originating from a cancer is reduced by at least about 20%-80%. In one embodiment, the size of a tumor from cancer is reduced by at least about 30%-80%. In one embodiment, the size of a tumor from cancer is reduced by at least about 40%-80%. In one embodiment, the size of a tumor from cancer is reduced by at least about 50%-80%. In one embodiment, the size of a tumor from cancer is reduced by at least about 60%-80%. In one embodiment, the size of a tumor from cancer is reduced by at least about 70%-80%. In one embodiment, the size of a tumor from cancer is reduced by at least about 80%. In one embodiment, the size of a tumor from cancer is reduced by at least about 85%. In one embodiment, the size of a tumor from cancer is reduced by at least about 90%. In one embodiment, the size of a tumor originating from cancer is reduced by at least about 95%. In one embodiment, the size of a tumor originating from cancer is reduced by at least about 98%. In one embodiment, the size of a tumor originating from cancer is reduced by at least about 99%. In one embodiment, the size of a tumor originating from cancer is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70% or at least 80% relative to the size of the tumor originating from cancer before administration of the antibody or antibody-drug conjugate described herein. In one embodiment, the size of a tumor originating from cancer is reduced by at least 10%-80%. In one embodiment, the size of a tumor originating from cancer is reduced by at least 20%-80%. In one embodiment, the size of a tumor from cancer is reduced by at least 30%-80%. In one embodiment, the size of a tumor from cancer is reduced by at least 40%-80%. In one embodiment, the size of a tumor from cancer is reduced by at least 50%-80%. In one embodiment, the size of a tumor from cancer is reduced by at least 60%-80%. In one embodiment, the size of a tumor from cancer is reduced by at least 70%-80%. In one embodiment, the size of a tumor from cancer is reduced by at least 80%. In one embodiment, the size of a tumor from cancer is reduced by at least 85%. In one embodiment, the size of a tumor from cancer is reduced by at least 90%. In one embodiment, the size of a tumor from cancer is reduced by at least 95%. In one embodiment, the size of a tumor from cancer is reduced by at least 98%. In one embodiment, the size of a tumor from cancer is reduced by at least 99%. In one embodiment, the size of a tumor from cancer is reduced by 100%. In one embodiment, the size of a tumor from cancer is measured by magnetic resonance imaging (MRI). In one embodiment, the size of a tumor from cancer is measured by computed tomography (CT). In one embodiment, the size of a tumor from cancer is measured by positron emission tomography (PET). In one embodiment, the size of a tumor arising from cancer is measured by ultrasound.
在本文所提供之方法或用途或使用產物的一個實施例中，對用本文所描述之抗αvβ6抗體或抗體藥物結合物治療之反應促進來源於癌症之腫瘤的消退。在一個實施例中，來源於癌症之腫瘤相對於投與本文所描述之抗體或抗體藥物結合物之前的來源於癌症之腫瘤的尺寸消退至少約10%、至少約15%、至少約20%、至少約25%、至少約30%、至少約35%、至少約40%、至少約45%、至少約50%、至少約60%、至少約70%或至少約80%。在一個實施例中，來源於癌症之腫瘤消退至少約10%至約80%。在一個實施例中，來源於癌症之腫瘤消退至少約20%至約80%。在一個實施例中，來源於癌症之腫瘤消退至少約30%至約80%。在一個實施例中，來源於癌症之腫瘤消退至少約40%至約80%。在一個實施例中，來源於癌症之腫瘤消退至少約50%至約80%。在一個實施例中，來源於癌症之腫瘤消退至少約60%至約80%。在一個實施例中，來源於癌症之腫瘤消退至少約70%至約80%。在一個實施例中，來源於癌症之腫瘤消退至少約80%。在一個實施例中，來源於癌症之腫瘤消退至少約85%。在一個實施例中，來源於癌症之腫瘤消退至少約90%。在一個實施例中，來源於癌症之腫瘤消退至少約95%。在一個實施例中，來源於癌症之腫瘤消退至少約98%。在一個實施例中，來源於癌症之腫瘤消退至少約99%。在一個實施例中，來源於癌症之腫瘤相對於在投與本文所描述之抗體或抗體藥物結合物之前的來源於癌症之腫瘤的尺寸消退至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少60%、至少70%或至少80%。在一個實施例中，來源於癌症之腫瘤消退至少10%至80%。在一個實施例中，來源於癌症之腫瘤消退至少20%至80%。在一個實施例中，來源於癌症之腫瘤消退至少30%至80%。在一個實施例中，來源於癌症之腫瘤消退至少40%至80%。在一個實施例中，來源於癌症之腫瘤消退至少50%至80%。在一個實施例中，來源於癌症之腫瘤消退至少60%至80%。在一個實施例中，來源於癌症之腫瘤消退至少70%至80%。在一個實施例中，來源於癌症之腫瘤消退至少80%。在一個實施例中，來源於癌症之腫瘤消退至少85%。在一個實施例中，來源於癌症之腫瘤消退至少90%。在一個實施例中，來源於癌症之腫瘤消退至少95%。在一個實施例中，來源於癌症之腫瘤消退至少98%。在一個實施例中，來源於癌症之腫瘤消退至少99%。在一個實施例中，來源於癌症之腫瘤消退100%。在一個實施例中，腫瘤之消退係藉由利用磁共振成像(MRI)量測腫瘤之尺寸來確定。在一個實施例中，腫瘤之消退係藉由利用電腦斷層攝影術(CT)量測腫瘤之尺寸來確定。在一個實施例中，腫瘤之消退係藉由利用正電子發射斷層攝影術(PET)量測腫瘤之尺寸來確定。在一個實施例中，腫瘤之消退係藉由利用超音波量測腫瘤之尺寸來確定。In one embodiment of the methods or uses or products of use provided herein, the response to treatment with an anti-αvβ6 antibody or antibody-drug conjugate described herein promotes regression of a tumor derived from a cancer. In one embodiment, the tumor derived from a cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from the cancer prior to administration of the antibody or antibody-drug conjugate described herein. In one embodiment, the tumor derived from a cancer is reduced by at least about 10% to about 80%. In one embodiment, the tumor derived from a cancer is reduced by at least about 20% to about 80%. In one embodiment, the tumor from cancer regresses at least about 30% to about 80%. In one embodiment, the tumor from cancer regresses at least about 40% to about 80%. In one embodiment, the tumor from cancer regresses at least about 50% to about 80%. In one embodiment, the tumor from cancer regresses at least about 60% to about 80%. In one embodiment, the tumor from cancer regresses at least about 70% to about 80%. In one embodiment, the tumor from cancer regresses at least about 80%. In one embodiment, the tumor from cancer regresses at least about 85%. In one embodiment, the tumor from cancer regresses at least about 90%. In one embodiment, the tumor from cancer regresses at least about 95%. In one embodiment, the tumor from cancer regresses by at least about 98%. In one embodiment, the tumor from cancer regresses by at least about 99%. In one embodiment, the tumor from cancer regresses by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80% relative to the size of the tumor from cancer before administration of the antibody or antibody drug conjugate described herein. In one embodiment, the tumor from cancer regresses by at least 10% to 80%. In one embodiment, the tumor from cancer regresses by at least 20% to 80%. In one embodiment, the tumor from cancer regresses by at least 30% to 80%. In one embodiment, the tumor from cancer regresses at least 40% to 80%. In one embodiment, the tumor from cancer regresses at least 50% to 80%. In one embodiment, the tumor from cancer regresses at least 60% to 80%. In one embodiment, the tumor from cancer regresses at least 70% to 80%. In one embodiment, the tumor from cancer regresses at least 80%. In one embodiment, the tumor from cancer regresses at least 85%. In one embodiment, the tumor from cancer regresses at least 90%. In one embodiment, the tumor from cancer regresses at least 95%. In one embodiment, the tumor from cancer regresses at least 98%. In one embodiment, the tumor from cancer regresses at least 99%. In one embodiment, a tumor from cancer regresses 100%. In one embodiment, the regression of the tumor is determined by measuring the size of the tumor using magnetic resonance imaging (MRI). In one embodiment, the regression of the tumor is determined by measuring the size of the tumor using computed tomography (CT). In one embodiment, the regression of the tumor is determined by measuring the size of the tumor using positron emission tomography (PET). In one embodiment, the regression of the tumor is determined by measuring the size of the tumor using ultrasound.
在本文所描述之方法或用途或使用產物的一個實施例中，對用本文所描述之抗αvβ6抗體或抗體藥物結合物治療之反應係藉由量測在投與本文所描述之抗體或抗體藥物結合物之後的無進展存活期之時間來評估。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約1個月、至少約2個月、至少約3個月、至少約4個月、至少約5個月、至少約6個月、至少約7個月、至少約8個月、至少約9個月、至少約10個月、至少約11個月、至少約12個月、至少約十八個月、至少約兩年、至少約三年、至少約四年或至少約五年之無進展存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約6個月之無進展存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約一年之無進展存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約兩年之無進展存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約三年之無進展存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約四年之無進展存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約五年之無進展存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少1個月、至少2個月、至少3個月、至少4個月、至少5個月、至少6個月、至少7個月、至少8個月、至少9個月、至少10個月、至少11個月、至少12個月、至少十八個月、至少兩年、至少三年、至少四年或至少五年之無進展存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少6個月之無進展存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少一年之無進展存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少兩年之無進展存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少三年之無進展存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少四年之無進展存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少五年之無進展存活期。In one embodiment of the methods or uses or products of use described herein, response to treatment with an anti-αvβ6 antibody or antibody-drug conjugate described herein is assessed by measuring the time of progression-free survival following administration of the antibody or antibody-drug conjugate described herein. In some embodiments, following administration of the antibody or antibody-drug conjugate described herein, the subject exhibits a progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about two years, at least about three years, at least about four years, or at least about five years. In some embodiments, following administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a progression-free survival of at least about 6 months. In some embodiments, following administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a progression-free survival of at least about one year. In some embodiments, following administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a progression-free survival of at least about two years. In some embodiments, following administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a progression-free survival of at least about three years. In some embodiments, following administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a progression-free survival of at least about four years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a progression-free survival period of at least about five years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a progression-free survival period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least two years, at least three years, at least four years, or at least five years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a progression-free survival period of at least 6 months. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a progression-free survival period of at least one year. In some embodiments, following administration of an antibody or antibody drug conjugate described herein, the subject exhibits a progression-free survival of at least two years. In some embodiments, following administration of an antibody or antibody drug conjugate described herein, the subject exhibits a progression-free survival of at least three years. In some embodiments, following administration of an antibody or antibody drug conjugate described herein, the subject exhibits a progression-free survival of at least four years. In some embodiments, following administration of an antibody or antibody drug conjugate described herein, the subject exhibits a progression-free survival of at least five years.
在本文所描述之方法或用途或使用產物的一個實施例中，對用本文所描述之抗αvβ6抗體或抗體藥物結合物治療之反應係藉由量測在投與本文所描述之抗體或抗體藥物結合物之後的總存活期之時間來評估。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約1個月、至少約2個月、至少約3個月、至少約4個月、至少約5個月、至少約6個月、至少約7個月、至少約8個月、至少約9個月、至少約10個月、至少約11個月、至少約12個月、至少約十八個月、至少約兩年、至少約三年、至少約四年或至少約五年之總存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約6個月之總存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約一年之總存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約兩年之總存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約三年之總存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約四年之總存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少約五年之總存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少1個月、至少2個月、至少3個月、至少4個月、至少5個月、至少6個月、至少7個月、至少8個月、至少9個月、至少10個月、至少11個月、至少12個月、至少十八個月、至少兩年、至少三年、至少四年或至少五年之總存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少6個月之總存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少一年之總存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少兩年之總存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少三年之總存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少四年之總存活期。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，個體展現出至少五年之總存活期。In one embodiment of the methods or uses or products of use described herein, the response to treatment with an anti-αvβ6 antibody or antibody-drug conjugate described herein is assessed by measuring the time of overall survival following administration of the antibody or antibody-drug conjugate described herein. In some embodiments, following administration of the antibody or antibody-drug conjugate described herein, the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about two years, at least about three years, at least about four years, or at least about five years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a total survival of at least about 6 months. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a total survival of at least about one year. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a total survival of at least about two years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a total survival of at least about three years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a total survival of at least about four years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits a total survival of at least about five years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits an overall survival of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least two years, at least three years, at least four years, or at least five years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits an overall survival of at least 6 months. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits an overall survival of at least one year. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, an individual exhibits an overall survival of at least two years. In some embodiments, following administration of an antibody or antibody drug conjugate described herein, the individual exhibits an overall survival of at least three years. In some embodiments, following administration of an antibody or antibody drug conjugate described herein, the individual exhibits an overall survival of at least four years. In some embodiments, following administration of an antibody or antibody drug conjugate described herein, the individual exhibits an overall survival of at least five years.
在本文所描述之方法或用途或使用產物的一個實施例中，對用本文所描述之抗αvβ6抗體或抗體藥物結合物治療之反應係藉由量測在投與本文所描述之抗體或抗體藥物結合物之後的對本文所描述之抗體或抗體藥物結合物之反應持續時間來評估。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物的反應持續時間為至少約1個月、至少約2個月、至少約3個月、至少約4個月、至少約5個月、至少約6個月、至少約7個月、至少約8個月、至少約9個月、至少約10個月、至少約11個月、至少約12個月、至少約十八個月、至少約兩年、至少約三年、至少約四年或至少約五年。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物之反應持續時間為至少約6個月。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物之反應持續時間為至少約一年。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物之反應持續時間為至少約兩年。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物之反應持續時間為至少約三年。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物之反應持續時間為至少約四年。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物之反應持續時間為至少約五年。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物之反應持續時間為至少1個月、至少2個月、至少3個月、至少4個月、至少5個月、至少6個月、至少7個月、至少8個月、至少9個月、至少10個月、至少11個月、至少12個月、至少十八個月、至少兩年、至少三年、至少四年或至少五年。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物之反應持續時間為至少6個月。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物之反應持續時間為至少一年。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物之反應持續時間為至少兩年。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物之反應持續時間為至少三年。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物之反應持續時間為至少四年。在一些實施例中，在投與本文所描述之抗體或抗體藥物結合物之後，對本文所描述之抗體或抗體藥物結合物之反應持續時間為至少五年。In one embodiment of the methods or uses or products of use described herein, the response to treatment with an anti-αvβ6 antibody or antibody-drug conjugate described herein is assessed by measuring the duration of the response to the antibody or antibody-drug conjugate described herein following administration of the antibody or antibody-drug conjugate described herein. In some embodiments, the duration of the response to the antibody or antibody-drug conjugate described herein following administration of the antibody or antibody-drug conjugate described herein is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about two years, at least about three years, at least about four years, or at least about five years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, the duration of response to an antibody or antibody-drug conjugate described herein is at least about 6 months. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, the duration of response to an antibody or antibody-drug conjugate described herein is at least about one year. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, the duration of response to an antibody or antibody-drug conjugate described herein is at least about two years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, the duration of response to an antibody or antibody-drug conjugate described herein is at least about three years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, the duration of response to an antibody or antibody-drug conjugate described herein is at least about four years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, the duration of response to an antibody or antibody-drug conjugate described herein is at least about five years. In some embodiments, after administration of an antibody or antibody-drug conjugate described herein, the duration of response to an antibody or antibody-drug conjugate described herein is at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least two years, at least three years, at least four years, or at least five years. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least 6 months after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least one year after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least two years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the duration of response to an antibody or antibody-drug conjugate described herein is at least three years after administration of an antibody or antibody-drug conjugate described herein. In some embodiments, the response to the antibodies or antibody-drug conjugates described herein persists for at least four years following administration of the antibodies or antibody-drug conjugates described herein. In some embodiments, the response to the antibodies or antibody-drug conjugates described herein persists for at least five years following administration of the antibodies or antibody-drug conjugates described herein.
通常，在臨床試驗(例如I期、II期、II/III期或III期試驗)中，相對於僅接受標準療法(或加上安慰劑)之患者的對照組，用標準療法加上單獨或呈結合物形式之抗αvβ6抗體治療的患者之中值無進展存活期及/或總存活期及/或反應率及/或反應持續時間的前述增加為統計學上顯著的，例如呈p = 0.05或0.01或甚至0.001水準。完全及部分反應率係藉由常用於癌症之臨床試驗中之客觀準則來確定，例如由國家癌症研究所(National Cancer Institute)及/或食品與藥物管理局(Food and Drug Administration)所列或所公認的客觀準則。Typically, in a clinical trial (e.g., a Phase I, Phase II, Phase II/III, or Phase III trial), the foregoing increase in median progression-free survival and/or overall survival and/or response rate and/or duration of response in patients treated with standard therapy plus an anti-αvβ6 antibody, alone or in conjugate form, relative to a control group of patients receiving standard therapy alone (or plus a placebo) is statistically significant, e.g., at the p = 0.05 or 0.01 or even 0.001 level. Complete and partial response rates are determined by objective criteria commonly used in clinical trials of cancer, such as those listed or recognized by the National Cancer Institute and/or the Food and Drug Administration.
在一些實施例中，來自個體之至少約0.1%、至少約1%、至少約2%、至少約3%、至少約4%、至少約5%、至少約6%、至少約7%、至少約8%、至少約9%、至少約10%、至少約15%、至少約20%、至少約25%、至少約30%、至少約35%、至少約40%、至少約45%、至少約50%、至少約60%、至少約70%或至少約80%癌細胞表現PD-L1。在一些實施例中，來自個體之至少0.1%、至少1%、至少2%、至少3%、至少4%、至少5%、至少6%、至少7%、至少8%、至少9%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少60%、至少70%或至少80%癌細胞表現PD-L1。在本文中之任何實施例中之一些中，個體之腫瘤表現PD-L1，其中腫瘤比例評分(TPS) ≥1%。在本文中之任何實施例中之一些中，個體之腫瘤表現PD-L1，其中TPS ≥5%。在本文中之任何實施例中之一些中，個體之腫瘤表現PD-L1，其中TPS ≥10%。在本文中之任何實施例中之一些中，個體之腫瘤表現PD-L1，其中TPS ≥15%。在本文中之任何實施例中之一些中，個體之腫瘤表現PD-L1，其中TPS ≥20%。在本文中之任何實施例中之一些中，個體之腫瘤表現PD-L1，其中TPS ≥25%。在本文中之任何實施例中之一些中，個體之腫瘤表現PD-L1，其中TPS ≥30%。在本文中之任何實施例中之一些中，個體之腫瘤表現PD-L1，其中TPS ≥35%。在本文中之任何實施例中之一些中，個體之腫瘤表現PD-L1，其中TPS ≥40%。在本文中之任何實施例中之一些中，個體之腫瘤表現PD-L1，其中TPS ≥45%。在本文中之一些實施例中，個體之腫瘤具有高PD-L1表現，其中TPS≥50%。在本文中之一些實施例中，個體之腫瘤表現PD-L1，其中綜合陽性評分(CPS) ≥1%。參見US 2017/0285037。在本文中之一些實施例中，個體之腫瘤表現PD-L1，其中CPS ≥5%。在本文中之一些實施例中，個體之腫瘤表現PD-L1，其中CPS ≥10%。在本文中之一些實施例中，個體之腫瘤表現PD-L1，其中CPS ≥15%。在本文中之一些實施例中，個體之腫瘤表現PD-L1，其中CPS ≥20%。在本文中之一些實施例中，個體之腫瘤表現PD-L1，其中CPS ≥25%。在本文中之一些實施例中，個體之腫瘤表現PD-L1，其中CPS ≥30%。在本文中之一些實施例中，個體之腫瘤表現PD-L1，其中CPS ≥35%。在本文中之一些實施例中，個體之腫瘤表現PD-L1，其中CPS ≥40%。在本文中之一些實施例中，個體之腫瘤表現PD-L1，其中CPS≥＞45%。在本文中之一些實施例中，個體之腫瘤表現PD-L1，其中CPS ≥50%。在一些實施例中，表現PD-L1之細胞百分比係使用免疫組織化學(IHC)測定。在一些實施例中，表現PD-L1之細胞百分比係使用流式細胞量測術測定。在一些實施例中，表現PD-L1之細胞百分比係使用酶聯結免疫吸附劑分析法(ELISA)測定。在一些實施例中，表現PD-L1之細胞百分比在本文所描述之方法或用途或使用產物之前評估。 IX. 製品及套組In some embodiments, at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of cancer cells from a subject express PD-L1. In some embodiments, at least 0.1%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80% of cancer cells from a subject express PD-L1. In some of any embodiments herein, the individual's tumor expresses PD-L1, wherein the tumor proportion score (TPS) is ≥1%. In some of any embodiments herein, the individual's tumor expresses PD-L1, wherein the TPS is ≥5%. In some of any embodiments herein, the individual's tumor expresses PD-L1, wherein the TPS is ≥10%. In some of any embodiments herein, the individual's tumor expresses PD-L1, wherein the TPS is ≥15%. In some of any embodiments herein, the individual's tumor expresses PD-L1, wherein the TPS is ≥20%. In some of any embodiments herein, the individual's tumor expresses PD-L1, wherein the TPS is ≥25%. In some of any embodiments herein, the individual's tumor expresses PD-L1, wherein the TPS is ≥30%. In some of any embodiments herein, the individual's tumor expresses PD-L1, wherein TPS ≥35%. In some of any embodiments herein, the individual's tumor expresses PD-L1, wherein TPS ≥40%. In some of any embodiments herein, the individual's tumor expresses PD-L1, wherein TPS ≥45%. In some embodiments herein, the individual's tumor has high PD-L1 expression, wherein TPS ≥50%. In some embodiments herein, the individual's tumor expresses PD-L1, wherein the comprehensive positive score (CPS) ≥1%. See US 2017/0285037. In some embodiments herein, the individual's tumor expresses PD-L1, wherein CPS ≥5%. In some embodiments herein, the individual's tumor expresses PD-L1, wherein the CPS is ≥10%. In some embodiments herein, the individual's tumor expresses PD-L1, wherein the CPS is ≥15%. In some embodiments herein, the individual's tumor expresses PD-L1, wherein the CPS is ≥20%. In some embodiments herein, the individual's tumor expresses PD-L1, wherein the CPS is ≥25%. In some embodiments herein, the individual's tumor expresses PD-L1, wherein the CPS is ≥30%. In some embodiments herein, the individual's tumor expresses PD-L1, wherein the CPS is ≥35%. In some embodiments herein, the individual's tumor expresses PD-L1, wherein the CPS is ≥40%. In some embodiments herein, the individual's tumor expresses PD-L1, wherein the CPS ≥＞45%. In some embodiments herein, the individual's tumor expresses PD-L1, wherein the CPS ≥50%. In some embodiments, the percentage of cells expressing PD-L1 is determined using immunohistochemistry (IHC). In some embodiments, the percentage of cells expressing PD-L1 is determined using flow cytometry. In some embodiments, the percentage of cells expressing PD-L1 is determined using enzyme-linked immunosorbent assay (ELISA). In some embodiments, the percentage of cells expressing PD-L1 is assessed prior to the methods or uses described herein or the use of the product.IX. Products and Kits
在另一態樣中，提供包含本文所描述之抗αvβ6抗體或抗αvβ6抗體藥物結合物之製品或套組。製品或套組可進一步包含本文所描述之抗αvβ6抗體或抗αvβ6抗體藥物結合物在本發明之方法中的使用說明。因此，在某些實施例中，製品或套組包含本文所描述之抗αvβ6抗體或抗αvβ6抗體藥物結合物在用於治療個體之癌症(例如非小細胞肺癌(NSCLC) (鱗狀及腺)、頭頸癌(包括頭頸部鱗狀癌瘤)、食道癌、乳癌(包括乳房侵襲性癌)、卵巢癌、膀胱癌(包括尿道上皮癌)、皮膚癌(鱗狀細胞癌或SCC)、腎癌(包括腎透明細胞、腎乳頭狀細胞及腎難染細胞)、子宮頸癌、胃癌、前列腺癌(包括前列腺腺癌)、子宮內膜癌(包括子宮癌肉瘤及子宮體子宮內膜)、直腸腺癌、甲狀腺癌、結腸腺癌、胃腺癌及胰臟癌(包括胰臟腺癌))的方法中之使用說明，其包含向個體投與有效量的本文所描述之抗αvβ6抗體或抗αvβ6抗體藥物結合物。在一些實施例中，癌症為NSCLC。在一些實施例中，NSCLC為鱗狀細胞癌。在一些實施例中，NSCLC為非鱗狀細胞癌。在一些實施例中，NSCLC為腺癌。在一些實施例中，NSCLC不具有賦予審批通過之靶向療法合格性的已知突變/變化(例如表皮生長因子受體(EGFR)、退行性淋巴瘤激酶(ALK)等)。在一些實施例中，NSCLC具有一或多種賦予審批通過之靶向療法合格性的已知突變/變化(例如表皮生長因子受體(EGFR)、退行性淋巴瘤激酶(ALK)等)。在一些實施例中，NSCLC具有已知的EGFR突變。在一些實施例中，NSCLC具有已知的ALK突變。在一些實施例中，癌症為頭頸癌。在一些實施例中，頭頸癌為鱗狀細胞癌。在一些實施例中，癌症為食道癌。在一些實施例中，食道癌為食道鱗狀細胞癌。在一些實施例中，癌症為乳癌。在一些實施例中，乳癌為HER2陰性乳癌。在一些實施例中，乳癌為乳房侵襲性癌。在一些實施例中，癌症為卵巢癌。在一些實施例中，卵巢癌為高級漿液性上皮卵巢癌。在一些實施例中，癌症為原發性腹膜癌。在一些實施例中，癌症為輸卵管癌。在一些實施例中，癌症為腎癌。在一些實施例中，腎癌為腎透明細胞癌。在一些實施例中，腎癌為腎乳頭狀細胞癌。在一些實施例中，腎癌為腎難染細胞癌。在一些實施例中，癌症為子宮內膜癌。在一些實施例中，子宮內膜癌為子宮癌肉瘤。在一些實施例中，子宮內膜癌為子宮體子宮內膜癌。在一些實施例中，癌症為胃癌(stomach cancer)。在一些實施例中，胃癌為胃腺癌。在一些實施例中，癌症為膀胱癌。在一些實施例中，膀胱癌為尿道上皮癌。在一些實施例中，癌症為皮膚癌。在一些實施例中，皮膚癌為皮膚鱗狀細胞癌。在一些實施例中，癌症為前列腺癌。在一些實施例中，前列腺癌為前列腺腺癌。在一些實施例中，癌症為直腸腺癌。在一些實施例中，癌症為甲狀腺癌。在一些實施例中，癌症為結腸腺癌。在一些實施例中，癌症為子宮頸癌。在一些實施例中，癌症為胃癌(gastric cancer)。在一些實施例中，癌症為胰臟癌。在一些實施例中，胰臟癌為外分泌胰臟腺癌。在一些實施例中，個體為人類。In another aspect, an article of manufacture or kit comprising an anti-αvβ6 antibody or anti-αvβ6 antibody-drug conjugate described herein is provided. The article of manufacture or kit may further comprise instructions for use of the anti-αvβ6 antibody or anti-αvβ6 antibody-drug conjugate described herein in the methods of the invention. Thus, in certain embodiments, an article of manufacture or kit comprises an anti-αvβ6 antibody or anti-αvβ6 antibody-drug conjugate described herein for use in treating a cancer (e.g., non-small cell lung cancer (NSCLC)) in an individual. Instructions for use in a method of treating cancer of the following types: ovarian cancer, bladder cancer (including urothelial carcinoma), skin cancer (squamous cell carcinoma or SCC), renal cancer (including renal clear cell, renal papillary cell and renal refractory cell), cervical cancer, gastric cancer, prostate cancer (including prostate adenocarcinoma), endometrial cancer (including uterine carcinoma sarcoma and corpus endometrium), rectal adenocarcinoma, thyroid cancer, colon adenocarcinoma, gastric adenocarcinoma and pancreatic cancer (including pancreatic adenocarcinoma)), comprising administering to a subject an effective amount of an anti-αvβ6 antibody or an anti-αvβ6 antibody-drug conjugate described herein. In some embodiments, the cancer is NSCLC. In some embodiments, the NSCLC is squamous cell carcinoma. In some embodiments, the NSCLC is non-squamous cell carcinoma. In some embodiments, the NSCLC is adenocarcinoma. In some embodiments, the NSCLC does not have a known mutation/variation that qualifies for approved targeted therapy (e.g., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), etc.). In some embodiments, the NSCLC has one or more known mutations/variations that qualify for approved targeted therapy (e.g., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), etc.). In some embodiments, the NSCLC has a known EGFR mutation. In some embodiments, the NSCLC has a known ALK mutation. In some embodiments, the cancer is head and neck cancer. In some embodiments, the head and neck cancer is squamous cell carcinoma. In some embodiments, the cancer is esophageal cancer. In some embodiments, the esophageal cancer is esophageal squamous cell carcinoma. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is HER2-negative breast cancer. In some embodiments, the breast cancer is invasive breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is high-grade serous epithelial ovarian cancer. In some embodiments, the cancer is primary peritoneal cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the kidney cancer is kidney clear cell carcinoma. In some embodiments, the kidney cancer is kidney papillary cell carcinoma. In some embodiments, the renal cancer is renal refractory cell carcinoma. In some embodiments, the cancer is endometrial cancer. In some embodiments, the endometrial cancer is carcinosarcoma of the uterus. In some embodiments, the endometrial cancer is endometrial cancer of the corpus uteri. In some embodiments, the cancer is stomach cancer. In some embodiments, the stomach cancer is gastric adenocarcinoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the bladder cancer is urothelial carcinoma. In some embodiments, the cancer is skin cancer. In some embodiments, the skin cancer is squamous cell carcinoma of the skin. In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is prostate adenocarcinoma. In some embodiments, the cancer is rectal adenocarcinoma. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is exocrine pancreatic cancer. In some embodiments, the individual is a human.
製品或套組可進一步包含容器。適合容器包括例如瓶子、小瓶(例如雙腔室小瓶)、注射器(諸如單腔室注射器或雙腔室注射器)及試管。在一些實施例中，容器為小瓶。容器可由各種材料(諸如玻璃或塑膠)形成。容器容納調配物。The article or kit may further comprise a container. Suitable containers include, for example, bottles, vials (e.g., dual-chamber vials), syringes (e.g., single-chamber syringes or dual-chamber syringes), and test tubes. In some embodiments, the container is a vial. The container may be formed of a variety of materials (e.g., glass or plastic). The container holds the formulation.
製品或套組可進一步包含位於容器上或與容器相連之標籤或藥品說明書，其可指示復原及/或使用調配物之指導。標籤或藥品說明書可進一步指示調配物適用於或意欲用於皮下、靜脈內(例如靜脈內輸注)或其他投與模式以治療個體之癌症(例如非小細胞肺癌(NSCLC) (鱗狀及腺)、頭頸癌(包括頭頸部鱗狀癌瘤)、食道癌、乳癌(包括乳房侵襲性癌)、卵巢癌、膀胱癌(包括尿道上皮癌)、皮膚癌(鱗狀細胞癌或SCC)、腎癌(包括腎透明細胞、腎乳頭狀細胞及腎難染細胞)、子宮頸癌、胃癌、前列腺癌(包括前列腺腺癌)、子宮內膜癌(包括子宮癌肉瘤及子宮體子宮內膜)、直腸腺癌、甲狀腺癌、結腸腺癌、胃腺癌及胰臟癌(包括胰臟腺癌))。容納調配物之容器可為單次使用型小瓶或多次使用型小瓶，其允許重複投與經復原之調配物。製品或套組可進一步包含第二容器，其包含適合稀釋劑。製品或套組可進一步包括自商業、治療性及使用者觀點來看所需之其他材料，包括其他緩衝液、稀釋劑、過濾器、針、注射器及具有使用說明之藥品說明書。The article of manufacture or kit may further include a label or package insert on or associated with the container, which may indicate instructions for reconstitution and/or use of the formulation. The label or package insert may further indicate that the formulation is suitable or intended for subcutaneous, intravenous (e.g., intravenous infusion), or other modes of administration for treating cancer (e.g., non-small cell lung cancer (NSCLC)) in an individual. The invention relates to cancers of the kidney (including ovarian cancer, bladder cancer, and urothelial cancer), ovarian cancer, bladder cancer, and skin cancer (squamous cell carcinoma or SCC), kidney cancer (including renal clear cell, renal papillary cell, and renal refractory cell), cervical cancer, gastric cancer, prostate cancer (including prostate adenocarcinoma), endometrial cancer (including uterine carcinoma sarcoma and corpus endometrium), rectal adenocarcinoma, thyroid cancer, colon adenocarcinoma, gastric adenocarcinoma, and pancreatic cancer (including pancreatic adenocarcinoma). The container for holding the formulation may be a single-use vial or a multiple-use vial, which allows repeated administration of the reconstituted formulation. The article of manufacture or kit may further comprise a second container comprising a suitable diluent. The article of manufacture or kit may further include other materials necessary from a commercial, therapeutic and user perspective, including other buffers, diluents, filters, needles, syringes and a package insert with instructions for use.
本文中之製品或套組視情況進一步包含容器，該容器包含第二藥劑，其中抗αvβ6抗體或抗αvβ6抗體藥物結合物為第一藥劑，且製品或套組進一步包含在標籤或藥品說明書上之用於以有效量用第二藥劑治療個體的說明書。在一些實施例中，第二藥劑用於使一或多種不良事件消退或減輕其嚴重程度。The article of manufacture or kit herein optionally further comprises a container comprising a second agent, wherein the anti-αvβ6 antibody or anti-αvβ6 antibody drug conjugate is the first agent, and the article of manufacture or kit further comprises instructions on the label or package insert for treating a subject with the second agent in an effective amount. In some embodiments, the second agent is used to resolve or reduce the severity of one or more adverse events.
在一些實施例中，抗αvβ6抗體或抗αvβ6抗體藥物結合物以凍乾粉形式存在於容器中。在一些實施例中，凍乾粉於密閉性密封之容器中，諸如小瓶、安瓿或藥囊，指示活性劑之量。在藉由注射投與醫藥時的情況下，一安瓿用於注射之無菌水或生理鹽水可例如視情況作為套組之部分形式提供，以使得成分可在投與之前混合。若需要，則此類套組可進一步包括各種習知醫藥組分中之一或多者，諸如具有一或多種醫藥學上可接受之載劑的容器、額外的容器等，如對於熟習此項技術者而言顯而易見的。套組中亦可包括呈插頁或呈標籤形式之印刷說明書，指示待投與之組分之量、投與指南及/或用於混合組分之指南。 X. 其他應用In some embodiments, the anti-αvβ6 antibody or anti-αvβ6 antibody drug conjugate is present in a container as a lyophilized powder. In some embodiments, the lyophilized powder is in a hermetically sealed container, such as a vial, ampoule or sachet, indicating the amount of active agent. In the case where the drug is administered by injection, an ampoule of sterile water for injection or saline may be provided, for example, as part of a kit, as appropriate, so that the ingredients can be mixed prior to administration. If desired, such kits may further include one or more of a variety of known pharmaceutical components, such as a container with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be apparent to one skilled in the art. The kit may also include printed instructions in the form of an insert or label indicating the amounts of the components to be administered, administration instructions, and/or instructions for mixing the components.X. Other Applications
本文所描述之抗αvβ6抗體(諸如人源化抗αvβ6抗體)可用於在臨床診斷或治療之情形下或研究中偵測αvβ6。αvβ6在癌症上之表現提供癌症適合於用本發明之抗體進行治療的指示。抗體亦可以用於實驗室研究之研究試劑形式出售，用於偵測攜帶αvβ6之細胞及其對各種刺激之反應。在此類用途中，單株抗體可用螢光分子、自旋標記分子、酶或放射性同位素標記，且可以具有對進行αvβ6之分析而言必需的所有試劑之套組形式提供。本文所描述之抗體可用於偵測αvβ6蛋白質表現且確定癌症是否適合於用αvβ6 ADC治療。The anti-αvβ6 antibodies described herein (such as humanized anti-αvβ6 antibodies) can be used to detect αvβ6 in clinical diagnostic or therapeutic situations or in research. Expression of αvβ6 on a cancer provides an indication that the cancer is suitable for treatment with the antibodies of the invention. The antibodies can also be sold in the form of research reagents for use in laboratory research to detect cells carrying αvβ6 and their responses to various stimuli. In such uses, the monoclonal antibodies can be labeled with fluorescent molecules, spin-labeled molecules, enzymes, or radioisotopes, and can be provided in a kit with all the reagents necessary to perform an analysis of αvβ6. The antibodies described herein can be used to detect αvβ6 protein expression and determine whether a cancer is suitable for treatment with an αvβ6 ADC.
上文或下文引用之所有專利申請案、網站、其他公開案、寄存編號及其類似者出於所有目的以全文引用之方式併入，其引用程度如同各個別物件特定且個別地指示為如此以引用之方式併入一般。若在不同時間序列之不同版本與寄存編號相關，則意謂版本在本申請案之有效申請日時與寄存編號相關。有效申請日意謂實際申請日或提及寄存編號之優先權申請案之申請日中之較早者(若適用)。同樣，若在不同時間公開公開案、網站或其類似者之不同版本，則除非另外指明，否則意謂在本申請案之有效申請日時最近公開之版本。除非另外特別指示，否則本發明之任何特徵、步驟、要素、實施例或態樣可與任何其他組合使用。儘管出於清楚及理解之目的已藉助於說明及實例相當詳細地描述本發明，但顯而易見可在所附申請專利範圍之範疇內實踐某些改變及修改。 實例 實例1：晚期實體腫瘤中之SGN-B6A的1期研究All patent applications, websites, other publications, deposit numbers, and the like cited above or below are incorporated by reference in their entirety for all purposes to the same extent as if each individual item was specifically and individually indicated to be so incorporated by reference. If different versions in different time series are associated with a deposit number, it means the version associated with the deposit number as of the effective filing date of the present application. The effective filing date means the earlier of the actual filing date or the filing date of the priority application to which the deposit number is referred, as applicable. Similarly, if different versions of a publication, website, or the like are published at different times, it means the version most recently published as of the effective filing date of the present application, unless otherwise indicated. Unless otherwise specifically indicated, any feature, step, element, embodiment, or aspect of the present invention may be used in combination with any other. Although the present invention has been described in considerable detail by way of illustration and example for purposes of clarity and understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims.ExamplesExample 1: Phase 1 Study of SGN-B6A in Advanced Solid Tumors
SGN-B6A為靶向整合素β-6 (AVB6)(一種在若干類型之癌症中具有高發病率之細胞表面黏附蛋白)之抗體藥物結合物(ADC)。SGN-B6A包含經由可裂解肽連接子與破壞微管蛋白之抗有絲分裂藥物單甲基奧瑞他汀E (MMAE)結合的人源化IgG1抗整合素β-6單株抗體(h2A2)。在惡性細胞表面上結合於整合素β-6時，SGN-B6A經設計以內化且釋放細胞毒性MMAE。研究人員手冊(Investigator's Brochure，IB)中提供與SGN-B6A及其在人類個體中之研究有關之臨床及非臨床資料的概述。SGN-B6A is an antibody-drug conjugate (ADC) targeting integrin beta-6 (AVB6), a cell surface adhesion protein with high incidence in several types of cancer. SGN-B6A comprises a humanized IgG1 anti-integrin beta-6 monoclonal antibody (h2A2) conjugated to the anti-tubulin-disrupting antimitotic drug monomethyl auristatin E (MMAE) via a cleavable peptide linker. Upon binding to integrin beta-6 on the surface of malignant cells, SGN-B6A is designed to internalize and release cytotoxic MMAE. An overview of clinical and nonclinical data related to SGN-B6A and its studies in human subjects is provided in the Investigator's Brochure (IB).
Keytruda®(帕博利珠單抗)係一種強效人源化IgG4單株抗體(mAb)，其具有結合於計劃性細胞死亡1 (PD-1)受體之高特異性，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)之相互作用。基於臨床前活體外資料，帕博利珠單抗對PD-1具有高親和力及強效受體阻斷活性。帕博利珠單抗具有可接受之臨床前安全概況且作為用於晚期惡性腫瘤之靜脈內(IV)免疫療法經審批通過且處於臨床研發。帕博利珠單抗適用於治療若干適應症之患者。對於詳細背景，參考帕博利珠單抗產品資訊。Keytruda® (pembrolizumab) is a potent humanized IgG4 monoclonal antibody (mAb) that binds with high specificity to the programmed cell death 1 (PD-1) receptor, thereby inhibiting the receptor's interaction 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. Pembrolizumab has an acceptable preclinical safety profile and is approved and in clinical development as an intravenous (IV) immunotherapy for advanced malignancies. Pembrolizumab is indicated for the treatment of patients for several indications. For detailed background, refer to the pembrolizumab product information.
此首次用於人類(first-in-human，FIH)的研究經設計以評估SGN-B6A單一療法(部分A及B)及與帕博利珠單抗組合(部分C及D)在患有選擇晚期實體腫瘤之成人中的安全性、耐受性、藥物動力學及抗腫瘤活性。This first-in-human (FIH) study was designed to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of SGN-B6A monotherapy (Parts A and B) and in combination with pembrolizumab (Parts C and D) in adults with selected advanced solid tumors.
此為1期開放標記之多中心研究，其經設計以評估SGN-B6A在患有選擇晚期實體腫瘤之成人中的安全性、耐受性、PK及抗腫瘤活性。研究將包括劑量遞增及劑量擴增，其中多個疾病特異性群組及一生物學群組在劑量擴增中。生物學群組將針對試驗之其他部分中產生的資料進行閘控且將需要額外活檢。在針對特定時程之劑量遞增完成時，至多9個疾病特異性擴增群組及一生物學群組可由發起人與安全性監測委員會(Safety Monitoring Committee，SMC)協商來啟用。部分B中之擴增群組將選入符合入選部分A條件之所選擇的腫瘤類型。方法This is a Phase 1, open-label, multicenter study designed to evaluate the safety, tolerability, PK, and antitumor activity of SGN-B6A in adults with select advanced solid tumors. The study will include dose escalation and dose expansion, with multiple disease-specific cohorts and one biological cohort in dose expansion. The biological cohort will be gated to data generated in other parts of the trial and will require additional biopsies. Upon completion of dose escalation for a specific schedule, up to 9 disease-specific expansion cohorts and one biological cohort may be activated by the Sponsor in consultation with the Safety Monitoring Committee (SMC). The expansion cohorts in Part B will enroll selected tumor types that are eligible for inclusion in Part A.method
此研究為患有晚期實體腫瘤之個體中的1期劑量遞增研究。部分A之主要目標為評估SGN-B6A在患有晚期實體腫瘤之個體中的安全性及耐受性以鑑別最大耐受劑量(MTD)且鑑別建議劑量及時程。SGN-B6A最初將在21天週期之第1天、第8天及第15天藉由靜脈內(IV)輸注給與。可探究其他給藥方案。將使用經修改之毒性機率區間(modified toxicity probability interval，mTPI)方法來進行研究之劑量遞增部分(部分A)，以測定表明25%之劑量限制性毒性(DLT)速率與5%裕度的劑量。對於研究之劑量遞增部分(部分A)，SGN-B6A劑量水準(dose level)及投與時程將由群組分配限定。基於安全性、藥物動力學(PK)及藥效學生物標記物之評估，確定劑量擴增部分(部分B)之劑量及時程。對於劑量擴增部分(B部分)，依部分A中所確定，SGN-B6A等於或低於MTD及/或建議劑量及時程。This study is a Phase 1 dose-escalation study in subjects with advanced solid tumors. The primary objectives of Part A are to evaluate the safety and tolerability of SGN-B6A in subjects with advanced solid tumors to identify the maximum tolerated dose (MTD) and to identify a recommended dose and schedule. SGN-B6A will initially be administered by intravenous (IV) infusion on Days 1, 8, and 15 of a 21-day cycle. Other dosing schedules may be explored. The dose-escalation portion of the study (Part A) will be conducted using a modified toxicity probability interval (mTPI) approach to determine the dose that demonstrates a 25% dose-limiting toxicity (DLT) rate with a 5% margin. For the dose escalation portion of the study (Part A), the SGN-B6A dose level and schedule will be determined by group assignment. The dose and schedule for the dose escalation portion (Part B) will be determined based on evaluations of safety, pharmacokinetic (PK), and pharmacodynamic biomarkers. For the dose escalation portion (Part B), SGN-B6A is at or below the MTD and/or recommended dose and schedule as determined in Part A.
由於整合素β-6在若干腫瘤類型中表現，因此SGN-B6A可在許多種惡性腫瘤中具有活性。在部分A中之劑量遞增期間，靶向以下十種特定腫瘤類型以用於初步臨床評估：非小細胞肺癌(NSCLC)、頭頸部鱗狀細胞癌(HNSCC)、晚期人類表皮生長因子受體2 (HER2)陰性乳癌、食道鱗狀細胞癌(ESCC)、高級漿液性卵巢癌(HGSOC)、皮膚鱗狀細胞癌(cSCC)、外分泌胰臟腺癌、膀胱癌、子宮頸癌及胃癌。在特定時程之劑量遞增完成時，將在部分B中啟用至多9個疾病特異性擴增群組及1個生物學群組以進一步評估SGN-B6A之安全性及初始抗腫瘤療效。Since integrin beta-6 is expressed in several tumor types, SGN-B6A may be active in many malignancies. During the dose escalation phase in Part A, ten specific tumor types were targeted for initial clinical evaluation: non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), advanced human epidermal growth factor receptor 2 (HER2)-negative breast cancer, esophageal squamous cell carcinoma (ESCC), high-grade serous ovarian cancer (HGSOC), cutaneous squamous cell carcinoma (cSCC), exocrine pancreatic cancer, bladder cancer, cervical cancer, and gastric cancer. Upon completion of dose escalation at specified times, up to nine disease-specific expansion cohorts and one biological cohort will be initiated in Part B to further evaluate the safety and initial anti-tumor efficacy of SGN-B6A.
部分C之主要目標為評估SGN-B6A與帕博利珠單抗組合之安全性及耐受性。在部分C完成時，將啟用2個疾病特異性擴增群組(NSCLC及HNSCC)以進一步評估SGN-B6A與帕博利珠單抗組合(部分D)之安全性及初始抗腫瘤活性。The primary objective of Part C is to evaluate the safety and tolerability of the combination of SGN-B6A and pembrolizumab. Upon completion of Part C, two disease-specific expansion cohorts (NSCLC and HNSCC) will be initiated to further evaluate the safety and initial antitumor activity of the combination of SGN-B6A and pembrolizumab (Part D).
此研究之部分C及部分D的帕博利珠單抗之計劃劑量為200 mg Q3W或400 mg Q6W。基於帕博利珠單抗研發項目中產生之全部資料，200 mg Q3W及400 mg Q6W為對於歷經所有適應症之成人的合適帕博利珠單抗劑量。依下文所概述，此劑量由以下調整： ● 黑色素瘤及NSCLC適應症中8個隨機分組研究的臨床資料表明，2 mg/kg Q3W至10 mg/kg每2週(Q2W)之劑量-功效關係及暴露-功效關係平穩，其表示大致5至7.5倍暴露範圍 ● 群體PK分析顯示固定給藥及基於重量之給藥兩者提供對PK可變性之類似控制，暴露分佈具有相當大的重疊，支持200 mg Q3W之適合性 ● 臨床資料顯示以200 mg Q3W在多種適應症中效益-風險之有意義的改善，包括總存活期，及 ● 藥理學資料顯示以200 mg Q3W在全身循環(根據PK資料推斷)及腫瘤(根據生理學上基於PK分析推斷)兩者中之完全目標飽和。The planned dose of pembrolizumab in Parts C and D of this study is 200 mg Q3W or 400 mg Q6W. Based on all data generated in the pembrolizumab development program, 200 mg Q3W and 400 mg Q6W are appropriate pembrolizumab doses for adults across all indications. As summarized below, this dose is adjusted by:● Clinical data from 8 randomized studies in melanoma and NSCLC indications demonstrated a robust dose-efficacy and exposure-efficacy relationship from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), representing an approximately 5- to 7.5-fold exposure range● Population PK analysis showed that both fixed and weight-based dosing provided similar control of PK variability with considerable overlap in exposure profiles, supporting the suitability of 200 mg Q3W● Clinical data demonstrated meaningful improvements in benefit-risk, including overall survival, with 200 mg Q3W in multiple indications, and● Pharmacology data demonstrated that 200 mg Q3W Q3W complete target saturation both in systemic circulation (inferred from PK data) and in tumors (inferred physiologically based on PK analysis).
部分partAA--劑量遞增群組Dose escalation group
此試驗之劑量遞增部分(A部分)將使用mTPI方法在大致85名個體中進行。部分A經設計以評估安全性及耐受性且鑑別SGN-B6A之MTD。若未達到MTD，則安全性、PK、藥效學及生物標記物分析以及初步抗腫瘤活性可用於確定建議劑量。The dose escalation portion of this trial (Part A) will be conducted in approximately 85 subjects using the mTPI method. Part A is designed to assess safety and tolerability and identify the MTD of SGN-B6A. If the MTD is not reached, safety, PK, pharmacodynamic and biomarker analyses and preliminary antitumor activity can be used to determine the recommended dose.
mTPI方法使用貝氏統計框架(Bayesian statistical framework)及β-二項階層式模型(binomial hierarchical model)來計算3次間隔的後驗機率，其反映各劑量水準之毒性率與目標DLT率之間的相對距離。針對25%之目標DLT率與5%裕度確定給藥決策規則。3次間隔將為(0, 20%)、(20%, 30%)及(30%, 100%)，且對應劑量決策規則將為： 1. 若當前DLT率最可能＜20%，則遞增 2. 若當前DLT率最可能在20%與30%之間，則保持 3. 若當前DLT率可能＞30%，則遞減The mTPI method uses a Bayesian statistical framework and a beta-binomial hierarchical model to calculate posterior probabilities for three intervals that reflect the relative distance between the toxicity rate and the target DLT rate at each dose level. The dosing decision rule is determined for a target DLT rate of 25% and a 5% margin. The three intervals will be (0, 20%), (20%, 30%), and (30%, 100%), and the corresponding dosing decision rules will be:1. If the current DLT rate is most likely <20%, then increase2. If the current DLT rate is most likely between 20% and 30%, then maintain3. If the current DLT rate is likely >30%, then decrease
劑量探索決策示於表1中。「E」表示遞增劑量，「S」表示維持相同劑量，且「D」表示遞減劑量。決策「DU」意謂當前劑量水準因為高毒性而可為不可接受的。若DLT率高於25%的後驗機率大於95%，則將劑量定義為具有不可接受的毒性。The dose exploration decisions are shown in Table 1. "E" means escalate the dose, "S" means maintain the same dose, and "D" means decrease the dose. Decision "DU" means that the current dose level may be unacceptable due to high toxicity. A dose is defined as having unacceptable toxicity if the posterior probability of a DLT rate above 25% is greater than 95%.
將按群組進行此研究之入選。完成各群組後，關於劑量遞增及後續群組規模的決策將由發起人與安全性監測委員會(SMC)協商來作出。每劑量水準將治療至少2名DLT可評估(DE)個體，直至觀測到第一DLT。在觀測到第一DLT之後，將需要每劑量水準最少3名DE個體，隨後遞增至所有較高劑量。在劑量遞增期間初步評估劑量水準之後，2名個體不可同一天接受初始劑量之研究藥物。可替換在第1週期期間視為對DLT不可評估之個體。在MTD確定之前，將以估測之MTD觀測到最少6名DE個體。將基於所有評估劑量中所有個體的資料來估測MTD。MTD定義為不會引起不可接受的副作用之最高評估劑量，由mTPI設計測定。Enrollment in this study will be done on a cohort basis. Decisions regarding dose escalation and subsequent cohort sizes will be made by the Sponsor in consultation with the Safety Monitoring Committee (SMC) upon completion of each cohort. A minimum of 2 DLT-evaluable (DE) subjects will be treated at each dose level until the first DLT is observed. After the first DLT is observed, a minimum of 3 DE subjects per dose level will be required with subsequent escalation to all higher doses. After the initial assessment of dose levels during the dose escalation period, 2 subjects may not receive an initial dose of study drug on the same day. Subjects deemed unevaluable for DLT during Cycle 1 may be substituted. A minimum of 6 DE subjects will be observed at the estimated MTD before the MTD is determined. The MTD will be estimated based on data from all individuals at all doses evaluated. The MTD is defined as the highest evaluated dose that does not cause unacceptable adverse effects, as determined by the mTPI design.
可在由發起人與SMC協商之任何時間進行遞減至較低劑量水準。Reductions to lower dose levels may be made at any time by agreement between the Sponsor and the SMC.
在劑量遞增期間，可以視為可耐受之測試劑量水準選入額外個體(下文稱為「回填(backfilling)」)。在較低劑量水準下觀測到之DLT將與全部資料一起考慮；SMC將基於在觀測到回填DLT之當前及較低劑量水準下的mTPI模型建議來作出未來遞增決策。 表1：MTPI之劑量探索試算表
SGN-B6A劑量水準及投與時程將由群組分配限定。最初將以表2中所示之計劃劑量在21天週期之第1天、第8天及第15天投與SGN-B6A。可在與SMC協商之後的劑量遞增期間評估較長給藥間隔(例如僅第1天及第8天或僅21天週期之第1天或在28天週期中兩週一次)。mTPI劑量遞增規則將分開應用於各給藥時程。SMC亦可建議對較低及/或中間劑量水準之研究，在此情況下，將繼續應用mTPI劑量遞增規則。 表2：劑量遞增方案
疾病特異性群組：在完成針對特定時程之劑量遞增時，為了進一步表徵SGN-B6A之安全性、PK及抗腫瘤活性，至多360名額外個體可入選至多9個疾病特異性擴增群組。擴增群組可各自選入符合入選劑量遞增條件之所選擇的腫瘤類型之大致40名個體。對於各疾病特異性群組，首先將選入15名個體。對於擴增群組，若可行，則需要進行基線新鮮腫瘤組織活檢。可收集視情況選用之方案指定的治療期(on-treatmen)或治療結束(end of treatment，EOT)研究活檢以用於SGN-B6A腫瘤暴露及抗腫瘤活性之探究性相關研究。無效性分析將使用預測成功機率(PPoS)方法來進行，其中成功定義為具有大於0.70的後驗機率，亦即反應率大於背景反應率。若疾病特異性群組中PPoS ＜15%，則可確定無效性。當背景反應率為0.05時，若在前15名個體中觀測到至少一個客觀反應(OR)，則可選入至多25名額外個體；若在前15名個體中未觀測到OR，則SMC將評估全部資料，且若前15名個體中存在臨床益處之初步跡象，則可建議繼續選入至多25名額外個體。臨床益處之跡象可包括由研究人員評估之疾病相關症狀的穩定或改善，或在成像上之疾病消退。擴增群組之劑量、時程及疾病設定將由發起人與SMC協商確定且可在群組之間有所不同。Disease-Specific Cohorts: Upon completion of dose escalation for a specific schedule, up to 360 additional subjects may be enrolled in up to 9 disease-specific expansion cohorts to further characterize the safety, PK, and anti-tumor activity of SGN-B6A. The expansion cohorts may each enroll approximately 40 subjects of the selected tumor type who meet the eligibility criteria for dose escalation. For each disease-specific cohort, 15 subjects will be enrolled initially. For the expansion cohorts, a baseline fresh tumor tissue biopsy will be required, if feasible. On-treatment or end of treatment (EOT) study biopsies, as appropriate, may be collected for exploratory correlation studies of SGN-B6A tumor exposure and antitumor activity. Futility analyses will be performed using the predicted probability of success (PPoS) approach, where success is defined as having a posterior probability greater than 0.70, i.e., a response rate greater than the background response rate. Futility will be determined if the PPoS is <15% in disease-specific cohorts. When the background response rate is 0.05, if at least one objective response (OR) is observed in the first 15 subjects, up to 25 additional subjects may be enrolled; if no OR is observed in the first 15 subjects, the SMC will evaluate all data and if there are preliminary signs of clinical benefit in the first 15 subjects, it may be recommended to continue to enroll up to 25 additional subjects. Signs of clinical benefit may include stabilization or improvement of disease-related symptoms assessed by the investigator, or disease regression on imaging. The dose, schedule, and disease setting of the expansion group will be determined by the sponsor in consultation with the SMC and may vary between groups.
生物學群組：患有任何所選擇的腫瘤類型之同意進行方案指定之研究活檢的額外至多30名個體可能符合入選生物學群組之條件。將要求生物學群組中之個體提供治療前及治療後腫瘤樣品以表徵臨床作用機制(MOA)及在MTD或建議劑量下的敏感性/抗性之相關性。部分C-與帕博利珠單抗組合之SGN-B6ABiological Group: Up to 30 additional individuals with any selected tumor type who consent to protocol-specified study biopsies may be eligible for inclusion in the Biological Group. Individuals in the Biological Group will be asked to provide pre- and post-treatment tumor samples to characterize the clinical mechanism of action (MOA) and correlation of sensitivity/resistance at the MTD or proposed dose.PartC-SGNin Combination with Pembrolizumab-B6A
部分C經設計以評估SGN-B6A與帕博利珠單抗組合之安全性及耐受性。SGN-B6A將以部分A中所限定之建議劑量及時程開始與帕博利珠單抗(每3週200 mg或每6週400 mg)組合進行投與。部分C將使用mTPI方法進行，最小群組規模為3。必要時，劑量將遞減至劑量水準-1，依部分A中所測定。部分D-組合治療擴增群組Part C is designed to evaluate the safety and tolerability of SGN-B6A in combination with pembrolizumab. SGN-B6A will be administered in combination with pembrolizumab (200 mg every 3 weeks or 400 mg every 6 weeks) starting at the recommended dose and schedule defined in Part A. Part C will be conducted using the mTPI approach with a minimum cohort size of 3. If necessary, the dose will be reduced to dose level -1 as determined in Part A.PartD-Combination Treatment Expansion Cohort
為進一步表徵SGN-B6A與帕博利珠單抗組合之安全性、PK及抗腫瘤活性，NSCLC (局部測試之TPS ≥50)及HNSCC (局部測試之CPS ≥1)的2個擴增群組各自將入選至多大致40名個體。部分C中所評估之劑量方案將告知針對擴增群組之劑量及時程的選擇，待由發起人與SMC協商來確定。群組之間的劑量及時程可有所不同。治療之持續時間To further characterize the safety, PK, and antitumor activity of the combination of SGN-B6A and pembrolizumab, 2 expansion cohorts of NSCLC (TPS ≥50 on local testing) and HNSCC (CPS ≥1 on local testing) will enroll up to approximately 40 subjects each. The dosing regimens evaluated in Section C will inform the selection of dose and schedule for the expansion cohorts, to be determined by the Sponsor in consultation with the SMC. Dosing and schedule may vary between cohorts.Duration of Treatment
在所有部分中，個體可繼續用SGN-B6A治療直至疾病進展、不可接受之毒性、研究人員決策、撤回同意書、開始後續抗癌療法、妊娠或由發起人終止研究為止，以先者為準。在部分C及D中，可投與帕博利珠單抗直至按照iRECIST確認之疾病進展、不可接受之毒性、研究人員決策、撤回同意書、開始後續抗癌療法、妊娠或由發起人終止研究為止，或持續至多24個月，以先者為準。劑量限制性毒性In all parts, subjects may continue treatment with SGN-B6A until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, initiation of subsequent anticancer therapy, pregnancy, or study termination by the sponsor, whichever occurs first. In Parts C and D, pembrolizumab may be administered until disease progression confirmed by iRECIST, unacceptable toxicity, investigator decision, withdrawal of consent, initiation of subsequent anticancer therapy, pregnancy, or study termination by the sponsor, or for up to 24 months, whichever occurs first.Dose-Limiting Toxicity
將在劑量遞增期間評估DLT。DLT評估時段將為第一週期(21天或28天)。將根據國家癌症研究所通用不良事件術語準則(National Cancer Institute Common Terminology Criteria for Adverse Events，NCI CTCAE)，v5.0分級。DLT will be assessed during dose escalation. DLT assessment period will be the first cycle (21 days or 28 days). It will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v5.0.
對於部分A，若由研究人員評估為臨床上顯著且與SGN-B6A治療相關，則DLT定義為在DLT評估時段期間以下中之任一者。For Part A, a DLT was defined as any of the following during the DLT Assessment Period if assessed by the Investigator to be clinically significant and related to SGN-B6A treatment.
對於部分C，DLT定義為視為與SGN-B6A或與帕博利珠單抗組合相關但無法單獨歸因於帕博利珠單抗的以下中之任一者。 ● 5級毒性 ● ≥3級非血液毒性(非實驗室)，以下除外： ○ 在具有或不具有干預情況下之72小時消退的3級疲勞、發熱或便秘 ○ 在無標準照護防治情況下之3級噁心、嘔吐或腹瀉 ○ 在具有或不具有干預情況下之在24小時內消退至≤2級的3級IRR ○ 若在≥20%之個體(亦即，前10名個體中之2名或更多名)中發生3級IRR，則所有後續個體將需要前驅用藥(premedication)及/或按照SMC建議修改輸注方法，且將修改方案。對於後續個體，任何≥3級IRR將視為DLT。 ● 在以下情況下的3級或4級非血液學實驗室異常： ○ 該異常需要住院或臨床上顯著之醫療干預，或 ○ 該異常持續＞7天，或 ● 4級貧血或血小板減少症 ● 持續＞7天的4級血液毒性(除貧血/血小板減少症以外) ● 3級血小板減少症，伴有需要血小板輸注之臨床顯著之出血 ● ≥3級發熱性嗜中性球減少症 ● 劑量延遲≥14天(歸因於毒性)目標For Part C, DLTs are defined as any of the following that are considered related to SGN-B6A or in combination with pembrolizumab but cannot be attributed to pembrolizumab alone. ● Grade 5 toxicities● ≥Grade 3 non-hematologic toxicities (non-laboratory), except for the following: ○ Grade 3 fatigue, pyrexia, or constipation that resolves within 72 hours with or without intervention ○ Grade 3 nausea, vomiting, or diarrhea without standard of care prevention ○ Grade 3 IRR that resolves within 24 hours to ≤Grade 2 with or without intervention ○ If Grade 3 IRR occurs in ≥20% of subjects (i.e., 2 or more of the first 10 subjects), all subsequent subjects will require premedication and/or modification of infusion method as recommended by the SMC, and the protocol will be modified. For subsequent subjects, any ≥ Grade 3 IRR will be considered a DLT. ● Grade 3 or 4 non-hematologic laboratory abnormality if: ○ The abnormality requires hospitalization or clinically significant medical intervention, or ○ The abnormality persists for >7 days, or ● Grade 4 anemia or thrombocytopenia ● Grade 4 hematologic toxicity (other than anemia/thrombocytopenia) persisting for >7 days ● Grade 3 thrombocytopenia with clinically significant bleeding requiring platelet transfusion ● ≥Grade 3 febrile neutropenia ● Dose delay ≥14 days (attributable to toxicity)Target
此研究將評估患有以下組織學或細胞學上確診之轉移性或不可切除性癌症的成人中之SGN-B6A的功效、安全性及PK：NSCLC、HNSCC、晚期HER2陰性乳癌、ESCC、EAC/GEJ腺癌、HGSOC、cSCC、外分泌胰臟腺癌、膀胱癌、子宮頸癌或胃癌。此研究亦將評估SGN-B6A與帕博利珠單抗組合在患有轉移性或不可切除性NSCLC或HNSCC之成人中的功效、安全性及PK。研究之特定目標及對應終點概述於表3中。表3：目標及對應終點
客觀反應率- ORR (不考慮確認)定義為按照RECIST v1.1獲得PR或CR之個體的比例。確認之ORR定義為具有CR或PR之個體的比例，其隨後根據RECIST v1.1評估加以確認。無法按照反應準則評估疾病反應之個體將被評為對於計算ORR而言「不可評估」。在ORR之計算中，不具有基線後反應評估或具有「不可評估」之反應的個體將視為無反應者。Objective Response Rate - ORR (regardless of confirmation) is defined as the proportion of subjects with a PR or CR per RECIST v1.1. Confirmed ORR is defined as the proportion of subjects with a CR or PR who are subsequently assessed and confirmed per RECIST v1.1. Subjects whose disease response could not be assessed per the response criteria were scored as "Not Evaluable" for the calculation of ORR. Subjects without a post-baseline response assessment or with a response that was "Not Evaluable" were considered non-responders for the calculation of ORR.
無進展存活期- PFS定義為自任何研究治療開始至首先記錄PD (基於按照RECIST v1.1之放射照相評估)或至由任何原因所致之死亡(以先者為準)的時間。在分析時存活及未進展之個體將在最後腫瘤評估日進行檢查。在第一次給藥後不具有腫瘤反應評估之個體將在1天時進行檢查。Progression-Free Survival - PFS is defined as the time from the start of any study treatment to the first documented PD (based on radiographic assessment per RECIST v1.1) or to death from any cause, whichever comes first. Subjects alive and not progressing at the time of analysis will be censored at the last tumor assessment day. Subjects who do not have a tumor response assessment after the first dose will be censored at 1 day.
總存活期- OS定義為自任何研究治療開始至由任何原因所致之死亡日期的時間。特定言之， OS = 死亡日期-任何研究治療之第一次給藥的日期+1。 在其最後一次接觸日存活之個體，包括失訪之彼等個體的OS在最後一次接觸日進行檢查。若個體已知存活之最後記錄日期為任何研究治療之第一次給藥的日期，則將在任何研究治療之第一次給藥的日期(亦即，1天之OS持續時間)檢查存活時間。Overall Survival - OS is defined as the time from the start of any study treatment to the date of death from any cause. Specifically,OS = date of death - date of first dose of any study treatment + 1.OS for subjects alive on their last contact date, including those lost to visit, was censored at the last contact date. If the last recorded date of survival for an individual was the date of first dose of any study treatment, survival was censored at the date of first dose of any study treatment (i.e., 1 day OS duration).
反應持續時間- DOR定義為自首次記錄客觀反應(隨後經確認之CR或PR)至首次記錄PD或至由任何原因所致之死亡(以先者為準)的時間。對於在分析時不具有腫瘤進展且仍在研究中、接受除研究治療以外之抗腫瘤治療或在記錄腫瘤進展之前自研究移除的個體，DOR資料將在記錄無PD之最後一次充分的疾病評估日進行檢查。將僅計算獲得確認反應之個體的DOR。研究群體Duration of Response - DOR is defined as the time from the first documented objective response (subsequently confirmed CR or PR) to the first documented PD or to death from any cause, whichever comes first. For subjects who do not have tumor progression at the time of analysis and remain on study, receive anti-cancer therapy other than study treatment, or are removed from the study before documented tumor progression, DOR data will be censored at the last adequate disease assessment date with documented freedom from PD. DOR will be calculated only for subjects with a confirmed response.Study Population
個體必須滿足符合此研究條件的所有入選準則。研究人員不可放棄合格性準則且在良好臨床規範稽查及/或健康管理機構檢查的情況下對合格性準則進行審查。納入準則1. 疾病適應症 a. 對於部分A： 個體必須患有以下列出之腫瘤類型之一內的組織學或細胞學上確診之轉移性或不可切除性實體惡性腫瘤。個體必須患有疾病，該疾病為復發性或難治性的或對標準照護療法不耐受，且根據研究人員之判斷，應不具有適當的標準照護治療選擇方案。若尚未投與可供使用的標準照護療法，則必須記錄療法不合適的原因。 ● NSCLC ● HNSCC ● 晚期HER2陰性乳癌 ● ESCC ● EAC/GEJ ● HGSOC ● cSCC ● 外分泌胰臟腺癌 ● 膀胱癌 ● 子宮頸癌 ● 胃癌 b. 對於部分B： 個體可進入至多9個疾病特異性擴增群組。除非有禁忌，否則個體必須患有組織學或細胞學上確診之疾病，該疾病為復發性或難治性的或對依下文所指定之標準照護療法不耐受： - NSCLC： − 個體必須患有局部晚期或轉移性非小細胞肺癌 − 先前療法：若按照當地標準照護可行且適用，個體必須已接受基於鉑之療法及PD-1/PD-L1抑制劑。此等藥劑可作為單一藥劑或以組合形式投與。 − 具有記錄之可操作基因體改變的個體應已接受經批准之酪胺酸激酶抑制劑(TKI；例如ALK、ROS-1基因重排或EGFR突變或其他可適用的靶向療法)治療以按照當地指南進行各別基因體改變。此等個體應在局部晚期或轉移性情況下接受不超過3種全身性療法線。維持療法不應視為單獨的療法線。 - HNSCC： − 個體必須患有局部晚期或轉移性頭頸部鱗狀細胞癌。 − 先前療法：若符合生物標記物狀態及當地標準照護的條件，則個體必須已接受基於鉑之療法及PD-1/PD-L1抑制劑。此等藥劑可能已作為單一藥劑或以組合形式投與 - 晚期HER2陰性乳癌： − 個體必須患有局部晚期或轉移性HER2陰性乳癌(根據美國臨床腫瘤學會(American Society of Clinical Oncology)/美國病理學家學會(College of American Pathologists) [ASCO/CAP] 2018指南)。 − 個體必須已接受1或多種用於局部晚期或轉移性疾病之先前療法線。先前療法必須包括以單一藥劑形式或以組合形式投與之紫杉烷。 − 除非有禁忌，否則激素受體陽性個體另外必須已接受CDK4/6-抑制劑療法，及至少1種先前激素導向療法。 − 若符合生物標記物狀態的條件且符合標準照護，則必須已接受聚ADP核糖聚合酶(PARP)抑制劑、PD-1/PD-L1抑制劑及/或磷酸肌醇3-激酶(PI3K)抑制劑。 - ESCC： − 個體必須患有局部晚期或轉移性食道鱗狀細胞癌。 − 個體必須已接受先前基於鉑之化學療法。 − 若符合生物標記物狀態的條件且符合標準照護，則必須已接受先前PD-1/PD-L1抑制劑。 - EAC/GEJ腺癌： − 個體必須患有局部晚期或轉移性EAC或GEJ腺癌。 − 個體必須已接受先前基於鉑之化學療法。 − 若符合生物標記物狀態的條件且符合標準照護，則必須已接受先前PD-1/PD-L1抑制劑或HER-2導向療法。 - HGSOC： − 個體必須患有高級漿液性上皮卵巢癌、原發性腹膜癌或輸卵管癌。 − 個體必須患有鉑抗性疾病，其定義為在先前含鉑化學療法之後6個月內有進展或復發。若符合條件，則必須已接受含貝伐珠單抗之方案。若符合生物標記物狀態的條件且符合標準照護，則必須已接受PARP抑制劑。 - cSCC： − 個體必須患有局部晚期或轉移性皮膚鱗狀細胞癌。 − 個體必須接受PD-1/PD-L1抑制劑。 c. 對於部分C： ● 個體必須患有以下列出之腫瘤類型之一內的組織學或細胞學上確診之轉移性或不可切除性實體惡性腫瘤。 o NSCLC o HNSCC o ESCC o cSCC ● 個體必須符合按照當地標準照護之帕博利珠單抗單一療法的條件。 d. 對於部分D： ● 個體可進入至多2個疾病特異性擴增群組。個體必須患有組織學或細胞學上確診之疾病，且未曾接受用於局部晚期或轉移性疾病之一線全身性療法(允許先前接受過確定的預期或輔助療法，PD-[L]1除外)。 ● 患有NSCLC之個體必須通過當地測試具有TPS ≥50，從而符合SGN-B6A與帕博利珠單抗組合之群組測試的條件。 ● 患有HNSCC之個體必須通過當地測試具有CPS ≥1，從而選入SGN-B6A與帕博利珠單抗組合之群組測試。 2. 入選以下研究部分之個體應具有可進行活檢的腫瘤部位且同意如下進行活檢： - 疾病特異性擴增群組(部分B及部分D)：需要進行基線新鮮腫瘤活檢。可使用在90天內收集之存檔活體組織切片。若在與醫學監測者討論之後在醫學上不可行(例如病變無法藉由不表示有重大風險之微創手術獲得)，則可放棄此活檢 - 生物學擴增群組：治療前活檢及治療期(第1週期)活檢。若對於疾病特異性擴增及生物學群組中之所有個體可行，則需要額外視情況選用之活檢體。 3. 年齡為18歲或更大。 4. 東部腫瘤協作組(Eastern Cooperative Oncology Group，ECOG)體能狀態評分為0或1。 5. 在基線有按照RECIST v1.1之可量測疾病。 6. 以下基線實驗室資料： - 絕對嗜中性白血球計數(ANC) ≥1500/µL - 血紅素(Hgb) ≥9 g/dL - 血小板計數≥100,000/μL - 血清膽紅素≤1.5×正常上限(ULN)或對於患有吉爾伯氏病(Gilbert's disease)之個體而言，≤3×ULN - 適用時使用腎病飲食調整(Modification of Diet in Renal Disease，MDRD)研究方程式估算之腎小球濾過率(GFR) ≥45 mL/min/1.73 m2- 丙胺酸轉胺酶(ALT)及天冬胺酸轉胺酶(AST)≤3×ULN (若有惡性疾病累及肝臟的跡象，則≤5×ULN) 7. 有生育能力之個體，在以下條件下： a. 在SGN-B6A之第一次給藥前7天內，血清或尿液妊娠測試(最低靈敏度25 mIU/mL或等效單位的β人絨毛膜促性腺激素[β-hCG])結果必須呈陰性。具有假陽性結果且有記錄證明個體未懷孕的個體符合參與條件。 b. 必須同意在研究期間及投與研究藥物最後一次劑量之後的至少2個月內不嘗試懷孕。 c. 必須同意自知情同意時開始且持續至投與研究藥物最後一次劑量之後2個月不進行母乳餵養或捐獻卵子。 d. 若有可能導致懷孕之性行為，則自知情同意時開始且持續整個研究以及投與研究藥物最後一次劑量之後至少2個月內，必須堅持使用至少2種可接受的節育(避孕)方法，其中至少一者必須為高效的。 8. 可使他人懷孕之個體，在以下條件下： a. 必須同意自知情同意時開始且持續整個研究期且在最終研究藥物投與之後至少4個月內不捐獻精子。 b. 若與具有生育能力之人有可能導致懷孕之性行為，則自知情同意時開始且持續整個研究以及投與研究藥物最後一次劑量之後至少4個月內，必須堅持使用至少2種可接受的節育(避孕)方法，其中至少1者必須為高效的。 c. 若與懷孕或哺乳之人有性行為，則必須自知情同意時開始且持續整個研究以及投與研究藥物最後一次劑量之後至少4個月內堅持使用避孕套。 9. 個體必須提供書面知情同意書。排除準則1. 在研究藥物之第一次給藥前3年內之另一惡性腫瘤的病史，或先前診斷之惡性腫瘤之殘留疾病的任何跡象。例外為具有可忽略的轉移或死亡風險(例如5年OS ≥90%)之惡性腫瘤，諸如經充分治療之子宮頸原位癌、非黑色素瘤皮膚癌、局部前列腺癌、乳腺管原位癌或I期子宮癌。 2. 已知的活性中樞神經系統轉移。患有先前治療之腦轉移瘤的個體可參與，其限制條件為該等個體在腦轉移治療之後進入研究之前在臨床上穩定至少4週，該等個體不患有新的或擴大的腦轉移瘤，且在研究藥物第一次給藥之前停用針對與腦轉移有關之症狀開處的皮質類固醇至少7天。 3. 癌性腦膜炎。 4. 先前接受含MMAE藥劑或靶向整合素β-6之藥劑。 5. 按照NCI CTCAE v5.0預先存在≥2級之神經病變。 6. 在SGN-B6A之第一次給藥前2週內之任何不受控的≥3級(按照NCI CTCAE, v5.0)病毒、細菌或真菌感染。允許常規的抗微生物防治。 7. 不受控的糖尿病，定義為血紅素A1C (Hgb A1c) ≥8.0%或Hgb A1c在7與＜8.0%之間，伴隨未另外說明之相關糖尿病症狀(多尿或煩渴)。 8. 根據表面抗原表現對B型肝炎呈陽性。活性C型肝炎感染(在最近6個月內根據聚合酶鏈反應[PCR]或對C型肝炎之抗病毒療法呈陽性)。若已針對C型肝炎感染接受治療的個體已記錄有12週的持續病毒反應，則允許該等個體。 9. 已知對人類免疫缺乏病毒(HIV)呈陽性。 10. 在其SGN-B6A之第一次給藥前6個月內有腦血管事件(中風或短暫性缺血發作)、不穩定絞痛症、心肌梗塞、充血性心臟衰竭或符合紐約心臟協會(New York Heart Association) III-IV級之心臟症狀的記錄病史。 11. 根據紐約心臟協會準則，III級或IV級充血性心臟衰竭。 12. 與潛在惡性腫瘤無關的≥3級肺病。 13. 僅在劑量遞增期間，在研究藥物給藥之14天內使用強力細胞色素P450 3A (CYP3A)抑制劑。 14. 在研究藥物之第一次給藥的前4週，或若潛在疾病在治療時進展則在研究藥物之第一次給藥的前2週內未完成的化學療法、免疫療法、生物製劑及/或其他批准或研究用的抗腫瘤治療。 15. 在SGN-B6A之第一次給藥的前2週未完成的局部放射療法或大型手術。 16. 自知情同意時直至投與研究藥物最後一次劑量之後2個月，哺乳、懷孕或計劃懷孕之個體。 17. 已知對SGN-B6A之藥物調配物中所含之任何賦形劑過敏。 18. 所估測之預期壽命＜12週 19. 在研究人員看來，會減弱個體接受或耐受計劃治療及隨訪之能力的其他嚴重潛在醫學病狀。 20. 在第一次研究藥物給藥之30天內接受活毒疫苗之個體。 僅部分C： 21. 已接受使用PD-1抑制劑、抗PD-L1或抗PD-L2藥劑或使用針對另一刺激或共抑制T細胞受體(例如CTLA-4、OX 40、CD137)之藥劑的先前療法，且由於3級或更高的免疫介導之不良事件(IMAE)而中斷該治療。 僅部分D： 22. 患有具有可操作基因體改變(例如ALK、ROS-1基因重排或EGFR突變)之NSCLC。 僅部分C及D： 23. 診斷患有免疫缺乏，或在研究藥物之第一次給藥前7天內接受慢性全身性類固醇療法(給藥超過每日10 mg之普賴松等效物)或任何其他形式之免疫抑制療法。 24. 具有在過去2年內需要全身性治療(亦即，使用疾病調節劑、皮質類固醇或免疫抑制藥物)之活性自體免疫疾病。替代療法(例如針對腎上腺或垂體不足之甲狀腺素、胰島素或生理學皮質類固醇替代療法)可不考慮為全身性治療形式且予以允許。 25. 具有需要類固醇之(非感染性)肺炎病史或目前患有肺炎。 26. 具有間質性肺病病史。 27. 在試驗治療之第一次給藥的6個月內已接受＞30 Gy的針對肺之放射療法。 28. 進行過同種異體組織/實體器官移植。投與之治療Subjects must meet all inclusion criteria to be eligible for this study. Eligibility criteria may not be waived by the Investigator and will be reviewed by the Investigator at the time of a Good Clinical Practice Audit and/or Health Care Authority inspection.Inclusion Criteria 1. Disease Indications a. For Section A: Subjects must have a histologically or cytologically confirmed metastatic or unresectable solid malignant tumor of one of the tumor types listed below. Subjects must have a disease that is relapsed or refractory or intolerant to standard of care therapy and, in the judgment of the Investigator, has no adequate standard of care treatment options. If available standard of care therapy has not been administered, the reason why the therapy is inappropriate must be documented. ● NSCLC ● HNSCC ● Advanced HER2-negative breast cancer● ESCC ● EAC/GEJ ● HGSOC ● cSCC ● Exocrine pancreatic cancer● Bladder cancer● Cervical cancer● Gastric cancerb. For Part B: Individuals may enter up to 9 disease-specific expansion groups. Unless contraindicated, individuals must have histologically or cytologically confirmed disease that is relapsed or refractory or intolerant to standard of care therapy as specified below: - NSCLC: − Individuals must have locally advanced or metastatic non-small cell lung cancer− Prior therapy: Individuals must have received platinum-based therapy and a PD-1/PD-L1 inhibitor, if feasible and appropriate per local standard of care. These agents may be administered as single agents or in combination. − Individuals with documented actionable genomic alterations should have received treatment with an approved tyrosine kinase inhibitor (TKI; e.g., ALK, ROS-1 gene rearrangement, or EGFR mutation or other applicable targeted therapy) for the respective genomic alteration as per local guidelines. These individuals should have received no more than 3 lines of systemic therapy in the locally advanced or metastatic setting. Maintenance therapy should not be considered as a single line of therapy. - HNSCC: − Individuals must have locally advanced or metastatic head and neck squamous cell carcinoma. − Prior therapy: Individuals must have received platinum-based therapy and a PD-1/PD-L1 inhibitor if eligible by biomarker status and local standard of care. These agents may have been administered as single agents or in combination - Advanced HER2-negative breast cancer: − Individuals must have locally advanced or metastatic HER2-negative breast cancer (per the American Society of Clinical Oncology/College of American Pathologists [ASCO/CAP] 2018 guidelines). − Individuals must have received 1 or more prior lines of therapy for locally advanced or metastatic disease. Prior therapy must have included a taxane administered as a single agent or in combination. − Hormone receptor-positive individuals must have additionally received CDK4/6-inhibitor therapy, and at least 1 prior hormone-directed therapy, unless contraindicated. − If eligible by biomarker status and eligible for standard of care, must have received a poly ADP ribose polymerase (PARP) inhibitor, PD-1/PD-L1 inhibitor, and/or phosphoinositide 3-kinase (PI3K) inhibitor. - ESCC: − Subjects must have locally advanced or metastatic esophageal squamous cell carcinoma. − Subjects must have received prior platinum-based chemotherapy. − If eligible by biomarker status and eligible for standard of care, must have received prior PD-1/PD-L1 inhibitor. - EAC/GEJ adenocarcinoma: − Subjects must have locally advanced or metastatic EAC or GEJ adenocarcinoma. − Subjects must have received prior platinum-based chemotherapy. − If eligible by biomarker status and eligible for standard of care, must have received prior PD-1/PD-L1 inhibitor or HER-2 directed therapy. - HGSOC: − Subjects must have high-grade serous epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. − Subjects must have platinum-resistant disease, defined as progression or relapse within 6 months of prior platinum-containing chemotherapy. If eligible, must have received a bevacizumab-containing regimen. If eligible by biomarker status and eligible for standard of care, must have received a PARP inhibitor. - cSCC: − Subjects must have locally advanced or metastatic cutaneous squamous cell carcinoma. − Subjects must have received a PD-1/PD-L1 inhibitor. c. For Part C: ● Individuals must have a histologically or cytologically confirmed metastatic or unresectable solid malignancy in one of the tumor types listed below. o NSCLC o HNSCC o ESCC o cSCC ● Individuals must be eligible for pembrolizumab monotherapy per local standard of care. d. For Part D: ● Individuals may enter up to 2 disease-specific expansion cohorts. Individuals must have histologically or cytologically confirmed disease and have not received first line systemic therapy for locally advanced or metastatic disease (prior treatment with established anticipatory or adjuvant therapy, excluding PD-[L]1, is permitted). ● Individuals with NSCLC must have a TPS ≥50 by local testing to be eligible for the cohort testing of the SGN-B6A and pembrolizumab combination. ● Individuals with HNSCC must have a CPS ≥1 by local testing to be selected for the cohort testing of the SGN-B6A and pembrolizumab combination. 2. Individuals enrolled in the following study parts should have a biopsyable tumor site and consent to biopsy as follows: - Disease-Specific Expansion Cohorts (Part B and Part D): Baseline fresh tumor biopsy is required. Archival biopsies collected within 90 days may be used. If medically impractical after discussion with the medical monitor (e.g., lesions are not accessible by minimally invasive surgery that does not present a significant risk), this biopsy may be waived - Biological expansion group: pre-treatment biopsy and on-treatment (Cycle 1) biopsy. Additional optional biopsies are required if feasible for all individuals in the disease-specific expansion and biological groups. 3. Age 18 years or older. 4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. 5. Measurable disease per RECIST v1.1 at baseline. 6. The following baseline laboratory data: - Absolute neutrophil count (ANC) ≥1500/µL - Hemoglobin (Hgb) ≥9 g/dL - Platelet count ≥100,000/μL - Serum bilirubin ≤1.5×ULN or ≤3×ULN for individuals with Gilbert's disease - Glomerular filtration rate (GFR) estimated using the Modification of Diet in Renal Disease (MDRD) study equation ≥45 mL/min/1.73m2 when applicable - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3×ULN (≤5×ULN if there is evidence of malignant disease involving the liver) 7. Subjects of childbearing potential, under the following conditions: a. Must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) within 7 days prior to the first dose of SGN-B6A. Subjects with a false positive result and documented non-pregnancy status are eligible. b. Must agree not to attempt pregnancy during the study and for at least 2 months after the last dose of study drug. c. Must agree not to breastfeed or donate eggs, beginning at the time of informed consent and continuing until 2 months after the last dose of study drug. d. If sexual behavior could lead to pregnancy, at least 2 acceptable birth control (contraception) methods must be used consistently, at least one of which must be highly effective, starting from the time of informed consent and continuing throughout the study and for at least 2 months after the last dose of the study drug. 8. Individuals who can impregnate others, under the following conditions: a. Must agree not to donate sperm starting from the time of informed consent and continuing throughout the study period and for at least 4 months after the last dose of the study drug. b. If sexual behavior with a person of fertile potential could lead to pregnancy, at least 2 acceptable birth control (contraception) methods must be used consistently, at least one of which must be highly effective, starting from the time of informed consent and continuing throughout the study and for at least 4 months after the last dose of the study drug. c. If having sexual intercourse with a pregnant or breastfeeding person, condom use must be adhered to starting at the time of informed consent and continuing throughout the study and for at least 4 months after the last dose of study drug. 9. Individuals must provide written informed consent.Exclusion Criteria 1. A history of another malignant tumor within 3 years before the first dose of study drug, or any signs of residual disease from a previously diagnosed malignant tumor. Exceptions are malignant tumors with a negligible risk of metastasis or death (e.g., 5-year OS ≥90%), such as adequately treated cervical carcinoma in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ of the breast, or stage I uterine cancer. 2. Known active central nervous system metastasis. Subjects with previously treated brain metastases may participate provided that they have been clinically stable for at least 4 weeks prior to study entry following treatment of brain metastases, that they do not have new or enlarging brain metastases, and that they have discontinued corticosteroids prescribed for symptoms related to brain metastases for at least 7 days prior to the first dose of study drug. 3. Carcinomatous meningitis. 4. Prior receipt of MMAE-containing agents or agents targeting integrin beta-6. 5. Pre-existing neuropathy of ≥ Grade 2 per NCI CTCAE v5.0. 6. Any uncontrolled Grade ≥ 3 (per NCI CTCAE, v5.0) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of SGN-B6A. Routine antimicrobial prophylaxis is permitted. 7. Uncontrolled diabetes, defined as hemoglobin A1C (Hgb A1c) ≥8.0% or Hgb A1c between 7 and <8.0% with associated diabetic symptoms not otherwise specified (polyuria or thirst). 8. Positive for hepatitis B based on surface antigen expression. Active hepatitis C infection (positive within the last 6 months based on polymerase chain reaction [PCR] or antiviral therapy for hepatitis C). Individuals who have been treated for hepatitis C infection are permitted if they have documented a sustained viral response for 12 weeks. 9. Known positive for human immunodeficiency virus (HIV). 10. Documented history of cerebrovascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure, or cardiac symptoms consistent with New York Heart Association Class III-IV within 6 months prior to their first dose of SGN-B6A. 11. Class III or IV congestive heart failure according to New York Heart Association guidelines. 12. Grade ≥ 3 pulmonary disease not related to underlying malignancy. 13. Use of strong cytochrome P450 3A (CYP3A) inhibitors within 14 days of study drug administration during the dose escalation period only. 14. Chemotherapy, immunotherapy, biologics, and/or other approved or investigational anti-cancer therapy that was not completed within 4 weeks of the first dose of study drug, or within 2 weeks of the first dose of study drug if the underlying disease progressed on treatment. 15. Localized radiation therapy or major surgery that was not completed within 2 weeks of the first dose of SGN-B6A. 16. Individuals who are breastfeeding, pregnant, or planning to become pregnant from the time of informed consent until 2 months after the last dose of study drug. 17. Known hypersensitivity to any formulation contained in the drug formulation of SGN-B6A. 18. Estimated life expectancy < 12 weeks 19. Other serious underlying medical conditions that, in the opinion of the investigator, would impair the individual's ability to accept or tolerate planned treatment and follow-up. 20. Individuals who received a live virus vaccine within 30 days of the first dose of study drug. Part C only: 21. Have received prior therapy with a PD-1 inhibitor, anti-PD-L1 or anti-PD-L2 agent, or with an agent that targets another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and discontinued that therapy due to a Grade 3 or higher immune-mediated adverse event (IMAE). Part D only: 22. NSCLC with actionable genomic alterations (e.g., ALK, ROS-1 gene rearrangements, or EGFR mutations). Parts C and D only: 23. Diagnosed with immunodeficiency or receiving chronic systemic steroid therapy (dosages exceeding 10 mg of prazol equivalents per day) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 24. 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 therapy and are permitted. 25. History of (non-infectious) pneumonitis requiring steroids or current pneumonitis. 26. History of interstitial lung disease. 27. Received >30 Gy of radiation therapy to the lung within 6 months of the first dose of the trial therapy. 28. Underwent allogeneic tissue/solid organ transplant.Treatment Administered
所有個體將接受SGN-B6A，在此方案中之研究下的研究用藥劑。SGN-B6A為一種由與破壞微管蛋白之抗有絲分裂劑MMAE結合之抗整合素β-6抗體(h2A2)構成的ADC。部分C及部分D中之個體亦將接受帕博利珠單抗。SGN-B6A為用於IV投與之復原用無菌不含防腐劑之白色至灰白色凍乾餅或粉末。SGN-B6A供應於單劑量玻璃小瓶中。在用注射用水(WFI) (美國藥典(United States Pharmacopoeia，USP))或等效物復原時，復原之藥品為透明至淺乳白色、無色至淺黃色溶液且無可見顆粒物質。劑量及投與All subjects will receive SGN-B6A, the investigational agent studied in this protocol. SGN-B6A is an ADC composed of an anti-integrin beta-6 antibody (h2A2) conjugated to the anti-tubulin-disrupting anti-mitotic agent MMAE. Subjects in Parts C and D will also receive pembrolizumab. SGN-B6A is a sterile, preservative-free, white to off-white lyophilized cookie or powder for reconstitution for IV administration. SGN-B6A is supplied in single-dose glass vials. When reconstituted with Water for Injection (WFI) (United States Pharmacopoeia, USP) or equivalent, the reconstituted drug product is a clear to light opalescent, colorless to light yellow solution with no visible particulate matter.Dosage and Administration
SGN-B6A劑量水準及投與時程將由群組分配限定。SGN-B6A將藉由IV輸注投與。給藥頻率(連續、間斷、Q3W或兩週一次)概述於下文。劑量遞增階段中之個體將需要在完成輸注之後第1週期第1天經歷4小時觀察期。建議個體在第1週期第1天投與SGN-B6A之後24小時仍保持在醫療機構附近，以在延遲IRR之情況下能夠進行即時評估。若第一輸注具有良好耐受性且無IRR出現，則後續輸注之觀察期可按照機構標準減少。SGN-B6A dose levels and dosing schedule will be determined by group assignment. SGN-B6A will be administered by IV infusion. Dosing frequency (continuous, intermittent, Q3W, or biweekly) is outlined below. Subjects in the dose escalation phase will need to undergo a 4-hour observation period on Cycle 1 Day 1 after completing the infusion. It is recommended that subjects remain in close proximity to a medical facility for 24 hours following administration of SGN-B6A on Cycle 1 Day 1 to allow for immediate assessment in the event of a delayed IRR. If the first infusion is well tolerated and no IRRs occur, the observation period for subsequent infusions may be reduced per institutional standards.
SGN-B6A最初將在21天週期之第1天、第8天及第15天投與。若由SMC建議，則可實施每21天週期之降低頻率的給藥，諸如僅在第1天及第8天或僅第1天給藥，或每28天週期之兩週一次。在無情況下，應相隔少於5天給與SGN-B6A之劑量。詳細給藥方案● 21天週期
SGN-B6A在投與之前需要稀釋。SGN-B6A needs to be diluted before administration.
基於重量之給藥係基於個體在基線之體重或按照機構標準。若有指示，則SMC可建議實施經調整之理想體重(AIBW)給藥。對於經歷體重相對於基線變化≥10%的個體，必須調整劑量。允許按照機構標準進行體重相對於基線變化＜10%的其他劑量調整。在標稱劑量之5%內，允許四捨五入至最接近的毫克整數。Weight-based dosing is based on the individual's weight at baseline or per institutional standards. If indicated, the SMC may recommend adjusted ideal body weight (AIBW) dosing. Dose adjustments must be made for individuals who experience a change in weight from baseline of ≥10%. Additional dose adjustments are permitted for a change in weight from baseline of <10% per institutional standards. Rounding to the nearest milligram is permitted within 5% of the nominal dose.
輸注持續時間將視輸注投與方法及劑量而變化。輸注速率應按照機構標準，但不應超過250毫升/小時。在劑量遞增部分A中，SGN-B6A應經輸注大致30分鐘。在審查彙總個體資料後，SMC可建議或需要較長或較短的輸注持續時間。Infusion duration will vary depending on the infusion administration method and dose. Infusion rate should be per institutional standards but should not exceed 250 mL/hour. In dose escalation section A, SGN-B6A should be infused over approximately 30 minutes. Longer or shorter infusion durations may be recommended or required by the SMC after review of aggregated individual data.
若個別個體不耐受輸注，則該個體之輸注持續時間可增加；後續輸注之輸注持續時間亦可按照研究人員與醫學監測者協商的判斷而增加。相反，若個體在無IRR＞1級之情況下耐受連續輸注，則輸注持續時間可由研究人員與醫學監測者協商而酌情縮短(亦即，以較快速率投與)，其實施可為劑量群體特異性的。If an individual is intolerant to the infusion, the duration of the infusion for that individual may be increased; the duration of the subsequent infusion may also be increased at the discretion of the investigator in consultation with the medical monitor. Conversely, if the individual tolerates the continuous infusion without an IRR>Grade 1, the duration of the infusion may be shortened (i.e., administered at a faster rate) at the discretion of the investigator in consultation with the medical monitor, and its implementation may be dose-specific.
在投與期間及投與後之任何時間，密切監測輸注部位之發紅、腫脹、疼痛及感染情況。應建議個體在投與時或輸注之後即時報告發紅或不適。將遵循機構指南來投與化學療法劑且按照機構標準採取防護措施以防止滲出。Closely monitor the infusion site for redness, swelling, pain, and infection during and at any time after administration. Individuals should be advised to report redness or discomfort immediately during or after administration. Chemotherapy agents will be administered in accordance with institutional guidelines and precautions will be taken per institutional standards to prevent extravasation.
隨著使用SGN-B6A之臨床經驗有所進展，可評估SGN-B6A投與及給藥之替代方法，包括但不限於以固定輸注速率投與、重量上限(weight-capped)之劑量投與、AIBW劑量投與或均一劑量投與。As clinical experience with SGN-B6A progresses, alternative methods of administration and dosing of SGN-B6A may be evaluated, including but not limited to administration at a fixed infusion rate, weight-capped dosing, AIBW dosing, or uniform dosing.
若在SMC建議後實施固定輸注速率，則以固定速率而非在固定時間內投與劑量。If a fixed infusion rate is implemented following SMC recommendation, the dose will be administered at a fixed rate rather than over a fixed time.
舉例而言，對於50 mg/hr之固定輸注速率，將在2小時內輸注100 mg之劑量。隨著以固定輸注速率投與之臨床經驗的發展，該速率可基於累積安全性資料及/或SMC建議而增加或降低。For example, for a fixed infusion rate of 50 mg/hr, a dose of 100 mg would be infused over 2 hours. As clinical experience with administration at a fixed infusion rate develops, the rate may be increased or decreased based on cumulative safety data and/or SMC recommendations.
隨著PK、藥效學及臨床活性資料發展，重量上限之IV劑量投與可在SMC建議後實施。與基於重量之給藥(其中計算總劑量而無對於個體重量之上限)相比，重量上限之給藥限制待用於總劑量計算之重量。待用於劑量計算之上限應基於新出現之資料而限定。As PK, pharmacodynamic, and clinical activity data develop, weight-capped IV dosing may be implemented upon SMC recommendation. Compared to weight-based dosing (where total dose is calculated without an upper limit on individual weight), weight-capped dosing limits the weight to be used in total dose calculations. The upper limit to be used in dose calculations should be defined based on emerging data.
舉例而言，若重量上限為100 kg，則體重≥100 kg之個體將使用100 kg重量來計算待投與之總劑量。在體重＜100 kg之個體中，使用個體之實際體重來計算待投與之總劑量。For example, if the upper weight limit is 100 kg, individuals weighing ≥100 kg will use 100 kg to calculate the total dose to be administered. In individuals weighing <100 kg, the individual's actual weight will be used to calculate the total dose to be administered.
若個體之實際總重量(TBW)高於或低於其IBW，則AIBW提供對理想體重(IBW)之調整。由於使用個體之性別、身高及TBW計算AIBW，所以總劑量之調整百分比將視目標身體質量指數(BMI)組而定。劑量修改AIBW provides adjustments to ideal body weight (IBW) if an individual's actual total body weight (TBW) is above or below their IBW. Because AIBW is calculated using the individual's sex, height, and TBW, the percentage adjustment to the total dose will depend on the target BMI group.Dose Modifications
對於SGN-B6A，針對毒性(包括DLT)之劑量減少或給藥間隔延長可按個體由研究人員與醫學監測者協商而核准。對於以最低劑量水準治療之個體，劑量可降低至最近投與劑量之25%，可降低給藥頻率(例如若在21天週期中，初次給藥為第1天、第8天及第15天，則給藥可更改為第1天及第8天或僅第1天)，或個體可中斷治療。For SGN-B6A, dose reductions or dosing interval extensions for toxicity (including DLT) may be approved on an individual basis by the investigator in consultation with the medical monitor. For subjects treated at the lowest dose level, the dose may be reduced to 25% of the most recently administered dose, the dosing frequency may be reduced (e.g., if the initial dosing is on Days 1, 8, and 15 of a 21-day cycle, dosing may be changed to Days 1 and 8 or Day 1 only), or the subject may have treatment interrupted.
除非充分地管理毒性，否則在第1週期中經歷DLT之個體不應接受用SGN-B6A之進一步治療，研究人員認為恢復SGN-B6A為適當的，且與醫學監測者進行協商。將考慮所觀測之AE的類型及嚴重程度，以為決策提供資訊。若個體在DLT及相同劑量限制性毒性復發之後繼續治療，則治療必須永久地中斷。經歷符合用於永久性中斷SGN-B6A準則之AE的個體可能不會恢復SGN-B6A，包括以較低或經修改之劑量或經降低之給藥頻率。Subjects who experience a DLT during Cycle 1 should not receive further treatment with SGN-B6A unless toxicity is adequately managed and resumption of SGN-B6A is deemed appropriate by the investigator, in consultation with the Medical Monitor. The type and severity of AEs observed will be considered to inform this decision. If a subject continues treatment after a DLT and recurrence of the same dose-limiting toxicity, treatment must be permanently discontinued. Subjects who experience AEs that meet criteria for permanent discontinuation of SGN-B6A may not resume SGN-B6A, including at a lower or modified dose or reduced dosing frequency.
若個體在第1週期之下一安排的給藥日或之後具有臨床上顯著、未消退的治療引發之不良事件(TEAE)，則下一劑量可延遲至多7天。歸因於其他原因或持續＞7天之延遲必須與醫學監測者討論。由於未消退之TEAE而需要劑量延遲＞7天的個體可在後續週期中以降低之劑量或可經與醫學監測者協商而降低之給藥頻率給藥。If a subject has a clinically significant, unresolved treatment-emergent adverse event (TEAE) on or after the next scheduled dosing day in Cycle 1, the next dose may be delayed up to 7 days. Delays attributable to other reasons or lasting >7 days must be discussed with the medical monitor. Subjects who require a dose delay of >7 days due to an unresolved TEAE may be dosed in subsequent cycles at a reduced dose or with a reduced dosing frequency in consultation with the medical monitor.
在DLT期期間，除非醫學上有指示，否則不贊成生長因子及輸注載體；在此時段期間因除DLT外之原因接受生長因子(例如顆粒球群落刺激因子[G-CSF]或顆粒球巨噬細胞群落刺激因子[GM-CSF])或輸注載體之個體可對於DLT為不可評估的。應考慮將生長因子載體(growth factor support)用於在後續週期中預防或治療血球減少症。儘管使用生長因子，但對於患有復發性4級嗜中性球減少症之個體，可考慮中斷或低於當前劑量之降低至1劑量水準的劑量(參見表2)。Growth factor and vehicle infusions are not contraindicated during the DLT period unless medically indicated; subjects who receive growth factors (e.g., granulocyte colony-stimulating factor [G-CSF] or granulocyte macrophage colony-stimulating factor [GM-CSF]) or vehicle infusions during this time period for reasons other than DLT may be unevaluable for DLT. Growth factor support should be considered for prevention or treatment of cytopenias in subsequent cycles. Despite the use of growth factors, interruption or dose reduction to 1 dose level below the current dose may be considered for subjects with recurrent Grade 4 neutropenia (see Table 2).
應在劑量延遲期間至少每週一次收集綜合代謝組(comprehensive metabolic panel，CMP)及全血球計數(CBC)。若除嗜中性球減少症以外之AE復發，儘管有2次劑量減少，但在與醫學監測者討論之後可准許額外劑量減少。A comprehensive metabolic panel (CMP) and complete blood count (CBC) should be collected at least weekly during the dose delay period. If an AE other than neutropenia recurs, despite 2 dose reductions, additional dose reductions may be permitted after discussion with the medical monitor.
表4描述用於研究治療相關毒性之建議劑量修改。在發生可能與SGN-B6A治療相關之≥3級AE之後，繼續研究治療需要進行醫學監測者協商。 表4：潛在SGN-B6A相關毒性之建議劑量修改
帕博利珠單抗為阻斷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。帕博利珠單抗為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.
帕博利珠單抗將以100 mg/4 mL (25 mg/mL)溶液形式供應於單次使用型小瓶中。用於注射之帕博利珠單抗為無菌、不含防腐劑的透明至淺乳白色、無色至淺黃色溶液，其需要稀釋以用於IV輸注。各小瓶含有含100 mg帕博利珠單抗之4 mL溶液。各1 mL溶液含有25 mg帕博利珠單抗且經調配於L-組胺酸、聚山梨醇酯、蔗糖及WFI USP中。Pembrolizumab will be supplied as a 100 mg/4 mL (25 mg/mL) solution in single-use vials. Pembrolizumab for injection is a sterile, preservative-free, clear to light opalescent, colorless to light 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, polysorbate, sucrose, and WFI USP.
在SGN-B6A之輸注之前，將在各21天週期之第1天或每6週分別以200 mg或400 mg之劑量使用30分鐘IV輸注在部分C及D群組中投與帕博利珠單抗之研究治療。必須在開始投與SGN-B6A之前至少30分鐘完成帕博利珠單抗之投與。部位應盡一切努力以使輸注時序目標定為儘可能接近30分鐘。然而，鑒於部位與部位的輸注泵之變化性，准許在-5分鐘與+10分鐘之間的窗口(亦即，輸注時間為30分鐘-5分鐘/+10分鐘)。Study treatment with pembrolizumab will be administered as a 30-minute IV infusion on Day 1 of each 21-day cycle or every 6 weeks in Cohorts C and D at a dose of 200 mg or 400 mg, respectively, prior to infusion of SGN-B6A. Administration of pembrolizumab must be completed at least 30 minutes prior to the start of administration of SGN-B6A. Sites should make every effort to target an infusion schedule as close to 30 minutes as possible. However, given site-to-site variability in infusion pumps, a window between -5 minutes and +10 minutes is permitted (i.e., an infusion time of 30 minutes -5 minutes/+10 minutes).
除非另外規定，否則應按照產品資訊或機構指南進行研究治療藥物之投與。劑量修改Unless otherwise specified, study therapeutics should beadministered according to product information or institutional guidance.
請參考帕博利珠單抗劑量修改之EU SmPC及帕博利珠單抗之毒性管理指南。Please refer to the EU SmPC for pembrolizumab dosing modifications and the guidelines for toxicity management of pembrolizumab.
僅對於部分C及D：AE可歸因於1種單獨試驗治療或試驗治療之組合。由研究人員酌情作出關於因果關係之最終決策。若事件明確地與藥劑之一相關，則遵循特定針對於該藥劑之說明書。若事件與多於1種藥劑有關，則遵循與其相關之所有藥劑的說明書。當個體可不耐受組合療法但可受益於用單獨1種藥劑治療時，可能存在某些情況。此等情況必須在個體可繼續治療之前由發起人討論及批准。在可能難以歸因於個別研究治療之情形中，停止或中斷研究治療之管理操作應適用於SGN-B6A及帕博利珠單抗兩者。反應/功效評估-按照RECIST之臨床反應For Sections C and D only: The AE may be attributable to 1 single trial treatment or a combination of trial treatments. The final decision regarding causality is at the discretion of the Investigator. If the event is clearly related to one of the drug(s), the instructions specific to that drug(s) are followed. If the event is related to more than 1 drug(s), the instructions for all drug(s) to which it is related are followed. There may be certain situations when an individual may not tolerate the combination therapy but may benefit from treatment with 1 drug alone. These situations must be discussed and approved by the Sponsor before the individual can continue treatment. In cases where attribution to individual study treatments is difficult, management practices to stop or interrupt study treatment should apply to both SGN-B6A and pembrolizumab.Response/Efficacy Assessments-Clinical ResponseAccording toRECIST
反應將藉由在以下時間進行放射照相腫瘤評估來評估：21天週期(第2週期、第4週期、第6週期及其後每個第3週期)之第15-21天，或自28天週期中之第1週期第1天(C1D1)每6週+/- 7天至第24週(每6週4次反應評估)，其後每8週進行。在疾病進展之前中斷治療或開始新抗癌療法的個體將接受體檢且在EOT後長達3年內繼續根據此時程評估反應，直至記錄PD或開始新療法。將藉由胸部、腹部及骨盆之CT及/或MRI掃描進行腫瘤評估。若有涉及此頸部區域之記錄或疑似涉及此頸部區域，則亦必須獲得頸部之成像。掃描必須具有診斷品質，且除非醫學上有禁忌，否則必須使用IV顯影(contrast)。對於各經評估之病變，應在整個研究持續時間內使用相同模態。Response will be assessed by radiographic tumor assessments on Days 15-21 of a 21-day cycle (Cycle 2, 4, 6, and every 3rd cycle thereafter), or every 6 weeks +/- 7 days from Cycle 1 Day 1 (C1D1) through Week 24 of a 28-day cycle (4 response assessments every 6 weeks), and every 8 weeks thereafter. Subjects who interrupt treatment or start new anticancer therapy prior to disease progression will undergo physical examination and continue to be assessed on this schedule for up to 3 years after EOT until PD is documented or new therapy is started. Tumor assessments will be performed by CT and/or MRI scans of the chest, abdomen, and pelvis. Imaging of the neck must also be obtained if there is documented or suspected involvement of this area of the neck. Scans must be of diagnostic quality, and IV contrast must be used unless medically contraindicated. The same modality should be used throughout the duration of the study for each lesion evaluated.
抗腫瘤活性之確定將基於由所有群組之RECIST v1.1定義之評估。研究人員之治療決策將基於部分A及B之RECIST v1.1及部分C及D之iRECIST。按照研究人員及不滿足停止準則之個體，對於部分C及D中得到臨床益處之個體，可考慮按照RECIST v1.1超出疾病進展的治療。按照RECIST v1.1超出疾病進展進行治療的個體可繼續直至出現由研究人員評估之按照iRECIST確認之疾病進展。確認掃描必須在疾病進展之初始日期之後4至9週進行。藥物動力學及免疫原性評估Determination of antitumor activity will be based on assessments defined by RECIST v1.1 for all cohorts. Treatment decisions by the investigator will be based on RECIST v1.1 for Parts A and B and iRECIST for Parts C and D. For subjects who receive clinical benefit in Parts C and D according to the investigator and who do not meet stopping criteria, treatment beyond disease progression according to RECIST v1.1 may be considered. Subjects treated beyond disease progression according to RECIST v1.1 may continue until there is confirmed disease progression according to iRECIST as assessed by the investigator. Confirmatory scans must be performed 4 to 9 weeks after the initial date of disease progression.Pharmacokinetic and Immunogenicity Assessments
將在可適用收集時程之時間點收集用於PK及ADA評估之血液樣品。Blood samples for PK and ADA assessments will be collected at time points as per the applicable collection schedule.
將使用經驗證之分析測定血漿中SGN-B6A ac-MMAE、總抗體(TAb)及MMAE濃度。分析可包括ELISA或液相層析與串聯質譜法(LC-MS/MS)以及其他分析(若需要進一步表徵)。對SGN-B6A ADC濃度之分析可使用未經驗證之方法以探究性方式在一部分樣品中進行。將剩餘PK樣品存檔以用於可能的SGN-B6A相關物質分析。將在部分D群組中收集帕博利珠單抗之PK及ADA樣品且將其保存；若認為必要，則可作為探究性分析來分析。SGN-B6A ac-MMAE, total antibody (TAb), and MMAE concentrations in plasma will be determined using validated assays. Assays may include ELISA or liquid chromatography and tandem mass spectrometry (LC-MS/MS) and other assays if further characterization is required. Analysis of SGN-B6A ADC concentrations may be performed in a subset of samples in an exploratory manner using unvalidated methods. The remaining PK samples will be archived for possible SGN-B6A related substance analysis. PK and ADA samples for pembrolizumab will be collected in a subset of cohorts D and stored; if deemed necessary, they may be analyzed as exploratory assays.
合格的電致化學發光分析將用於評估血清中針對SGN-B6A的ADA含量。藥效學及生物標記物評估Qualified electrochemical luminescence analysis will be used to evaluate the level of ADA in serum against SGN-B6A.Pharmacodynamics and biomarker evaluation
生物標記物評估將在周邊血液及腫瘤組織中進行，依此章節中所概述。生物標記物評估將不用於個體選擇。在用SGN-B6A治療之前及期間，將監測與反應、抗性或安全性觀測結果相關之探究性、預測性及預後生物標記物。藥效學評估將包括疾病負荷監測、目標表現之變化及血漿中之可溶性B6整合素。將進行相關研究以更好理解目標-反應關係、預測性/預後生物標記物、MOA、抗性機制及藥效學。在生物學群組中及潛在疾病特異性擴增群組中獲得之治療期及EOT活體組織切片(視情況選用之活體組織切片)將用於研究SGN-B6A之作用機制(MOA)及抗性機制。Biomarker assessments will be performed in peripheral blood and tumor tissues as outlined in this section. Biomarker assessments will not be used for subject selection. Exploratory, predictive, and prognostic biomarkers that correlate with response, resistance, or safety observations will be monitored prior to and during treatment with SGN-B6A. Pharmacodynamic assessments will include disease burden monitoring, changes in target expression, and soluble B6 integrin in plasma. Related studies will be conducted to better understand target-response relationships, predictive/prognostic biomarkers, MOA, mechanisms of resistance, and pharmacodynamics. On-treatment and EOT biopsies obtained in the biological cohorts and potential disease-specific expansion cohorts (optional biopsies) will be used to investigate the mechanism of action (MOA) and resistance mechanisms of SGN-B6A.
腫瘤樣品要求視個體入選之群組而定，依下文所描述。若活檢不可行或不合適，則在與醫學監測者討論之後可放棄活檢。Tumor sample requirements depend on the group into which the individual is enrolled, as described below. If a biopsy is not feasible or appropriate, it may be foregone after discussion with the medical monitor.
若在研究期間獲得腫瘤樣品作為標準照護之一部分，則在個體同意之情況下，應將該樣品之一部分提交至發起人以用於生物標記物測試。應由經適當培訓之臨床機構人員(例如負責內部腫瘤活檢之介入放射學家；經培訓之人員，諸如負責皮膚腫瘤活檢之皮膚病學家)收集活體組織切片。當可行時，強烈建議病理學家在活檢期間在場以確保活檢位置有足夠腫瘤含量，且確認活檢獲取及處理技術為最佳的。If a tumor sample is obtained as part of standard care during the study, a portion of that sample should be submitted to the sponsor for biomarker testing, with the individual's consent. Biopsies should be collected by appropriately trained clinical staff (e.g., interventional radiologists for internal tumor biopsies; trained staff, such as dermatologists for cutaneous tumor biopsies). When feasible, it is strongly recommended that a pathologist be present during the biopsy to ensure adequate tumor content at the biopsy site and to confirm that the biopsy acquisition and handling technique is optimal.
SGN-B6A對腫瘤細胞之主要作用可引起局部、腫瘤相關及周邊免疫細胞之活化狀態發生變化。為表徵惡性腫瘤及免疫反應，周邊血液中之生物標記物評估可包括但不限於量測循環血球群之基線及藥物誘導之變化、免疫分析、基因表現、細胞遺傳學、遺傳多形性、與癌症相關之體細胞突變以及循環免疫功能及疾病標記物。亦可監測SGN-B6A與周邊血液細胞及組織之相互作用。分析可包括但不限於全血之下一代定序(next generation sequencing)、蛋白質組方法、作為腫瘤反應或療法抗性之標記物的免疫分析及免疫功能之標記物，包括大量免疫細胞亞群及細胞介素。分析方法可包括但不限於IHC、RNA及DNA之下一代定序及免疫分析，諸如流式細胞量測術及ELISA。此等方法可有助於深入瞭解與SGN-B6A有關的治療相關變化。The primary effect of SGN-B6A on tumor cells can cause changes in the activation state of local, tumor-associated, and peripheral immune cells. To characterize malignant tumors and immune responses, biomarker assessments in peripheral blood may include, but are not limited to, measuring baseline and drug-induced changes in circulating blood cell populations, immunoassays, gene expression, cytogenetics, genetic polymorphisms, cancer-related somatic cell mutations, and circulating immune function and disease markers. Interactions of SGN-B6A with peripheral blood cells and tissues may also be monitored. Analysis may include, but is not limited to, next generation sequencing of whole blood, proteomic methods, immunoassays as markers of tumor response or therapy resistance, and markers of immune function, including a broad range of immune cell subsets and cytokines. Analytical methods may include, but are not limited to, IHC, next generation sequencing of RNA and DNA, and immunoassays such as flow cytometry and ELISA. These methods may provide insight into treatment-related changes associated with SGN-B6A.
為理解治療之前腫瘤的生物特徵與個體結果之間的關係，將檢測來自治療前(存檔或新獲得之樣本)、治療期及EOT腫瘤活體組織切片之組織。若組織可獲自在入選之後收集的標準臨床照護活體組織切片，則亦可對其進行檢測。將針對腫瘤中之特定藥效學、預測性及預後生物標記物評估活體組織切片。為表徵SGN-B6A滲透至腫瘤中、惡性腫瘤及對研究治療之反應，腫瘤生物樣本中之生物標記物評估可包括但不限於量測SGN-B6A及其潛在代謝物(諸如MMAE)，以及表徵腫瘤微環境、藥物目標、腫瘤亞型、分析體細胞突變及/或基因表現。分析可包括但不限於LC-MS/MS、IHC以及RNA及DNA之下一代定序。在基線之人口統計資料及特徵(劑量遞增)To understand the relationship between the biological characteristics of the tumor prior to treatment and individual outcomes, tissue from pre-treatment (archival or newly obtained samples), treatment period, and EOT tumor biopsies will be tested. If tissue is available from standard clinical care biopsies collected after enrollment, these may also be tested. Biopsies will be evaluated for specific pharmacodynamic, predictive, and prognostic biomarkers in the tumor. To characterize SGN-B6A penetration into tumors, malignancy, and response to study treatment, biomarker assessment in tumor biospecimens may include, but is not limited to, measurement of SGN-B6A and its potential metabolites (e.g., MMAE), as well as characterization of the tumor microenvironment, drug targets, tumor subtypes, analysis of somatic mutations, and/or gene expression. Analysis may include, but is not limited to, LC-MS/MS, IHC, and next generation sequencing of RNA and DNA.Demographics and Characteristics at Baseline(Dose Escalation)
表5顯示已入選研究中之個體在基線的人口統計資料及特徵。 表5. 個體人口統計資料及特徵
表6顯示個體在已評估之劑量遞增研究中之客觀反應率。包括患有所有腫瘤類型之個體。 表6. 客觀反應率
圖1顯示在劑量遞增研究之NSCLC子集中SGN-B6A的抗腫瘤活性。個體已接受中值3.5 (範圍：1-8)之先前療法線。來自圖1之NSCLC個體的客觀反應示於表7中。 表7. 劑量遞增研究之NSCLC子集的客觀反應率
圖2顯示劑量遞增研究之食道癌(EC)子集中SGN-B6A的抗腫瘤活性。個體已接受中值3.0 (範圍：1-5)之先前療法線。來自圖2之EC個體的客觀反應示於表8中。表8.劑量遞增研究之EC子集的客觀反應率
圖3顯示在劑量遞增研究之HNSCC子集中SGN-B6A的抗腫瘤活性。個體已接受中值3.0 (範圍：1-4)之先前療法線。來自圖3之HNSCC個體的客觀反應示於表9中。表9.劑量遞增研究之HNSCC子集的客觀反應率
圖4顯示劑量擴增研究之HNSCC 2Q3W子集中SGN-B6A的抗腫瘤活性。個體已接受中值3.0 (範圍：1-6)之先前療法線。功效可評估組包括所有治療之患者，其按照RECIST v1.1進行基線及至少1個可評估基線後疾病評估(由研究人員評估)或中斷治療。2名個體由於缺乏符合功效分析條件的基線後評估而未展示。來自圖4之HNSCC個體的客觀反應示於表10中。表10.劑量擴增研究之HNSCC2Q3W子集的客觀反應率
依實例1中所描述治療患有NSCLC之個體。 表11: 在各種劑量下之ORR
此等結果表明，相較於鱗狀細胞癌，患有非鱗狀細胞癌之個體的反應約高2倍，且相較於先前經紫杉烷治療之個體，未曾經紫杉烷治療之個體的反應約高3倍。表13：各種劑量下患有非鱗狀NSCLC之未曾經紫杉烷治療之個體的ORR
BALB/c小鼠(n=10隻小鼠/組)經皮下植入有經工程改造以表現人類整合素β-6之同基因型Renca細胞。mSGN-B6A及抗小鼠PD-1 (抗mPD1)每週給藥三劑(單獨地或以組合形式)。延遲劑量處理組在第一mSGN-B6A劑量之後1週接受第一劑量之抗mPD1。圖5A顯示卡普蘭-邁耶曲線圖，其中腫瘤增加為存活終點。圖5B及表11顯示，用mSGN-B6A處理之個別小鼠顯示在第19天觀察到2次完全消退且1次完全消退維持持久直至研究結束(第58天)。用mSGN-B6A及抗mPD1以1 mg/kg處理之個別小鼠在第19天具有3次CTR，其中1次為維持持久的完全腫瘤消退(dCTR)。用mSGN-B6A及mPD1以3 mg/kg處理之個別小鼠在第19天具有3次CTR，其中3次維持為dCTR。延遲劑量組中之個別動物在第19天顯示5次CTR，其中在研究結束時有4次dCTR。 表14. RENCA人類整合素Β-6同基因型模型中之腫瘤生長抑制
圖1為顯示以下的圖：按照RECIST v1.1在劑量遞增研究之NSCLC子組中，目標病變直徑總和(SoD)相對於基線之最佳百分比變化。Q3W=每3週投與一次。2Q3W=每3週投與兩次。2Q4W=每4週投與兩次。Q1W=每週投與一次。Figure 1 is a graph showing the best percent change from baseline in sum of target lesion diameters (SoD) in the NSCLC subgroup of the dose escalation study according to RECIST v1.1. Q3W = once every 3 weeks. 2Q3W = twice every 3 weeks. 2Q4W = twice every 4 weeks. Q1W = once a week.
圖2為顯示以下的圖：按照RECIST v1.1在劑量遞增研究之食道癌(EC)子組中，目標病變SoD相對於基線之最佳百分比變化。Q3W=每3週投與一次。2Q3W=每3週投與兩次。2Q4W=每4週投與兩次。Q1W=每週投與一次。Figure 2 is a graph showing the best percent change in target lesion SoD from baseline in the esophageal cancer (EC) subgroup of the dose escalation study according to RECIST v1.1. Q3W = once every 3 weeks. 2Q3W = twice every 3 weeks. 2Q4W = twice every 4 weeks. Q1W = once a week.
圖3為顯示以下的圖：按照RECIST v1.1在劑量遞增研究之HNSCC子組中，目標病變SoD相對於基線之最佳百分比變化。2Q3W=每3週投與兩次。2Q4W=每4週投與兩次。Q1W=每週投與一次。Figure 3 is a graph showing the best percent change in target lesion SoD from baseline in the HNSCC subgroup of the dose escalation study according to RECIST v1.1. 2Q3W = twice every 3 weeks. 2Q4W = twice every 4 weeks. Q1W = once a week.
圖4為顯示以下的圖：按照RECIST v1.1在劑量擴增研究之HNSCC 2Q3W子組中，目標病變SoD相對於基線之最佳百分比變化。2Q3W=每3週投與兩次。Figure 4 is a graph showing the best percent change in target lesion SoD from baseline in the HNSCC 2Q3W subgroup of the dose escalation study according to RECIST v1.1. 2Q3W = twice administered every 3 weeks.
圖5A為顯示存活百分比隨時間推移之卡普蘭-邁耶曲線圖(Kaplan-Meier plot)，其中4倍腫瘤增加為小鼠皮下植入有經工程改造以表現人類整合素β-6之同基因型Renca細胞的存活終點。圖5B為顯示用SGN-B6A之小鼠替代物(mSGN-B6A)、小鼠抗PD-1抗體(抗mPD1)或兩者處理之個別小鼠的腫瘤生長隨時間推移之一系列圖。所有測試品每週給藥3次劑量。黑色三角形顯示mSGN-B6A之給藥時程。藍色/灰色三角形顯示抗mPD1之給藥時程。FIG5A is a Kaplan-Meier plot showing percent survival over time, with a 4-fold tumor increase as the survival endpoint for mice implanted subcutaneously with isogenic Renca cells engineered to express human integrin beta-6. FIG5B is a series of graphs showing tumor growth over time for individual mice treated with a mouse surrogate of SGN-B6A (mSGN-B6A), a mouse anti-PD-1 antibody (anti-mPD1), or both. All test articles were dosed 3 times per week. Black triangles show dosing schedule for mSGN-B6A. Blue/grey triangles show dosing schedule for anti-mPD1.
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| Publication number | Publication date |
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| CN120435319A (en) | 2025-08-05 |
| AU2023372538A1 (en) | 2025-05-01 |
| WO2024097816A1 (en) | 2024-05-10 |
| MX2025005210A (en) | 2025-06-02 |
| EP4611819A1 (en) | 2025-09-10 |
| IL320603A (en) | 2025-07-01 |
| KR20250089558A (en) | 2025-06-18 |
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