本揭露總體上關於使用胸腺基質淋巴細胞生成素（TSLP）特異性抗體治療皮質類固醇依賴性重度氣喘之方法。The present disclosure generally relates to methods of treating corticosteroid-dependent severe asthma using thymic stromal lymphopoietin (TSLP)-specific antibodies.
氣喘係一種慢性炎症性氣道疾病，其特徵係支氣管高反應性和可逆性氣流受限，引起喘息、呼吸急促、咳嗽和胸悶。儘管有幾種治療方法可用（例如ICS、LABA和長效毒蕈鹼拮抗劑[LAMA]），但重度氣喘患者的醫療需求仍明顯未得到滿足。Asthma is a chronic inflammatory airway disease characterized by bronchial hyperresponsiveness and reversible airflow limitation, causing wheezing, shortness of breath, cough, and chest tightness. Despite the availability of several treatments (e.g., ICS, LABA, and long-acting muscarinic antagonists [LAMA]), there remains a significant unmet medical need for patients with severe asthma.
生物療法可以為重度氣喘患者提供另外的氣喘控制。奧馬珠單抗（Omalizumab）可適用於已證實對空氣過敏原有反應性且血清免疫球蛋白E（IgE）水平升高的使用ICS加LABA仍不能充分控制的患者亞組（XOLAIR US PI 2019）。另外的生物製劑（諸如美泊利單抗（mepolizumab）、瑞利珠單抗（reslizumab）、貝那利珠單抗（benralizumab）和度匹魯單抗（dupilumab）已被批准用於具有嗜酸性球表型的重度氣喘（NUCALA US PI 2019，CINQAIR US PI 2020，FASENRA US 2017，DUPIXENT US 2017）。靶向IL-5、IgE和IL-4的生物製劑作為高劑量ICS/LABA治療但氣喘仍未得到控制的患者之附加治療現在被納入國際治療指南（Global Initiative for Asthma[全球氣喘倡議][GINA 2022]）。Biologic therapies can provide additional asthma control for patients with severe asthma. Omalizumab may be indicated for the subgroup of patients with documented reactivity to air allergens and elevated serum immunoglobulin E (IgE) levels who are not adequately controlled with ICS plus LABA (XOLAIR US PI 2019). Additional biologics (such as mepolizumab, reslizumab, benralizumab, and dupilumab) have been approved for severe asthma with an eosinophilic phenotype (NUCALA US PI 2019, CINQAIR US PI 2020, FASENRA US 2017, DUPIXENT US 2017). Biologics targeting IL-5, IgE, and IL-4 are now included in international treatment guidelines as add-on treatments for patients whose asthma is not controlled on high-dose ICS/LABA therapy (Global Initiative for Asthma [GINA 2022]).
然而，即使使用目前可用的生物製劑，相當一部分患者繼續經歷加重，並且可能受益於靶向不同分子途徑的藥劑（Wenzel 2012，Froidure等人 2016，Swedin等人 2017）。因此，儘管有該等另外的治療選擇，但使用目前可用的療法無法獲得完全氣喘控制的重度氣喘患者（與IgE狀態或嗜酸性球水平無關）的醫療需求仍明顯未得到滿足。However, even with currently available biologics, a significant proportion of patients continue to experience exacerbations and may benefit from agents targeting different molecular pathways (Wenzel 2012, Froidure et al. 2016, Swedin et al. 2017). Therefore, despite these additional treatment options, there remains a significant unmet medical need for patients with severe asthma (independent of IgE status or eosinophil levels) who are unable to achieve complete asthma control with currently available therapies.
胸腺基質淋巴細胞生成素係一種上皮細胞衍生的細胞介素，其響應於促炎刺激（例如，感染性、過敏性和環境刺激）和創傷而產生。TSLP在炎症反應的啟動中具有上游和中心作用，並且可以激活廣泛的細胞類型，包括嗜酸性球、肥大細胞、T細胞、樹突狀細胞、2型先天淋巴細胞和嗜鹼性球（Tedeschi等人 2017，Watson和Gauvreau, 2014）。經典地，TSLP可能是T輔助細胞2（Th2）反應的啟動和持續以及由此產生的與Th2驅動的氣喘相關的細胞介素級聯中的關鍵成分（Kaur和Brightling 2012）。氣喘現在被認為是一種異質性疾病，其患者亞群沒有表現出Th2相關疾病（Wenzel 2012）。有新數據表明，TSLP也可能介導非過敏性（非T輔助細胞2）炎症（Tanaka等人, 2009，Ziegler等人, 2013）。鑒於TSLP係一種上游多效性細胞介素，因此TSLP的阻斷預計會對氣喘中可見的炎症反應譜產生廣泛影響。Thymic stromal lymphopoietin is an epithelial cell-derived cytokine produced in response to proinflammatory stimuli (e.g., infectious, allergic, and environmental stimuli) and trauma. TSLP has an upstream and central role in the initiation of inflammatory responses and can activate a broad range of cell types, including eosinophils, mast cells, T cells, dendritic cells, type 2 innate lymphoid cells, and basophils (Tedeschi et al. 2017, Watson and Gauvreau, 2014). Classically, TSLP may be a key component in the initiation and perpetuation of T helper cell 2 (Th2) responses and the resulting interleukin cascade associated with Th2-driven asthma (Kaur and Brightling 2012). Asthma is now considered a heterogeneous disease with subsets of patients not displaying Th2-related disease (Wenzel 2012). Emerging data suggest that TSLP may also mediate non-allergic (non-T helper cell 2) inflammation (Tanaka et al., 2009, Ziegler et al., 2013). Given that TSLP is an upstream pleiotropic interleukin, blockade of TSLP would be expected to have broad effects on the spectrum of inflammatory responses seen in asthma.
泰派魯單抗（Tezepelumab）（也稱為AMG 157）（Gilliet,等人, J Exp Med[實驗醫學雜誌] 2003; 197:1059-63）係一種靶向胸腺基質淋巴細胞生成素（TSLP）的完全人單株抗體（免疫球蛋白G2λ），TSLP係一種上皮細胞衍生的細胞介素，其通過其對多種途徑的活性促進對環境刺激的炎症反應，包括（但不限於）對樹突細胞（Gilliet,等人, 2003；Soumelis等人, Nat Immunol[自然免疫學]. 3:673-680, 2002；Reche,等人, J Immunol[免疫學雜誌] 2001; 167:336-43）和肥大細胞（Allakhverdi等人, J Exp Med[實驗醫學雜誌]. 204:253-258, 2007）的活性。藉由與TSLP結合，泰派魯單抗阻止其與TSLP受體複合物的相互作用，並抑制多種下游炎症途徑。Tezepelumab (also known as AMG 157) (Gilliet, et al., J Exp Med 2003; 197:1059-63) is a fully human monoclonal antibody (immunoglobulin G2λ) that targets thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine that promotes inflammatory responses to environmental stimuli through its activity on multiple pathways, including, but not limited to, dendritic cells (Gilliet, et al., 2003; Soumelis et al., Nat Immunol 3:673-680, 2002; Reche, et al., J Immunol 2001; 167:336-43) and mast cell activity (Allakhverdi et al., J Exp Med. 204:253-258, 2007). By binding to TSLP, tepirumab prevents its interaction with the TSLP receptor complex and inhibits multiple downstream inflammatory pathways.
本文所述之抗TSLP抗體解決了皮質類固醇依賴性氣喘患者未滿足的需求，其中其他藥物可能無法控制症狀。例如，抗體療法可以減少或消除對諸如口服皮質類固醇的療法的需求。The anti-TSLP antibodies described herein address an unmet need for patients with corticosteroid-dependent asthma, where other medications may not control symptoms. For example, antibody therapy may reduce or eliminate the need for treatments such as oral corticosteroids.
本揭露提供了一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括以140 mg至420 mg的劑量每2週或每4週間隔投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。The present disclosure provides a method for treating corticosteroid-dependent asthma in a subject, the method comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at intervals of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain, which comprises: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain, which comprises: i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5 NO:7, and iii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2.
本揭露提供了一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括以140 mg至420 mg的劑量每2週或每4週間隔投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含a.輕鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；以及b. 重鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。The present disclosure provides a method for treating corticosteroid-dependent asthma in a subject, the method comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at intervals of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain, which comprises a. a light chain variable domain, which is selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions; and b. A heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO:10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9; iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
本揭露進一步提供了一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括選擇需要治療皮質類固醇依賴性氣喘的受試者，並以140 mg至420 mg的劑量每2週或每4週間隔投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。The present disclosure further provides a method for treating corticosteroid-dependent asthma in a subject, the method comprising selecting a subject in need of treatment for corticosteroid-dependent asthma, and administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain, which comprises: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain, which comprises: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain, which comprises: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5 NO:6; ii. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
還提供了一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括選擇需要治療皮質類固醇依賴性氣喘的受試者，以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；以及b. 重鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Also provided is a method for treating corticosteroid-dependent asthma in a subject, the method comprising selecting a subject in need of treatment for corticosteroid-dependent asthma, administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 12 under moderately stringent conditions; NO:11; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO:10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9; iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
在多個實施方式中，輕鏈可變結構域在SEQ ID NO:12中列出並且重鏈可變結構域在SEQ ID NO:10中列出。In various embodiments, the light chain variable domain is set forth in SEQ ID NO:12 and the heavy chain variable domain is set forth in SEQ ID NO:10.
在多個實施方式中，抗體或抗體變體每4週投與。In various embodiments, the antibody or antibody variant is administered every 4 weeks.
在多個實施方式中，抗體或抗體變體每2週以210 mg的劑量投與。在多個實施方式中，抗體或抗體變體每4週以210 mg的劑量投與。In various embodiments, the antibody or antibody variant is administered at a dose of 210 mg every 2 weeks. In various embodiments, the antibody or antibody variant is administered at a dose of 210 mg every 4 weeks.
在多個實施方式中，受試者也正在接受皮質類固醇治療。在多個實施方式中，皮質類固醇係口服皮質類固醇。在多個實施方式中，口服皮質類固醇為強體松、強體松龍、皮質酮、氫化皮質酮、甲潑尼龍、曲安西龍、貝皮質醇、地塞米松和地夫可特中的一或多種。In various embodiments, the subject is also receiving corticosteroid therapy. In various embodiments, the corticosteroid is an oral corticosteroid. In various embodiments, the oral corticosteroid is one or more of prednisone, prednisolone, corticosterone, hydrocorticosterone, methylprednisolone, triamcinolone, becortin, dexamethasone, and deflazacort.
在多個實施方式中，該方法包括將抗TSLP抗體或抗體變體與口服皮質類固醇聯合投與，其中受試者經歷OCS療法之優化階段、OCS療法之減少階段和OCS療法之維持階段。In various embodiments, the method comprises administering an anti-TSLP antibody or antibody variant in combination with an oral corticosteroid, wherein the subject undergoes an optimization phase of OCS therapy, a taper phase of OCS therapy, and a maintenance phase of OCS therapy.
在多個實施方式中，該方法包括當受試者接受治療之減少階段時減少皮質類固醇的劑量。在多個實施方式中，皮質類固醇的劑量每4週減少一次，持續約20週。在多個實施方式中，皮質類固醇的劑量在每個減少間隔減少5 mg/天或2.5 mg/天。In various embodiments, the method comprises reducing the dose of the corticosteroid while the subject is undergoing a taper phase of treatment. In various embodiments, the dose of the corticosteroid is reduced every 4 weeks for about 20 weeks. In various embodiments, the dose of the corticosteroid is reduced by 5 mg/day or 2.5 mg/day at each taper interval.
在多個實施方式中，提供了一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括選擇需要治療口服皮質類固醇（OCS）依賴性氣喘的受試者，以210 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的口服皮質類固醇和抗TSLP抗體或抗體變體，其中該受試者接受OCS療法之優化階段、OCS療法之減少階段和OCS療法之維持階段，並且其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。In various embodiments, a method for treating corticosteroid-dependent asthma in a subject is provided, the method comprising selecting a subject in need of treatment for oral corticosteroid (OCS)-dependent asthma, administering to the subject a therapeutically effective amount of an oral corticosteroid and an anti-TSLP antibody or antibody variant at a dose of 210 mg every 2 weeks or every 4 weeks, wherein the subject undergoes an optimization phase of OCS therapy, a reduction phase of OCS therapy, and a maintenance phase of OCS therapy, and wherein two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising SEQ ID NO: 4; iii. a light chain CDR3 sequence comprising SEQ ID NO: 5; iv. a light chain CDR4 sequence comprising SEQ ID NO: 6; iv. a light chain CDR5 sequence comprising SEQ ID NO: 7; iii. a light chain CDR6 sequence comprising SEQ ID NO: 8; iv. a light chain CDR7 sequence comprising SEQ ID NO: 9; iv. a light chain CDR8 sequence comprising SEQ ID NO: 10; iv. a light chain CDR9 sequence comprising SEQ ID NO: 11; iv. a light chain CDR1 sequence comprising SEQ ID NO: 12; iv. a light chain CDR1 sequence comprising SEQ ID NO: 13; iv. a light chain CDR1 sequence comprising SEQ ID NO: 14; iv. a light chain CDR1 sequence comprising SEQ ID NO: 15 NO:4; iii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain, which contains: i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:7, and iii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
本揭露進一步提供了一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括選擇需要治療口服皮質類固醇（OCS）依賴性氣喘的受試者，以210 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該受試者接受OCS療法之優化階段、OCS療法之減少階段和OCS療法之維持階段，並且其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；以及b. 重鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。The present disclosure further provides a method for treating corticosteroid-dependent asthma in a subject, the method comprising selecting a subject in need of treatment for oral corticosteroid (OCS)-dependent asthma, administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant to the subject at a dose of 210 mg every 2 weeks or every 4 weeks, wherein the subject undergoes an optimization phase of OCS therapy, a reduction phase of OCS therapy, and a maintenance phase of OCS therapy, and wherein two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity to SEQ ID NO: 12; ii. a light chain variable domain having at least 80% identity to SEQ ID NO: 13; iii. a light chain variable domain having at least 80% identity to SEQ ID NO: 14; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 15; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 16; iii. a light chain variable domain having at least 80% identity to SEQ ID NO: 17; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 18; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 19; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 11; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 12; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 13; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 11; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 11; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: NO:11 has at least 80% identity encoded by an amino acid sequence; iii. an amino acid sequence encoded by a polynucleotide hybridized under moderately stringent conditions with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO:10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9; iii. an amino acid sequence encoded by a polynucleotide hybridized under moderately stringent conditions with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to the SEQ ID NO:10. NO: The TSLP polypeptide represented by amino acids 29-159 of 2.
在多個實施方式中，提供了一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括選擇需要治療皮質類固醇依賴性氣喘的受試者，以210 mg的劑量每4週間隔向該受試者投與治療有效量的全身性皮質類固醇和抗TSLP抗體或抗體變體，其中該受試者接受OCS療法之優化階段、OCS療法之減少階段和OCS療法之維持階段，並且其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。In various embodiments, a method for treating corticosteroid-dependent asthma in a subject is provided, the method comprising selecting a subject in need of treatment for corticosteroid-dependent asthma, administering to the subject a therapeutically effective amount of systemic corticosteroids and an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks, wherein the subject undergoes an optimization phase of OCS therapy, a reduction phase of OCS therapy, and a maintenance phase of OCS therapy, and wherein two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising SEQ ID NO: 4; iii. a light chain CDR3 sequence comprising SEQ ID NO: 5; iv. a light chain CDR4 sequence comprising SEQ ID NO: 6; iv. a light chain CDR5 sequence comprising SEQ ID NO: 7; iii. a light chain CDR6 sequence comprising SEQ ID NO: 8; iv. a light chain CDR7 sequence comprising SEQ ID NO: 9; iv. a light chain CDR8 sequence comprising SEQ ID NO: 10; iv. a light chain CDR9 sequence comprising SEQ ID NO: 11; iv. a light chain CDR1 sequence comprising SEQ ID NO: 12; iv. a light chain CDR1 sequence comprising SEQ ID NO: 13; iv. a light chain CDR1 sequence comprising SEQ ID NO: 14; iv. a light chain CDR1 sequence comprising SEQ ID NO: 15 NO:4; iii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain, which contains: i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:7, and iii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
本揭露進一步提供了一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括選擇需要治療口服皮質類固醇（OCS）依賴性氣喘的受試者，以210 mg的劑量每4週間隔向該受試者投與治療有效量的全身性皮質類固醇和抗TSLP抗體或抗體變體，其中該受試者接受OCS療法之優化階段、OCS療法之減少階段和OCS療法之維持階段，並且其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；以及b. 重鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。The present disclosure further provides a method for treating corticosteroid-dependent asthma in a subject, the method comprising selecting a subject in need of treatment for oral corticosteroid (OCS)-dependent asthma, administering to the subject a therapeutically effective amount of systemic corticosteroids and an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks, wherein the subject undergoes an optimization phase of OCS therapy, a reduction phase of OCS therapy, and a maintenance phase of OCS therapy, and wherein two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity to SEQ ID NO: 12; ii. a light chain variable domain having at least 80% identity to SEQ ID NO: 13; iii. a light chain variable domain having at least 80% identity to SEQ ID NO: 14; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 15; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 16; iii. a light chain variable domain having at least 80% identity to SEQ ID NO: 17; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 18; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 19; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 11; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 12; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 12; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 13; iv. a light chain variable domain having at least 80% identity to SEQ ID NO: 11; iv. a light chain variable domain having at least 80% identity to SEQ ID NO:11 has at least 80% identity encoded by an amino acid sequence; iii. an amino acid sequence encoded by a polynucleotide hybridized under moderately stringent conditions with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO:10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9; iii. an amino acid sequence encoded by a polynucleotide hybridized under moderately stringent conditions with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to the SEQ ID NO:10. NO: The TSLP polypeptide represented by amino acids 29-159 of 2.
在多個實施方式中，輕鏈可變結構域在SEQ ID NO:12中列出並且重鏈可變結構域在SEQ ID NO:10中列出。In various embodiments, the light chain variable domain is set forth in SEQ ID NO:12 and the heavy chain variable domain is set forth in SEQ ID NO:10.
在多個實施方式中，優化階段包括OCS的劑量為30 mg/天、25 mg/天、20 mg/天、15 mg/天、10 mg/天、7.5 mg/天或5 mg/天。In various embodiments, the optimization phase includes a dose of OCS of 30 mg/day, 25 mg/day, 20 mg/day, 15 mg/day, 10 mg/day, 7.5 mg/day, or 5 mg/day.
在多個實施方式中，減少階段包括OCS的劑量為25 mg/天、20 mg/天、15 mg/天、10 mg/天、7.5 mg/天、5 mg/天、2.5 mg/天或0 mg/天。In various embodiments, the taper phase comprises a dose of OCS of 25 mg/day, 20 mg/day, 15 mg/day, 10 mg/day, 7.5 mg/day, 5 mg/day, 2.5 mg/day, or 0 mg/day.
在多個實施方式中，維持階段包括OCS的劑量為15 mg/天、10 mg/天、7.5 mg/天、5 mg/天、2.5 mg/天或0 mg/天。In various embodiments, the maintenance phase comprises a dose of OCS of 15 mg/day, 10 mg/day, 7.5 mg/day, 5 mg/day, 2.5 mg/day, or 0 mg/day.
在多個實施方式中，抗TSLP抗體變體在人類中具有與泰派魯單抗-ekko基本上相似的pK特徵。In various embodiments, the anti-TSLP antibody variant has a pK profile in humans that is substantially similar to that of teplumab-ekko.
在多個實施方式中，抗體或抗體變體投與至少4個月、6個月、9個月、1年、2年或更長時間的時期。In various embodiments, the antibody or antibody variant is administered for a period of at least 4 months, 6 months, 9 months, 1 year, 2 years, or longer.
在多個實施方式中，抗TSLP抗體或其抗體變體係二價的並且選自由以下組成之群組：人抗體、人源化抗體、嵌合抗體、單株抗體、重組抗體、抗原結合抗體片段、單鏈抗體、單體抗體、雙抗體、三抗體、四抗體、Fab片段、IgG1抗體、IgG2抗體、IgG3抗體和IgG4抗體。In various embodiments, the anti-TSLP antibody or antibody variant thereof is bivalent and selected from the group consisting of: a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single-chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.
在一個實施方式中，抗TSLP抗體變體選自由以下組成之群組：雙抗體、三抗體、四抗體、Fab片段、單域抗體、scFv，其中劑量經調整，使得該等結合位點相對於給藥二價抗體之結合位點係等莫耳的。In one embodiment, the anti-TSLP antibody variant is selected from the group consisting of a diabody, a triabody, a tetrabody, a Fab fragment, a single domain antibody, a scFv, wherein the dose is adjusted such that the binding sites are equimolar relative to the binding site of the administered bivalent antibody.
在多個實施方式中，抗體為IgG2抗體。In various embodiments, the antibody is an IgG2 antibody.
在一個實施方式中，抗體或抗體變體為人抗體。In one embodiment, the antibody or antibody variant is a human antibody.
在多個實施方式中，抗體為泰派魯單抗。在多個實施方式中，泰派魯單抗為具有分別在SEQ ID NO: 13和14中列出的全長重鏈和輕鏈胺基酸序列的IgG2抗體。In various embodiments, the antibody is teplumab. In various embodiments, teplumab is an IgG2 antibody having the full-length heavy chain and light chain amino acid sequences set forth in SEQ ID NOs: 13 and 14, respectively.
在多個實施方式中，抗體或抗體變體在包含藥學上可接受的載劑或賦形劑的藥物組成物中投與給受試者。In various embodiments, the antibody or antibody variant is administered to a subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.
在多個實施方式中，皮質類固醇依賴性氣喘係在患有重度氣喘的受試者中。In various embodiments, the corticosteroid-dependent asthma is in a subject with severe asthma.
在多個實施方式中，該抗體係泰派魯單抗或本領域中描述的另一個抗TSLP抗體。實施方式中進一步描述了例示性抗體。In various embodiments, the antibody is teplumab or another anti-TSLP antibody described in the art. Exemplary antibodies are further described in the embodiments.
在多個實施方式中，受試者為成人。在多個實施方式中，受試者為兒童或青少年。In various embodiments, the subject is an adult. In various embodiments, the subject is a child or a teenager.
在多個實施方式中，投與降低受試者投與皮質類固醇的頻率或水平。在多個實施方式中，皮質類固醇係口服皮質類固醇。在多個實施方式中，口服皮質類固醇選自由強體松、強體松龍、皮質酮、氫化皮質酮、甲潑尼龍、曲安西龍、貝皮質醇、地塞米松和地夫可特組成之群組。In various embodiments, the administration reduces the frequency or level of corticosteroid administration to the subject. In various embodiments, the corticosteroid is an oral corticosteroid. In various embodiments, the oral corticosteroid is selected from the group consisting of prednisone, prednisolone, corticosterone, hydrocorticosterone, methylprednisolone, triamcinolone, becortin, dexamethasone and deflazacort.
在多個實施方式中，皮質類固醇水平的降低係與患有皮質類固醇依賴性氣喘的受試者的基線相比，每日維持OCS相對於基線降低，包括其中降低為90%至100%降低、75%至90%降低、0%至75%降低或30%至50%降低。在多個實施方式中，該方法導致OCS中斷，而不喪失氣喘控制。In various embodiments, the reduction in corticosteroid levels is a daily maintenance of a reduction in OCS relative to baseline in a subject with corticosteroid-dependent asthma, including wherein the reduction is a 90% to 100% reduction, a 75% to 90% reduction, a 0% to 75% reduction, or a 30% to 50% reduction. In various embodiments, the method results in discontinuation of OCS without loss of asthma control.
在多個實施方式中，投與降低受試者共投與療法的頻率或水平。視需要，共投與療法係吸入性皮質類固醇（ICS）、長效β2促效劑（LABA）、白三烯受體拮抗劑（LTRA）、長效抗毒蕈鹼藥（LAMA）、色酮、短效β2促效劑（SABA）和茶鹼。在多個實施方式中，吸入性皮質類固醇選自由二丙酸倍氯米松、二丙酸倍氯米松、環索奈德、糠酸氟替卡松、（Arnuity® Ellipta®）、丙酸氟替卡松、布地奈德、糠酸莫米松、糠酸莫米松、二丙酸倍氯米松（例如，Fostair®）、丙酸氟替卡松（例如，Seretide®、Advair®）、糠酸氟替卡松（例如，Relvar® Ellipta®、Breo® Ellipta®）、布地奈德（例如，Symbicort®）和糠酸莫米松（例如，Dulera®）組成之群組。In various embodiments, administration reduces the frequency or level of a subject's co-administered therapy, which may include, if necessary, inhaled corticosteroids (ICS), long-acting beta2 agonists (LABA), leukotriene receptor antagonists (LTRA), long-acting antimuscarinic drugs (LAMA), chromones, short-acting beta2 agonists (SABA), and theophylline. In various embodiments, the inhaled corticosteroid is selected from the group consisting of beclomethasone dipropionate, beclomethasone dipropionate, ciclesonide, fluticasone furoate, (Arnuity® Ellipta®), fluticasone propionate, budesonide, mometasone furoate, mometasone furoate, beclomethasone dipropionate (e.g., Fostair®), fluticasone propionate (e.g., Seretide®, Advair®), fluticasone furoate (e.g., Relvar® Ellipta®, Breo® Ellipta®), budesonide (e.g., Symbicort®), and mometasone furoate (e.g., Dulera®).
進一步提供了抗TSLP抗體或抗體變體的投與降低受試者中Th2細胞介素的水平。Further provided is that administration of an anti-TSLP antibody or antibody variant reduces the level of Th2 cytokines in a subject.
在多個實施方式中，抗TSLP抗體或抗體變體的投與改善了選自由以下組成之群組的受試者之皮質類固醇依賴性氣喘的一或多種測量值：用力呼氣容積（FEV）、FEV1可逆性、用力肺活量（FVC）、FeNO、氣喘控制問卷-6得分和AQLQ(S)+12得分、BD前FEV1相對於基線的變化、每日維持OCS劑量相對於基線的減少、每日維持OCS劑量≤ 5 mg、以及每日維持OCS劑量相對於基線減少≥ 50%、藉由AAER測量的氣喘加重、首次氣喘加重的時間、與急診室（ER）就診、緊急護理就診或住院相關的氣喘加重率、以及未經歷氣喘加重的參與者比例、每週平均居家PEF（早晚）和/或聖喬治呼吸問卷（SGRQ）得分。進一步提供，投與降低受試者腎上腺功能不全的發生率。In various embodiments, administration of an anti-TSLP antibody or antibody variant improves one or more measures of corticosteroid-dependent asthma in a subject selected from the group consisting of: forced expiratory volume (FEV1),FEV1 reversibility, forced vital capacity (FVC), FeNO, Asthma Control Questionnaire-6 score and AQLQ(S)+12 score, change from baseline in pre-BDFEV1 , reduction in daily maintenance OCS dose from baseline, daily maintenance OCS dose ≤ 5 mg, and daily maintenance OCS dose reduction ≥ 10 mg from baseline. 50%, asthma exacerbations as measured by AAER, time to first asthma exacerbation, rate of asthma exacerbations associated with emergency room (ER) visits, urgent care visits, or hospitalizations, and the proportion of participants who experienced no asthma exacerbations, average weekly home PEF (morning and evening), and/or St. George's Respiratory Questionnaire (SGRQ) scores. Further provided that administration reduced the incidence of adrenal insufficiency in the subjects.
在一個實施方式中，如藉由氣喘症狀日誌所測量，投與改善氣喘的一或多種症狀。In one embodiment, administration improves one or more symptoms of asthma as measured by an asthma symptom diary.
在多個實施方式中，用抗TSLP抗體或抗體變體治療調節皮質類固醇依賴性氣喘的一或多種生物標誌物的水平，包括鼻上皮中細胞介素、IgE、CCL17、CCL18、CCL22和RNA轉錄變化。在多個實施方式中，用抗TSLP治療降低Th2細胞介素的水平。在多個實施方式中，治療調節（降低或緩和）IL-4、IL-5、IL-13、IL-17、IL-22、IL-23、IL-31、IL-33或其組合中一或多種的水平或活性。In various embodiments, treatment with an anti-TSLP antibody or antibody variant modulates the level of one or more biomarkers of corticosteroid-dependent asthma, including interleukins, IgE, CCL17, CCL18, CCL22, and RNA transcriptional changes in the nasal epithelium. In various embodiments, treatment with anti-TSLP reduces the level of Th2 interleukins. In various embodiments, treatment modulates (reduces or alleviates) the level or activity of one or more of IL-4, IL-5, IL-13, IL-17, IL-22, IL-23, IL-31, IL-33, or a combination thereof.
本文提供了一種在患有OCS依賴性氣喘的受試者中與基線相比減少每日維持口服皮質類固醇（OCS）之方法，該方法包括以140 mg至420 mg的劑量每2週或每4週間隔投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗原結合蛋白特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Provided herein is a method for reducing daily maintenance oral corticosteroids (OCS) in subjects with OCS-dependent asthma compared to baseline, the method comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 5; and b. a heavy chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 5; and b. a heavy chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 5 NO:6; ii. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antigen binding protein specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
進一步提供了一種在患有OCS依賴性氣喘的受試者中與基線相比減少每日維持口服皮質類固醇（OCS）之方法，該方法包括以1400 mg至420 mg的劑量每2週或每4週間隔投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；以及b. 重鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域。Further provided is a method of reducing daily maintenance oral corticosteroids (OCS) in subjects with OCS-dependent asthma compared to baseline, the method comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 1400 mg to 420 mg every 2 weeks or every 4 weeks, wherein both binding sites of the antibody have identical binding to TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity to SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide hybridizing under moderately stringent conditions with a complementary sequence of a polynucleotide consisting of SEQ ID NO: 11; and b. A heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 9; iii. an amino acid sequence encoded by a polynucleotide that hybridizes with a complementary sequence of a polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).
本文還提供了一種在患有皮質類固醇依賴性氣喘的受試者中降低ACQ-6得分之方法，該方法包括以140 mg至420 mg的劑量每2週或每4週間隔投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗原結合蛋白特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Also provided herein is a method for reducing ACQ-6 scores in subjects with corticosteroid-dependent asthma, the method comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at intervals of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 7; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 8; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 9; ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 10 NO:7, and iii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antigen binding protein specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2.
進一步提供了一種在患有皮質類固醇依賴性氣喘的受試者中降低ACQ-6得分之方法，該方法包括以1400 mg至420 mg的劑量每2週或每4週間隔投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；以及b. 重鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域。Further provided is a method for reducing ACQ-6 scores in a subject with corticosteroid-dependent asthma, the method comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 1400 mg to 420 mg every 2 weeks or every 4 weeks, wherein both binding sites of the antibody have identical binding to TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity to SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide hybridized under moderately stringent conditions with a complementary sequence of a polynucleotide consisting of SEQ ID NO: 11; and b. A heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 9; iii. an amino acid sequence encoded by a polynucleotide that hybridizes with a complementary sequence of a polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).
進一步提供了一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括選擇需要治療皮質類固醇依賴性氣喘的受試者，以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽，其中該抗體為IgG2抗體。Further provided is a method for treating corticosteroid-dependent asthma in a subject, the method comprising selecting a subject in need of treatment for corticosteroid-dependent asthma, administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5 NO:6; ii. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2, wherein the antibody is an IgG2 antibody.
本文提供了一種在患有皮質類固醇依賴性氣喘的受試者中降低皮質類固醇依賴性哮加重頻率之方法，該方法包括選擇需要治療皮質類固醇依賴性氣喘的受試者，以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗原結合蛋白特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Provided herein is a method for reducing the frequency of exacerbations of corticosteroid-dependent asthma in a subject suffering from corticosteroid-dependent asthma, the method comprising selecting a subject in need of treatment for corticosteroid-dependent asthma, administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. A heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:7, and iii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antigen binding protein specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
進一步提供了一種在患有皮質類固醇依賴性氣喘的受試者中降低皮質類固醇依賴性氣喘加重頻率之方法，該方法包括選擇需要治療皮質類固醇依賴性氣喘的受試者，以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；以及b. 重鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域。Further provided is a method for reducing the frequency of exacerbations of corticosteroid-dependent asthma in a subject suffering from corticosteroid-dependent asthma, the method comprising selecting a subject in need of treatment for corticosteroid-dependent asthma, administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity to SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 12 under moderately stringent conditions; NO:11; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO:10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9; iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b).
還提供了一種降低受試者中皮質類固醇依賴性加重頻率之方法，該方法包括選擇需要治療皮質類固醇依賴性氣喘的受試者，以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗原結合蛋白特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Also provided is a method for reducing the frequency of exacerbations of corticosteroid dependence in a subject, the method comprising selecting a subject in need of treatment for corticosteroid-dependent asthma, administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5 NO:6; ii. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antigen binding protein specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
還提供了一種降低受試者中皮質類固醇依賴性氣喘加重頻率之方法，該方法包括選擇需要治療皮質類固醇依賴性氣喘的受試者，以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；以及b. 重鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域。Also provided is a method for reducing the frequency of exacerbations of corticosteroid-dependent asthma in a subject, the method comprising selecting a subject in need of treatment for corticosteroid-dependent asthma, administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks, wherein the two binding sites of the antibody have identical binding to TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity to SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions; and b. A heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 9; iii. an amino acid sequence encoded by a polynucleotide that hybridizes with a complementary sequence of a polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).
在多個實施方式中，輕鏈可變結構域在SEQ ID NO:12中列出並且重鏈可變結構域在SEQ ID NO:10中列出。In various embodiments, the light chain variable domain is set forth in SEQ ID NO:12 and the heavy chain variable domain is set forth in SEQ ID NO:10.
在多個實施方式中，抗體為泰派魯單抗。In various embodiments, the antibody is teprenolol.
在多個實施方式中，抗體或抗體變體每4週投與。在多個實施方式中，抗體或抗體變體每2週以210 mg的劑量投與。在多個實施方式中，抗體或抗體變體每4週以210 mg的劑量投與。In various embodiments, the antibody or antibody variant is administered every 4 weeks. In various embodiments, the antibody or antibody variant is administered at a dose of 210 mg every 2 weeks. In various embodiments, the antibody or antibody variant is administered at a dose of 210 mg every 4 weeks.
在多個實施方式中，該方法包括將抗TSLP抗體或抗體變體與口服皮質類固醇聯合投與，其中受試者經歷OCS療法之優化階段、OCS療法之減少階段和OCS療法之維持階段。In various embodiments, the method comprises administering an anti-TSLP antibody or antibody variant in combination with an oral corticosteroid, wherein the subject undergoes an optimization phase of OCS therapy, a taper phase of OCS therapy, and a maintenance phase of OCS therapy.
在多個實施方式中，本揭露提供了一種在患有皮質類固醇依賴性氣喘的受試者中消除口服皮質類固醇需求之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體至少2年，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗原結合蛋白特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。In various embodiments, the present disclosure provides a method for eliminating the need for oral corticosteroids in a subject with corticosteroid-dependent asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks for at least 2 years, wherein the two binding sites of the antibody have identical binding to TSLP, and the antibody comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO:6; ii. A heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:7, and iii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antigen binding protein specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2.
在多個實施方式中，本揭露提供了一種在患有皮質類固醇依賴性氣喘的受試者中消除口服皮質類固醇需求之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體至少2年，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；以及b. 重鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域。In various embodiments, the disclosure provides a method of eliminating the need for oral corticosteroids in a subject with corticosteroid-dependent asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks for at least 2 years, wherein both binding sites of the antibody have identical binding to TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity to SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide hybridizing under moderately stringent conditions with a complementary sequence of a polynucleotide consisting of SEQ ID NO: 11; and b. A heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 9; iii. an amino acid sequence encoded by a polynucleotide that hybridizes with a complementary sequence of a polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).
在多個實施方式中，本揭露提供了一種在患有皮質類固醇依賴性氣喘的受試者中將每日維持口服皮質類固醇的量減少至≤ 5 mg/天之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體至少2年，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗原結合蛋白特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。In various embodiments, the present disclosure provides a method for reducing the daily maintenance oral corticosteroid to ≤ 5 mg/day in a subject with corticosteroid-dependent asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks for at least 2 years, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5 NO:6; ii. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antigen binding protein specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
在多個實施方式中，本揭露提供了一種在患有皮質類固醇依賴性氣喘的受試者中將每日維持口服皮質類固醇的量減少至≤ 5 mg/天之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體至少2年，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；以及b. 重鏈可變結構域，其選自由以下組成之群組：i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域。In various embodiments, the present disclosure provides a method for reducing the daily maintenance oral corticosteroid to ≤ 5 mg/day in a subject with corticosteroid-dependent asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks for at least 2 years, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity to SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 12 under moderately stringent conditions; NO:11; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO:10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9; iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b).
在多個實施方式中，輕鏈可變結構域在SEQ ID NO:12中列出並且重鏈可變結構域在SEQ ID NO:10中列出。In various embodiments, the light chain variable domain is set forth in SEQ ID NO:12 and the heavy chain variable domain is set forth in SEQ ID NO:10.
提供上述給藥以及抗體和抗體變體類型適用於本文所述之每種方法。The above-described administrations and types of antibodies and antibody variants are provided as being suitable for use in each of the methods described herein.
在多個實施方式中，抗體或抗體變體在包含藥學上可接受的載劑或賦形劑的藥物組成物中投與給受試者。In various embodiments, the antibody or antibody variant is administered to a subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.
在多個實施方式中，與未接受抗TSLP抗體的受試者相比，投與延遲了皮質類固醇依賴性氣喘加重的時間。In various embodiments, administration delays the time to exacerbations of corticosteroid-dependent asthma compared to subjects not receiving the anti-TSLP antibody.
在多個實施方式中，投與降低受試者共投與療法的頻率或水平。視需要，共投與療法係度匹魯單抗、免疫抑制或免疫調節藥物（例如，全身性皮質類固醇、環孢素、嗎替麥考酚酯、干擾素（IFN）-γ、Janus激酶抑制劑、硫唑嘌呤、胺甲喋呤）、抗IL-13抗體、抗IL-5途徑抗體（貝那利珠單抗、美泊利單抗、瑞利珠單抗）或其組合。In various embodiments, administration reduces the frequency or level of a co-administered therapy to the subject. Optionally, the co-administered therapy is dopilumab, an immunosuppressive or immunomodulatory drug (e.g., systemic corticosteroids, cyclosporine, mycophenolate mofetil, interferon (IFN)-γ, Janus kinase inhibitors, azathioprine, methotrexate), an anti-IL-13 antibody, an anti-IL-5 pathway antibody (benralizumab, mepolizumab, reslizumab), or a combination thereof.
在多個實施方式中，投與消除對皮質類固醇療法的需要。In various embodiments, administration eliminates the need for corticosteroid therapy.
在多個實施方式中，投與為皮下或靜脈內。In various embodiments, administration is subcutaneous or intravenous.
在多個實施方式中，抗體為泰派魯單抗或本領域中例如表A中描述的另一種抗TSLP抗體。示例性抗體在詳細說明中進一步描述。In various embodiments, the antibody is teplumab or another anti-TSLP antibody described in the art, e.g., in Table A. Exemplary antibodies are further described in the Detailed Description.
還提供了用於本文所述方法的抗TSLP抗體或抗體變體。Also provided are anti-TSLP antibodies or antibody variants for use in the methods described herein.
在一個實施方式中，本揭露提供了用於治療受試者之皮質類固醇依賴性氣喘的抗TSLP抗體或抗體變體，其包括以每2週或每4週間隔投與140 mg至420 mg的劑量的治療有效量，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。In one embodiment, the present disclosure provides an anti-TSLP antibody or antibody variant for treating corticosteroid-dependent asthma in a subject, comprising a therapeutically effective amount of 140 mg to 420 mg administered at intervals of every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain, comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain, comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5 NO:7, and iii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2.
還提供了抗TSLP抗體或抗體變體在製備用於本文所述方法的藥物中之用途。Also provided is the use of an anti-TSLP antibody or antibody variant in the preparation of a medicament for use in the methods described herein.
在一個實施方式中，本揭露提供了抗TSLP抗體或抗體變體在製備用於治療受試者之皮質類固醇依賴性氣喘的藥物中之用途，其包括以每2週或每4週間隔投與140 mg至420 mg的劑量的治療有效量，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含a.輕鏈可變結構域，其包含：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。In one embodiment, the present disclosure provides the use of an anti-TSLP antibody or antibody variant in the preparation of a medicament for treating corticosteroid-dependent asthma in a subject, comprising administering a therapeutically effective amount of 140 mg to 420 mg at intervals of every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises a. a light chain variable domain, comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain, comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain, comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5 NO:6; ii. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
應當理解，本文所述之每個特徵或實施方式或組合係本發明任何方面的非限制性、說明性示例，並且因此，意在與本文所述之任何其他特徵或實施方式或組合相結合。例如，在使用如「一個實施方式」、「一些實施方式」、「某些實施方式」、「另外的實施方式」、「特定的示例性實施方式」和/或「另一個實施方式」的語言描述特徵的情況下，該等實施方式的類型中的每一種均為旨在與本文所述之任何其他特徵或特徵的組合相結合而不必列出每一種可能的組合的特徵的非限制性示例。這樣的特徵或特徵的組合適用於本發明之任何方面。在揭露了落在範圍內的值的示例的情況下，該等示例中的任一個作為範圍的可能端點提供，提供了該等端點之間的任何和所有數值，並且設想了上端點和下端點的任何和所有組合。It should be understood that each feature or implementation or combination described herein is a non-limiting, illustrative example of any aspect of the invention, and therefore, is intended to be combined with any other feature or implementation or combination described herein. For example, where features are described using language such as "one implementation," "some implementations," "certain implementations," "additional implementations," "specific exemplary implementations," and/or "another implementation," each of those types of implementations is a non-limiting example of a feature that is intended to be combined with any other feature or combination of features described herein without necessarily listing every possible combination. Such features or combinations of features are applicable to any aspect of the invention. Where examples of values falling within a range are disclosed, any of those examples are provided as possible endpoints of the range, any and all values between those endpoints are provided, and any and all combinations of upper and lower endpoints are contemplated.
本文的標題係為了方便讀者，而不旨在進行限制。本發明之其他方面、實施方式和變化將自實施方式和/或附圖和/或申請專利範圍變得顯而易見。The titles of this article are for the convenience of the reader and are not intended to be limiting. Other aspects, embodiments and variations of the present invention will become apparent from the embodiments and/or drawings and/or the scope of the patent application.
相關申請的交叉引用Cross-references to related applications
本申請要求2023年5月18日提交的美國臨時專利申請案號63/503,089、2023年11月8日提交的美國臨時專利申請案號63/597,219和2023年11月9日提交的美國臨時專利申請案號63/547,945之優先權，其每一個均藉由引用以其全文併入本文。 藉由引用併入以電子方式提交的材料This application claims priority to U.S. Provisional Patent Application No. 63/503,089 filed May 18, 2023, U.S. Provisional Patent Application No. 63/597,219 filed November 8, 2023, and U.S. Provisional Patent Application No. 63/547,945 filed November 9, 2023, each of which is incorporated herein by reference in its entirety.Incorporation by Reference of Electronically Submitted Materials
藉由引用以其全文併入的是與本文同時提交的電腦可讀核苷酸/胺基酸序列表，並且其標識如下：文件案名：59127_SeqListing.xml；大小：15,642位元組；創建於：2024年5月7日。Incorporated by reference in its entirety is the computer-readable nucleotide/amino acid sequence listing filed concurrently with this article and identified as follows: File Name: 59127_SeqListing.xml; Size: 15,642 bytes; Created on: May 7, 2024.
抗TSLP抗體的使用解決了皮質類固醇依賴性氣喘患者未滿足的需求，在該等患者中，其他藥物可能無法控制中度至重度症狀。據提供，使用抗TSLP抗體諸如泰派魯單抗治療可以消除常規疾病活動，使更多患者在治療皮質類固醇依賴性氣喘中不使用類固醇或減少使用類固醇的需求。定義The use of anti-TSLP antibodies addresses an unmet need in patients with corticosteroid-dependent asthma, in whom other medications may not be able to control moderate to severe symptoms. It is provided that treatment with anti-TSLP antibodies such as teprenolumab may eliminate conventional disease activity, allowing more patients to be steroid-free or reduce the need for steroid use in the treatment of corticosteroid-dependent asthma.Definition
除非另有說明，否則用於本申請（包括說明書和申請專利範圍）中的以下術語具有以下給出的定義。Unless otherwise stated, the following terms used in this application (including the specification and claims) have the definitions given below.
除非上下文另外清楚規定，否則如說明書及所附申請專利範圍中所用，不定冠詞「一個/種（a/an）」及定冠詞「該（the）」包括複數以及單數指示物。As used in the specification and appended claims, the indefinite article "a" or "an" and the definite article "the" include plural as well as singular referents unless the context clearly dictates otherwise.
除非另外定義，否則本文所用的所有技術和科學術語均具有與本揭露所屬領域的普通技術者通常所理解的含義相同的含義。以下參考文獻為技術者提供關於本揭露中使用的許多術語的通用定義，包括但不限於：Singleton等人, DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY [微生物學與分子生物學詞典]（第2版1994）；THE CAMBRIDGE DICTIONARY OF SCIENCE AND TECHNOLOGY [劍橋科技詞典]（Walker編輯, 1988）；THE GLOSSARY OF GENETICS [遺傳學術語表], 第5版, R. Rieger等人（編輯）, Springer Verlag [施普林格出版公司] (1991)；以及Hale和Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY [哈珀·柯林斯生物學詞典] (1991)。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The following references provide the skilled artisan with general definitions of many of the terms used in this disclosure, including, but not limited to: Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY (2nd ed. 1994); THE CAMBRIDGE DICTIONARY OF SCIENCE AND TECHNOLOGY (Walker ed., 1988); THE GLOSSARY OF GENETICS, 5th ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale and Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY (1991).
術語「約」或「大約」意指如由熟悉該項技術者所確定的特殊值的可接受誤差，其部分地取決於如何測量或確定該值。在某些實施方式中，術語「約」或「大約」意指1、2、3或4個標準差內。在某些實施方式中，術語「約」或「大約」意指給定值或範圍的30%、25%、20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%或0.05%內。每當術語「約」或「大約」在一系列兩個或更多個數值中的第一數值前面時，應瞭解術語「約」或「大約」適用於該系列中的每個數值。The term "about" or "approximately" means the acceptable error of a particular value as determined by one skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. Whenever the term "about" or "approximately" precedes the first value in a series of two or more numerical values, it should be understood that the term "about" or "approximately" applies to each numerical value in the series.
本文所用的術語「皮質類固醇依賴性氣喘」係指患有重度氣喘的受試者，其除了高劑量ICS加LABA外，還需要長期維持OCS治療，使用或不使用其他氣喘控制劑。The term "corticosteroid-dependent asthma" as used herein refers to subjects with severe asthma who require long-term maintenance OCS therapy in addition to high-dose ICS plus LABA, with or without other asthma controllers.
本文所用的術語「皮質類固醇依賴性氣喘加重」係指導致以下任一種的皮質類固醇依賴性氣喘惡化：需要至少連續3天的爆發全身性皮質類固醇治療或單次貯庫注射皮質類固醇劑量治療或導致急診科就診（定義為在ER或緊急護理中心進行＜ 24小時的評估和治療），需要全身性皮質類固醇（如上所述）或因氣喘住院（定義為入住住院機構和/或在醫療機構評估和治療≥ 24小時）。As used herein, the term “corticosteroid-dependent asthma exacerbation” refers to a worsening of corticosteroid-dependent asthma that results in any of the following: requiring a burst of systemic corticosteroid therapy or a single depot corticosteroid dose for at least 3 consecutive days or leading to an emergency department visit (defined as evaluation and treatment in an ER or urgent care center for < 24 hours), requiring systemic corticosteroids (as described above), or hospitalization for asthma (defined as admission to an inpatient facility and/or evaluation and treatment in a medical facility for ≥ 24 hours).
術語「皮質類固醇依賴性氣喘的惡化」係指新的或增加的症狀和/或體征（檢查），它們可與患有皮質類固醇依賴性氣喘的受試者有關（受試者驅動）或與患者每日日記警報有關（日記驅動）。The term "worsening of corticosteroid-dependent asthma" refers to new or increased symptoms and/or signs (examinations) that are either associated with a subject having corticosteroid-dependent asthma (subject-driven) or are associated with daily diary alerts in the patient (diary-driven).
如本文所用的術語「細胞介素」係指由細胞釋放的一或多種小（5-20 kD）蛋白質，其對細胞之間的相互作用和通信或對諸如免疫細胞增殖和分化的細胞行為具有特定作用。免疫系統中細胞介素的功能包括促進循環的白血球和淋巴細胞流入免疫碰撞位點；刺激B細胞、T細胞、周邊血單核細胞（PBMC）以及其他免疫細胞的發育和增殖；以及提供抗微生物活性。示例性免疫細胞介素包括但不限於IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-9、IL-10、IL-12、IL-13、IL-15、IL17A、IL-17F、IL-18、IL-21、IL-22、IL-23、IL-31、IL-33、干擾素（包括IFN α、β和γ）、腫瘤壞死因子（包括TNF α、β）、轉化生長因子（包括TGF α、β）、粒細胞集落刺激因子（GCSF）、粒細胞巨噬細胞集落刺激因子（GMCSF）和胸腺基質淋巴細胞生成素（TSLP）。As used herein, the term "interleukin" refers to one or more small (5-20 kD) proteins released by cells that have specific effects on cell-to-cell interactions and communication or on cell behavior such as immune cell proliferation and differentiation. The functions of interleukins in the immune system include promoting the influx of circulating leukocytes and lymphocytes to immune collision sites; stimulating the development and proliferation of B cells, T cells, peripheral blood mononuclear cells (PBMCs), and other immune cells; and providing antimicrobial activity. Exemplary immunocytokines include, but are not limited to, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-15, IL17A, IL-17F, IL-18, IL-21, IL-22, IL-23, IL-31, IL-33, interferons (including IFN α, β and γ), tumor necrosis factor (including TNF α, β), transforming growth factor (including TGF α, β), granulocyte colony stimulating factor (GCSF), granulocyte macrophage colony stimulating factor (GMCSF) and thymic stromal lymphopoietin (TSLP).
「輔助性T細胞（Th）1細胞介素」或「Th1特異性細胞介素」係指由Th1 T細胞表現（細胞內和/或分泌）的細胞介素，並且包括IFN-g、TNF-a和IL-12。「Th2細胞介素」或「Th2特異性細胞介素」係指由Th2 T細胞表現（細胞內和/或分泌）的細胞介素，包括IL-4、IL-5、IL-13和IL-10。「Th17細胞介素」或「Th17特異性細胞介素」係指由Th17 T細胞表現（細胞內和/或分泌）的細胞介素，包括IL-17A、IL-17F、IL-22和IL-21。除本文中所列出的Th17細胞介素的外，Th17細胞的某些群體還表現IFN-g和/或IL-2。多功能CTL細胞介素包括IFN-g、TNF-a、IL-2和IL-17。"Helper T cell (Th) 1 cytokines" or "Th1-specific cytokines" refer to cytokines expressed (intracellular and/or secreted) by Th1 T cells and include IFN-g, TNF-a, and IL-12. "Th2 cytokines" or "Th2-specific cytokines" refer to cytokines expressed (intracellular and/or secreted) by Th2 T cells and include IL-4, IL-5, IL-13, and IL-10. "Th17 cytokines" or "Th17-specific cytokines" refer to cytokines expressed (intracellular and/or secreted) by Th17 T cells and include IL-17A, IL-17F, IL-22, and IL-21. In addition to the Th17 cytokines listed herein, certain populations of Th17 cells also express IFN-g and/or IL-2. Multifunctional CTL cytokines include IFN-g, TNF-a, IL-2, and IL-17.
術語「特異性地結合」為「抗原特異性的」、「對抗原具有特異性」、「選擇性結合劑」、「特異性結合劑」、「抗原靶標」或與抗原「免疫反應」係指抗體或多肽以比相似序列的其他抗原更大的親和力結合靶標抗原。本文提供了該試劑特異性結合用於鑒定免疫細胞類型的靶蛋白，例如表面抗原（例如，T細胞受體、CD3）、細胞介素（例如，TSLP、IL-4、IL-5、IL-13、IL-17、IFN-g、TNF-a）等。在多個實施方式中，抗體特異性地結合靶標抗原，但可以與密切相關的物種的同源物交叉反應，例如抗體可結合人類蛋白並且還結合密切相關的靈長類動物蛋白質。The term "specifically binds" as "antigen-specific", "specific for an antigen", "selective binder", "specific binder", "antigen target" or "immunoreactive" with an antigen refers to an antibody or polypeptide that binds to a target antigen with greater affinity than other antigens of similar sequence. Provided herein are reagents that specifically bind to target proteins for identifying immune cell types, such as surface antigens (e.g., T cell receptors, CD3), interleukins (e.g., TSLP, IL-4, IL-5, IL-13, IL-17, IFN-g, TNF-a), etc. In various embodiments, the antibody specifically binds a target antigen but may cross-react with homologs from closely related species, e.g., an antibody may bind a human protein and also bind a closely related primate protein.
術語「抗體」或「免疫球蛋白」係指由各自包含可變區和恒定區的兩條重鏈和兩條輕鏈組成的四聚體糖蛋白。「重鏈」和「輕鏈」係指基本上全長的標準免疫球蛋白的輕鏈和重鏈（參見例如Immunobiology [免疫學], 第5版（Janeway和Travers等人編輯, 2001））。抗原結合部分可藉由重組DNA技術或藉由完整抗體的酶促或化學裂解產生。術語「抗體」包括單株抗體、多株抗體、嵌合抗體、人抗體和人源化抗體。出於本發明之申請專利範圍之目的，術語「抗體」和「抗TSLP抗體」係指由兩條重鏈和兩條輕鏈組成的四聚體糖蛋白，每條鏈包括可變區和恒定區，並具有IgG1、IgG2、IgG3或IgG4 Fc區。The term "antibody" or "immunoglobulin" refers to a tetrameric glycoprotein composed of two heavy chains and two light chains, each comprising a variable region and a constant region. "Heavy chain" and "light chain" refer to the light and heavy chains of a substantially full-length standard immunoglobulin (see, e.g., Immunobiology, 5th edition (Janeway and Travers et al., eds., 2001)). The antigen-binding portion can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. The term "antibody" includes monoclonal antibodies, polyclonal antibodies, chimeric antibodies, human antibodies, and humanized antibodies. For the purpose of the patent application scope of the present invention, the terms "antibody" and "anti-TSLP antibody" refer to a tetrameric glycoprotein composed of two heavy chains and two light chains, each chain including a variable region and a constant region, and having an IgG1, IgG2, IgG3 or IgG4 Fc region.
抗體變體包括抗體片段和變為標準四聚體抗體的結構的類抗體蛋白。通常，抗體變體包括恒定區發生變化的V區，或替代地以非典型方式將V區添加到恒定區。實例包括可結合抗原的抗體片段（例如，Fab'、F'(ab)2、Fv）、包含上述的雙互補位和重組肽，只要它們表現出所需的生物活性。變體可能包含來自IgG抗體的Fc區，例如IgG1、IgG2、IgG3或IgG4 Fc區。Antibody variants include antibody fragments and antibody-like proteins that have been changed into the structure of standard tetrameric antibodies. Typically, antibody variants include V regions in which the constant region has been changed, or alternatively V regions are added to the constant region in an atypical manner. Examples include antigen-binding antibody fragments (e.g., Fab', F'(ab)2, Fv), containing the above-mentioned double complementary sites and recombinant peptides, as long as they exhibit the desired biological activity. Variants may include Fc regions from IgG antibodies, such as IgG1, IgG2, IgG3 or IgG4 Fc regions.
本文提供的抗體變體還包括具有SEQ ID NO: 3-8中列出的CDR的抗體衍生物，但由於製造或純化程序的結果，或由於製造或純化程序的改進，可以在SEQ ID NO: 10或12的可變區胺基酸或SEQ ID NO: 13或14中列出的Fc區胺基酸中具有胺基酸變化或化學修飾（例如，氧化、甲基化）。泰派魯單抗的抗體變體/衍生物在PCT/US22/25994（國際公開WO 2022/226339）和PCT/US22/25999（國際公開WO 2022/226342）中進行了描述，其藉由引用整體併入文中。Antibody variants provided herein also include antibody derivatives having the CDRs listed in SEQ ID NOs: 3-8, but as a result of, or due to improvements in, the manufacturing or purification procedures, may have amino acid changes or chemical modifications (e.g., oxidation, methylation) in the variable region amino acids of SEQ ID NOs: 10 or 12 or the Fc region amino acids listed in SEQ ID NOs: 13 or 14. Antibody variants/derivatives of teplumab are described in PCT/US22/25994 (International Publication WO 2022/226339) and PCT/US22/25999 (International Publication WO 2022/226342), which are incorporated herein by reference in their entirety.
抗體片段包括抗體的抗原結合部分，尤其包括Fab、Fab'、F(ab')2、Fv、結構域抗體（dAb）、互補決定區（CDR）片段、CDR接枝抗體或其變體或衍生物，以及含有至少一部分足以賦予多肽特異性抗原結合的免疫球蛋白的多肽，例如一個、兩個、三個、四個、五個或六個CDR序列，只要抗體保持所需的生物活性。Antibody fragments include antigen-binding portions of antibodies, particularly Fab, Fab', F(ab')2, Fv, domain antibodies (dAb), complementary determining region (CDR) fragments, CDR-grafted antibodies or variants or derivatives thereof, as well as polypeptides containing at least a portion of an immunoglobulin sufficient to confer specific antigen binding to the polypeptide, such as one, two, three, four, five or six CDR sequences, as long as the antibody retains the desired biological activity.
「價數（valency）」係指靶向表位的各抗體或抗體片段上的抗原結合位點的數目。典型全長IgG分子或F(ab)2係「二價」的，因為其具有兩個相同的靶標結合位點。具有單個抗原結合位點的「單價」抗體片段，例如F(ab)’或scFv。三價或四價抗原結合蛋白還可工程改造成多價。"Valency" refers to the number of antigen binding sites on each antibody or antibody fragment that targets an epitope. A typical full-length IgG molecule or F(ab)2 is "bivalent" because it has two identical target binding sites. "Monovalent" antibody fragments, such as F(ab)' or scFv, have a single antigen binding site. Trivalent or tetravalent antigen binding proteins can also be engineered to be multivalent.
術語「單株抗體」係指自基本上均質的抗體群體（即構成該群體的個體抗體除可少量存在的天然存在的可能突變外均一致）獲得的抗體。The term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population (ie, the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts).
術語「抑制TSLP活性」包括抑制以下任一或多個：TSLP結合其受體；在TSLP存在下表現TSLPR的細胞的增殖、活化或分化；在極化分析中在TSLP存在下Th2細胞介素產生的抑制；在TSLP存在下樹突狀細胞活化或成熟；以及在TSLP存在下肥大細胞細胞介素釋放。參見例如美國專利7982016 B2的第6欄和實例8，以及US 2012/0020988 A1的實例7-10。The term "inhibiting TSLP activity" includes inhibiting any one or more of the following: TSLP binding to its receptor; proliferation, activation or differentiation of cells expressing TSLPR in the presence of TSLP; inhibition of Th2 cytokine production in the presence of TSLP in polarization assays; dendritic cell activation or maturation in the presence of TSLP; and mast cell cytokine release in the presence of TSLP. See, for example, column 6 and example 8 of U.S. Patent No. 7982016 B2, and examples 7-10 of US 2012/0020988 A1.
術語「樣本」或「生物樣本」係指自受試者獲得以用於本發明之方法中的樣本，並且包括尿、全血、血漿、血清、唾液、痰液、皮膚或組織切片、腦脊髓液、有活體外刺激的周邊血單核細胞、無活體外刺激的周邊血單核細胞、有活體外刺激的腸淋巴組織、無活體外刺激的腸淋巴組織、腸灌洗液、支氣管肺泡灌洗液、鼻灌洗液和誘導的痰液。The term "sample" or "biological sample" refers to a sample obtained from a subject for use in the method of the present invention, and includes urine, whole blood, plasma, serum, saliva, sputum, skin or tissue sections, cerebrospinal fluid, peripheral blood mononuclear cells stimulated in vitro, peripheral blood mononuclear cells without in vitro stimulation, intestinal lymphoid tissue stimulated in vitro, intestinal lymphoid tissue without in vitro stimulation, intestinal lavage fluid, bronchoalveolar lavage fluid, nasal lavage fluid and induced sputum.
術語「治療（treat、treating和treatment）」係指與本文所述之炎性病症有關的事件、疾病或病況的臨床症狀、表現或進展暫時或永久、部分或完全地消除、減少、壓制或改善。如相關領域中所認識到，用作治療劑的藥物可降低既定疾病狀態的嚴重度，但不必消除疾病的每種表現才被認為是有用治療劑。相似地，預防性投與的治療不必完全有效地預防病症發作才可成為可行的預防劑。僅僅降低疾病的影響（例如藉由減少其症狀的次數或降低其症狀的嚴重度，或藉由增加另一治療的有效性，或藉由產生另一有益作用）或降低疾病在受試者中發生或惡化的可能性即為足夠。本揭露之一個實施方式涉及一種用於確定治療效果之方法，該方法包括向患者投與治療劑，其量和時間足以誘導反映特定病症的嚴重程度的指標相對於基線的持續改善。The terms "treat," "treating," and "treatment" refer to the temporary or permanent, partial or complete elimination, reduction, suppression, or improvement of the clinical symptoms, manifestations, or progression of an event, disease, or condition associated with an inflammatory disorder as described herein. As recognized in the relevant art, drugs used as therapeutic agents can reduce the severity of a given disease state, but do not necessarily eliminate every manifestation of the disease to be considered a useful treatment. Similarly, a prophylactically administered treatment does not have to be completely effective in preventing the onset of the disorder to be a viable preventive. It is sufficient to simply reduce the impact of the disease (e.g., by reducing the number of its symptoms or reducing the severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect) or to reduce the likelihood that the disease will occur or worsen in the subject. One embodiment of the present disclosure relates to a method for determining the effectiveness of a treatment, the method comprising administering to a patient a therapeutic agent in an amount and for a period of time sufficient to induce a sustained improvement relative to a baseline in an indicator reflecting the severity of a particular condition.
術語「治療有效量」係指治療劑有效改善或減輕與疾病或病症有關的症狀或徵象的量。重度氣喘The term "therapeutically effective amount" refers to an amount of a therapeutic agent effective to improve or alleviate the symptoms or signs associated with a disease or condition.
患有不受控制的重度氣喘的參與者可能需要長期的OCS每日維持治療。然而，當長時間給藥時，OCS與多種且可能使人衰弱的不良結局有關。該等包括但不限於代謝紊亂，例如葡萄糖不耐受和血脂異常（Gounarides等人 2008，de Oliveira等人 2011）、骨質疏鬆症（Sambrook等人 1990）、腎上腺軸功能不全以及脂肪沈積過多和異常（Gounarides等人 2008）。發生OCS相關副作用的幾率與長期（≥ 6個月）OCS使用劑量依賴性相關，從每天5 mg或甚至更低劑量的強體松開始（Dalal等人 2016）。重度氣喘患者的慢性OCS給藥也與直接醫療成本和資源利用增加有關。因此，在需要長期維持OCS使用的重度氣喘患者中，減少OCS劑量將具有臨床意義。Participants with uncontrolled severe asthma may require long-term daily maintenance therapy with OCS. However, when given for long periods of time, OCS is associated with multiple and potentially debilitating adverse outcomes. These include, but are not limited to, metabolic disturbances such as glucose intolerance and dyslipidemia (Gounarides et al. 2008, de Oliveira et al. 2011), osteoporosis (Sambrook et al. 1990), adrenal axis insufficiency, and excessive and abnormal fat deposits (Gounarides et al. 2008). The incidence of OCS-related side effects is associated with dosage dependence with long-term (≥ 6 months) OCS use, starting with prednisone at 5 mg daily or even lower doses (Dalal et al. 2016). Chronic OCS administration in patients with severe asthma is also associated with increased direct medical costs and resource utilization. Therefore, reducing OCS dosage would be clinically meaningful in patients with severe asthma who require long-term maintenance OCS use.
先前的靶向2型（T2）細胞介素，特別是白血球介素[IL]-4/IL-13和IL-5或它們各自受體的單株抗體的隨機對照試驗已經證明，在需要OCS維持治療的重度氣喘患者中（Bel等人 2014，Nair等人 2017，Rabe等人 2018），特別是在患有嗜酸性球氣喘的那些患者中，每日OCS劑量逐漸減少或中斷。Previous randomized controlled trials of monoclonal antibodies targeting type 2 (T2) interleukins, specifically interleukin [IL]-4/IL-13 and IL-5, or their respective receptors, have demonstrated the efficacy of tapering or interrupting the daily OCS dose in patients with severe asthma who require maintenance OCS therapy (Bel et al. 2014, Nair et al. 2017, Rabe et al. 2018), particularly in those with eosinophilic asthma.
儘管OCS療法可以有效治療幾種炎症性疾病，但它對與健康相關的生活品質產生不利影響（Swedin等人, 2017；Sweeney等人, 2016），並與多種副作用有關，包括骨質疏鬆症、高血壓和抑鬱症（Dinsen等人, 2013）。長期使用OCS抑制下視丘垂體-腎上腺（HPA）軸並阻止皮質醇產生（Neogi等人, 2010；Nicholas等人, 2018）。停用OCS後，HPA軸的恢復可能需要更長的時間，從而導致約50%的患者出現腎上腺功能不全（AI）（Dinsen等人, 2013）。AI之症狀和體征通常是非特異性的，可能包括疲勞和噁心；此外，在例如手術、身體損傷或嚴重全身感染期間的生理創傷情況下，皮質醇誘導的應激反應受損可能危及生命（腎上腺危象）（Alves等人, 2008；Dinsen等人, 2013；Johnson等人, 2014；Joseph等人, 2016）。因此，在向下滴定OCS劑量的同時篩選和監測患者的AI係重要的，特別是一旦患者達到生理劑量，其被定義為每天約5 mg口服強體松（Alves等人, 2008）。Although OCS therapy is effective in treating several inflammatory diseases, it has a negative impact on health-related quality of life (Swedin et al., 2017; Sweeney et al., 2016) and is associated with multiple side effects, including osteoporosis, hypertension, and depression (Dinsen et al., 2013). Long-term use of OCS suppresses the hypothalamic-pituitary-adrenal (HPA) axis and blocks cortisol production (Neogi et al., 2010; Nicholas et al., 2018). After discontinuation of OCS, recovery of the HPA axis may take longer, resulting in adrenal insufficiency (AI) in approximately 50% of patients (Dinsen et al., 2013). Signs and symptoms of AI are often nonspecific and may include fatigue and nausea; furthermore, in situations of physiological trauma, such as during surgery, physical injury, or severe systemic infection, an impairment of the corticosteroid-induced stress response may be life-threatening (adrenaline crisis) (Alves et al., 2008; Dinsen et al., 2013; Johnson et al., 2014; Joseph et al., 2016). Therefore, it is important to screen and monitor patients for AI while down-titrating OCS dosing, particularly once patients have achieved physiologic dosing, which is defined as approximately 5 mg of oral prednisone per day (Alves et al., 2008).
在保留OCS的3期研究SOURCE（NCT03406078）中，與安慰劑相比，泰派魯單抗在OCS依賴性氣喘參與者中減少了OCS使用，但差異無統計學顯著性。與安慰劑治療的參與者相比，更高比例的泰派魯單抗治療的參與者將每日OCS劑量減少了90%-100%。對SOURCE數據的事後分析表明，泰派魯單抗對OCS劑量減少的影響缺乏顯著性可能部分歸因於研究設計特徵（Wechsler等人 2022）。此外，與安慰劑治療的參與者相比，基線血液嗜酸性球計數＜ 150個細胞/µL的泰派魯單抗治療的參與者的OCS保留效果較小。In the Phase 3 OCS-sparing study SOURCE (NCT03406078), teprenolumab reduced OCS use in participants with OCS-dependent asthma compared with placebo, but the difference was not statistically significant. A higher proportion of participants treated with teprenolumab reduced their daily OCS dose by 90%-100% compared with those treated with placebo. Post hoc analyses of the SOURCE data suggested that the lack of significance of teprenolumab’s effect on OCS dose reduction may be due in part to study design characteristics (Wechsler et al. 2022). Additionally, participants treated with tepilumab who had baseline blood eosinophil counts <150 cells/µL had less OCS preservation than those treated with placebo.
據提供，投與改善了選自由以下組成之群組的皮質類固醇依賴性氣喘的一或多種測量值：用力呼氣容積（FEV）、FEV1可逆性、用力肺活量（FVC）、FeNO、氣喘控制問卷-6得分和AQLQ(S)+12得分、BD前FEV1相對於基線的變化、每日維持OCS劑量相對於基線的減少、每日維持OCS劑量≤ 5 mg、以及每日維持OCS劑量相對於基線減少≥ 50%、藉由AAER測量的氣喘加重和首次氣喘加重的時間、與急診室（ER）就診、緊急護理就診或住院相關的氣喘加重率、以及未經歷氣喘加重的參與者比例、每週平均居家PEF（早晚）和/或聖喬治呼吸問卷（SGRQ）得分。進一步提供，投與降低受試者腎上腺功能不全的發生率。It is provided that administration improves one or more measures of corticosteroid-dependent asthma selected from the group consisting of: forced expiratory volume (FEV1),FEV1 reversibility, forced vital capacity (FVC), FeNO, Asthma Control Questionnaire-6 score and AQLQ(S)+12 score, change from baseline in pre-BDFEV1 , reduction from baseline in daily maintenance OCS dose, maintenance OCS dose ≤ 5 mg per day, and reduction from baseline in daily maintenance OCS dose ≥ 50%, asthma exacerbations and time to first asthma exacerbation as measured by AAER, asthma exacerbation rates associated with emergency room (ER) visits, urgent care visits, or hospitalizations, and the proportion of participants experiencing no asthma exacerbations, and average weekly home PEF (morning and evening) and/or St. George's Respiratory Questionnaire (SGRQ) scores. Further, administration reduces the incidence of adrenal insufficiency in the subjects.
用於得分和確定其中各種測量值的減少的方法如本文所述和本領域已知的。Methods for scoring and determining reductions in the various measurements therein are as described herein and known in the art.
整體氣喘症狀係每天早晚對氣喘症狀的評估（0到3）。晚上和隨後的早上單個總體項目得分（0到6）的總和將用於警報系統。Global Asthma Symptoms is an assessment of asthma symptoms in the morning and evening each day (0 to 3). The sum of the individual global item scores (0 to 6) for the evening and the following morning will be used for the alarm system.
氣喘控制問卷（ACQ-6）係對氣喘症狀（夜間醒來、醒來症狀、活動受限、呼吸急促、喘息和短效β促效劑使用）的評估。平均ACQ-6得分為反應平均值。平均得分≤ 0.75表示氣喘控制良好，得分在0.75和＜ 1.5之間表示氣喘部分控制，得分≥ 1.5表示氣喘控制不好。至少0.5的個體變化被認為具有臨床意義，減少至少0.5係ACQ-6的反應者定義。The Asthma Control Questionnaire (ACQ-6) is an assessment of asthma symptoms (nighttime awakenings, awakening symptoms, activity limitation, shortness of breath, wheezing, and short-acting beta-agonist use). The mean ACQ-6 score is the mean response. A mean score ≤ 0.75 indicates good asthma control, a score between 0.75 and < 1.5 indicates partial asthma control, and a score ≥ 1.5 indicates poor asthma control. An individual change of at least 0.5 is considered clinically significant, and a decrease of at least 0.5 is a responder definition for the ACQ-6.
AQLQ(S)+12係測量氣喘參與者所經歷的與健康相關的生活品質的問卷。該問卷包含4個獨立領域（症狀、活動限制、情緒功能和環境刺激）。參與者被要求回憶他們在過去2週內的經歷，並以範圍從7（無損傷）到1（嚴重損傷）的7分量表對每個問題進行得分。總得分計為對所有問題的平均反應。AQLQ(s)+12的反應者定義為比基線改善了0.5分。The AQLQ(S)+12 is a questionnaire that measures the health-related quality of life experienced by participants with asthma. The questionnaire contains 4 separate domains (symptoms, activity limitations, emotional functioning, and environmental stimuli). Participants are asked to recall their experiences over the past 2 weeks and score each question on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The total score is calculated as the average response to all questions. A responder on the AQLQ(s)+12 is defined as an improvement of 0.5 points from baseline.
聖喬治呼吸問卷SGRQ係一種50項PRO工具，用於測量患有氣道阻塞疾病的參與者的健康狀況。該總分表示為總體損傷的百分比，其中100表示最差的可能健康狀況，0表示最好的可能健康狀況。根據經驗數據和對患者的訪談，4個單位的平均變化得分與最小臨床重要差異（MCID）相關。The St. George's Respiratory Questionnaire (SGRQ) is a 50-item PRO instrument that measures health status in participants with obstructive airway disease. The total score is expressed as a percentage of global impairment, where 100 represents the worst possible health status and 0 represents the best possible health status. A mean change score of 4 units is associated with the minimal clinically important difference (MCID) based on empirical data and interviews with patients.
EQ-5D-5L問卷評估5個維度：活動能力、自我護理、日常活動、疼痛/不適和焦慮/抑鬱。每個維度具有反映難度水平增加的5個反應選項（無問題、輕微問題、中度問題、嚴重問題和極端問題）。問卷還包括視覺模擬量表（VAS），其中參與者將被要求對當前健康狀況進行0到100的得分，0係可以想像到的最差健康狀況The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 response options reflecting increasing levels of difficulty (no problem, slight problem, moderate problem, severe problem, and extreme problem). The questionnaire also includes a visual analog scale (VAS) in which participants are asked to rate their current health status on a scale of 0 to 100, with 0 being the worst health status imaginable.
EuroQOL生活品質5維3水平版本（EQ-5D-3L）係一種標準化工具，用於衡量健康相關的生活品質（HRQoL），並由EuroQol（Brooks, 1996）開發。它從5個維度定義健康：活動能力、自我護理、日常活動、疼痛/不適和焦慮/抑鬱。以及3個順序的嚴重程度：1，沒有問題；2，一些問題；以及3，問題嚴重。總體健康狀態定義為5位數。問卷還包括VAS，參與者將被要求使用0到100的量表對當前健康狀況進行得分，其中0係可以想像到的最差健康狀況。TSLPThe EuroQOL Quality of Life 5 Dimensions 3 Levels version (EQ-5D-3L) is a standardized instrument to measure health-related quality of life (HRQoL) and was developed by EuroQol (Brooks, 1996). It defines health in terms of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. And 3 ordinal levels of severity: 1, no problems; 2, some problems; and 3, severe problems. The overall health status is defined as a 5-digit number. The questionnaire also includes a VAS, where participants are asked to score their current health status using a scale of 0 to 100, where 0 is the worst health status imaginable.TSLP
胸腺基質淋巴細胞生成素（TSLP）係一種上皮細胞衍生的細胞介素，其係對促炎性刺激起反應而產生，且主要經由其在樹突狀細胞（Gilliet, J Exp Med.[實驗醫學雜誌] 197:1059-1067, 2003；Soumelis, Nat Immunol.[自然免疫學] 3:673-680, 2002；Reche, J Immunol[免疫學雜誌]. 167:336-343, 2001）、肥大細胞（Allakhverdi, J Exp Med[實驗醫學雜誌]. 204:253-258, 2007）和CD34+先驅細胞上的活性驅動過敏性炎症反應。TSLP通過由白血球介素（IL）-7受體α（IL-7Rα）鏈和常見γ鏈樣受體（TSLPR）組成的異二聚體受體發信號（Pandey, Nat Immunol.[自然免疫學] 1:59-64, 2000；Park, J Exp Med.[實驗醫學雜誌] 192:659-669, 2000）。Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that is produced in response to proinflammatory stimuli and drives allergic inflammatory responses primarily through its activity on dendritic cells (Gilliet, J Exp Med. 197:1059-1067, 2003; Soumelis, Nat Immunol. 3:673-680, 2002; Reche, J Immunol. 167:336-343, 2001), mast cells (Allakhverdi, J Exp Med. 204:253-258, 2007), and CD34+ pioneer cells. TSLP signals through a heterodimeric receptor composed of the interleukin (IL)-7 receptor alpha (IL-7Rα) chain and the common gamma chain-like receptor (TSLPR) (Pandey, Nat Immunol. 1:59-64, 2000; Park, J Exp Med. 192:659-669, 2000).
來自其他研究的數據表明TSLP可經由與Th2無關的途徑，諸如氣道平滑肌與肥大細胞之間的串擾，引起氣道炎症（Allakhverdi等人, J Allergy Clin Immunol.[過敏與臨床免疫雜誌] 123(4):958-60, 2009；Shikotra等人, 同上）。TSLP還可以促進T細胞分化為Th-17-細胞介素產生細胞的誘導，從而導致在更重度氣喘中常見的嗜中性球炎症的增加（Tanaka等人, Clin Exp Allergy[臨床和實驗過敏].39(1):89-100, 2009）。該等數據和其他出現的證據表明阻斷TSLP可用於壓制多個生物途徑，包括但不限於涉及Th2細胞介素（IL-4/13/5）的途徑。Data from other studies suggest that TSLP can cause airway inflammation via pathways independent of Th2, such as crosstalk between airway smooth muscle and mast cells (Allakhverdi et al., J Allergy Clin Immunol. 123(4):958-60, 2009; Shikotra et al., supra). TSLP can also promote the induction of T cell differentiation into Th-17-interleukin-producing cells, leading to the increased neutrophilic inflammation seen in more severe asthma (Tanaka et al., Clin Exp Allergy. 39(1):89-100, 2009). These data and other emerging evidence suggest that blocking TSLP could be used to suppress multiple biological pathways, including but not limited to those involving Th2 interleukins (IL-4/13/5).
在抗TSLP抗體泰派魯單抗的PATHWAY 2b期研究（NCT02054130）中，無論基線疾病表型如何，泰派魯單抗顯著降低患有重度、未控制氣喘的成人的加重高達71%（Corren等人 2017）。在NAVIGATOR（NCT03347279）3期研究中，無論T2炎症生物標誌物（血液嗜酸性球計數、FeNO和血清總IgE）的基線水平、過敏狀態和基線維持OCS使用如何，泰派魯單抗降低患有重度、未控制氣喘的患者之加重（Menzies Gow等人 2021）。在該等研究中，泰派魯單抗還改善了整個群體的肺功能、氣喘控制和患者健康相關的生活品質。In the Phase 2b PATHWAY study of the anti-TSLP antibody teprenumab (NCT02054130), teprenumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, regardless of baseline disease phenotype (Corren et al. 2017). In the Phase 3 NAVIGATOR (NCT03347279) study, teprenumab reduced exacerbations in patients with severe, uncontrolled asthma, regardless of baseline levels of T2 inflammatory biomarkers (blood eosinophil count, FeNO, and serum total IgE), allergy status, and baseline maintenance OCS use (Menzies Gow et al. 2021). In these studies, teprenumab also improved lung function, asthma control, and health-related quality of life in the entire population.
在SOURCE（NCT03406078）3期研究中，泰派魯單抗在OCS依賴性氣喘群體中耐受性良好。在這項研究中，71.6%（53/74）的泰派魯單抗治療參與者和85.5%（65/76）的安慰劑治療參與者報告不良事件（AE），14.9%（11/74）和21.1%（16/76）分別報告嚴重不良事件（SAE）。泰派魯單抗組和安慰劑組之間AE的頻率和類型沒有顯著差異。In the Phase 3 SOURCE (NCT03406078) study, tepilumab was well tolerated in the OCS-dependent asthma population. In this study, 71.6% (53/74) of tepilumab-treated participants and 85.5% (65/76) of placebo-treated participants reported adverse events (AEs), and 14.9% (11/74) and 21.1% (16/76) reported serious adverse events (SAEs), respectively. There were no significant differences in the frequency and type of AEs between the tepilumab and placebo groups.
在NAVIGATOR 3期研究中，泰派魯單抗組共有77.1%（407/528）的參與者和安慰劑組共有79.5%（422/531）的參與者報告治療中的AE，8.7%（46/528）和13.2（70/531）分別報告SAE。在基線時或基線後，泰派魯單抗組中4.9%（26/527）的參與者和安慰劑組中8.3%（44/530）的參與者的抗藥物抗體呈陽性。在每組中的1名（0.2%）參與者中檢測到中和抗體（Menzies-Gow等人 2021）。抗體In the Phase 3 NAVIGATOR study, 77.1% (407/528) of participants in the teprenolumab group and 79.5% (422/531) of participants in the placebo group reported treatment-emergent AEs, and 8.7% (46/528) and 13.2 (70/531) reported SAEs, respectively. At baseline or after baseline, 4.9% (26/527) of participants in the teprenolumab group and 8.3% (44/530) of participants in the placebo group were positive for anti-drug antibodies. Neutralizing antibodies were detected in 1 (0.2%) participant in each group (Menzies-Gow et al. 2021).Antibodies
據提供，TSLP特異性抗體或抗體變體可用於治療皮質類固醇依賴性氣喘，包括使用皮質類固醇或其他治療無法控制的重度氣喘。It is provided that TSLP-specific antibodies or antibody variants can be used to treat corticosteroid-dependent asthma, including severe asthma that is uncontrolled with corticosteroids or other treatments.
諸如結合靶標抗原（例如TSLP）的特異性結合劑（諸如抗體和抗體變體或片段）可用於本揭露之方法中。在一個實施方式中，特異性結合劑係抗體。該等抗體可為單株抗體（MAb）；重組抗體；嵌合抗體；人源化抗體，如互補決定區（CDR）移植抗體；人抗體；抗體變體，包括單鏈；和/或雙特異性的；以及其片段；變體；或其衍生物。抗體片段包括抗體的結合目的多肽的表位的那些部分。此類片段之實例包括由全長抗體的酶促裂解產生的Fab和F(ab')片段。其他結合片段包括由重組DNA技術產生的片段，該等技術如表現含有編碼抗體可變區的核酸序列的重組質體。Specific binding agents (such as antibodies and antibody variants or fragments) that bind to a target antigen (e.g., TSLP) can be used in the methods disclosed herein. In one embodiment, the specific binding agent is an antibody. The antibodies may be monoclonal antibodies (MAbs); recombinant antibodies; chimeric antibodies; humanized antibodies, such as complementary determining region (CDR) grafted antibodies; human antibodies; antibody variants, including single chains; and/or bispecific; and fragments thereof; variants; or derivatives thereof. Antibody fragments include those portions of the antibody that bind to an epitope of a polypeptide of interest. Examples of such fragments include Fab and F(ab') fragments produced by enzymatic cleavage of full-length antibodies. Other binding fragments include fragments produced by recombinant DNA techniques, such as recombinant plasmids expressing nucleic acid sequences encoding variable regions of antibodies.
單株抗體可經修飾用作治療劑或診斷劑。一個實施方式為「嵌合」抗體，其中一部分重鏈（H）和/或輕鏈（L）與來源於特定物種或屬於特定抗體類別或子類的抗體中的對應序列相同或同源，而鏈的剩餘部分與來源於另一物種或屬於另一抗體類別或子類的抗體中的對應序列相同或同源。還包括此類抗體的片段，只要其展現所需生物活性即可。參見美國專利案號4,816,567；Morrison等人, 1985, Proc. Natl. Acad. Sci.[美國國家科學院院刊] 81:6851-55。Monoclonal antibodies can be modified for use as therapeutic or diagnostic agents. One embodiment is a "chimeric" antibody in which a portion of the heavy (H) and/or light (L) chains are identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass. Also included are fragments of such antibodies, as long as they exhibit the desired biological activity. See U.S. Patent No. 4,816,567; Morrison et al., 1985, Proc. Natl. Acad. Sci. 81:6851-55.
在另一個實施方式中，單株抗體係「人源化」抗體。用於將非人抗體人源化的方法為本領域中所熟知。參見美國專利案號5,585,089和5,693,762。通常，人源化抗體具有一或多個自非人類來源引入其中的胺基酸殘基。可例如使用本領域中所述之方法（Jones等人, 1986, Nature [自然] 321:522-25；Riechmann等人, 1998, Nature [自然] 332:323-27；Verhoeyen等人, 1988, Science [科學] 239:1534-36），藉由用齧齒類動物互補決定區的至少一部分代替人抗體的對應區域來進行人源化。例如，通過CDR移植，將非人CDR序列插入人框架區域（Lu等人 Journal of Biomedical Science[生物醫學科學雜誌] (2020) 27:1）。In another embodiment, the monoclonal antibody is a "humanized" antibody. Methods for humanizing non-human antibodies are well known in the art. See U.S. Patent Nos. 5,585,089 and 5,693,762. Typically, a humanized antibody has one or more amino acid residues introduced therein from a non-human source. Humanization can be performed, for example, using methods described in the art (Jones et al., 1986, Nature 321:522-25; Riechmann et al., 1998, Nature 332:323-27; Verhoeyen et al., 1988, Science 239:1534-36), by replacing at least a portion of a rodent complement determining region with a corresponding region of a human antibody. For example, through CDR grafting, non-human CDR sequences are inserted into the human framework region (Lu et al. Journal of Biomedical Science (2020) 27:1).
本揭露還涵蓋結合TSLP的人抗體和抗體變體（包括抗體片段）。人抗體係指由人免疫球蛋白序列產生並包含人可變區和恒定區的抗體。使用在缺少內源性免疫球蛋白產生時能夠產生人抗體譜的轉基因動物（例如小鼠），藉由用多肽抗原（即具有至少6個相鄰胺基酸）進行免疫接種，視需要結合載劑，來產生此類抗體。參見，例如Jakobovits等人, 1993, Proc. Natl. Acad. Sci.[美國國家科學院院刊] 90:2551-55；Jakobovits等人, 1993, Nature [自然] 362:255-58；Bruggermann等人, 1993, Year in Immuno.[免疫學年評]7:33。還參見PCT申請案號PCT/US96/05928和PCT/US93/06926。其他方法描述於美國專利案號5,545,807、PCT申請案號PCT/US91/245和PCT/GB89/01207、以及歐洲專利案號546073B1和546073A1中。人抗體也可以藉由在宿主細胞中表現重組DNA或藉由在融合瘤細胞中表現、使用噬菌體展示文庫或藉由單個B細胞選殖來產生（Lu等人 Journal of Biomedical Science[生物醫學科學雜誌] (2020) 27:1）。The present disclosure also encompasses human antibodies and antibody variants (including antibody fragments) that bind to TSLP. Human antibodies refer to antibodies generated from human immunoglobulin sequences and comprising human variable and constant regions. Such antibodies are generated using transgenic animals (e.g., mice) that are capable of producing a human antibody repertoire in the absence of endogenous immunoglobulin production by immunizing with a polypeptide antigen (i.e., having at least 6 adjacent amino acids), optionally in combination with a carrier. See, e.g., Jakobovits et al., 1993, Proc. Natl. Acad. Sci. [Proceedings of the National Academy of Sciences of the United States of America] 90:2551-55; Jakobovits et al., 1993, Nature [Nature] 362:255-58; Bruggermann et al., 1993, Year in Immuno. [Annual Review of Immunology] 7:33. See also PCT Application Nos. PCT/US96/05928 and PCT/US93/06926. Other methods are described in U.S. Patent No. 5,545,807, PCT Application Nos. PCT/US91/245 and PCT/GB89/01207, and European Patent Nos. 546073B1 and 546073A1. Human antibodies can also be produced by expressing recombinant DNA in host cells or by expressing in fusion tumor cells, using phage display libraries, or by single B cell cloning (Lu et al. Journal of Biomedical Science (2020) 27:1).
嵌合的、CDR移植的以及人源化抗體和/或抗體變體通常藉由重組方法產生。將編碼抗體的核酸引入宿主細胞中並且使用本文所述之材料和程序表現。在較佳的實施方式中，在如CHO細胞的哺乳動物宿主細胞中產生抗體。單選殖（例如人）抗體可藉由在宿主細胞中表現重組DNA或藉由在如本文所述之融合瘤細胞中表現來產生。Chimeric, CDR-grafted, and humanized antibodies and/or antibody variants are typically produced by recombinant methods. Nucleic acids encoding the antibodies are introduced into host cells and expressed using the materials and procedures described herein. In a preferred embodiment, antibodies are produced in mammalian host cells such as CHO cells. Monoclonal (e.g., human) antibodies can be produced by expressing recombinant DNA in host cells or by expressing in fusion tumor cells as described herein.
可用於本方法的抗體和抗體變體（包括抗體片段）包含抗TSLP抗體，其包含：a. 輕鏈可變結構域，其含有：i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體或抗體變體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Antibodies and antibody variants (including antibody fragments) that can be used in the present method include anti-TSLP antibodies, which include: a. a light chain variable domain, which includes: i. a light chain CDR1 sequence including the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence including the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence including the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain, which includes: i. a heavy chain CDR1 sequence including the amino acid sequence shown in SEQ ID NO:6; ii. a heavy chain CDR2 sequence including the amino acid sequence shown in SEQ ID NO:7, and iii. a heavy chain CDR3 sequence including the amino acid sequence shown in SEQ ID NO:8, wherein the antibody or antibody variant specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
還提供了抗體或抗體變體，其包含a.輕鏈可變結構域，該輕鏈可變結構域選自由以下組成之群組：i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；以及b. 重鏈可變結構域，該重鏈可變結構域選自由以下組成之群組：i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列；ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列；iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域，其中該抗體或抗體變體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Also provided are antibodies or antibody variants comprising a. a light chain variable domain, the light chain variable domain being selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide hybridized under moderately stringent conditions with a complementary sequence of a polynucleotide consisting of SEQ ID NO: 11; and b. a heavy chain variable domain, the heavy chain variable domain being selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 9; iii. an amino acid sequence encoded by a polynucleotide hybridized under moderately stringent conditions with a complementary sequence of a polynucleotide consisting of SEQ ID NO: 11; NO:9; or c. (a) the light chain variable domain and (b) the heavy chain variable domain, wherein the antibody or antibody variant specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
泰派魯單抗為一種示例性抗TSLP抗體，其具有：a. i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列；ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列；iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；以及b. 重鏈可變結構域，其含有：i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列；ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，以及iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列。Taipirumab is an exemplary anti-TSLP antibody having: a. i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and b. a heavy chain variable domain containing: i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:7, and iii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8.
泰派魯單抗還包含輕鏈可變結構域，該輕鏈可變結構域具有SEQ ID NO:12中列出的胺基酸序列；由SEQ ID NO:11中列出的多核苷酸序列編碼；和具有SEQ ID NO:10中列出的由SEQ ID NO:9中列出的多核苷酸序列編碼的胺基酸序列之重鏈可變結構域。Taipilumab also comprises a light chain variable domain having the amino acid sequence set forth in SEQ ID NO:12; encoded by the polynucleotide sequence set forth in SEQ ID NO:11; and a heavy chain variable domain having the amino acid sequence set forth in SEQ ID NO:10, encoded by the polynucleotide sequence set forth in SEQ ID NO:9.
泰派魯單抗為IgG2抗體。包括IgG2鏈的泰派魯單抗的全長重鏈和輕鏈的序列分別在SEQ ID NO: 13和14中列出。Taipelumab is an IgG2 antibody. The sequences of the full-length heavy chain and light chain of Taipelumab including the IgG2 chain are listed in SEQ ID NOs: 13 and 14, respectively.
泰派魯單抗之示例性序列也在美國專利7,982,016 SEQ ID NO: 13、60、105、145、173、212；SEQ ID NO: 361和363中列出；和輕鏈，該輕鏈包含含有SEQ ID NO:363所示的胺基酸序列之輕鏈可變結構域和含有SEQ ID NO:369所示的胺基酸序列之λ輕鏈恒定結構域；和重鏈，該重鏈包含含有SEQ ID NO:361所示的胺基酸序列之重鏈可變結構域和含有SEQ ID NO:365所示的胺基酸序列之IgG2重鏈恒定結構域，藉由引用併入本文。Exemplary sequences of teprenumab are also listed in U.S. Patent 7,982,016 SEQ ID NOs: 13, 60, 105, 145, 173, 212; SEQ ID NOs: 361 and 363; and a light chain comprising a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 363 and a lambda light chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 369; and a heavy chain comprising a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 361 and an IgG2 heavy chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 365, incorporated herein by reference.
在多個實施方式中，抗TSLP抗體衍生物在國際專利公開WO 2022/226342和WO 2022/226339中進行了描述，其全部藉由引用併入本文。示例性衍生物包括可能在抗體純化後或長期儲存後進行修飾的泰派魯單抗抗體，包括但不限於異構化衍生物、脫醯胺衍生物、氧化衍生物、糖基化衍生物、二硫異構物衍生物和/或高分子量（HMW）物種或抗體片段。示例性衍生物也可為具有WO 2022/226342的SEQ ID NO: 13-36中列出的胺基酸序列之變體，以及其中SEQ ID NO: 3-8的變體，例如，包括在抗TSLP抗體泰派魯單抗CDR（SEQ ID NO: 3-8）或可變區（SEQ ID NO: 10和12）被鑒定為穩定性降低的可能來源的殘基，其包括CDRH1 M34、CDRH2 W52、CDRH2 D54、CDRH2 N57、CDRH2 D62、CDRH3 W102、FRH1 N25、FRH1 N26、CDRL2 D49、CDRL2 D50、FRL2 N65、CDRL3 W90、CDRL3 D91、CDRL3 S92,S93,S94和/或CDRL3 D95。In various embodiments, anti-TSLP antibody derivatives are described in International Patent Publications WO 2022/226342 and WO 2022/226339, which are incorporated herein by reference in their entirety. Exemplary derivatives include teplumab antibodies that may be modified after antibody purification or after long-term storage, including but not limited to isomerized derivatives, deamidated derivatives, oxidized derivatives, glycosylated derivatives, disulfide isomer derivatives, and/or high molecular weight (HMW) species or antibody fragments. Exemplary derivatives may also be variants having the amino acid sequences listed in SEQ ID NOs: 13-36 of WO 2022/226342, as well as variants of SEQ ID NOs: 3-8, for example, comprising residues identified as possible sources of reduced stability in the anti-TSLP antibody teprumumab CDRs (SEQ ID NOs: 3-8) or variable regions (SEQ ID NOs: 10 and 12), including CDRH1 M34, CDRH2 W52, CDRH2 D54, CDRH2 N57, CDRH2 D62, CDRH3 W102, FRH1 N25, FRH1 N26, CDRL2 D49, CDRL2 D50, FRL2 N65, CDRL3 W90, CDRL3 D91, CDRL3 S92, S93, S94 and/or CDRL3 D95.
在多個實施方式中，抗TSLP抗體或其抗體變體係二價的並且選自由以下組成之群組：人抗體、人源化抗體、嵌合抗體、單株抗體、重組抗體、抗原結合抗體片段、單鏈抗體、單體抗體、雙抗體、三抗體、四抗體、Fab片段、IgG1抗體、IgG2抗體、IgG3抗體和IgG4抗體。In various embodiments, the anti-TSLP antibody or antibody variant thereof is bivalent and selected from the group consisting of: a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single-chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.
在多個實施方式中，抗TSLP抗體為二價的並選自由人抗體、人源化抗體、嵌合抗體、單株抗體、重組抗體、IgG1抗體、IgG2抗體、IgG3抗體和IgG4抗體組成之群組。In various embodiments, the anti-TSLP antibody is bivalent and is selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, and IgG4 antibodies.
據提供，抗體或抗體變體為IgG2抗體。人IgG2恒定區的示例性序列能以Uniprot編號P01859自Uniprot數據庫獲得，該Uniprot數據庫藉由引用併入本文。包括關於其他抗體重鏈及輕鏈恒定區的序列資訊之資訊還可經由Uniprot數據庫以及在抗體工程改造及產生領域熟知的其他數據庫公開獲得。It is provided that the antibody or antibody variant is an IgG2 antibody. An exemplary sequence of a human IgG2 constant region can be obtained from the Uniprot database under Uniprot number P01859, which is incorporated herein by reference. Information including sequence information about other antibody heavy chain and light chain constant regions can also be publicly obtained from the Uniprot database and other databases known in the field of antibody engineering and production.
據提供，抗TSLP抗體變體或抗TSLP衍生物在人類中具有與泰派魯單抗-ekko基本上相似的pK特徵。It is provided that the anti-TSLP antibody variant or anti-TSLP derivative has a pK profile in humans that is substantially similar to that of teplumab-ekko.
在某些實施方式中，抗體衍生物包括四聚體糖基化抗體，其中與親本多肽的胺基酸序列相比，糖基化位點的數目和/或類型改變。在某些實施方式中，變體包含比天然蛋白質更多或更少數目的N連接的糖基化位點。可替代地，消除此序列的取代將移除已存在的N連接的碳水化合物鏈。還提供N連接的碳水化合物鏈的重排，其中消除一或多個N連接的糖基化位點（典型地天然存在的那些）並且創造一或多個新的N連接的位點。另外的較佳的抗體變體包括半胱胺酸變體，其中與親本胺基酸序列相比，一或多個半胱胺酸殘基缺失或取代另一個胺基酸（例如絲胺酸）。當抗體必須重新折疊成生物學上活性構象時，如在分離不溶性包涵體之後，半胱胺酸變體可能有用。半胱胺酸變體一般具有少於天然蛋白質的半胱胺酸殘基，且典型地具有偶數個以使由未配對的半胱胺酸引起的相互作用最小。In certain embodiments, antibody derivatives include tetrameric glycosylated antibodies, wherein the number and/or type of glycosylation sites are altered compared to the amino acid sequence of the parent polypeptide. In certain embodiments, variants include more or less N-linked glycosylation sites than native proteins. Alternatively, substitutions that eliminate this sequence will remove existing N-linked carbohydrate chains. Rearrangements of N-linked carbohydrate chains are also provided, wherein one or more N-linked glycosylation sites (typically naturally occurring ones) are eliminated and one or more new N-linked sites are created. Other preferred antibody variants include cysteine variants, wherein one or more cysteine residues are deleted or substituted for another amino acid (e.g., serine) compared to the parent amino acid sequence. Cysteine variants may be useful when the antibody must be refolded into a biologically active conformation, such as after the isolation of insoluble inclusion bodies. Cysteine variants generally have fewer cysteine residues than the native protein, and typically have an even number to minimize interactions caused by unpaired cysteines.
所希望的胺基酸取代（無論保守或非保守）可由熟悉該項技術者在需要此類取代時來確定。在某些實施方式中，胺基酸取代可用於鑒別人TSLP的抗體的重要殘基，或增加或減少抗體對本文所述之人TSLP的親和力。Desired amino acid substitutions (whether conservative or non-conservative) can be determined by those skilled in the art when such substitutions are desired. In certain embodiments, amino acid substitutions can be used to identify important residues of antibodies to human TSLP, or to increase or decrease the affinity of antibodies to human TSLP as described herein.
根據某些實施方式，較佳的胺基酸取代為以下那些：(1) 降低對蛋白質水解的敏感性；(2) 降低對氧化的敏感性；(3) 改變用於形成蛋白質複合物的結合親和力；(4) 改變結合親和力和/或 (4) 賦予或改變此類多肽上的其他生理化學特性或功能特性。根據某些實施方式，可在天然存在的序列中（在某些實施方式中，在形成分子間接觸的一或多個結構域外的多肽部分中）進行單個或多個胺基酸取代（在某些實施方式中為保守胺基酸取代）。在某些實施方式中，保守胺基酸取代典型地基本上不會改變親本序列的結構特性（例如替代胺基酸不應傾向於使親本序列中存在的螺旋斷裂，或破壞親本序列特徵性的其他類型二級結構）。領域公認的多肽二級和三級結構的實例描述於Proteins, Structures and Molecular Principles [蛋白質、結構和分子原理] (Creighton編輯, W. H. Freeman and Company [W.H.弗裡曼公司], 紐約 (1984))；Introduction to Protein Structure [蛋白質結構簡介] (C. Branden及J. Tooze編, Garland Publishing [加蘭出版社], 紐約, 紐約州。(1991))；以及Thornton等人 Nature [自然] 354:105 (1991)，將該等文獻各自藉由引用併入本文。投與方法According to certain embodiments, preferred amino acid substitutions are those that: (1) reduce susceptibility to proteolysis; (2) reduce susceptibility to oxidation; (3) alter binding affinity for forming protein complexes; (4) alter binding affinity and/or (4) confer or alter other physiochemical properties or functional properties on such polypeptides. According to certain embodiments, single or multiple amino acid substitutions (in certain embodiments, conservative amino acid substitutions) may be made in the naturally occurring sequence (in certain embodiments, in the portion of the polypeptide outside of one or more structural domains that form intermolecular contacts). In certain embodiments, conservative amino acid substitutions typically do not substantially alter the structural properties of the parent sequence (e.g., the replacement amino acid should not tend to disrupt the helix present in the parent sequence, or disrupt other types of secondary structures that are characteristic of the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, ed., WH Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, NY (1991)); and Thornton et al., Nature 354:105 (1991), each of which is incorporated herein by reference.Methods of Administration
在一方面，本揭露之方法包括投與本文所述之治療性抗TSLP抗體或抗體變體的步驟，該抗體或抗體變體視需要在藥學上可接受的載劑或賦形劑中。在某些實施方式中，藥物組成物為無菌組成物。In one aspect, the methods of the present disclosure include the step of administering a therapeutic anti-TSLP antibody or antibody variant described herein, optionally in a pharmaceutically acceptable carrier or formulation. In certain embodiments, the pharmaceutical composition is a sterile composition.
本文提供了治療受試者皮質類固醇依賴性氣喘的方法，包括重度氣喘。在多個實施方式中，該方法包括選擇需要治療口服皮質類固醇依賴性氣喘的受試者，以及投與本文所述之抗TSLP抗體。Provided herein are methods for treating corticosteroid-dependent asthma, including severe asthma, in a subject. In various embodiments, the method comprises selecting a subject in need of treatment for oral corticosteroid-dependent asthma and administering an anti-TSLP antibody described herein.
據提供，本文所述之可用於治療皮質類固醇依賴性氣喘的抗TSLP抗體還包括表A中列出的出版物中描述的抗體和WO 2023098491A1、WO 2021155634A1、WO 2022166072A1、WO 2021043221A1、WO 2022184074A1、WO 2021104053A1、WO 2023116925A1、WO 2021155861A1、WO 2022116858A1、WO 2022117079A1、WO 2020244544A1、WO 2021152488A1、WO 2022253147A1、WO 2023070948A1、WO 2023142309A1、WO 2022095689A1、WO 2021115240A1、WO 2022166739A1、WO 2019100111A1、WO 2017/042701、WO 2016/142426、US 20170066823、US 20120020988和US 8637019中描述的抗體，其中每一個的揭露內容藉由引用併入。 [表A]
在多個實施方式中，抗體為泰派魯單抗或泰派魯單抗變體或泰派魯單抗衍生物。In various embodiments, the antibody is tepezumab or a tepezumab variant or tepezumab derivative.
據提供，待治療的受試者為人類。受試者可為成人、青少年或兒童。It is provided that the subject to be treated is a human being. The subject may be an adult, adolescent or child.
治療性抗體（或抗體變體）組成物可在多個部位遞送至患者。多次投與可同時進行或可在一段時間內投與。在某些情況下，提供治療性組成物的連續流動為有益的。可週期性投與其他療法，例如每小時、每日、每週、每2週、每3週、每月、每兩月或以更長時間間隔。The therapeutic antibody (or antibody variant) composition can be delivered to the patient at multiple sites. Multiple administrations can be made simultaneously or can be administered over a period of time. In some cases, it is beneficial to provide a continuous flow of the therapeutic composition. Other therapies can be administered periodically, such as every hour, daily, weekly, every 2 weeks, every 3 weeks, monthly, every two months, or at longer intervals.
在多個實施方式中，既定劑量的治療劑（如具有兩個TSLP結合位點的二價抗體）的量可根據療法投與的個體的體型以及所治療的病症的特徵而變化。In various embodiments, the amount of a given dose of a therapeutic agent (e.g., a bivalent antibody having two TSLP binding sites) may vary depending on the size of the individual to whom the therapy is administered and the characteristics of the disorder being treated.
在示例性治療中，抗TSLP抗體或抗體變體以每劑量約140 mg至約420 mg的劑量範圍投與。在多個實施方式中，劑量能以約140 mg、210 mg、280 mg或420 mg給予。在多個實施方式中，抗TSLP抗體或抗體變體可以每劑約140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300、310、320、330、340、350、360、370、380、390、400、410或420 mg的劑量投與。該等濃度能以單個劑型或多個劑量投與。以上劑量每兩週或每四週給予。在多個實施方式中，抗TSLP抗體或抗體變體以210 mg的單次劑量每兩週或每四週投與。在多個實施方式中，抗TSLP抗體或抗體變體以210 mg的單次劑量每四週投與。In an exemplary treatment, the anti-TSLP antibody or antibody variant is administered in a dosage range of about 140 mg to about 420 mg per dose. In various embodiments, the dose can be given at about 140 mg, 210 mg, 280 mg, or 420 mg. In various embodiments, the anti-TSLP antibody or antibody variant can be administered at a dose of about 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, or 420 mg per dose. Such concentrations can be administered in a single dose or in multiple doses. The above doses are given every two weeks or every four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered in a single dose of 210 mg every two weeks or every four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered in a single dose of 210 mg every four weeks.
對於抗體變體，抗體變體的量應使劑量中的TSLP結合位點的數目與上述標準二價抗體的TSLP結合位點數目係等莫耳的。For antibody variants, the amount of the antibody variant should be such that the number of TSLP binding sites in the dose is equimolar to the number of TSLP binding sites in the standard bivalent antibody described above.
據提供，抗TSLP抗體或抗體變體每2週或每4週投與，持續至少4個月、6個月、9個月、1年、2年或更長時間的時期。在多個實施方式中，投與為皮下或靜脈內。在多個實施方式中，該投與為皮下。It is provided that the anti-TSLP antibody or antibody variant is administered every 2 weeks or every 4 weeks for a period of at least 4 months, 6 months, 9 months, 1 year, 2 years or longer. In various embodiments, the administration is subcutaneous or intravenous. In various embodiments, the administration is subcutaneous.
提供抗TSLP抗體或抗體變體的治療以改善包括以下的皮質類固醇依賴性氣喘的一或多種測量值：用力呼氣容積（FEV）、FEV1可逆性、用力肺活量（FVC）、FeNO、氣喘控制問卷（ACQ）-6得分和AQLQ(S)+12得分、BD前FEV1相對於基線的變化、每日維持OCS劑量相對於基線的減少、每日維持OCS劑量≤ 5 mg、以及每日維持OCS劑量相對於基線減少≥ 50%、藉由AAER測量的氣喘加重和首次氣喘加重的時間、與急診室（ER）就診、緊急護理就診或住院相關的氣喘加重率、以及未經歷氣喘加重的參與者比例、每週平均居家PEF（早晚）和/或聖喬治呼吸問卷（SGRQ）得分。進一步提供，投與降低受試者腎上腺功能不全的發生率。Treatment with an anti-TSLP antibody or antibody variant is provided to improve one or more measures of corticosteroid-dependent asthma including: forced expiratory volume (FEV1), reversibility ofFEV1 , forced vital capacity (FVC), FeNO, Asthma Control Questionnaire (ACQ)-6 score and AQLQ(S)+12 score, change from baseline in pre-BDFEV1 , reduction in daily maintenance OCS dose from baseline, maintenance OCS dose ≤ 5 mg per day, and reduction in daily maintenance OCS dose ≥ 5 mg per day from baseline 50%, asthma exacerbations and time to first asthma exacerbation as measured by AAER, asthma exacerbation rates associated with emergency room (ER) visits, urgent care visits, or hospitalizations, and the proportion of participants experiencing no asthma exacerbations, and average weekly home PEF (morning and evening) and/or St. George's Respiratory Questionnaire (SGRQ) scores. Further, administration reduces the incidence of adrenal insufficiency in the subjects.
在一個實施方式中，投與改善受試者中皮質類固醇依賴性氣喘的一或多種症狀，包括但不限於肺功能，例如支氣管擴張劑前1秒用力呼氣量（BD前FEV1），和/或每日維持OCS劑量，同時維持氣喘控制。在多個實施方式中，投與導致OCS中斷，而不喪失氣喘控制。In one embodiment, administration improves one or more symptoms of corticosteroid-dependent asthma in a subject, including but not limited to lung function, such as forced expiratory volume in 1 second before bronchodilator (pre-BDFEV1 ), and/or maintains daily OCS dose while maintaining asthma control. In various embodiments, administration results in discontinuation of OCS without loss of asthma control.
在多個實施方式中，用抗TSLP治療調節慢性鼻竇炎的一或多種生物標誌物的水平，包括鼻上皮中細胞介素、IgE、CCL17、CCL18、CCL22和RNA轉錄變化。在多個實施方式中，用抗TSLP治療降低Th2細胞介素的水平。在多個實施方式中，治療調節IL-4、IL-5、IL-13、IL-17、IL-22、IL-23、IL-31和/或IL-33或其組合的水平或活性。In various embodiments, treatment with anti-TSLP modulates the level of one or more biomarkers of chronic sinusitis, including interleukins, IgE, CCL17, CCL18, CCL22, and RNA transcriptional changes in the nasal epithelium. In various embodiments, treatment with anti-TSLP reduces the level of Th2 interleukins. In various embodiments, treatment modulates the level or activity of IL-4, IL-5, IL-13, IL-17, IL-22, IL-23, IL-31, and/or IL-33, or a combination thereof.
在多個實施方式中，與未接受抗TSLP抗體的受試者相比，用抗TSLP抗體治療延遲了氣喘加重或發作的時間。In various embodiments, treatment with the anti-TSLP antibody delays the time to asthma exacerbations or attacks compared to subjects not receiving the anti-TSLP antibody.
本揭露中還提供了多種藥劑的投與，例如與本文所述之第二藥劑結合的抗體組成物，包括但不限於抗炎劑或氣喘療法。Also provided herein are administration of a variety of agents, such as antibody compositions in combination with a second agent described herein, including but not limited to anti-inflammatory agents or asthma therapies.
然而，據提供，在多個實施方式中，投與降低受試者中共投與療法的頻率或水平，例如，與受試者的基線頻率/水平相比或與對照相比。示例性共投與療法包括但不限於全身性皮質類固醇、度匹魯單抗、免疫抑制或免疫調節藥物（例如，環孢素、嗎替麥考酚酯、干擾素（IFN）-γ、Janus激酶抑制劑、硫唑嘌呤、胺甲喋呤）、抗IL-13抗體、抗IL-5途徑抗體（貝那利珠單抗、美泊利單抗、瑞利珠單抗）或其組合。在多個實施方式中，投與消除對皮質類固醇療法或其他輔助療法的需要。However, it is provided that in various embodiments, administration reduces the frequency or level of a co-administered therapy in a subject, e.g., compared to the subject's baseline frequency/level or compared to a control. Exemplary co-administered therapies include, but are not limited to, systemic corticosteroids, dupilumab, immunosuppressive or immunomodulatory drugs (e.g., cyclosporine, mycophenolate mofetil, interferon (IFN)-γ, Janus kinase inhibitors, azathioprine, methotrexate), anti-IL-13 antibodies, anti-IL-5 pathway antibodies (benralizumab, mepolizumab, reslizumab), or combinations thereof. In various embodiments, administration eliminates the need for corticosteroid therapy or other adjunctive therapy.
在多個實施方式中，受試者也正在接受皮質類固醇治療。在多個實施方式中，皮質類固醇係選自由強體松、強體松龍、皮質酮、氫化皮質酮、甲潑尼龍、曲安西龍、貝皮質醇、地塞米松和地夫可特中一或多種組成之群組的口服皮質類固醇。In various embodiments, the subject is also receiving corticosteroid therapy. In various embodiments, the corticosteroid is an oral corticosteroid selected from the group consisting of one or more of prednisone, prednisolone, corticosterone, hydrocorticosterone, methylprednisolone, triamcinolone, becortin, dexamethasone, and deflazacort.
在多個實施方式中，該方法包括將抗TSLP抗體或抗體變體與口服皮質類固醇聯合投與，其中受試者經歷OCS療法之優化階段、OCS療法之減少階段和OCS療法之維持階段。In various embodiments, the method comprises administering an anti-TSLP antibody or antibody variant in combination with an oral corticosteroid, wherein the subject undergoes an optimization phase of OCS therapy, a taper phase of OCS therapy, and a maintenance phase of OCS therapy.
在多個實施方式中，該方法包括當受試者接受治療之減少階段時減少皮質類固醇的劑量。在多個實施方式中，皮質類固醇的劑量每4週減少一次，持續約20週。在多個實施方式中，皮質類固醇的劑量減少5 mg/天或2.5 mg/天。In various embodiments, the method comprises reducing the dose of the corticosteroid while the subject is undergoing a taper phase of treatment. In various embodiments, the dose of the corticosteroid is reduced every 4 weeks for about 20 weeks. In various embodiments, the dose of the corticosteroid is reduced by 5 mg/day or 2.5 mg/day.
在多個實施方式中，優化階段包括OCS的劑量為30 mg/天、25 mg/天、20 mg/天、15 mg/天、10 mg/天、7.5 mg/天或5 mg/天。在多個實施方式中，減少階段包括OCS的劑量為25 mg/天、20 mg/天、15 mg/天、10 mg/天、7.5 mg/天、5 mg/天、2.5 mg/天或0 mg/天。在多個實施方式中，維持階段包括OCS的劑量為15 mg/天、10 mg/天、7.5 mg/天、5 mg/天、2.5 mg/天或0 mg/天。In various embodiments, the optimization phase comprises a dose of OCS of 30 mg/day, 25 mg/day, 20 mg/day, 15 mg/day, 10 mg/day, 7.5 mg/day, or 5 mg/day. In various embodiments, the reduction phase comprises a dose of OCS of 25 mg/day, 20 mg/day, 15 mg/day, 10 mg/day, 7.5 mg/day, 5 mg/day, 2.5 mg/day, or 0 mg/day. In various embodiments, the maintenance phase comprises a dose of OCS of 15 mg/day, 10 mg/day, 7.5 mg/day, 5 mg/day, 2.5 mg/day, or 0 mg/day.
據提供，投與的口服皮質類固醇劑量根據所投與的治療藥物進行調整，例如，如圖2B所示，以提供等效劑量。例如，可能需要較高劑量的皮質酮來提供與強體松龍等效的劑量，或者可能需要較低劑量的地塞米松來提供與強體松龍等效的劑量。技術者將理解如何根據需要調整劑量。It is provided that the amount of oral corticosteroid administered is adjusted according to the therapeutic agent being administered, for example, as shown in Figure 2B, to provide an equivalent dosage. For example, a higher dose of corticosterone may be required to provide an equivalent dosage to prednisolone, or a lower dose of dexamethasone may be required to provide an equivalent dosage to prednisolone. The skilled person will understand how to adjust the dosage as needed.
在多個實施方式中，投與消除了對口服皮質類固醇療法的長期需求，例如，6個月、1年、2年、3年或無限期。配製物In various embodiments, administration eliminates the need for long-term oral corticosteroid therapy, e.g., 6 months, 1 year, 2 years, 3 years, or indefinitely.Formulations
在一些實施方式中，本揭露提供了藥物組成物的用途，該藥物組成物包含治療有效量的抗TSLP抗體或抗體變體以及藥學上可接受的稀釋劑、載劑、增溶劑、乳化劑、防腐劑和/或佐劑。另外，本揭露提供藉由投與此類藥物組成物治療受試者之方法。In some embodiments, the present disclosure provides the use of a pharmaceutical composition comprising a therapeutically effective amount of an anti-TSLP antibody or antibody variant and a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative and/or adjuvant. In addition, the present disclosure provides a method for treating a subject by administering such a pharmaceutical composition.
在某些實施方式中，可接受的配製物物質較佳的是在所用劑量和濃度下對接受者無毒。在某些實施方式中，藥物組成物可含有用於改變、維持或保持例如組成物的pH值、滲透壓度、黏性、透明度、顏色、等滲性、氣味、無菌性、穩定性、溶解或釋放速率、吸附或穿透的配製物物質。在此類實施方式中，適合的配製物物質包括但不限於胺基酸（如甘胺酸、麩醯胺酸、天冬醯胺、精胺酸或離胺酸）；抗微生物劑；抗氧化劑（如抗壞血酸、亞硫酸鈉或亞硫酸氫鈉）；緩衝液（如硼酸鹽、碳酸氫鹽、Tris-HCl、檸檬酸鹽、磷酸鹽或其他有機酸）；疏鬆劑（如甘露糖醇或甘胺酸）；螯合劑（如乙二胺四乙酸（EDTA））；複合劑（如咖啡因、聚乙烯吡咯啶酮、β-環糊精或羥丙基-β-環糊精）；填充劑；單糖；二糖；和其他碳水化合物（如葡萄糖、蔗糖、甘露糖或糊精）；蛋白質（如血清白蛋白、明膠或免疫球蛋白）；著色劑、調味劑和稀釋劑；乳化劑；親水聚合物（如聚乙烯吡咯啶酮）；低分子量多肽；成鹽抗衡離子（如鈉）；防腐劑（如氯化苄烷銨、苯甲酸、水楊酸、硫柳汞、苯乙醇、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯、氯己定、山梨酸或過氧化氫）；溶劑（如甘油、丙二醇或聚乙二醇）；糖醇（如甘露糖醇或山梨糖醇）；助懸劑；界面活性劑或潤濕劑（如普朗尼克（pluronics）、PEG、脫水山梨聚糖、聚山梨醇酯（如聚山梨醇酯20、聚山梨醇酯）、氚核、胺丁三醇、卵磷脂、膽固醇、泰洛沙星（tyloxapal））；穩定性增強劑（如蔗糖或山梨糖醇）；張力增強劑（如鹼金屬鹵化物、較佳的是氯化鈉或氯化鉀，甘露糖醇，山梨糖醇）；遞送媒介物；稀釋劑；賦形劑和/或藥用輔助劑。參見REMINGTON'S PHARMACEUTICAL SCIENCES [雷明頓藥物科學], 第18''版, （A. R. Genrmo編輯）, 1990, Mack Publishing Company [麥克出版公司]。In certain embodiments, acceptable formulation materials are preferably nontoxic to recipients at the dosages and concentrations employed. In certain embodiments, the pharmaceutical composition may contain formulation materials used to alter, maintain or preserve, for example, the pH, osmotic pressure, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption or penetration of the composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids (e.g., glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (e.g., ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (e.g., borates, bicarbonates, Tris-HCl, citrate, phosphates, or other organic acids); relaxants (e.g., mannitol or glycine); chelating agents (e.g., Ethylenediaminetetraacetic acid (EDTA); complexing agents (such as caffeine, polyvinylpyrrolidone, β-cyclodextrin or hydroxypropyl-β-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, sucrose, mannose or dextrin); proteins (such as serum albumin, gelatin or immunoglobulins); colorants, flavorings and diluents; emulsifiers; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight peptides; salt-forming counterions (such as sodium); preservatives (such as benzyl ammonium chloride, benzoic acid, salicylic acid, thimerosal, phenylethyl alcohol, methyl paraben, propyl paraben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerol, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PE G, dehydrated sorbitan, polysorbates (e.g., polysorbate 20, polysorbate 50), tritium, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancers (e.g., sucrose or sorbitol); tonicity enhancers (e.g., alkali metal halides, preferably sodium chloride or potassium chloride, mannitol, sorbitol); delivery vehicles; diluents; excipients and/or pharmaceutical adjuvants. See REMINGTON'S PHARMACEUTICAL SCIENCES, 18'' ed., (A. R. Genrmo, ed.), 1990, Mack Publishing Company.
適合的媒介物或載劑可為注射用水、生理鹽水溶液或人造腦脊髓液，可能補充有組成物中常見的用於腸胃外投與的其他物質。中性緩衝鹽水或與血清白蛋白混合的鹽水係另外的示例性媒介物。在特定實施方式中，藥物組成物包含約pH 7.0-8.5的Tris緩衝液或約pH 4.0-5.5的乙酸鹽緩衝液，且可進一步包括山梨糖醇或其適合取代物。Suitable vehicles or carriers may be water for injection, physiological saline solution or artificial cerebrospinal fluid, possibly supplemented with other substances commonly used in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are other exemplary vehicles. In a specific embodiment, the pharmaceutical composition comprises a Tris buffer of about pH 7.0-8.5 or an acetate buffer of about pH 4.0-5.5, and may further include sorbitol or a suitable substitute thereof.
配製物組分較佳的是以對投與部位可接受的濃度存在。在某些實施方式中，使用緩衝液以將組成物維持在生理pH值或稍低pH值下，典型地在約4.5至約8的pH值範圍內。包括約4.5、約4.6、約4.7、約4.8、約4.9、約5.0、約5.1、約5.2、約5.3、約5.4、約5.5、約5.6、約5.7、約5.8、約5.9、約6.0、約6.1、約6.2、約6.3、約6.4、約6.5、約6.6、約6.7、約6.8、約6.9、約7.0、約7.1、約7.2、約7.3、約7.4、約7.5、約7.6、約7.7、約7.8、約7.9和約8.0。The formulation components are preferably present at concentrations acceptable to the site of administration. In certain embodiments, a buffer is used to maintain the composition at physiological pH or slightly lower pH, typically in the pH range of about 4.5 to about 8. Including about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9 and about 8.0.
在多個實施方式中，抗TSLP抗體或抗體變體在含有一或多種鹼性胺基酸（例如精胺酸、組胺酸或離胺酸）或其鹽，或鈣或鎂鹽，以及界面活性劑的配製物中。在多個實施方式中，配製物包含0.005%（w/v）至約0.015%（w/v）的聚山梨醇酯20或聚山梨醇酯80。在多個實施方式中，配製物的pH在4.5和6.8之間。在多個實施方式中，配製物中的抗體或抗體片段的濃度大於110 mg/ml，例如，約110 mg/ml至約250 mg/ml，例如，約140 mg/ml至約250 mg/ml，約160 mg/mL至約250 mg/mL，或約140 mg/mL至約210 mg/mL，或約180 mg/ml或約210 mg/ml。該配製物可在2℃至8℃或-20℃至-70℃下儲存。示例性配製物在共同擁有的申請PCT/US2021/17880中進行了描述，藉由引用併入本文。In various embodiments, the anti-TSLP antibody or antibody variant is in a formulation containing one or more basic amino acids (e.g., arginine, histidine, or lysine) or a salt thereof, or a calcium or magnesium salt, and a surfactant. In various embodiments, the formulation comprises 0.005% (w/v) to about 0.015% (w/v) polysorbate 20 or polysorbate 80. In various embodiments, the pH of the formulation is between 4.5 and 6.8. In various embodiments, the concentration of the antibody or antibody fragment in the formulation is greater than 110 mg/ml, e.g., about 110 mg/ml to about 250 mg/ml, e.g., about 140 mg/ml to about 250 mg/ml, about 160 mg/mL to about 250 mg/mL, or about 140 mg/mL to about 210 mg/mL, or about 180 mg/ml or about 210 mg/ml. The formulation can be stored at 2°C to 8°C or -20°C to -70°C. Exemplary formulations are described in commonly owned application PCT/US2021/17880, incorporated herein by reference.
在多個實施方式中，抗TSLP抗體或抗體變體在包含大於約100 mg/mL抗TSLP抗體、界面活性劑、脯胺酸和緩衝劑的配製物中。在示例性情況中，界面活性劑，例如聚山梨醇酯80，以約0.005%（w/v）、0.010%（w/v）或0.015%（w/v）的濃度存在於組成物中。在示例性方面中，組成物包含等於或小於約3.0%（w/v）脯胺酸，例如，約2.4%（w/v）至約2.8%（w/v）脯胺酸或約2.5%（w/v）至約2.8%（w/v）脯胺酸。在示例性實例中，該脯胺酸係L-脯胺酸。在某些方面中，脯胺酸係存在於該組成物中的唯一胺基酸。在示例性方面中，該緩衝劑選自由以下組成之群組：琥珀酸鹽、麩胺酸鹽、組胺酸和乙酸鹽。在一些實施方式中，緩衝劑係乙酸鹽。在示例性方面中，該組成物包含約1 mM至約50 mM緩衝劑，例如約10 mM至約30 mM緩衝劑，視需要，約15 mM至約30 mM緩衝劑、約20 mM至約30 mM緩衝劑、或約10 mM至約25 mM緩衝劑。示例性配製物在共同擁有的申請PCT/US2021/018561中進行了描述，藉由引用併入本文。In various embodiments, the anti-TSLP antibody or antibody variant is in a formulation comprising greater than about 100 mg/mL of anti-TSLP antibody, a surfactant, proline, and a buffer. In exemplary cases, the surfactant, such as polysorbate 80, is present in the composition at a concentration of about 0.005% (w/v), 0.010% (w/v), or 0.015% (w/v). In exemplary aspects, the composition comprises equal to or less than about 3.0% (w/v) proline, for example, about 2.4% (w/v) to about 2.8% (w/v) proline or about 2.5% (w/v) to about 2.8% (w/v) proline. In exemplary examples, the proline is L-proline. In certain aspects, proline is the only amino acid present in the composition. In exemplary aspects, the buffer is selected from the group consisting of succinate, glutamate, histidine, and acetate. In some embodiments, the buffer is acetate. In exemplary aspects, the composition comprises about 1 mM to about 50 mM buffer, such as about 10 mM to about 30 mM buffer, optionally, about 15 mM to about 30 mM buffer, about 20 mM to about 30 mM buffer, or about 10 mM to about 25 mM buffer. Exemplary formulations are described in commonly owned application PCT/US2021/018561, which is incorporated herein by reference.
在多個實施方式中，抗TSLP抗體以在10 mM乙酸鹽、3.0%（w/v）L-脯胺酸、0.01%（w/v）聚山梨醇酯80，pH 5.2中110 mg/mL的劑量投與。In various embodiments, the anti-TSLP antibody is administered at a dose of 110 mg/mL in 10 mM acetate, 3.0% (w/v) L-proline, 0.01% (w/v) polysorbate 80, pH 5.2.
當提供腸胃外投與時，使用的治療組成物可以以無熱原、腸胃外可接受的水溶液的形式提供，該水溶液在藥學上可接受的媒介物中包含所需的抗TSLP抗體。一種尤其適合腸胃外注射的媒介物為無菌蒸餾水，其中抗體配製成適當防腐的無菌等滲溶液。在某些實施方式中，該製備可以涉及用可以提供產物（該產物可以經由儲庫注射來遞送）的受控或持續釋放的藥劑（如可注射微球體、生物可侵蝕顆粒、聚合物化合物（如聚乳酸或聚乙醇酸）、珠粒或脂質體）配製所希望分子。在某些實施方式中，也可以使用透明質酸，該透明質酸具有促進循環持續時間的作用。在某些實施方式中，可植入的藥物遞送裝置可用於引入抗體。在多個實施方式中，可以經由預填充注射器或自動注射器投與。在多個實施方式中，自動注射器係Ypsomed YpsoMate®。在多個實施方式中，自動注射器揭露於WO 2018/226565、WO 2019/094138、WO 2019/178151、WO 20120/072577、WO2020/081479、WO 2020/081480、PCT/US20/70590、PCT/US20/70591、PCT/US20/53180、PCT/US20/53179、PCT/US20/53178、或PCT/US20/53176。套組When parenteral administration is provided, the therapeutic composition used may be provided in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising the desired anti-TSLP antibody in a pharmaceutically acceptable vehicle. One vehicle particularly suitable for parenteral injection is sterile distilled water, wherein the antibody is formulated as a sterile isotonic solution that is appropriately preserved. In certain embodiments, the preparation may involve formulating the desired molecule with an agent that can provide a controlled or sustained release of a product that can be delivered via depot injection, such as injectable microspheres, bioerodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads, or liposomes. In certain embodiments, hyaluronic acid may also be used, which has the effect of promoting circulation duration. In certain embodiments, an implantable drug delivery device may be used to introduce the antibody. In various embodiments, administration can be via a prefilled syringe or an autoinjector. In various embodiments, the autoinjector is a Ypsomed YpsoMate®. In various embodiments, the autoinjector is disclosed in WO 2018/226565, WO 2019/094138, WO 2019/178151, WO 20120/072577, WO 2020/081479, WO 2020/081480, PCT/US20/70590, PCT/US20/70591, PCT/US20/53180, PCT/US20/53179, PCT/US20/53178, or PCT/US20/53176.Kit
作為另外的一方面，本揭露包括含有一或多種化合物或組成物的套組（kit），該化合物或組成物以有利於其用於實施本揭露方法的方式包裝。在一個實施方式中，這種套組包括本文所述之化合物或組成物，該化合物或組成物包裝在容器，如密封的瓶或容器中，標籤貼在容器上或包括在包裝中，該標籤描述了化合物或組成物在實踐該方法中之用途。較佳的是，如本文所述，將化合物或組成物包裝成單位劑型用於投與。套組可進一步包括適於根據特定的投與途徑投與組成物的裝置或適於實踐篩選測定。較佳的是，套組含有描述抗體組成物的用途的標籤。As another aspect, the disclosure includes a kit containing one or more compounds or compositions packaged in a manner that facilitates their use in practicing the methods of the disclosure. In one embodiment, such a kit includes a compound or composition described herein, packaged in a container, such as a sealed bottle or container, with a label affixed to the container or included in the package, the label describing the use of the compound or composition in practicing the method. Preferably, the compound or composition is packaged in a unit dosage form for administration as described herein. The kit may further include a device suitable for administering the composition according to a specific route of administration or suitable for practicing a screening assay. Preferably, the kit contains a label describing the use of the antibody composition.
本揭露之另外的方面和細節將從以下實例中顯而易見，該等實例旨在說明而非限制。 實例實例1-評估泰派魯單抗對口服皮質類固醇依賴性氣喘影響的3期研究Additional aspects and details of the present disclosure will be apparent from the following examples, which are intended to be illustrative and not limiting. ExamplesExample1 - Phase3StudyEvaluating the Effect of Taipilumab on Oral Corticosteroid-Dependent Asthma
在先前的2b期研究，PATHWAY（NCT02054130）和3期NAVIGATOR（NCT03347279）研究中，泰派魯單抗治療降低了52週內的年化氣喘加重率（AAER），並改善了患有重度、不受控氣喘的患者之肺功能、氣喘控制和健康相關生活品質（HRQoL），包括接受維持OCS的患者（Corren J等人 N Engl J Med[新英格蘭醫學雜誌] 2017;377:936–46；Menzies-Gow A等人 N Engl J Med[新英格蘭醫學雜誌] 2021; 384:1800–9）。In previous phase 2b studies, PATHWAY (NCT02054130), and the phase 3 NAVIGATOR (NCT03347279) studies, tepilumab treatment reduced the annualized asthma exacerbation rate (AAER) over 52 weeks and improved lung function, asthma control, and health-related quality of life (HRQoL) in patients with severe, uncontrolled asthma, including those receiving maintenance OCS (Corren J et al N Engl J Med 2017;377:936–46; Menzies-Gow A et al N Engl J Med 2021;384:1800–9).
本研究之目的係研究泰派魯單抗對重度口服皮質類固醇（OCS）依賴性氣喘參與者的療效和安全性，該等參與者接受中等或高劑量吸入性皮質類固醇（ICS）≥ 12個月，LABA和高劑量ICS ≥ 3個月，OCS ≥ 6個月，以及每天7.5 mg至≤ 30 mg OCS的穩定劑量≥ 1個月，以實現氣喘控制。The aim of this study was to investigate the efficacy and safety of tepilumab in participants with severe oral corticosteroid (OCS)-dependent asthma who were receiving moderate- or high-dose inhaled corticosteroids (ICS) for ≥ 12 months, LABA and high-dose ICS for ≥ 3 months, OCS for ≥ 6 months, and stable doses of 7.5 mg to ≤ 30 mg OCS daily for ≥ 1 month to achieve asthma control.
來自全球研究地點的約207名患者按2 : 1隨機分組，每4週接受泰派魯單抗210 mg或安慰劑。對參與者進行評估，以確保最多20%的參與者在篩選時的基線血液嗜酸性球計數（BEC）＜ 150個細胞/μL；該等患者在進入研究前的12個月內必須有BEC ≥ 300個細胞/μL的病史。約40%的參與者在篩選時的BEC ≥ 300個細胞/μL。Approximately 207 patients from study sites worldwide were randomized 2:1 to receive either teprenolomab 210 mg or placebo every 4 weeks. Participants were assessed to ensure that up to 20% had a baseline blood eosinophil count (BEC) < 150 cells/μL at screening; these patients must have a history of BEC ≥ 300 cells/μL in the 12 months prior to study entry. Approximately 40% of participants had a BEC ≥ 300 cells/μL at screening.
在篩選時按區域和BEC對治療分配進行分層（＜ 150個細胞/μL；150-＜ 300個細胞/µL；≥ 300個細胞/μL），以確保跨區域和血液嗜酸性球亞組的治療分配平衡。參與者係患有重度氣喘的成人，除了高劑量ICS加LABA外，還需要每天或每天等效的維持OCS療法，使用或不使用其他氣喘控制劑，並且在過去2年中至少有1次氣喘加重，並接受過至少一劑研究干預。Treatment allocation was stratified by region and BEC at screening (<150 cells/µL; 150-<300 cells/µL; ≥300 cells/µL) to ensure balanced treatment allocation across regions and blood eosinophil subgroups. Participants were adults with severe asthma who required daily or daily equivalent maintenance OCS therapy in addition to high-dose ICS plus LABA, with or without other asthma controllers, and who had at least 1 asthma exacerbation in the past 2 years and received at least 1 dose of study intervention.
本研究的納入標準：Inclusion criteria for this study:
1.簽署知情同意書時，參與者必須年滿18歲至80歲（含）。1. When signing the informed consent form, participants must be between 18 and 80 years old (inclusive).
2.第1次就診之前至少12個月記錄在案的醫生診斷的氣喘。2. Asthma diagnosed by a physician at least 12 months before the first visit.
3.參與者必須在第1次就診之前至少12個月內根據GINA指南（GINA 2022）接受醫生開具的中等或高劑量ICS（中等劑量ICS對應於500 μg，高劑量ICS對應於＞ 500 μg丙酸氟替卡松乾粉配製物或等效物）。3. Participants must have received a physician-prescribed medium- or high-dose ICS (medium-dose ICS corresponds to 500 μg, high-dose ICS corresponds to > 500 μg fluticasone propionate dry powder formulation or equivalent) according to GINA guidelines (GINA 2022) for at least 12 months prior to the first visit.
4.參與者必須在第1次就診之前至少3個月內接受醫生開具的LABA和高劑量ICS（總日劑量＞ 500 μg丙酸氟替卡松乾粉配製物或等效物）。ICS和LABA可為組合產品的一部分或由單獨的吸入器提供。(a) 等效ICS劑量詳見附錄G4. Participants must have received LABA and high-dose ICS (total daily dose > 500 μg fluticasone propionate dry powder formulation or equivalent) prescribed by a physician for at least 3 months prior to the first visit. ICS and LABA may be part of a combination product or delivered by separate inhalers. (a) See Appendix G for equivalent ICS doses
5.根據標準護理實踐，允許另外的維持氣喘控制藥物，即白三烯受體拮抗劑（LTRA）、茶鹼、長效毒蕈鹼拮抗劑（LAMA）和色酮。該等藥物的使用必須在第1次就診前記錄至少3個月。5. Additional medications to maintain asthma control, i.e., leukotriene receptor antagonists (LTRAs), theophyllines, long-acting muscarinic antagonists (LAMAs), and chromones, are permitted according to standard nursing practice. The use of these medications must be documented for at least 3 months prior to the first visit.
6.參與者必須在第1次就診前至少6個月內接受OCS治療氣喘，並在第1次就診前至少一個月內接受每日或每日等效穩定劑量≥ 7.5至≤ 30 mg（強體松或強體松龍）。OCS劑量可以每隔一天投與（或每隔一天投與不同劑量）；2天內的平均劑量=每日劑量。6. Participants must have received OCS for asthma for at least 6 months prior to visit 1 and a daily or daily equivalent stable dose of ≥ 7.5 to ≤ 30 mg (prednisone or prednisolone) for at least 1 month prior to visit 1. OCS doses may be given every other day (or different doses every other day); average dose over 2 days = daily dose.
7.在第1次就診或第2次就診時，早上BD前FEV1必須＜ 80%預測正常值。7. Morning pre-BDFEV1 must be < 80% of predicted normal value at the 1st or 2nd visit.
8.氣喘證據記錄如下：(a) BD後（沙丁胺醇/舒喘寧）反應性測試結果：FEV1≥ 12%且≥ 200 mL（投與4口沙丁胺醇/舒喘寧後15-30分鐘），記錄在第1次就診或第2次就診或第3次就診前60個月內或就診時；或 (b) 第1次就診前60個月內記錄的氣道高反應性（乙醯甲膽鹼：引起陽性反應的激發濃度[PC20]＜ 8 mg/mL）。8. Evidence of asthma was documented as follows: (a) post-BD (albuterol/salbutamol) responsiveness test result: FEV1 ≥ 12% and ≥ 200 mL (15-30 minutes after administration of 4 puffs of albuterol/salbutamol), recorded within 60 months before or at the time of the first visit, second visit, or third visit; or (b) airway hyperresponsiveness (acetylcholine: provocative concentration to elicit a positive reaction [PC20] < 8 mg/mL) documented within 60 months before the first visit.
9.第1次就診時的血液嗜酸性球≥ 150個細胞/μL（≥ 0.15 x 109/L或≥ 0.15 x 103/µl）或第1次就診前12個月內記錄的EOS ≥ 300個細胞/μL（≥ 0.3 x 109/L或≥ 0.3 x 103/µl）。9. Blood eosinophils ≥ 150 cells/μL (≥ 0.15 x 109 /L or ≥ 0.15 x 103 /µl) at the first visit or EOS ≥ 300 cells/μL (≥ 0.3 x 109 /L or ≥ 0.3 x 103 /µl) recorded within 12 months before the first visit.
10.參與者必須在第1次就診前24個月內至少有一次氣喘加重事件的病史。出於本研究之目的，氣喘加重被定義為氣喘惡化，即：(a) 需要至少連續3天的爆發全身性皮質類固醇治療或單次貯庫注射皮質類固醇劑量治療或(b) 導致急診科就診（定義為在ER或緊急護理中心進行＜ 24小時的評估和治療），需要全身性皮質類固醇（如上所述）或(c) 因氣喘住院（定義為入住住院機構和/或在醫療機構評估和治療≥ 24小時）。10. Participants must have a history of at least one asthma exacerbation event within 24 months prior to visit 1. For the purposes of this study, an asthma exacerbation was defined as a worsening of asthma that: (a) required a burst of systemic corticosteroids or a single depot corticosteroid dose for at least 3 consecutive days or (b) resulted in an emergency department visit (defined as evaluation and treatment in an ER or urgent care center for < 24 hours), required systemic corticosteroids (as described above) or (c) was hospitalized for asthma (defined as admission to an inpatient facility and/or evaluation and treatment in a medical facility for ≥ 24 hours).
11.第1次就診時體重≥ 40 kg。11. Weight ≥ 40 kg at the first visit.
12.男性或女性。12. Male or female.
13.所有有生育能力的女性必須在第1次就診時血清妊娠測試結果為陰性，在隨機分組時尿液妊娠測試為陰性。13. All women of childbearing potential must have a negative serum pregnancy test at the first visit and a negative urine pregnancy test at the time of randomization.
14.與未絕育的男性伴侶發生性行為的有生育能力的女性參與者必須同意使用一種高效的節育方法，定義如下，從整個研究的入組到最後一劑研究干預後至少16週。在此之後停止避孕應與負責的醫生討論。定期禁欲（日曆法、症狀體溫法、排卵後法）、戒斷（性交中斷）、僅使用殺精子劑和哺乳期閉經。14. Female participants of reproductive potential who have sexual intercourse with nonsterile male partners must agree to use a highly effective method of birth control, as defined below, from study entry through at least 16 weeks after the last dose of study intervention. Discontinuation of contraception after this time should be discussed with the responsible physician. Periodic abstinence (calendar method, symptom temperature method, post-ovulation method), withdrawal (intercourse interruption), use of spermicides only, and amenorrhea during lactation.
排除標準包括：Exclusion criteria include:
1.除氣喘以外的任何臨床上重要的肺病（例如，活動性肺部感染、慢性阻塞性肺病（COPD）、支氣管擴張、肺纖維化、囊性纖維化、與肥胖相關的通氣不足綜合症、肺癌、α1抗胰蛋白酶缺乏症和原發性纖毛運動障礙）或曾被診斷患有與外周嗜酸性球計數升高相關的肺部或全身性疾病（氣喘除外）（例如，過敏性支氣管肺曲黴菌病/真菌病、查格-施特勞斯綜合症（Churg-Strauss syndrome）、嗜酸性球增多綜合症）。1. Any clinically significant lung disease other than asthma (e.g., active lung infection, chronic obstructive pulmonary disease (COPD), bronchiectasis, pulmonary fibrosis, cystic fibrosis, obesity-related hypoventilation syndrome, lung cancer, alpha-1 antitrypsin deficiency, and primary ciliary dyskinesia) or a history of a lung or systemic disease (other than asthma) associated with an elevated peripheral eosinophil count (e.g., allergic bronchopulmonary aspergillosis/fungal disease, Churg-Strauss syndrome, hypereosinophilic syndrome).
2.任何病症，包括但不限於心血管、胃腸道、肝臟、腎臟、神經、肌肉骨骼、感染、內分泌、代謝、血液、精神或重大身體損傷，研究者認為該等病症不穩定且可能：(a) 在整個研究過程中影響參與者的安全 (b) 影響研究結果或解釋 (c) 阻礙參與者完成整個研究的能力2. Any medical condition, including but not limited to cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, mental or major physical injury, which the Investigator considers to be unstable and may: (a) affect the safety of the Participant throughout the Study (b) affect the Study results or interpretation (c) hinder the Participant's ability to complete the Study
3.癌症病史：(a) 患有基底細胞癌、皮膚局部鱗狀細胞癌或宮頸原位癌的參與者有資格參加研究，前提是在第1次就診前至少12個月完成治癒性治療。(b) 患有其他惡性腫瘤的參與者符合條件，前提是在第1次就診前至少5年完成治癒性治療。3. History of Cancer: (a) Participants with basal cell carcinoma, localized squamous cell carcinoma of the skin, or carcinoma in situ of the cervix are eligible to participate in the study, provided that curative treatment has been completed at least 12 months before the first visit. (b) Participants with other malignancies are eligible, provided that curative treatment has been completed at least 5 years before the first visit.
4.氣喘加重，需要使用全身性皮質類固醇或增加OCS的維持劑量，在第1次就診前30天內完成。4. Worsening of asthma requiring use of systemic corticosteroids or increased OCS maintenance dose within 30 days prior to the first visit.
5.具有臨床意義的感染，包括上呼吸道或下呼吸道感染（分別為URTI和LRTI），需要在第1次就診前＜ 2週或磨合期內完成全身性抗生素或抗病毒藥物治療。5. Clinically significant infections, including upper or lower respiratory tract infections (URTI and LRTI, respectively), requiring completion of systemic antibiotic or antiviral therapy < 2 weeks before the first visit or during the run-in period.
6.在磨合期和優化期間有活動性COVID-19感染證據的參與者。評估將基於當前當地指南確定的當地護理標準。6. Participants with evidence of active COVID-19 infection during the run-in and optimization periods. Assessment will be based on local standards of care as determined by current local guidance.
7.在第1次就診前6個月內診斷出蠕蟲感染，但未接受過標準護理治療或對標準護理治療沒有反應。7. Helminth infection diagnosed within 6 months before the first visit but not receiving or not responding to standard care treatment.
8.在第1次就診前30天內接受短效β促效劑（SABA）維持治療的參與者。8. Participants who received short-acting beta-agonist (SABA) maintenance treatment within 30 days before the first visit.
9.當前吸煙者或吸煙史≥ 10包年的參與者以及使用電子煙產品（包括電子煙）的參與者。吸煙史＜ 10包年的既往吸煙者和電子煙或電子煙產品的使用者必須在第1次就診前停止至少6個月才有資格。9. Current smokers or participants with a smoking history ≥ 10 pack-years and participants who use electronic cigarette products (including e-cigarettes). Former smokers with a smoking history < 10 pack-years and users of e-cigarettes or e-cigarette products must have stopped for at least 6 months before the first visit to be eligible.
10.第1次就診前12個月內長期酗酒或吸毒。10. Long-term alcoholism or drug abuse within 12 months before the first visit.
11.第1次就診前12個月內需要治療的肺結核。11. Pulmonary tuberculosis requiring treatment within 12 months before the first visit.
12.第1次就診時人類免疫缺乏病毒（HIV）檢測呈陽性或參與者服用抗反轉錄病毒藥物或任何已知免疫缺乏病史，由病史和/或參與者的口頭報告確定。12. Positive human immunodeficiency virus (HIV) test at visit 1 or participant taking antiretroviral medication or any known history of immunodeficiency as determined by medical history and/or verbal report by the participant.
13.在第1次就診前8週內進行過大手術或在研究進行期間計畫需要全身麻醉或住院＞ 1天的外科手術。13. Major surgery within 8 weeks before the first visit or planned surgery requiring general anesthesia or hospitalization for > 1 day during the study.
14.在第1次就診前4個月或5個半衰期（以較長者為準）內接受任何上市或研究性生物製劑，或在第1次就診前30天或5個半衰期（以較長者為準）內接受任何研究性非生物製劑。14. Receipt of any marketed or investigational biologic within 4 months or 5 half-lives (whichever is longer) before the first visit, or any investigational non-biologic within 30 days or 5 half-lives (whichever is longer) before the first visit.
15.在第1次就診前的最後12週或5個半衰期（以較長者為準）內使用以下藥物進行治療：全身免疫抑制/免疫調節藥物（如胺甲喋呤、環孢素、口服/胃腸外/關節內皮質類固醇，用於氣喘治療以外的其他用途）15. Treatment with the following medications within the last 12 weeks or 5 half-lives (whichever is longer) before the first visit: systemic immunosuppressive/immunomodulatory drugs (e.g., methotrexate, cyclosporine, oral/parenteral/intra-articular corticosteroids for purposes other than asthma treatment)
16.在第1次就診前30天內接受免疫球蛋白或血液製品。16. Receipt of immunoglobulin or blood products within 30 days before the first visit.
17.在第1次就診前15天內接受T2細胞介素抑制劑甲磺司特。17. Received T2 interleukin inhibitor supelastin toluene within 15 days before the first visit.
18.在隨機分組日期前30天和研究期間（包括訪視期）接受減毒活疫苗。18. Received live attenuated vaccine 30 days before the randomization date and during the study period (including the visit period).
19.在隨機分組前28天內接種COVID-19疫苗。19. Received COVID-19 vaccine within 28 days before randomization.
20.在第1次就診前36個月內接受過支氣管熱成形術治療的參與者。20. Participants who have received bronchial thermoplasty within 36 months before the first visit.
21.對研究干預配製物的任何成分敏感或藥物或其他過敏史，研究者或醫療監督員認為該等禁忌他們參與。21. Allergy to any component of the study intervention formulation or a history of drug or other allergies that the investigator or medical supervisor considers contraindicated for their participation.
22.任何生物治療後的過敏反應史或有記錄的免疫複合物疾病（III型超敏反應）。22. Any history of allergic reactions after biological therapy or documented immune complex disease (type III hypersensitivity reaction).
23.同時參加另一項與IP相關的干預臨床試驗。23. Participate in another IP-related intervention clinical trial at the same time.
24.參與者隨機分組在其他正在進行或先前的泰派魯單抗研究中。24. Participants were randomized to other ongoing or previous tepilumab studies.
25.參與研究的計畫和/或實施（適用於阿斯利康公司（AstraZeneca）員工和/或現場員工），或由現場或贊助商員工或其親屬雇傭的參與者。25. Participants who were involved in the planning and/or conduct of the study (applicable to AstraZeneca employees and/or site staff), or who were employed by site or sponsor employees or their relatives.
26.磨合期內身體檢查、生命徵象、心電圖（ECG）、血液學、臨床化學或尿液分析中任何具有臨床意義的異常發現，研究者認為，這可能會使參與者因他/她參與研究而處於危險之中，或可能影響研究結果，或參與者完成整個研究的能力。26. Any clinically significant abnormal findings in physical examination, vital signs, electrocardiogram (ECG), hematology, clinical chemistry, or urinalysis during the run-in period that, in the opinion of the Investigator, may place the participant at risk for his/her participation in the study or may affect the study results or the participant's ability to complete the entire study.
27.第1次就診時有活動性肝病的證據，包括黃疸或天冬胺酸轉胺酶、丙胺酸轉胺酶或鹼性磷酸酶超過正常上限（ULN）的兩倍。27. Evidence of active liver disease at the first visit, including jaundice or aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase greater than twice the upper limit of normal (ULN).
28.第1次就診時B型肝炎表面抗原或C型肝炎病毒抗體血清學呈陽性，或B型肝炎或C型肝炎陽性病史。有B型肝炎疫苗接種史但沒有B型肝炎病史的參與者可以參加。28. Positive serology for hepatitis B surface antigen or hepatitis C virus antibody at the first visit, or a history of positive hepatitis B or hepatitis C. Participants with a history of hepatitis B vaccination but no history of hepatitis B can participate.
29.目前懷孕（經妊娠測試呈陽性確認）或母乳餵養或哺乳期的婦女。29. Women who are currently pregnant (confirmed by a positive pregnancy test) or breastfeeding or lactating.
30.研究者認為不願意或無法遵循研究程序或限制30. The researcher feels unwilling or unable to follow the research procedures or restrictions
31.既往同種異體骨髓移植。31. Previous allogeneic bone marrow transplantation.
32.在基因樣本採集後120天內輸注非白血球耗竭的全血。32. Administer non-leukocyte-depleted whole blood within 120 days of genetic sample collection.
33.在優化期內，在OCS劑量＜ 7.5 mg或＞ 30 mg下達到氣喘控制和/或連續3次劑量減少，之後仍然獲得氣喘控制。33. Achieve asthma control at an OCS dose of < 7.5 mg or > 30 mg and/or achieve asthma control after 3 consecutive dose reductions during the optimization period.
34.有臨床意義的感染（包括COVID-19）的證據或接受全身性抗生素或抗病毒藥物治療的參與者。34. Participants with evidence of clinically significant infection (including COVID-19) or receiving systemic antibiotics or antiviral medications.
35.儘管對參與者進行了篩選，但在研究水平上停止了入組/隨機分組。35. Despite screening of participants, enrollment/randomization was stopped at the study level.
方案：該研究包括2週的磨合期，隨後係長達8週的OCS優化階段，28週的治療期和12週的訪視期。OCS優化階段之目的係確定維持氣喘控制的最低OCS劑量。在此階段，根據圖1所示的滴定方案，在滿足OCS劑量減少的所有標準的情況下，每2週一次減少進入OCS劑量（表1）。治療期分為三個階段：誘導階段：4週（第0週至第4週），在此期間參與者保持優化的OCS劑量；OCS減少階段：20週（第4週至第24週），在此期間OCS劑量將在階段開始時減少，然後每4週減少一次，前提是滿足OCS減少的所有標準（表1）；維持階段：4週（第24週至第28週），在此期間參與者保持在減少階段達到的穩定維持OCS劑量，或者如果劑量減少到0 mg，則繼續不使用OCS。 [表1].優化階段的OCS劑量減少方案
泰派魯單抗在10 mM乙酸鹽、3.0%（w/v）L-脯胺酸、0.01%（w/v）聚山梨醇酯80，pH 5.2中以110 mg/mL投與。安慰劑係在10 mM乙酸鹽、250 mM L-脯胺酸、0.01%（w/v）聚山梨醇酯80，pH 5.0中的0.7%（w/v）羧甲基纖維素鈉。Taipilumab was administered at 110 mg/mL in 10 mM acetate, 3.0% (w/v) L-proline, 0.01% (w/v) polysorbate 80, pH 5.2. The placebo was 0.7% (w/v) sodium carboxymethylcellulose in 10 mM acetate, 250 mM L-proline, 0.01% (w/v) polysorbate 80, pH 5.0.
中等劑量ICS對應於500 μg，高劑量ICS對應於＞ 500 μg丙酸氟替卡松乾粉配製物或等效物，如圖2所示。參與者還可能接受其他醫生開具的氣喘控制藥物。Medium-dose ICS corresponds to 500 μg and high-dose ICS corresponds to > 500 μg of fluticasone propionate dry powder formulation or equivalent, as shown in Figure 2. Participants may also receive other asthma control medications as prescribed by their physician.
終點和評估Endpoints and Evaluation
主要終點包括評估泰派魯單抗與安慰劑相比在減少開具的維持OCS劑量同時維持氣喘控制方面的作用，如表3所示。療效將藉由第28週每日維持OCS劑量相對於基線的減少百分比同時維持氣喘控制來確定。 [表3].口服皮質類固醇劑量減少的氣喘控制標準
每日OCS劑量相對於基線的百分比變化的類別定義為：1.減少≥ 90%至≤ 100%；2.減少≥ 75%至＜ 90%；3.減少≥ 50%至＜ 75%；4.減少＞ 0%至＜ 50%；5.沒有變化或任何增加。該研究之次要目標係第28週支氣管擴張劑前1秒用力呼氣量（BD前FEV1）相對於基線的變化。The categories of percentage change in daily OCS dose from baseline were defined as: 1. ≥ 90% decrease to ≤ 100%; 2. ≥ 75% decrease to <90%; 3. ≥ 50% decrease to <75%; 4. > 0% decrease to <50%; 5. No change or any increase. The secondary objective of the study was the change from baseline in forced expiratory volume in 1 second before bronchodilator (pre-BD FEV1 ) at week 28.
次要終點包括泰派魯單抗改善肺功能、氣喘控制和HRQoL以及降低氣喘加重的能力，同時減少OCS劑量，例如藉由第28週BD前FEV1相對於基線的變化來測量。Secondary endpoints included the ability of tepilumab to improve lung function, asthma control, and HRQoL and reduce asthma exacerbations while reducing OCS dosage, as measured by change from baseline in pre-BDFEV1 at Week 28.
額外結局指標包括以下：Additional outcome indicators include the following:
評估泰派魯單抗與安慰劑相比對維持OCS日劑量的影響，每日維持OCS劑量比基線減少100%，每日維持OCS劑量≤ 5 mg，以及第28週每日維持OCS劑量比基線減少≥ 50%的第28週參與者的比例；To assess the effect of teprenolol compared with placebo on the proportion of participants maintaining a 100% reduction in daily OCS dose from baseline, maintaining a daily OCS dose ≤ 5 mg, and maintaining a ≥ 50% reduction in daily OCS dose from baseline at Week 28;
評估泰派魯單抗與安慰劑相比對氣喘加重的影響，藉由28週AAER和首次氣喘加重的時間測量，支援性結局變量包括28週內與急診室（ER）就診、緊急護理就診或住院相關的氣喘加重率，以及28週內未經歷氣喘加重的參與者比例；To assess the effect of teprenolol compared with placebo on asthma exacerbations as measured by the 28-week AAER and time to first asthma exacerbation. Supportive outcome variables included the rate of asthma exacerbations associated with emergency room (ER) visits, urgent care visits, or hospitalizations within 28 weeks, and the proportion of participants who did not experience an asthma exacerbation within 28 weeks.
評估泰派魯單抗與安慰劑相比對氣喘控制和其他氣喘控制指標的影響，例如第28週ACQ-6得分，和/或第28週每週平均居家PEF（早晚）相對於基線的變化To assess the effect of teprenol compared with placebo on asthma control and other measures of asthma control, such as ACQ-6 scores at Week 28, and/or the change from baseline in weekly mean home PEF (morning and evening) at Week 28
評估泰派魯單抗與安慰劑相比對氣喘相關生活品質的影響，藉由第28週AQLQ(s)+12總得分和/或第28週聖喬治呼吸問卷（SGRQ）得分相對於基線的變化來測量；To assess the effect of teprenolol compared with placebo on asthma-related quality of life measured by the change from baseline in the AQLQ(s)+12 total score at Week 28 and/or the St. George's Respiratory Questionnaire (SGRQ) score at Week 28;
評估泰派魯單抗對生物標誌物的影響，例如第28週FeNO、周邊血嗜酸性球和總血清IgE相對於基線的變化；To assess the effect of tepilumab on biomarkers such as change from baseline in FeNO, peripheral blood eosinophils, and total serum IgE at Week 28;
評估泰派魯單抗的藥物動力學，例如第0、12和28週的泰派魯單抗血清谷濃度；To assess the pharmacokinetics of tepilumab, such as tepilumab serum trough concentrations at Weeks 0, 12, and 28;
評估泰派魯單抗的免疫性，藉由第0、12、28和40週的抗藥物抗體發生率來測量。Immunity to tepilumab was assessed by the incidence of anti-drug antibodies at weeks 0, 12, 28, and 40.
進一步的評估包括評估泰派魯單抗與安慰劑相比對其他BD前肺功能測量值的影響，藉由第28週BD前用力肺活量（FVC），第28週超過25%-75%肺活量的用力呼氣流量（FEF25%-75%）相對於基線的變化來測量；評估泰派魯單抗與安慰劑相比對BD後肺功能的影響，藉由BD後1秒用力呼氣量（FEV1）、第28週用力肺活量（FVC）和第28週超過25%-75%肺活量的用力呼氣流量（FEF25%-75%）相對於基線的變化來測量；評估泰派魯單抗與安慰劑相比對總體健康相關生活品質的影響，藉由第28週歐洲生活品質-5維5水平問卷（EQ-5D-5L）得分相對於基線的變化來測量；評估泰派魯單抗與安慰劑相比對氣道阻塞疾病參與者健康狀況的影響，藉由第28週每週平均每日氣喘症狀日記（ASD）相對於基線的變化來測量；以及評估泰派魯單抗與安慰劑相比對健康資源利用的療效，藉由泰派魯單抗與安慰劑相比對健康資源利用的療效來測量。 [表4].氣喘惡化警報標準
肺活量測定：肺功能（FEV1；FEF 25%至75%和用力肺活量[FVC]）將使用中央供應商提供的設備在研究現場藉由肺活量測定進行測量。肺活量測定由研究者或授權代表根據美國胸科學會/歐洲呼吸學會（ATS/ERS）指南進行（Graham等人 2019）。全球肺功能倡議（GLI）方程用於確定預測的正常值（PNV），並將其預程序設計到肺活量計中（Quanjer等人 2012）。FEV1，表示為PNV的百分比，計算如下： PNV的FEV1% = (測量的FEV1/FEV1PNV) x 100Spirometry : Lung function (FEV1 ; FEF 25% to 75% and forced vital capacity [FVC]) will be measured by spirometry at the study site using equipment provided by a central supplier. Spirometry will be performed by the investigator or authorized representative according to the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines (Graham et al. 2019). The Global Lung Function Initiative (GLI) equation is used to determine the predicted normal value (PNV) and is preprogrammed into the spirometer (Quanjer et al. 2012). FEV1 , expressed as a percentage of PNV, is calculated as follows: FEV1 % of PNV = (measured FEV1 /FEV1 PNV) x 100
BD後肺活量測定和支氣管擴張劑反應性測試：進行BD後肺活量測定。可以使用沙丁胺醇（90 μg計量劑量）或舒喘寧（100 μg計量劑量）誘導支氣管擴張，最多吸入4次。在極少數情況下，其中參與者對沙丁胺醇/舒喘寧有不良或過敏反應，可以使用左旋沙丁胺醇（45 μg計量劑量；最多吸入4次）。BD前後最高FEV1用於確定支氣管擴張劑反應性。支氣管擴張劑反應性計算如下： %支氣管擴張劑反應性 = (BD後FEV1- BD前FEV1) × 100/BD前FEV1Post-BD Spirometry and Bronchodilator Responsiveness Testing: Post-BD spirometry was performed. Bronchodilation could be induced using albuterol (90 μg metered dose) or albuterol (100 μg metered dose) for up to 4 inhalations. In rare cases where participants had an adverse or allergic reaction to albuterol/albuterol, levalbuterol (45 μg metered dose; up to 4 inhalations) could be used. The highest pre- and post-BD FEV1 was used to determine bronchodilator responsiveness. Bronchodilator responsiveness was calculated as follows: % Bronchodilator responsiveness = (Post-BD FEV1 - Pre-BD FEV1 ) × 100/Pre-BD FEV1
居家PEF測試：在第1次就診時，向參與者提供用於測量PEF的電子掌上型肺活量計（ePEF計）。參與者在第1次就診時接受在家使用ePEF計的培訓。居家PEF測試由參與者在早上醒來時（在服用AM氣喘控制劑之前）和晚上就寢時（在服用PM氣喘控制劑之前）進行。HomePEFTesting : At Visit 1, participants were provided with an electronic handheld spirometer (ePEF meter) for measuring PEF. Participants were trained to use the ePEF meter at home at Visit 1. Home PEF testing was performed by participants upon awakening in the morning (before taking AM asthma controller) and at bedtime (before taking PM asthma controller).
呼出一氧化氮分數：使用標準化單次呼氣FeNO測試評估氣道炎症。將遵循製造商推薦的單次呼氣技術（Alving等人 2017）。參與者被問及他們在測量前2週內是否有呼吸道感染。在呼吸道感染後2週內不會進行FeNO測量。FeNO測試在肺活量測定之前進行。參與者在進行FeNO測試前一小時不應進食或飲水。參與者不應在測量後6小時內使用其搶救SABA藥物（例如沙丁胺醇/舒喘寧）。吸入的BD（包括ICS-LABA）應在BD肺活量測定要求特定的作用持續時間內保留。NIOX VERO®氣道炎症監測儀將用於測量FeNO。Fractional Exhaled Nitric Oxide: Airway inflammation will be assessed using a standardized single-breath FeNO test. The manufacturer's recommended single-breath technique will be followed (Alving et al. 2017). Participants are asked if they have had a respiratory infection in the 2 weeks prior to the measurement. FeNO measurements will not be performed within 2 weeks of a respiratory infection. FeNO testing is performed prior to spirometry. Participants should not eat or drink one hour prior to the FeNO test. Participants should not use their rescue SABA medication (e.g., albuterol/salbutamol) within 6 hours of the measurement. Inhaled BDs (including ICS-LABAs) should be withheld for the duration of action specified for BD spirometry. The NIOX VERO® Airway Inflammation Monitor will be used to measure FeNO.
下視丘-垂體-腎上腺軸評估。對於所有參與者，HPA軸完整性將在5 mg/天給藥4週後和逐漸減少OCS劑量之前進行評估（對於基線OCS劑量等於5 mg/天的參與者，將在第一劑泰派魯單抗投與後4週和OCS減少階段開始前進行評估）。在達到5 mg劑量OCS後4週，並在進一步減少劑量之前，將對所有參與者進行早上皮質醇測試。AI讀數包括：對於未服用含雌激素避孕藥的參與者：正常AI-＞ 350 nmol/L SI，不確定結果100-350 nmol/L SI；完全AI ＜ 100 nmol/L SI，對於服用含雌激素避孕藥的參與者：正常＞ 700 nmol/L，不確定結果200-700 nmol/L，完全AI ＜ 200 nmol/L。Hypothalamic-pituitary-adrenal axis assessment . For all participants, HPA axis integrity will be assessed after 4 weeks of 5 mg/day dosing and before tapering of the OCS dose (for participants with a baseline OCS dose equal to 5 mg/day, the assessment will be performed 4 weeks after the first dose of tadalafil and before the start of the OCS taper phase). Morning cortisol testing will be performed in all participants 4 weeks after reaching the 5 mg dose of OCS and before further dose reductions. AI readings included: for participants not taking estrogen-containing contraceptives: normal AI -> 350 nmol/L SI, indeterminate results 100-350 nmol/L SI; complete AI < 100 nmol/L SI, for participants taking estrogen-containing contraceptives: normal > 700 nmol/L, indeterminate results 200-700 nmol/L, complete AI < 200 nmol/L.
促腎上腺皮質激素刺激測試。當早上皮質醇水平在不確定範圍內時，將進行替可克肽（也稱為Synacthen、Cortrosyn或cosyntropin）ACTH刺激測試。正常、不確定和完全AI範圍與HPA軸測試相同。ACTH stimulation test. The Synactin (also called Synacthen, Cortrosyn, or cosyntropin) ACTH stimulation test is done when morning cortisol levels are in the indeterminate range. The normal, indeterminate, and complete AI ranges are the same as for the HPA axis test.
還收集患者報告的結局。Patient-reported outcomes were also collected.
氣喘每日日記：每日日記從第1次就診的晚上到第13次就診的早上每天完成。早上日記包括：氣喘症狀日記（ASD）早上項目、整體氣喘症狀項目、有關搶救藥物的問題、夜間覺醒和維持藥物的使用。晚上日記包括：ASD晚上項目、整體氣喘症狀項目、有關搶救藥物的問題和OCS使用。完成早晚問題後，參與者將完成呼氣峰流量評估。Asthma Daily Diary : Daily diaries are completed daily from the evening of Visit 1 to the morning of Visit 13. The morning diary includes: Asthma Symptom Diary (ASD) morning items, global asthma symptom items, questions about rescue medications, nighttime awakenings, and maintenance medication use. The evening diary includes: ASD evening items, global asthma symptom items, questions about rescue medications, and OCS use. After completing the morning and evening questions, participants will complete the peak expiratory flow assessment.
氣喘症狀日記：使用ASD記錄氣喘症狀（Globe等人 2015）。ASD包括10個項目（早上5個項目；晚上5個項目）。早上項目評估與喘息、呼吸短促、咳嗽和胸悶相關的夜間症狀嚴重程度，以及夜間覺醒的頻率。晚上項目評估與喘息、呼吸短促、咳嗽和胸悶相關的症狀嚴重程度，以及醒來後的活動限制。項目的得分範圍從「0」（無症狀、無夜間覺醒或無活動限制）到「4」（非常嚴重的症狀、無法入睡或極端活動限制）。每日ASD得分係10個項目的平均值。需要回答所有10個項目才能計算每日ASD得分；否則，它將被視為丟失。每日ASD得分的計算需要來自晚上日記評估和隨後的早上日記評估的數據。對於7天平均氣喘症狀得分，使用7天ASD得分中至少4個的平均值作為平均每週項目得分進行得分，無需插補。7天平均ASD得分範圍為0到4。Asthma Symptom Diary : Asthma symptoms were recorded using the ASD (Globe et al. 2015). The ASD consists of 10 items (5 items in the morning; 5 items in the evening). The morning items assess the severity of nighttime symptoms related to wheezing, shortness of breath, cough, and chest tightness, as well as the frequency of nighttime awakenings. The evening items assess the severity of symptoms related to wheezing, shortness of breath, cough, and chest tightness, as well as activity limitations after awakening. Item scores range from “0” (no symptoms, no nighttime awakenings, or no activity limitations) to “4” (very severe symptoms, inability to sleep, or extreme activity limitations). The daily ASD score is the average of the 10 items. All 10 items need to be answered to calculate the daily ASD score; otherwise, it will be considered missing. The calculation of the daily ASD score requires data from the evening diary assessment and the subsequent morning diary assessment. For the 7-day average asthma symptom score, the average of at least 4 of the 7-day ASD scores was used as the average weekly item score without interpolation. The 7-day average ASD score ranged from 0 to 4.
整體氣喘症狀項目：除ASD外，參與者還將每天早晚完成氣喘症狀的單項整體評估（0至3）。晚上和隨後的早上單個總體項目得分（0到6）的總和將用於警報系統。Global Asthma Symptom Item : In addition to ASD, participants will complete a single global assessment of asthma symptoms each morning and evening (0 to 3). The sum of the single global item scores (0 to 6) for the evening and the following morning will be used for the alarm system.
氣喘控制問卷：氣喘控制問卷（ACQ-6）係對氣喘症狀（夜間醒來、醒來症狀、活動受限、呼吸急促、喘息和短效β促效劑使用）的評估。參與者被要求藉由回答一個支氣管擴張劑使用問題和5個症狀問題來回憶他們在前一週的氣喘控制水平。問題同等地進行加權處理且得分為0（完全控制）至6（嚴重不受控制）。平均ACQ-6得分為反應平均值。平均得分≤ 0.75指示氣喘控制良好，得分在0.75與＜ 1.5之間指示氣喘得到部分控制，且得分≥ 1.5指示氣喘控制不佳（Juniper等人 2006）。至少0.5的個體變化被認為具有臨床意義，減少至少0.5係ACQ-6的反應者定義。Asthma Control Questionnaire : The Asthma Control Questionnaire (ACQ-6) is an assessment of asthma symptoms (nighttime awakenings, symptoms on awakening, activity limitation, shortness of breath, wheezing, and short-acting beta-agonist use). Participants were asked to recall their level of asthma control in the previous week by answering one question about bronchodilator use and five questions about symptoms. Questions were equally weighted and scored from 0 (completely controlled) to 6 (very uncontrolled). The mean ACQ-6 score is the mean of the responses. A mean score of ≤ 0.75 indicates good asthma control, a score between 0.75 and < 1.5 indicates partially controlled asthma, and a score ≥ 1.5 indicates poor asthma control (Juniper et al. 2006). An individual change of at least 0.5 was considered clinically significant, and a decrease of at least 0.5 was defined as a responder on the ACQ-6.
12歲及以上的標準化氣喘生活品質問卷（AQLQ(S)+12）：AQLQ(S)+12係測量氣喘參與者所經歷的與健康相關的生活品質的問卷。該問卷包含4個獨立領域（症狀、活動限制、情緒功能和環境刺激）。參與者被要求回憶他們在過去2週內的經歷，並以範圍從7（無損傷）到1（嚴重損傷）的7分量表對每個問題進行得分。總得分計為對所有問題的平均反應。4個單獨的領域得分（症狀、活動限制、情緒功能和環境刺激）為對各領域中問題的反應的平均值。AQLQ(s)+12的反應者定義為比基線改善了0.5分。Standardized Asthma Quality of Life Questionnaire (AQLQ(S)+12) for ages12 and older: The AQLQ(S)+12 is a questionnaire that measures the health-related quality of life experienced by participants with asthma. The questionnaire contains 4 separate domains (symptoms, activity limitations, emotional functioning, and environmental irritation). Participants are asked to recall their experiences in the past 2 weeks and score each question on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The total score is calculated as the average response to all questions. The 4 individual domain scores (symptoms, activity limitations, emotional functioning, and environmental irritation) are the average of the responses to the questions in each domain. A responder with AQLQ(s)+12 was defined as an improvement of 0.5 points from baseline.
聖喬治呼吸問卷（SGRQ）：SGRQ係一種50項PRO工具，用於測量患有氣道阻塞疾病的參與者的健康狀況（Jones等人 1991）。問卷分為兩部分：第1部分由與前4週呼吸道症狀的嚴重程度相關的8個項目組成；第2部分由與個體呼吸狀況的日常活動和心理社會影響相關的42個項目組成。SGRQ產生總分和3個成分得分（症狀、活動和影響）。總分表示疾病對整體健康狀況的影響。該總分表示為總體損傷的百分比，其中100表示最差的可能健康狀況，0表示最好的可能健康狀況。同樣，成分得分範圍從0到100，得分越高表示損傷越大。根據經驗數據和對患者的訪談，4個單位的平均變化得分與最小臨床重要差異（MCID）相關。得分演算法的特定細節由開發人員在用戶手冊中提供（Jones等人 2009）。St. George's Respiratory Questionnaire (SGRQ) : The SGRQ is a 50-item PRO instrument that measures health status in participants with obstructive airway disease (Jones et al. 1991). The questionnaire consists of two parts: Part 1 consists of 8 items related to the severity of respiratory symptoms in the previous 4 weeks; Part 2 consists of 42 items related to the daily activities and psychosocial impact of the individual's respiratory condition. The SGRQ produces a total score and 3 component scores (symptoms, activities, and impact). The total score represents the impact of the disease on overall health status. This total score is expressed as a percentage of overall impairment, where 100 represents the worst possible health status and 0 represents the best possible health status. Similarly, component scores range from 0 to 100, with higher scores indicating greater impairment. Based on empirical data and interviews with patients, a mean change score of 4 units is associated with the minimal clinically important difference (MCID). Specific details of the scoring algorithm are provided by the developers in the user manual (Jones et al. 2009).
歐洲生活品質-5維-5水平（EQ-5D-5L）：EQ-5D-5L問卷評估5個維度：活動能力、自我護理、日常活動、疼痛/不適和焦慮/抑鬱。每個維度具有反映難度水平增加的5個反應選項（無問題、輕微問題、中度問題、嚴重問題和極端問題）。參與者將被要求藉由在5個維度中的每一個中選擇最合適的級別來指示他/她的當前健康狀況。問卷還包括視覺模擬量表，其中參與者將被要求對當前健康狀況進行0到100的得分，0係可以想像到的最差健康狀況。European Quality of Life- 5Dimensions- 5Levels (EQ-5D-5L) : The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 response options reflecting increasing levels of difficulty (no problem, slight problem, moderate problem, severe problem, and extreme problem). The participant will be asked to indicate his/her current health status by selecting the most appropriate level in each of the 5 dimensions. The questionnaire also includes a visual analog scale in which the participant will be asked to score the current health status from 0 to 100, with 0 being the worst health status imaginable.
氣喘加重：在研究期間，氣喘加重被定義為氣喘惡化，導致以下任一種情況：Asthma Exacerbations : During the study period, an asthma exacerbation was defined as a worsening of asthma resulting in any of the following:
• 至少連續3天臨時性推注/爆發全身性皮質類固醇（或穩定OCS背景劑量的臨時增加），以治療氣喘惡化的症狀；單次可注射劑量的皮質類固醇將被認為相當於全身性皮質類固醇的3天爆發。• At least 3 consecutive days of temporary bolus/burst of systemic corticosteroids (or temporary increase in stable OCS background dose) to treat symptoms of worsening asthma; a single injectable dose of corticosteroids will be considered equivalent to a 3-day burst of systemic corticosteroids.
• 由於需要全身性皮質類固醇的氣喘（如上所述）而導致急診室或緊急護理就診（定義為在急診科或緊急護理中心進行＜ 24小時的評估和治療），和/或• Emergency room or urgent care visit due to asthma requiring systemic corticosteroids (as described above) (defined as evaluation and treatment in an emergency department or urgent care center < 24 hours), and/or
• 因氣喘住院（定義為進入住院機構和/或在醫療機構評估和治療≥ 24小時）。• Hospitalization for asthma (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥ 24 hours).
參與者需要在電子日記中報告以下任何一項：Participants were asked to report any of the following in their electronic diary:
• 與基線期間的平均使用量相比，至少連續2天增加4次或更多次的搶救藥物使用，或任一天使用12次/天，和/或；• An increase in rescue medication use of 4 or more times on at least 2 consecutive days, or 12 times/day on any one day, compared to average use during the baseline period, and/or;
• 與基線期間的平均使用量相比，至少連續2天額外使用霧化β2促效劑，和/或；• Additional use of aerosolized beta-2 agonists for at least 2 consecutive days compared to average use during the baseline period, and/or;
• 與基線期間的平均值相比，7天內因氣喘需要搶救藥物而醒來的夜晚增加2個或更多，和/或前7個夜晚中≥ 6個因氣喘需要搶救藥物而醒來（應連續2天滿足此標準）。• An increase of 2 or more nights awakening due to asthma requiring rescue medication over a 7-day period compared to the average during the baseline period and/or ≥ 6 nights awakening due to asthma requiring rescue medication in the preceding 7 nights (this criterion must be met for 2 consecutive days).
如果加重事件與至少1個預先指定的客觀測量值的惡化無關，則研究者必須證明將事件定義為加重的決定係合理的，並將其記錄在eCRF中。不受任何客觀評估支持的事件將不被視為方案定義的加重。If an exacerbation event is not associated with a worsening of at least 1 pre-specified objective measure, the investigator must justify the decision to define the event as an exacerbation and document this in the eCRF. Events not supported by any objective assessment will not be considered protocol-defined exacerbations.
加重的開始定義為全身性皮質類固醇的開始日期或穩定OCS背景劑量的暫時增加的開始日期，需要全身性皮質類固醇的ER或緊急護理就診日期，或因氣喘入院的日期，以較早發生者為準。加重的結束日期定義為全身性皮質類固醇的最後日期或穩定OCS背景劑量的暫時增加的最後日期，ER或緊急護理就診日期，或出院日期，以較晚發生者為準。The start of an exacerbation was defined as the start date of systemic corticosteroids or the start date of a temporary increase in stable background OCS dose, the date of an ER or urgent care visit requiring systemic corticosteroids, or the date of hospitalization for asthma, whichever occurred first. The end date of an exacerbation was defined as the last date of systemic corticosteroids or the last date of a temporary increase in stable background OCS dose, the date of an ER or urgent care visit, or the date of hospital discharge, whichever occurred later.
如果自氣喘加重的結束日期和新的氣喘加重的開始日期以來已經過去了不到7天，則第二次事件將被視為先前氣喘加重的復發If less than 7 days have passed since the end date of the asthma exacerbation and the start date of the new asthma exacerbation, the second event will be considered a recurrence of the previous asthma exacerbation
EQ-5D-3L。EuroQOL生活品質5維3水平版本（EQ-5D-3L）係一種標準化工具，用於衡量健康相關的生活品質（HRQoL），並由EuroQol（Brooks, 1996）開發。它從5個維度定義健康：活動能力、自我護理、日常活動、疼痛/不適和焦慮/抑鬱。每個維度都有3個順序嚴重程度水平：1，沒有問題；2，一些問題；以及3，問題嚴重。總體健康狀態定義為5位數。參與者將被要求藉由在5個維度中的每一個中選擇最合適的級別來指示他/她的當前健康狀況。問卷還包括VAS，參與者將被要求使用0到100的量表對當前健康狀況進行得分，其中0係可以想像到的最差健康狀況。EQ-5D-3L . The EuroQOL Quality of Life 5 Dimensions 3 Levels version (EQ-5D-3L) is a standardized instrument to measure health-related quality of life (HRQoL) and was developed by EuroQol (Brooks, 1996). It defines health in terms of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 ordinal severity levels: 1, no problems; 2, some problems; and 3, severe problems. The overall health status is defined as a 5-digit number. The participant will be asked to indicate his/her current health status by selecting the most appropriate level in each of the 5 dimensions. The questionnaire also includes a VAS, in which participants are asked to rate their current health status using a scale of 0 to 100, with 0 being the worst health status imaginable.
患者總體嚴重程度印象。PGI-S係一個單一項目，旨在使用5分分類反應量表（無症狀到非常嚴重的症狀）來獲取受試者在完成時對整體症狀嚴重程度的感知。Patient Global Impression of Severity . The PGI-S is a single item designed to elicit the subject's perception of overall symptom severity at the time of completion using a 5-point categorical response scale (no symptoms to very severe symptoms).
不良事件：研究者觀察到的或受試者報告的所有不良事件均應收集/報告，該等不良事件發生在第一劑研究藥物後至研究/安全性訪視訪視結束或最後一次投與研究藥物後20週。Adverse Events : All adverse events observed by the investigator or reported by the subjects should be collected/reported, which occurred after the first dose of study drug until the end of the study/safety visit or 20 weeks after the last administration of study drug.
生物標誌物Biomarkers
血清免疫球蛋白。根據SoA，總免疫球蛋白E（IgE）水平和過敏原特異性IgE（IgE FEIA）的存在評估將在IP投與前（給藥前）在預先指定的計畫訪視中收集，並由中心實驗室進行評估。Serum immunoglobulins . Based on the SoA, total immunoglobulin E (IgE) levels and the presence of allergen-specific IgE (IgE FEIA) will be collected before IP administration (pre-dose) at a pre-specified scheduled visit and evaluated by a central laboratory.
藥物動力學評估：採集約5 mL的全血樣本，用於測量泰派魯單抗的血清濃度。Pharmacokinetic Assessment : Collect approximately 5 mL of whole blood samples for measurement of serum concentrations of tepilumab.
統計分析Statistical analysis
對於主要終點，將使用針對協變量調整的邏輯回歸模型來測試治療效果。從該模型中，將報告將每個泰派魯單抗劑量組與安慰劑進行比較的比值比和95% CI。此外，每個治療組中有反應的受試者百分比以及每個泰派魯單抗劑量組和安慰劑之間反應受試者百分比的差異將以95%信賴間隔進行總結。 實例2-長期投與泰派魯單抗減少對口服皮質類固醇的需求For the primary endpoint, treatment effects will be tested using a logistic regression model adjusted for covariates. From the model, odds ratios and 95% CIs comparing each tepilumab dose group to placebo will be reported. In addition, the percentage of subjects who responded in each treatment group and the difference in the percentage of responding subjects between each tepilumab dose group and placebo will be summarized with 95% confidence intervals.Example 2 - Long-term administration of tepilumab reduces the need for oral corticosteroids
在泰派魯單抗在氣喘患者中的3期研究NAVIGATOR（NCT03347279）中，與安慰劑相比，泰派魯單抗治療顯著降低了患有重度、不受控制氣喘的患者之年化氣喘加重率（Menzies-Gow等人 N Engl J Med[新英格蘭醫學雜誌] 2021;384:1800–9）。一項單獨的3期研究SOURCE（NCT03406078）評估了泰派魯單抗在患有OCS依賴性氣喘的成人中的OCS保留效果。SOURCE（NCT03406078）未達到主要終點；然而，54%和46%的泰派魯單抗和安慰劑治療的患者分別中斷每日OCS使用（Wechsler ME等人 Lancet Respir Med[柳葉刀呼吸內科] 2022;10:650–60）。In the phase 3 NAVIGATOR study of teprenumab in patients with asthma (NCT03347279), treatment with teprenumab significantly reduced the annualized rate of asthma exacerbations compared with placebo in patients with severe, uncontrolled asthma (Menzies-Gow et al. N Engl J Med 2021;384:1800–9). A separate phase 3 study, SOURCE (NCT03406078), evaluated the OCS-sparing effect of teprenumab in adults with OCS-dependent asthma. SOURCE (NCT03406078) did not meet the primary endpoint; however, 54% and 46% of patients treated with tepilumab and placebo, respectively, discontinued daily OCS use (Wechsler ME et al. Lancet Respir Med 2022;10:650–60).
該實例描述了完成母研究NAVIGATOR（52週）或SOURCE（48週）的患者（12-80歲）（DESTINATION）的3期、多中心、隨機、安慰劑對照、雙盲、擴展研究。在母研究中隨機分組到泰派魯單抗（每4週皮下注射210 mg）的患者在DESTINATION中繼續接受泰派魯單抗。在母研究中隨機分組到安慰劑的患者在DESTINATION中按1 : 1重新隨機分組到泰派魯單抗或安慰劑。This example describes a Phase 3, multicenter, randomized, placebo-controlled, double-blind, extension study in patients (12-80 years) (DESTINATION) who completed the parent study, NAVIGATOR (52 weeks) or SOURCE (48 weeks). Patients randomized to tepilumab (210 mg subcutaneously every 4 weeks) in the parent study continued to receive tepilumab in DESTINATION. Patients randomized to placebo in the parent study were re-randomized 1:1 to tepilumab or placebo in DESTINATION.
在入組DESTINATION的患者中評估從基線到第104週每日OCS劑量減少100%且保持氣喘控制的患者比例。在先前的研究中，該等患者在第0週接受維持OCS。在入組本研究的患者中評估平均OCS劑量從基線到第104週的變化。OCS劑量滴定由研究人員按照通常的臨床實踐自行決定，並不受方案的強制要求。The proportion of patients who achieved a 100% reduction in daily OCS dose and maintained asthma control from baseline to Week 104 was assessed in patients enrolled in DESTINATION. In the previous study, these patients received maintenance OCS at Week 0. The change in mean OCS dose from baseline to Week 104 was assessed in patients enrolled in this study. OCS dose titration was at the discretion of the investigator according to usual clinical practice and was not mandated by the protocol.
在每個母研究中，每個治療組的參與者之間的基線人口統計學和臨床特徵均衡；然而，兩項母研究之間的患者存在重要的基線差異。總體而言，42名最初來自NAVIGATOR的患者和92名最初來自SOURCE的患者在基線時接受維持OCS。Baseline demographics and clinical characteristics were balanced between participants in each treatment group in each parent study; however, there were important baseline differences in patients between the two parent studies. Overall, 42 patients originally from NAVIGATOR and 92 patients originally from SOURCE were receiving maintenance OCS at baseline.
在來自NAVIGATOR的患者中，泰派魯單抗組在第104週中斷OCS的比例在數量上高於安慰劑組（37.9%與7.7%；圖4A）。在來自SOURCE的患者中，泰派魯單抗組在第48週（61.7%與53.1%）和第104週（66.7%與46.9%；圖1）中斷OCS的比例在數量上高於安慰劑組。Among patients from NAVIGATOR, a numerically higher proportion of patients in the tepilumab group discontinued OCS at week 104 than in the placebo group (37.9% vs. 7.7%; Figure 4A). Among patients in SOURCE, a numerically higher proportion of patients in the tepilumab group discontinued OCS at week 48 (61.7% vs. 53.1%) and week 104 (66.7% vs. 46.9%; Figure 1).
在來自NAVIGATOR的患者中，泰派魯單抗組的平均每日OCS劑量從基線時的12.67 mg降至第104週的4.76 mg（圖4A），在來自SOURCE的患者中，從基線的11.21 mg降至第104週的2.80 mg（圖4B）（OCS劑量滴定由研究人員自行決定，未強制要求）。在來自NAVIGATOR的患者中，安慰劑組的平均每日OCS劑量從基線時的16.35 mg降至第104週的10.73 mg（圖4A），在來自SOURCE的患者中，從基線的11.95 mg降至第104週的3.16 mg（圖4B）（OCS劑量減少在劑量減少階段（第4-40週）強制要求，然後從第48週到第104週酌情決定）。在來自SOURCE的患者中，泰派魯單抗接受者的每日OCS劑量在第104週降至5 mg或更低的比例高於安慰劑接受者（80.0%與71.9%）。The mean daily OCS dose in the tepilumab group decreased from 12.67 mg at baseline to 4.76 mg at week 104 in patients from NAVIGATOR (Figure 4A) and from 11.21 mg at baseline to 2.80 mg at week 104 in patients from SOURCE (Figure 4B). (OCS titration was at the discretion of the investigators and was not mandatory.) The mean daily OCS dose decreased from 16.35 mg at baseline to 10.73 mg at week 104 in the placebo group among patients from NAVIGATOR (Fig. 4A) and from 11.95 mg at baseline to 3.16 mg at week 104 among patients from SOURCE (Fig. 4B). (OCS dose reductions were mandatory during the dose-reduction phase (weeks 4 to 40) and then discretionary from week 48 to week 104.) Among patients from SOURCE, a higher proportion of tepilumab recipients than placebo recipients had their daily OCS dose reduced to 5 mg or less at week 104 (80.0% vs. 71.9%).
與安慰劑治療的患者相比，在數量上更多的泰派魯單抗治療的患者在104週內完全中斷OCS治療，而不喪失氣喘控制或從基線到第104週減少其每日OCS劑量。該等發現表明，泰派魯單抗可能隨時間有效減少重度OCS依賴性氣喘患者的維持OCS的每日劑量。 實例3-泰派魯單抗在重度氣喘中減少口服皮質類固醇使用的療效和安全性研究Numerously more patients treated with teprenolomab completely discontinued OCS therapy through Week 104 without losing asthma control or reducing their daily OCS dose from baseline to Week 104 compared with patients treated with placebo. These findings suggest that teprenolomab may be effective in reducing the daily dose of OCS over time in patients with severe OCS-dependent asthma.Example 3 - Efficacy and Safety Study of Teprenolomab in Reducing Oral Corticosteroid Use in Severe Asthma
相關的IIIb期研究WAYFINDER在不同的入組地點進行。WAYFINDER之目的係，在接受高劑量吸入性皮質類固醇（ICS）加長效β2促效劑（LABA）和長期OCS治療的患有重度氣喘的口服皮質類固醇（OCS）依賴性參與者中，評估能夠完全中斷OCS或減少到≤ 5 mg/天的參與者比例。參與者每4週（Q4W）一次基於開放標籤接受210 mg泰派魯單抗。OCS劑量的遞減將在維持氣喘控制和腎上腺功能不全（AI）測試的同時開始。在WAYFINDER研究中使用了與實例2中所述類似的滴定方案。示例性滴定方案如表5和圖6所示。 [表5].口服皮質類固醇滴定方案，直到達到5 mg/天周。The related Phase IIIb study WAYFINDER was conducted at different enrollment sites. The purpose of WAYFINDER was to assess the proportion of participants who were able to completely wean OCS or reduce to ≤ 5 mg/day in oral corticosteroid (OCS)-dependent participants with severe asthma who were receiving high-dose inhaled corticosteroids (ICS) plus long-acting β2 agonists (LABA) and long-term OCS therapy. Participants received 210 mg of tepilumab on an open label basis once every 4 weeks (Q4W). The reduction in OCS dose will be initiated while maintaining asthma control and adrenal insufficiency (AI) testing. A titration regimen similar to that described in Example 2 was used in the WAYFINDER study. An exemplary titration regimen is shown in Table 5 and Figure 6. [Table5]Oral corticosteroid titration regimen until5 mg/day/week is achieved.
本研究的主要終點包括評估在中斷OCS，而不失去氣喘控制的情況下的參與者比例，以及在不失去氣喘控制的情況下將OCS劑量降至≤ 5 mg/天的參與者比例。對於所有參與者，下視丘-垂體-腎上腺軸完整性將在5 mg/天給藥4週後和任何進一步減少OCS劑量之前進行評估（對於基線OCS劑量等於5 mg/天的參與者，將在第一劑泰派魯單抗投與後4週和OCS減少階段開始前進行評估）。將對所有參與者進行早上血清皮質醇篩選方法（上午8點至9點皮質醇水平），以確定參與者是否具有正常的皮質醇水平、完全的AI或不確定的結果。早上皮質醇水平正常的參與者將繼續向下滴定。具有完全AI的參與者將延遲滴定並在3個月後重複測試。對於顯示不確定結果的參與者，將進行ACTH刺激測試，並且關於如何繼續OCS向下滴定的決定將基於該測試的結果（見表6）。 [表6].促腎上腺皮質激素刺激測試The primary endpoints of this study include assessment of the proportion of participants who discontinue OCS without loss of asthma control and the proportion of participants who reduce their OCS dose to ≤ 5 mg/day without loss of asthma control. For all participants, hypothalamic-pituitary-adrenal axis integrity will be assessed after 4 weeks of 5 mg/day dosing and before any further reduction in OCS dose (for participants with a baseline OCS dose equal to 5 mg/day, assessment will be performed 4 weeks after the first dose of tadalafil and before the start of the OCS reduction phase). A morning serum cortisol screening method (8:00-9:00 AM cortisol level) will be performed on all participants to determine whether the participant has a normal cortisol level, a complete AI, or an indeterminate result. Participants with normal morning cortisol levels will continue to titrate down. Participants with complete AI will have delayed titration and repeat the test 3 months later. For participants with indeterminate results, an ACTH stimulation test will be performed, and the decision on how to continue OCS titration will be based on the results of this test (see Table 6). [Table6]ACTH stimulation test
研究表明，接受維持OCS劑量≤ 5 mg/天的患者比例隨時間增加（圖7A），OCS劑量減少≥ 50%的患者比例也隨時間增加（圖7B）。在接受泰派魯單抗的受試者中，中斷維持每日OCS的患者比例通常隨時間增加（圖8）。The study showed that the proportion of patients receiving maintenance OCS dose ≤ 5 mg/day increased over time (Figure 7A), and the proportion of patients with a ≥ 50% reduction in OCS dose also increased over time (Figure 7B). Among subjects receiving teprenolumab, the proportion of patients who discontinued maintenance daily OCS generally increased over time (Figure 8).
在同一研究中，還測定了支氣管後FED和患者對ACQ-6的得分。圖9A和9B顯示，BD後FEV1隨時間總體穩定，平均ACQ-6得分在28週結束時下降。In the same study, postbronchial FED and patients' scores on the ACQ-6 were also measured. Figures 9A and 9B show that FEV1 was generally stable over time after BD, and the mean ACQ-6 score decreased at the end of 28 weeks.
因此，應理解，本發明不限於所揭露的特定實施方式，而是旨在涵蓋在所附申請專利範圍所定義的本發明之精神和範圍內；上述說明書；以下編號的段落和/或附圖中所示的所有修改。Therefore, it should be understood that the present invention is not limited to the particular embodiments disclosed, but is intended to cover the spirit and scope of the present invention as defined by the appended claims; the above description; all modifications shown in the following numbered paragraphs and/or the accompanying drawings.
實施方式的實例：Examples of implementations:
段落1. 一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，其含有： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，其含有： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽，其中該抗體為IgG2抗體。Paragraph 1. A method for treating corticosteroid-dependent asthma in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprisesa. a light chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; and NO:6;ii. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:7; andiii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2, wherein the antibody is an IgG2 antibody.
段落2. 一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 2. A method for treating corticosteroid-dependent asthma in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprisesa. a light chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; andb. A heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:10;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
段落3. 如段落1或2所述之方法，其中該輕鏈可變結構域在SEQ ID NO:12中列出，並且該重鏈可變結構域在SEQ ID NO:10中列出。Paragraph 3. The method as described in paragraph 1 or 2, wherein the light chain variable domain is listed in SEQ ID NO:12 and the heavy chain variable domain is listed in SEQ ID NO:10.
段落4. 如段落1至3中任一項所述之方法，其中該抗體或抗體變體每2週或每4週投與一次。Paragraph 4. The method as described in any of paragraphs 1 to 3, wherein the antibody or antibody variant is administered once every 2 weeks or every 4 weeks.
段落5. 如段落1至4中任一項所述之方法，其中該抗體係IgG2抗體。Paragraph 5. The method as described in any of paragraphs 1 to 4, wherein the antibody is an IgG2 antibody.
段落6. 如段落1至5中任一項所述之方法，其中該抗體或抗體變體以210 mg的劑量投與。Paragraph 6. The method as described in any of paragraphs 1 to 5, wherein the antibody or antibody variant is administered in a dose of 210 mg.
段落7. 如段落1至6中任一項所述之方法，其中該抗體係泰派魯單抗。Paragraph 7. The method as described in any of paragraphs 1 to 6, wherein the antibody is teprenolol.
段落8. 一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，其含有： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，其含有： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 8. A method for treating corticosteroid-dependent asthma in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprisesa. a light chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6;ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. NO:7, andiii. A heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2.
段落9. 一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 9. A method for treating corticosteroid-dependent asthma in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprisesa. a light chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; andb. A heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:10;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
段落10. 如段落8或9所述之方法，其中該輕鏈可變結構域在SEQ ID NO:12中列出，並且該重鏈可變結構域在SEQ ID NO:10中列出。Paragraph 10. The method of paragraph 8 or 9, wherein the light chain variable domain is set forth in SEQ ID NO:12, and the heavy chain variable domain is set forth in SEQ ID NO:10.
段落11. 如段落1至10中任一項所述之方法，其中該抗體或抗體變體投與至少4個月、6個月、9個月、1年、2年或更長時間的時期。Paragraph 11. The method of any one of paragraphs 1 to 10, wherein the antibody or antibody variant is administered for a period of at least 4 months, 6 months, 9 months, 1 year, 2 years or longer.
段落12. 如段落1至11中任一項所述之方法，其中所述抗TSLP抗體或其抗體變體為二價的並選自由人抗體、人源化抗體、嵌合抗體、單株抗體、重組抗體、IgG1抗體、IgG2抗體、IgG3抗體和IgG4抗體組成之群組。Paragraph 12. The method as described in any one of paragraphs 1 to 11, wherein the anti-TSLP antibody or antibody variant thereof is bivalent and is selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies and IgG4 antibodies.
段落13. 如段落8至13中任一項所述之方法，其中該抗體係IgG2抗體。Paragraph 13. The method of any one of paragraphs 8 to 13, wherein the antibody is an IgG2 antibody.
段落14. 如段落6至11中任一項所述之方法，其中該抗體係泰派魯單抗。Paragraph 14. The method of any one of Paragraphs 6 to 11, wherein the antibody is teprenolomab.
段落15. 如段落1至14中任一項所述之方法，其中該抗體或抗體變體係人抗體。Paragraph 15. The method of any one of Paragraphs 1 to 14, wherein the antibody or antibody variant is a human antibody.
段落16. 如段落1至15中任一項所述之方法，其中該抗體或抗體變體在包含藥學上可接受的載劑或賦形劑的藥物組成物中投與給該受試者。Paragraph 16. The method of any one of Paragraphs 1 to 15, wherein the antibody or antibody variant is administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.
段落17. 如段落1至16中任一項所述之方法，其中該皮質類固醇依賴性氣喘為重度氣喘。Paragraph 17. The method of any one of Paragraphs 1 to 16, wherein the corticosteroid-dependent asthma is severe asthma.
段落18. 如段落1至17中任一項所述之方法，其中該皮質類固醇依賴性氣喘為口服皮質類固醇依賴性氣喘。Paragraph 18. The method of any one of Paragraphs 1 to 17, wherein the corticosteroid-dependent asthma is oral corticosteroid-dependent asthma.
段落19. 如段落1至18中任一項所述之方法，其中該受試者為成人。Paragraph 19. The method of any one of Paragraphs 1 to 18, wherein the subject is an adult.
段落20. 如段落1至19中任一項所述之方法，其中該受試者為兒童或青少年。Paragraph 20. The method of any one of paragraphs 1 to 19, wherein the subject is a child or a teenager.
段落21. 如段落1至20中任一項所述之方法，其中該投與改善了選自由以下組成之群組的皮質類固醇依賴性氣喘的一或多種測量值：用力呼氣容積（FEV）、FEV1可逆性、用力肺活量（FVC）、FeNO、氣喘控制問卷（ACQ）-6得分和AQLQ(S)+12得分、BD前FEV1相對於基線的變化、每日維持OCS劑量相對於基線的減少、每日維持OCS劑量≤ 5 mg、以及每日維持OCS劑量相對於基線減少≥ 50%、藉由AAER測量的氣喘加重和首次氣喘加重的時間、與急診室（ER）就診、緊急護理就診或住院相關的氣喘加重率、以及未經歷氣喘加重的參與者比例、每週平均居家PEF（早晚）、腎上腺功能不全和/或聖喬治呼吸問卷（SGRQ）得分。Paragraph 21. The method of any of paragraphs 1 to 20, wherein the administration improves one or more measures of corticosteroid-dependent asthma selected from the group consisting of: forced expiratory volume (FEV1),FEV1 reversibility, forced vital capacity (FVC), FeNO, Asthma Control Questionnaire (ACQ)-6 score and AQLQ(S)+12 score, change from baseline in pre-BD FEV1, reduction in daily maintenance OCS dose from baseline, daily maintenance OCS dose ≤ 5 mg, and daily maintenance OCS dose reduction from baseline ≥ 50%, time to first asthma exacerbation and first asthma exacerbation as measured by AAER, rate of asthma exacerbations associated with emergency room (ER) visits, urgent care visits, or hospitalizations, and proportion of participants experiencing no asthma exacerbations, mean weekly home PEF (morning and evening), adrenal insufficiency, and/or St. George's Respiratory Questionnaire (SGRQ) score.
段落22. 如段落1至21中任一項所述之方法，其中該投與改善了藉由患者症狀日記測量的皮質類固醇依賴性氣喘的一或多種症狀。Paragraph 22. The method of any of Paragraphs 1 to 21, wherein the administration improves one or more symptoms of corticosteroid-dependent asthma as measured by a patient symptom diary.
段落23. 如段落1至22中任一項所述之方法，其中該抗體每4週投與一次。Paragraph 23. The method of any one of paragraphs 1 to 22, wherein the antibody is administered once every 4 weeks.
段落24. 如段落1至23中任一項所述之方法，其中該抗體係泰派魯單抗。Paragraph 24. The method of any one of Paragraphs 1 to 23, wherein the antibody is teprenolomab.
段落25. 如段落24所述之方法，其中該抗體係IgG2抗體，並且具有分別在SEQ ID NO: 13和14中列出的全長重鏈和輕鏈序列。Paragraph 25. The method of paragraph 24, wherein the antibody is an IgG2 antibody and has the full-length heavy chain and light chain sequences set forth in SEQ ID NOs: 13 and 14, respectively.
段落26. 如段落1至25中任一項所述之方法，其中該抗體變體在人類中具有與泰派魯單抗-ekko基本上相似的pK特徵。Paragraph 26. The method of any one of paragraphs 1 to 25, wherein the antibody variant has a pK profile substantially similar to that of teplumab-ekko in humans.
段落27. 一種降低皮質類固醇依賴性氣喘受試者的氣喘加重頻率之方法，該方法包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，其含有： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，其含有： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗原結合蛋白特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 27. A method for reducing the frequency of asthma exacerbations in a subject with corticosteroid-dependent asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at intervals of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprisesa. a light chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;NO:6; ii. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antigen binding protein specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2.
段落28. 一種降低皮質類固醇依賴性氣喘受試者的氣喘加重頻率之方法，該方法包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域。Paragraph 28. A method for reducing the frequency of asthma exacerbations in a subject with corticosteroid-dependent asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprisesa. a light chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; andb. A heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:10;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).
段落29. 如段落27或28所述之方法，其中該輕鏈可變結構域在SEQ ID NO:12中列出，並且該重鏈可變結構域在SEQ ID NO:10中列出。Paragraph 29. The method of paragraph 27 or 28, wherein the light chain variable domain is set forth in SEQ ID NO:12, and the heavy chain variable domain is set forth in SEQ ID NO:10.
段落30. 如段落27至29中任一項所述之方法，其中該抗體或抗體變體每4週投與一次。Paragraph 30. The method of any one of paragraphs 27 to 29, wherein the antibody or antibody variant is administered once every 4 weeks.
段落31. 如段落27至30中任一項所述之方法，其中該抗體或抗體變體以210 mg的劑量投與。Paragraph 31. The method of any one of paragraphs 27 to 30, wherein the antibody or antibody variant is administered in a dose of 210 mg.
段落32. 如段落27至31中任一項所述之方法，其中該抗體或抗體變體投與至少4個月、6個月、9個月、1年、2年或更長時間的時期。Paragraph 32. The method of any one of paragraphs 27 to 31, wherein the antibody or antibody variant is administered for a period of at least 4 months, 6 months, 9 months, 1 year, 2 years or longer.
段落33. 如段落27至32中任一項所述之方法，其中所述抗TSLP抗體或抗體變體選自由人抗體、人源化抗體、嵌合抗體、單株抗體、重組抗體、IgG1抗體、IgG2抗體、IgG3抗體和IgG4抗體組成之群組。Paragraph 33. The method as described in any one of paragraphs 27 to 32, wherein the anti-TSLP antibody or antibody variant is selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies and IgG4 antibodies.
段落34. 如段落27至33中任一項所述之方法，其中該抗體或抗體變體係IgG2抗體。Paragraph 34. The method of any one of paragraphs 27 to 33, wherein the antibody or antibody variant is an IgG2 antibody.
段落35. 如段落27至34中任一項所述之方法，其中該抗體或抗體變體係人抗體。Paragraph 35. The method of any one of paragraphs 27 to 34, wherein the antibody or antibody variant is a human antibody.
段落36. 如段落27至35中任一項所述之方法，其中該抗體係泰派魯單抗。Paragraph 36. The method of any one of paragraphs 27 to 35, wherein the antibody is teprenolomab.
段落37. 如段落27至36中任一項所述之方法，其中該抗體或抗體變體在包含藥學上可接受的載劑或賦形劑的藥物組成物中投與給該受試者。Paragraph 37. The method of any one of paragraphs 27 to 36, wherein the antibody or antibody variant is administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.
段落38. 如段落27至37中任一項所述之方法，其中與未接受抗TSLP抗體的受試者相比，該投與延遲了氣喘加重的時間。Paragraph 38. The method of any of Paragraphs 27 to 37, wherein the administration delays the time to asthma exacerbations compared to a subject not receiving the anti-TSLP antibody.
段落39. 如段落27至38中任一項所述之方法，其中該投與降低受試者共投與療法的頻率或水平。Paragraph 39. The method of any of paragraphs 27 to 38, wherein the administration reduces the frequency or level of a co-administered therapy to the subject.
段落40. 如段落39所述之方法，其中該投與消除對口服皮質類固醇療法或吸入性皮質類固醇療法的需要。Paragraph 40. The method of paragraph 39, wherein the administration eliminates the need for oral corticosteroid therapy or inhaled corticosteroid therapy.
段落41. 如段落27至40中任一項所述之方法，其中該方法包括減少受試者在治療之減少階段接受的皮質類固醇的劑量，並使該受試者保持皮質類固醇的維持劑量。Paragraph 41. The method of any of paragraphs 27 to 40, wherein the method comprises reducing the dose of corticosteroid received by the subject during the taper phase of treatment and maintaining the subject on a maintenance dose of corticosteroid.
段落42. 如段落41所述之方法，其中皮質類固醇的劑量每4週減少一次，持續約20週。Paragraph 42. The method of Paragraph 41, wherein the dose of the corticosteroid is reduced every 4 weeks for about 20 weeks.
段落43. 如段落41或42所述之方法，其中皮質類固醇的劑量減少5 mg/天或2.5 mg/天。Paragraph 43. The method of paragraph 41 or 42, wherein the dose of the corticosteroid is reduced by 5 mg/day or 2.5 mg/day.
段落44. 一種在患有氣喘的受試者中消除口服皮質類固醇需求之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體至少2年，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，其含有： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，其含有： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗原結合蛋白特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 44. A method for eliminating the need for oral corticosteroids in a subject suffering from asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks for at least 2 years, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprisesa. a light chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6;ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6;ii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:7, andiii. A heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antigen binding protein specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2.
段落45. 一種在患有氣喘的受試者中消除口服皮質類固醇需求之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體至少2年，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域。Paragraph 45. A method of eliminating the need for oral corticosteroids in a subject suffering from asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks for at least 2 years, wherein both binding sites of the antibody have identical binding to TSLP, and the antibody comprisesa. A light chain variable domain selected from the group consisting of:i. An amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. An amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11; andb. A heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:10;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).
段落46. 一種在患有氣喘的受試者中將每日維持口服皮質類固醇的量減少至≤ 5 mg/天之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體至少2年，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，該輕鏈可變結構域包含： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，該重鏈可變結構域包含： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗原結合蛋白特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 46. A method for reducing the daily maintenance oral corticosteroid to ≤ 5 mg/day in a subject with asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks for at least 2 years, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprisesa. A light chain variable domain, the light chain variable domain comprising:i. A light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. A light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. A light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. A heavy chain variable domain, the heavy chain variable domain comprising:i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6;ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:7, andiii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antigen binding protein specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
段落47. 一種在患有氣喘的受試者中將每日維持口服皮質類固醇的量減少至≤ 5 mg/天之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體至少2年，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域。Paragraph 47. A method for reducing the daily maintenance oral corticosteroid to ≤ 5 mg/day in a subject with asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every 4 weeks for at least 2 years, wherein both binding sites of the antibody have identical binding to TSLP, and the antibody comprisesa. a light chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide that hybridizes with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; andb. A heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:10;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).
段落48. 如段落44至47中任一項所述之方法，其中該輕鏈可變結構域在SEQ ID NO:12中列出，並且該重鏈可變結構域在SEQ ID NO:10中列出。Paragraph 48. The method of any one of paragraphs 44 to 47, wherein the light chain variable domain is set forth in SEQ ID NO:12 and the heavy chain variable domain is set forth in SEQ ID NO:10.
段落49. 如段落27至48中任一項所述之方法，其中該抗TSLP抗體係泰派魯單抗。Paragraph 49. The method of any one of paragraphs 27 to 48, wherein the anti-TSLP antibody is teprenolumab.
段落50. 如段落49所述之方法，其中該抗體係IgG2抗體，並且具有分別在SEQ ID NO: 13和14中列出的全長重鏈和輕鏈序列。Paragraph 50. The method of paragraph 49, wherein the antibody is an IgG2 antibody and has the full-length heavy chain and light chain sequences set forth in SEQ ID NOs: 13 and 14, respectively.
段落51. 如段落27至50中任一項所述之方法，其中該受試者患有口服皮質類固醇依賴性氣喘。Paragraph 51. The method of any one of paragraphs 27 to 50, wherein the subject suffers from oral corticosteroid-dependent asthma.
段落52. 如段落1至51中任一項所述之方法，其中該投與為皮下或靜脈內。Paragraph 52. The method of any one of paragraphs 1 to 51, wherein the administration is subcutaneous or intravenous.
段落53. 一種治療受試者之皮質類固醇依賴性氣喘的抗TSLP抗體或抗體變體，其包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，其含有： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，其含有： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽，其中該抗體為IgG2抗體。Paragraph 53. An anti-TSLP antibody or antibody variant for treating corticosteroid-dependent asthma in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant to the subject at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprisesa. a light chain variable domain, which contains:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain, which contains:i. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain, which contains:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;NO:6;ii. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:7; andiii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2, wherein the antibody is an IgG2 antibody.
段落54. 一種治療受試者之皮質類固醇依賴性氣喘的抗TSLP抗體或抗體變體，其包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 54. An anti-TSLP antibody or antibody variant for treating corticosteroid-dependent asthma in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant to the subject at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprisesa. a light chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; andb. a heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:10;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
段落55. 抗TSLP抗體或抗體變體在製備用於治療受試者之皮質類固醇依賴性氣喘的藥物中之用途，其包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，其含有： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，其含有： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽，其中該抗體為IgG2抗體。Paragraph 55. Use of an anti-TSLP antibody or antibody variant in the preparation of a medicament for treating corticosteroid-dependent asthma in a subject, comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprisesa. a light chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;NO:6;ii. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:7; andiii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2, wherein the antibody is an IgG2 antibody.
段落56. 抗TSLP抗體或抗體變體在製備用於治療受試者之皮質類固醇依賴性氣喘的藥物中之用途，其包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體之兩個結合位點與TSLP具有相同的結合，並且該抗體包含 a. 輕鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 56. Use of an anti-TSLP antibody or antibody variant in the preparation of a medicament for treating corticosteroid-dependent asthma in a subject, comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprisesa. a light chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence having at least 80% identity with SEQ ID NO:12 under moderately stringent conditions; NO:11; andb. a heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:10;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
段落57. 如段落53至56中任一項所述使用的抗體或抗體變體或用途，其中該輕鏈可變結構域在SEQ ID NO:12中列出，並且該重鏈可變結構域在SEQ ID NO:10中列出。Paragraph 57. The antibody or antibody variant for use or use as described in any one of paragraphs 53 to 56, wherein the light chain variable domain is set forth in SEQ ID NO: 12 and the heavy chain variable domain is set forth in SEQ ID NO: 10.
段落58. 如段落53至57中任一項所述使用的抗體或抗體變體或用途，其中該抗體或抗體變體每2週或每4週投與一次。Paragraph 58. The antibody or antibody variant for use or the use as described in any one of paragraphs 53 to 57, wherein the antibody or antibody variant is administered once every 2 weeks or every 4 weeks.
段落59. 如段落53至58中任一項所述使用的抗體或抗體變體或用途，其中該抗體係IgG2抗體。Paragraph 59. The antibody or antibody variant for use or use as described in any one of paragraphs 53 to 58, wherein the antibody is an IgG2 antibody.
段落60. 如段落53至59中任一項所述使用的抗體或抗體變體或用途，其中該抗體或抗體變體以210 mg的劑量投與。Paragraph 60. The antibody or antibody variant for use or the use as described in any one of paragraphs 53 to 59, wherein the antibody or antibody variant is administered in a dose of 210 mg.
段落61. 如段落53至60中任一項所述使用的抗體或抗體變體或用途，其中該抗體係泰派魯單抗。Paragraph 61. The antibody or antibody variant for use or the use as described in any one of Paragraphs 53 to 60, wherein the antibody is teprenolomab.
段落62. 如段落53至61中任一項所述使用的抗體或抗體變體或用途，其中該輕鏈可變結構域在SEQ ID NO:12中列出，並且該重鏈可變結構域在SEQ ID NO:10中列出。Paragraph 62. The antibody or antibody variant for use or use as described in any one of paragraphs 53 to 61, wherein the light chain variable domain is set forth in SEQ ID NO: 12 and the heavy chain variable domain is set forth in SEQ ID NO: 10.
段落63. 如段落53至62中任一項所述使用的抗體或抗體變體或用途，其中該抗體或抗體變體每2週或每4週投與一次。Paragraph 63. The antibody or antibody variant for use or the use as described in any one of paragraphs 53 to 62, wherein the antibody or antibody variant is administered once every 2 weeks or every 4 weeks.
段落64. 如段落53至63中任一項所述使用的抗體或抗體變體或用途，其中該抗體係IgG2抗體。Paragraph 64. The antibody or antibody variant for use or use as described in any one of paragraphs 53 to 63, wherein the antibody is an IgG2 antibody.
段落65. 如段落53至64中任一項所述使用的抗體或抗體變體或用途，其中該抗體或抗體變體以210 mg的劑量投與。Paragraph 65. The antibody or antibody variant for use or the use as described in any one of paragraphs 53 to 64, wherein the antibody or antibody variant is administered in a dose of 210 mg.
段落66. 如段落53至65中任一項所述使用的抗體或抗體變體或用途，其中該抗體係泰派魯單抗。Paragraph 66. The antibody or antibody variant for use or the use as described in any one of Paragraphs 53 to 65, wherein the antibody is teprenolomab.
段落67. 一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP，其中該抗體包含 a. 輕鏈可變結構域，其含有： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，其含有： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽，其中該抗體為IgG2抗體。Paragraph 67. A method for treating corticosteroid-dependent asthma in a subject, the method comprising administering to the subject a therapeutically effective amount of anti-TSLP at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the antibody comprisesa. a light chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6;ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. NO:7, andiii. A heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2, wherein the antibody is an IgG2 antibody.
段落68. 一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體，其中該抗體包含 a. 輕鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 68. A method for treating corticosteroid-dependent asthma in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the antibody comprisesa. a light chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; andb. a heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; and NO:10 has at least 80% identity;ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. An amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. The light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
段落69. 如段落67或68所述之方法，其中該輕鏈可變結構域在SEQ ID NO:12中列出，並且該重鏈可變結構域在SEQ ID NO:10中列出。Paragraph 69. The method of paragraph 67 or 68, wherein the light chain variable domain is set forth in SEQ ID NO:12, and the heavy chain variable domain is set forth in SEQ ID NO:10.
段落70. 如段落67至69中任一項所述之方法，其中該抗體每2週或每4週投與一次。Paragraph 70. The method of any one of paragraphs 67 to 69, wherein the antibody is administered once every 2 weeks or every 4 weeks.
段落71. 如段落67至70中任一項所述之方法，其中該抗體係IgG2抗體。Paragraph 71. The method of any one of paragraphs 67 to 70, wherein the antibody is an IgG2 antibody.
段落72. 如段落67至71中任一項所述之方法，其中該抗體以210 mg的劑量投與。Paragraph 72. The method of any one of paragraphs 67 to 71, wherein the antibody is administered in a dose of 210 mg.
段落73. 如段落67至72中任一項所述之方法，其中該抗體係泰派魯單抗。Paragraph 73. The method of any one of paragraphs 67 to 72, wherein the antibody is teprenolomab.
段落74. 一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體，其中該抗體包含 a. 輕鏈可變結構域，其含有： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，其含有： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 74. A method for treating corticosteroid-dependent asthma in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody at a dose of 210 mg every 4 weeks, wherein the antibody comprisesa. a light chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6;ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:7, andiii. a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8. A heavy chain CDR3 sequence of the amino acid sequence shown in ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2.
段落75. 一種治療受試者之皮質類固醇依賴性氣喘之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體，其中該抗體包含 a. 輕鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 75. A method for treating corticosteroid-dependent asthma in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody at a dose of 210 mg every 4 weeks, wherein the antibody comprisesa. a light chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide that hybridizes with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; andb. a heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide that hybridizes with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; and NO:10 has at least 80% identity;ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. An amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. The light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to the TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
段落76. 如段落74或75所述之方法，其中該輕鏈可變結構域在SEQ ID NO:12中列出，並且該重鏈可變結構域在SEQ ID NO:10中列出。Paragraph 76. The method of paragraph 74 or 75, wherein the light chain variable domain is set forth in SEQ ID NO:12, and the heavy chain variable domain is set forth in SEQ ID NO:10.
段落77. 如段落67至76中任一項所述之方法，其中該抗體投與至少4個月、6個月、9個月、1年、2年或更長時間的時期。Paragraph 77. The method of any one of paragraphs 67 to 76, wherein the antibody is administered for a period of at least 4 months, 6 months, 9 months, 1 year, 2 years or longer.
段落78. 如段落67至77中任一項所述之方法，其中所述抗TSLP抗體為二價的並選自由人抗體、人源化抗體、嵌合抗體、單株抗體、重組抗體、IgG1抗體、IgG2抗體、IgG3抗體和IgG4抗體組成之群組。Paragraph 78. The method of any one of paragraphs 67 to 77, wherein the anti-TSLP antibody is bivalent and is selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies and IgG4 antibodies.
段落79. 如段落74至78中任一項所述之方法，其中該抗體係IgG2抗體。Paragraph 79. The method of any one of paragraphs 74 to 78, wherein the antibody is an IgG2 antibody.
段落80. 如段落74至79中任一項所述之方法，其中該抗體係泰派魯單抗。Paragraph 80. The method of any one of paragraphs 74 to 79, wherein the antibody is teprenolomab.
段落81. 如段落67至80中任一項所述之方法，其中該抗體係人抗體。Paragraph 81. The method of any one of paragraphs 67 to 80, wherein the antibody is a human antibody.
段落82. 如段落67至81中任一項所述之方法，其中該抗體在包含藥學上可接受的載劑或賦形劑的藥物組成物中投與給該受試者。Paragraph 82. The method of any one of paragraphs 67 to 81, wherein the antibody is administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.
段落83. 如段落67至82中任一項所述之方法，其中該皮質類固醇依賴性氣喘為重度氣喘。Paragraph 83. The method of any one of paragraphs 67 to 82, wherein the corticosteroid-dependent asthma is severe asthma.
段落84. 如段落67至83中任一項所述之方法，其中該皮質類固醇依賴性氣喘為口服皮質類固醇依賴性氣喘。Paragraph 84. The method of any one of paragraphs 67 to 83, wherein the corticosteroid-dependent asthma is oral corticosteroid-dependent asthma.
段落85. 如段落67至84中任一項所述之方法，其中該受試者為成人。Paragraph 85. The method of any one of paragraphs 67 to 84, wherein the subject is an adult.
段落86. 如段落67至85中任一項所述之方法，其中該受試者為兒童或青少年。Paragraph 86. The method of any one of paragraphs 67 to 85, wherein the subject is a child or a teenager.
段落87. 如段落67至86中任一項所述之方法，其中該投與改善了選自由以下組成之群組的皮質類固醇依賴性氣喘的一或多種測量值：用力呼氣容積（FEV）、FEV1可逆性、用力肺活量（FVC）、FeNO、氣喘控制問卷（ACQ）-6得分和AQLQ(S)+12得分、BD前FEV1相對於基線的變化、每日維持OCS劑量相對於基線的減少、每日維持OCS劑量≤ 5 mg、以及每日維持OCS劑量相對於基線減少≥ 50%、藉由AAER測量的氣喘加重和首次氣喘加重的時間、與急診室（ER）就診、緊急護理就診或住院相關的氣喘加重率、以及未經歷氣喘加重的參與者比例、每週平均居家PEF（早晚）、腎上腺功能不全和/或聖喬治呼吸問卷（SGRQ）得分。Paragraph 87. The method of any of paragraphs 67 to 86, wherein the administration improves one or more measures of corticosteroid-dependent asthma selected from the group consisting of forced expiratory volume (FEV1),FEV1 reversibility, forced vital capacity (FVC), FeNO, Asthma Control Questionnaire (ACQ)-6 score and AQLQ(S)+12 score, change from baseline in pre-BDFEV1 , reduction in daily maintenance OCS dose from baseline, daily maintenance OCS dose ≤ 5 mg, and daily maintenance OCS dose reduction from baseline ≥ 50%, time to first asthma exacerbation and first asthma exacerbation as measured by AAER, rate of asthma exacerbations associated with emergency room (ER) visits, urgent care visits, or hospitalizations, and proportion of participants experiencing no asthma exacerbations, mean weekly home PEF (morning and evening), adrenal insufficiency, and/or St. George's Respiratory Questionnaire (SGRQ) score.
段落88. 如段落67至87中任一項所述之方法，其中該投與改善了藉由患者症狀日記測量的皮質類固醇依賴性氣喘的一或多種症狀。Paragraph 88. The method of any of paragraphs 67 to 87, wherein the administration improves one or more symptoms of corticosteroid-dependent asthma as measured by a patient symptom diary.
段落89. 如段落67至88中任一項所述之方法，其中該抗體每4週投與一次。Paragraph 89. The method of any one of paragraphs 67 to 88, wherein the antibody is administered once every 4 weeks.
段落90. 如段落67至89中任一項所述之方法，其中該抗體係泰派魯單抗。Paragraph 90. The method of any one of paragraphs 67 to 89, wherein the antibody is teprenolomab.
段落91. 如段落90所述之方法，其中該抗體係IgG2抗體，並且具有分別在SEQ ID NO: 13和14中列出的全長重鏈和輕鏈序列。Paragraph 91. The method of paragraph 90, wherein the antibody is an IgG2 antibody and has the full-length heavy chain and light chain sequences listed in SEQ ID NOs: 13 and 14, respectively.
段落92. 如段落67至91中任一項所述之方法，其中該抗體變體在人類中具有與泰派魯單抗-ekko基本上相似的pK特徵。Paragraph 92. A method as described in any of paragraphs 67 to 91, wherein the antibody variant has a pK profile substantially similar to that of teplumab-ekko in humans.
段落93. 一種降低皮質類固醇依賴性氣喘受試者的氣喘加重頻率之方法，該方法包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體，其中該抗體包含 a. 輕鏈可變結構域，其含有： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，其含有： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗原結合蛋白特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 93. A method for reducing the frequency of asthma exacerbations in a subject with corticosteroid-dependent asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody at intervals of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the antibody comprisesa. a light chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6;ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. NO:7, andiii. A heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antigen binding protein specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2.
段落94. 一種降低皮質類固醇依賴性氣喘受試者的氣喘加重頻率之方法，該方法包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體，其中該抗體包含 a. 輕鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域。Paragraph 94. A method for reducing the frequency of asthma exacerbations in a subject with corticosteroid-dependent asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the antibody comprisesa. a light chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide that hybridizes with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; andb. a heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide that hybridizes with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; and ID NO:10;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b).
段落95. 如段落93或94所述之方法，其中該輕鏈可變結構域在SEQ ID NO:12中列出，並且該重鏈可變結構域在SEQ ID NO:10中列出。Paragraph 95. The method of paragraph 93 or 94, wherein the light chain variable domain is set forth in SEQ ID NO:12 and the heavy chain variable domain is set forth in SEQ ID NO:10.
段落96. 如段落93至95中任一項所述之方法，其中該抗體每4週投與一次。Paragraph 96. The method of any one of paragraphs 93 to 95, wherein the antibody is administered once every 4 weeks.
段落97. 如段落93至96中任一項所述之方法，其中該抗體以210 mg的劑量投與。Paragraph 97. The method of any one of paragraphs 93 to 96, wherein the antibody is administered in a dose of 210 mg.
段落98. 如段落93至97中任一項所述之方法，其中該抗體投與至少4個月、6個月、9個月、1年、2年或更長時間的時期。Paragraph 98. The method of any one of paragraphs 93 to 97, wherein the antibody is administered for a period of at least 4 months, 6 months, 9 months, 1 year, 2 years or longer.
段落99. 如段落93至98中任一項所述之方法，其中所述抗TSLP抗體選自由人抗體、人源化抗體、嵌合抗體、單株抗體、重組抗體、IgG1抗體、IgG2抗體、IgG3抗體和IgG4抗體組成之群組。Paragraph 99. The method as described in any one of paragraphs 93 to 98, wherein the anti-TSLP antibody is selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies and IgG4 antibodies.
段落100. 如段落93至99中任一項所述之方法，其中該抗體係IgG2抗體。Paragraph 100. The method of any of paragraphs 93 to 99, wherein the antibody is an IgG2 antibody.
段落101. 如段落93至100中任一項所述之方法，其中該抗體係人抗體。Paragraph 101. A method as described in any of paragraphs 93 to 100, wherein the antibody is a human antibody.
段落102. 如段落93至101中任一項所述之方法，其中該抗體係泰派魯單抗。Paragraph 102. The method of any of paragraphs 93 to 101, wherein the antibody is teprenolomab.
段落103. 如段落93至102中任一項所述之方法，其中該抗體在包含藥學上可接受的載劑或賦形劑的藥物組成物中投與給該受試者。Paragraph 103. The method of any of paragraphs 93 to 102, wherein the antibody is administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.
段落104. 如段落93至103中任一項所述之方法，其中與未接受抗TSLP抗體的受試者相比，該投與延遲了氣喘加重的時間。Paragraph 104. The method of any of paragraphs 93 to 103, wherein the administration delays the time to asthma exacerbations compared to a subject not receiving the anti-TSLP antibody.
段落105. 如段落93至104中任一項所述之方法，其中該投與降低受試者共投與療法的頻率或水平。Paragraph 105. The method of any of paragraphs 93 to 104, wherein the administration reduces the frequency or level of a co-administered therapy to the subject.
段落106. 如段落105所述之方法，其中該投與消除對口服皮質類固醇療法或吸入性皮質類固醇療法的需要。Paragraph 106. The method of paragraph 105, wherein the administration eliminates the need for oral corticosteroid therapy or inhaled corticosteroid therapy.
段落107. 如段落93至106中任一項所述之方法，其中該方法包括減少受試者在治療之減少階段接受的皮質類固醇的劑量，並使該受試者保持皮質類固醇的維持劑量。Paragraph 107. The method of any of paragraphs 93 to 106, wherein the method comprises reducing the dose of corticosteroid received by the subject during the taper phase of treatment and maintaining the subject on a maintenance dose of corticosteroid.
段落108. 如段落107所述之方法，其中皮質類固醇的劑量每4週減少一次，持續約20週。Paragraph 108. The method of paragraph 107, wherein the dose of the corticosteroid is reduced every 4 weeks for about 20 weeks.
段落109. 如段落107或108所述之方法，其中皮質類固醇的劑量減少5 mg/天或2.5 mg/天。Paragraph 109. The method of paragraphs 107 or 108, wherein the dose of the corticosteroid is reduced by 5 mg/day or 2.5 mg/day.
段落110. 一種在患有氣喘的受試者中消除口服皮質類固醇需求之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體至少2年，其中該抗體包含 a. 輕鏈可變結構域，其含有： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，其含有： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗原結合蛋白特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 110. A method of eliminating the need for oral corticosteroids in a subject suffering from asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody at a dose of 210 mg every 4 weeks for at least 2 years, wherein the antibody comprisesa. a light chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6;ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, andiii. A heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antigen binding protein specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2.
段落111. 一種在患有氣喘的受試者中消除口服皮質類固醇需求之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體至少2年，其中該抗體包含 a. 輕鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域。Paragraph 111. A method of eliminating the need for oral corticosteroids in a subject suffering from asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody at a dose of 210 mg every 4 weeks for at least 2 years, wherein the antibody comprisesa. a light chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide hybridized under moderately stringent conditions with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11; andb. a heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11; NO:10 has at least 80% identity;ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. An amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. The light chain variable domain of (a) and the heavy chain variable domain of (b).
段落112. 一種在患有氣喘的受試者中將每日維持口服皮質類固醇的量減少至≤ 5 mg/天之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體至少2年，其中該抗體包含 a. 輕鏈可變結構域，其含有： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，其含有： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗原結合蛋白特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 112. A method for reducing the daily maintenance oral corticosteroid to ≤ 5 mg/day in a subject suffering from asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody at a dose of 210 mg every 4 weeks for at least 2 years, wherein the antibody comprisesa. a light chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6;ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6;ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4; NO:7, andiii. A heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antigen binding protein specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2.
段落113. 一種在患有氣喘的受試者中將每日維持口服皮質類固醇的量減少至≤ 5 mg/天之方法，該方法包括以210 mg的劑量每4週間隔向該受試者投與治療有效量的抗TSLP抗體至少2年，該抗體包含輕鏈可變結構域，其選自由以下組成之群組： a. 輕鏈可變結構域，其含有： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域。Paragraph 113. A method of reducing the daily maintenance oral corticosteroid to ≤ 5 mg/day in a subject suffering from asthma, the method comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody at a dose of 210 mg every 4 weeks for at least 2 years, the antibody comprising a light chain variable domain selected from the group consisting of:a. a light chain variable domain containing:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide that hybridizes with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; andb. A heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:10;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).
段落114. 如段落110至113中任一項所述之方法，其中該輕鏈可變結構域在SEQ ID NO:12中列出，並且該重鏈可變結構域在SEQ ID NO:10中列出。Paragraph 114. The method of any one of paragraphs 110 to 113, wherein the light chain variable domain is listed in SEQ ID NO:12 and the heavy chain variable domain is listed in SEQ ID NO:10.
段落115. 如段落110至114中任一項所述之方法，其中該抗TSLP抗體係泰派魯單抗。Paragraph 115. The method of any of paragraphs 110 to 114, wherein the anti-TSLP antibody is teprenolomab.
段落116. 如段落115所述之方法，其中該抗體係IgG2抗體，並且具有分別在SEQ ID NO: 13和14中列出的全長重鏈和輕鏈序列。Paragraph 116. The method as described in paragraph 115, wherein the antibody is an IgG2 antibody and has the full-length heavy chain and light chain sequences listed in SEQ ID NO: 13 and 14, respectively.
段落117. 如段落110至116中任一項所述之方法，其中該受試者患有口服皮質類固醇依賴性氣喘。Paragraph 117. The method of any of paragraphs 110 to 116, wherein the subject suffers from oral corticosteroid-dependent asthma.
段落118. 如段落110至117中任一項所述之方法，其中該投與為皮下或靜脈內。Paragraph 118. The method of any of paragraphs 110 to 117, wherein the administration is subcutaneous or intravenous.
段落119. 一種治療受試者之皮質類固醇依賴性氣喘的抗TSLP抗體，其包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體包含 a. 輕鏈可變結構域，其含有： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，其含有： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽，其中該抗體為IgG2抗體。Paragraph 119. An anti-TSLP antibody for treating corticosteroid-dependent asthma in a subject, comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the antibody comprisesa. a light chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6;ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. NO:7, andiii. A heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2, wherein the antibody is an IgG2 antibody.
段落120. 一種治療受試者之皮質類固醇依賴性氣喘的抗TSLP抗體，其包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體或抗體變體，其中該抗體包含 a. 輕鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 120. An anti-TSLP antibody for treating corticosteroid-dependent asthma in a subject, comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the antibody comprisesa. a light chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; andb. A heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:10;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
段落121. 抗TSLP抗體在製備用於治療受試者之皮質類固醇依賴性氣喘的藥物中之用途，其包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體，其中該抗體包含 a. 輕鏈可變結構域，其含有： i. 包含SEQ ID NO:3所示的胺基酸序列之輕鏈CDR1序列； ii. 包含SEQ ID NO:4所示的胺基酸序列之輕鏈CDR2序列； iii. 包含SEQ ID NO:5所示的胺基酸序列之輕鏈CDR3序列；和 b. 重鏈可變結構域，其含有： i. 包含SEQ ID NO:6所示的胺基酸序列之重鏈CDR1序列； ii. 包含SEQ ID NO:7所示的胺基酸序列之重鏈CDR2序列，和 iii. 包含SEQ ID NO:8所示的胺基酸序列之重鏈CDR3序列，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽，其中該抗體為IgG2抗體。Paragraph 121. Use of an anti-TSLP antibody in the preparation of a medicament for treating corticosteroid-dependent asthma in a subject, comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody at a dose of 140 mg to 420 mg every 2 weeks or every 4 weeks, wherein the antibody comprisesa. a light chain variable domain comprising:i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:3;ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. a heavy chain variable domain comprising:i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO:6;ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:4;iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO:5; andb. NO:7, andiii. A heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:2, wherein the antibody is an IgG2 antibody.
段落122. 抗TSLP抗體在製備用於治療受試者之皮質類固醇依賴性氣喘的藥物中之用途，其包括以140 mg至420 mg的劑量每2週或每4週間隔向該受試者投與治療有效量的抗TSLP抗體，其中該抗體包含 a. 輕鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:12具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:11具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:11組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；和 b. 重鏈可變結構域，其選自由以下組成之群組： i. 與SEQ ID NO:10具有至少80%同一性的胺基酸序列； ii. 由與SEQ ID NO:9具有至少80%同一性的多核苷酸序列編碼的胺基酸序列； iii. 由在中等嚴格條件下與由SEQ ID NO:9組成的多核苷酸的互補序列雜交的多核苷酸編碼的胺基酸序列；或c. (a) 的輕鏈可變結構域和 (b) 的重鏈可變結構域，其中該抗體特異性地結合如SEQ ID NO:2的胺基酸29-159所示的TSLP多肽。Paragraph 122. Use of an anti-TSLP antibody in the preparation of a medicament for treating corticosteroid-dependent asthma in a subject, comprising administering to the subject a therapeutically effective amount of an anti-TSLP antibody at a dose of 140 mg to 420 mg at intervals of every 2 weeks or every 4 weeks, wherein the antibody comprisesa. a light chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:12;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:11;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:11 under moderately stringent conditions; andb. A heavy chain variable domain selected from the group consisting of:i. an amino acid sequence having at least 80% identity with SEQ ID NO:10;ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO:9;iii. an amino acid sequence encoded by a polynucleotide hybridized with a complementary sequence of a polynucleotide consisting of SEQ ID NO:9 under moderately stringent conditions; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide as shown in amino acids 29-159 of SEQ ID NO:2.
段落123. 如段落119至122中任一項所述使用的抗體或用途，其中該輕鏈可變結構域在SEQ ID NO:12中列出，並且該重鏈可變結構域在SEQ ID NO:10中列出。Paragraph 123. The antibody for use or the use as described in any one of paragraphs 119 to 122, wherein the light chain variable domain is listed in SEQ ID NO:12 and the heavy chain variable domain is listed in SEQ ID NO:10.
段落124. 如段落119至123中任一項所述使用的抗體或用途，其中該抗體每2週或每4週投與一次。Paragraph 124. The antibody for use or the use as described in any of paragraphs 119 to 123, wherein the antibody is administered once every 2 weeks or every 4 weeks.
段落125. 如段落119至124中任一項所述使用的抗體或用途，其中該抗體係IgG2抗體。Paragraph 125. The antibody for use or the use as described in any one of paragraphs 119 to 124, wherein the antibody is an IgG2 antibody.
段落126. 如段落119至125中任一項所述使用的抗體或用途，其中該抗體以210 mg的劑量投與。Paragraph 126. The antibody for use or the use as described in any of paragraphs 119 to 125, wherein the antibody is administered in a dose of 210 mg.
段落127. 如段落119至126中任一項所述使用的抗體或用途，其中該抗體係泰派魯單抗。Paragraph 127. The antibody for use or the use as described in any of paragraphs 119 to 126, wherein the antibody is teprenolol.
段落128. 如段落119至127中任一項所述使用的抗體或用途，其中該輕鏈可變結構域在SEQ ID NO:12中列出，並且該重鏈可變結構域在SEQ ID NO:10中列出。Paragraph 128. The antibody for use or the use as described in any one of paragraphs 119 to 127, wherein the light chain variable domain is listed in SEQ ID NO:12 and the heavy chain variable domain is listed in SEQ ID NO:10.
段落129. 如段落119至128中任一項所述使用的抗體或用途，其中該抗體每2週或每4週投與一次。Paragraph 129. The antibody for use or the use as described in any of paragraphs 119 to 128, wherein the antibody is administered once every 2 weeks or every 4 weeks.
段落130. 如段落119至129中任一項所述使用的抗體或用途，其中該抗體係IgG2抗體。Paragraph 130. An antibody for use or a use as described in any one of paragraphs 119 to 129, wherein the antibody is an IgG2 antibody.
段落131. 如段落119至130中任一項所述使用的抗體或用途，其中該抗體以210 mg的劑量投與。Paragraph 131. The antibody for use or the use as described in any of paragraphs 119 to 130, wherein the antibody is administered in a dose of 210 mg.
段落132. 如段落119至131中任一項所述使用的抗體或用途，其中該抗體係泰派魯單抗。參考文獻Paragraph 132. The antibody for use or the use as described in any one of paragraphs 119 to 131, wherein the antibody is teprenolumab.
Alves et al, J Pediatr (Rio J). 2008;84(3):192-202.Alves et al, J Pediatr (Rio J). 2008;84(3):192-202.
Alving et al., Pulm Ther. 2017e;3(1):207-18.Alving et al., Pulm Ther. 2017e;3(1):207-18.
Bel et al., N Engl J Med. 2014;371:1189-1197.Bel et al., N Engl J Med. 2014;371:1189-1197.
CINQAIR US Prescribing Information 2020CINQAIR US Prescribing Information 2020
Corren et al., N Engl J Med. 2017 377(10):936-46.Corren et al., N Engl J Med. 2017 377(10):936-46.
Dalal et al., J Manag. Care Spec Pharm. 2016;22:833-47.Dalal et al., J Manag. Care Spec Pharm. 2016;22:833-47.
de Oliveira et al., Lipids Health Dis. 2011;10:11.de Oliveira et al., Lipids Health Dis. 2011;10:11.
Dinsen et al, Eur J Intern Med. 2013;24(8):714-20.Dinsen et al, Eur J Intern Med. 2013;24(8):714-20.
DUPIXENT (dupilumab). Prescribing information.DUPIXENT (dupilumab). Prescribing information.
FASENRA (benralizumab). Prescribing information.FASENRA (benralizumab). Prescribing information.
Froidure et al., Eur Resp J. 2016;47:304-19.Froidure et al., Eur Resp J. 2016;47:304-19.
Gauvreau et al., N Engl J Med. 2014; 370:2102-10.Gauvreau et al., N Engl J Med. 2014; 370:2102-10.
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA). Updated 2022.Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA). Updated 2022.
Globe et al., Health Qual Life Outcomes. 2015;13-21.Globe et al., Health Qual Life Outcomes. 2015;13-21.
Gounarides et al., Endocrinology. 2008;149(2):758–66.Gounarides et al., Endocrinology. 2008;149(2):758–66.
Graham et al., Am J Respir Crit Care Med. 2019; 200(8):e70-e88.Graham et al., Am J Respir Crit Care Med. 2019; 200(8):e70-e88.
Johansson et al., J Allergy Clin Immunol. 2004; 113(5): 832-6.Johansson et al., J Allergy Clin Immunol. 2004; 113(5): 832-6.
Johnson et al, J Clin Epidemiol. 2014;67(6):706-14.Johnson et al, J Clin Epidemiol. 2014;67(6):706-14.
Jones et al., The St George’s Respiratory Questionnaire. Respir Med. 1991;85 Suppl B:25-31.Jones et al., The St George’s Respiratory Questionnaire. Respir Med. 1991;85 Suppl B:25-31.
Jones et al., Eur Respir J 2009, 34: 648–654.Jones et al., Eur Respir J 2009, 34: 648–654.
Joseph et al, Semin Arthritis Rheum. 2016;46(1):133-41.Joseph et al, Semin Arthritis Rheum. 2016;46(1):133-41.
Juniper et al., Respir Med 2006;100: 616-21.Juniper et al., Respir Med 2006;100: 616-21.
Kaur and Brightling. Chest. 2012;141: 494-9.Kaur and Brightling. Chest. 2012;141: 494-9.
Kemp et al., Allergy. 2008;63(8):1061-70.Kemp et al., Allergy. 2008;63(8):1061-70.
Kroger et al., MMWR. 2011;60(2):1-64.Kroger et al., MMWR. 2011;60(2):1-64.
Lieberman et al., J Allergy Clin Immunol. 2010;126(3):477-80.e1-42.Lieberman et al., J Allergy Clin Immunol. 2010;126(3):477-80.e1-42.
Menzies-Gow et al., N Engl J Med. 2021;384(19):1800-1809.Menzies-Gow et al., N Engl J Med. 2021;384(19):1800-1809.
Nair et al., N Engl J Med. 2017 376(25):2448-58.Nair et al., N Engl J Med. 2017 376(25):2448-58.
Neogi et al, Arthritis Rheum.2010;62(9):2582-91.Neogi et al, Arthritis Rheum.2010;62(9):2582-91.
Nicholas et al, J Cutan Med Surg. 2018;22(2):175-81.Nicholas et al, J Cutan Med Surg. 2018;22(2):175-81.
NUCALA (mepolizumab). US Prescribing information.NUCALA (mepolizumab). US Prescribing information.
Rabe et al., N Engl J Med. 2018;378:2475-85.Rabe et al., N Engl J Med. 2018;378:2475-85.
Quanjer et al., Eur Respir J. 2012;40(6):1324-43.Quanjer et al., Eur Respir J. 2012;40(6):1324-43.
Sambrook et al., J Bone Miner Res. 1990;5(12):1211–16.Sambrook et al., J Bone Miner Res. 1990;5(12):1211–16.
Simpson et al., Respirology. 2006;11(1):54-61.Simpson et al., Respirology. 2006;11(1):54-61.
Swedin et al., Pharmacol Ther. 2017;169:13-34.Swedin et al., Pharmacol Ther. 2017;169:13-34.
Sweeney et al, Thorax 2016;71(4):339-46.Sweeney et al, Thorax 2016;71(4):339-46.
Tanaka et al., Clin Exp Allergy. 2009 Jan;39(1):89-100.Tanaka et al., Clin Exp Allergy. 2009 Jan;39(1):89-100.
Tedeschi et al 2018 Apr;70(4):571-81.Tedeschi et al 2018 Apr;70(4):571-81.
Watson and Gauvreau, Expert Opin Ther Targets. 2014;18:771-85.Watson and Gauvreau, Expert Opin Ther Targets. 2014;18:771-85.
Wechsler et al., Respir Res. 2020;21:264.Wechsler et al., Respir Res. 2020;21:264.
Wechsler et al., Lancet Respir Med 2022;10:650–60.Wechsler et al., Lancet Respir Med 2022;10:650–60.
Wenzel SE. Nat Med. 2012;18:716-25.Wenzel SE. Nat Med. 2012;18:716-25.
Wenzel SE. Am J Respir Cell Mol Molex Biol. 2016;55:1-4.Wenzel SE. Am J Respir Cell Mol Molex Biol. 2016;55:1-4.
XOLAIR (omalizumab). Prescribing information.XOLAIR (omalizumab). Prescribing information.
Ziegler et al., Adv Pharmacol. 2013;66:129-55.Ziegler et al., Adv Pharmacol. 2013;66:129-55.
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[圖1] 描述了口服皮質類固醇滴定方案。[Figure 1] depicts the oral corticosteroid titration regimen.
[圖2A和2B] 顯示了吸入性皮質類固醇的估計日劑量。圖2C顯示了估計的OCS劑量治療等效性。[Figures 2A and 2B] show the estimated daily dose of inhaled corticosteroids. Figure 2C shows the estimated therapeutic equivalence of OCS doses.
[圖3] 顯示了在DESTINATION研究中，最初來自NAVIGATOR和SOURCE的患者之每日OCS劑量隨時間相對於基線（第0週）的減少。[Figure 3] shows the reduction in daily OCS dose over time relative to baseline (week 0) for patients initially enrolled in NAVIGATOR and SOURCE in the DESTINATION study.
[圖4A-4B] 顯示了來自NAVIGATOR的患者（圖4A）和來自SOURCE的患者（圖4B）在第104週的泰派魯單抗和安慰劑組的平均每日OCS劑量。[Figures 4A-4B] Shown are the mean daily OCS doses at week 104 in the tepilumab and placebo groups for patients from NAVIGATOR (Figure 4A) and patients from SOURCE (Figure 4B).
[圖5].抗TSLP抗體泰派魯單抗的序列。[Figure 5]. Sequence of the anti-TSLP antibody teplumab.
[圖6] 描述了OCS減少和維持階段的示例OCS劑量滴定方案。[Figure 6] depicts an example OCS dose titration scheme during the OCS reduction and maintenance phases.
[圖7A] 顯示了接受維持OCS劑量≤ 5 mg/天的患者比例。數據表示為維持OCS劑量≤ 5 mg/天的患者數除以達到時間點的患者數。圖7B顯示了OCS劑量減少≥ 50%的患者比例。數據表示為OCS劑量減少≥ 50%的患者數除以達到時間點的患者數。[Figure 7A] shows the proportion of patients who received a maintenance OCS dose of ≤ 5 mg/day. Data are expressed as the number of patients who maintained an OCS dose of ≤ 5 mg/day divided by the number of patients who reached the time point. Figure 7B shows the proportion of patients who achieved a ≥ 50% reduction in OCS dose. Data are expressed as the number of patients who achieved a ≥ 50% reduction in OCS dose divided by the number of patients who reached the time point.
[圖8] 顯示了中斷維持每日OCS的患者比例。數據表示為中斷OCS的患者數除以達到時間點的患者數。[Figure 8] shows the proportion of patients who discontinued daily OCS. Data are expressed as the number of patients who discontinued OCS divided by the number of patients who reached the time point.
[圖9A] 顯示了泰派魯單抗治療受試者隨時間的BD後FEV1。圖9B顯示了泰派魯單抗治療患者的ACQ-6得分隨時間相對於基線的變化。[Figure 9A] shows the post-BD FEV1 over time in subjects treated with teplumab. Figure 9B shows the change in ACQ-6 scores relative to baseline over time in patients treated with teplumab.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
| GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
| US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
| KR100272077B1 (en) | 1990-08-29 | 2000-11-15 | 젠팜인터내셔날,인코포레이티드 | Transgenic non-human animals capable of producing heterologous antibodies |
| US7982016B2 (en) | 2007-09-10 | 2011-07-19 | Amgen Inc. | Antigen binding proteins capable of binding thymic stromal lymphopoietin |
| US8359965B2 (en) | 2007-09-17 | 2013-01-29 | Oxford J Craig | Apparatus and method for broad spectrum radiation attenuation |
| PE20121646A1 (en) | 2009-11-04 | 2012-12-02 | Merck Sharp & Dohme | ANTI-TSLP ANTIBODY MODIFIED BY GENETIC ENGINEERING TECHNIQUES |
| WO2012007495A1 (en) | 2010-07-15 | 2012-01-19 | F. Hoffmann-La Roche Ag | Antibodies specifically binding to human tslpr and methods of use |
| AT510032B1 (en) | 2010-11-30 | 2012-01-15 | Steiner Erwin Ing | MOUNTING DEVICE FOR FAÇADE ELEMENTS |
| US9100245B1 (en) | 2012-02-08 | 2015-08-04 | Amazon Technologies, Inc. | Identifying protected media files |
| US9306926B2 (en) | 2013-03-15 | 2016-04-05 | Brian A. Truong | User authentication using unique hidden identifiers |
| UY36578A (en) | 2015-03-11 | 2016-09-30 | Glaxosmithkline Ip Dev Ltd | TSLP JOINT PROTEINS |
| AU2016320748B2 (en) | 2015-09-09 | 2019-05-02 | Novartis Ag | Thymic stromal lymphopoietin (TSLP)-binding antibodies and methods of using the antibodies |
| JP7200134B2 (en) | 2017-06-08 | 2023-01-06 | アムジエン・インコーポレーテツド | Torque driven drug delivery device |
| MX2020004736A (en) | 2017-11-10 | 2020-08-13 | Amgen Inc | Plungers for drug delivery devices. |
| WO2019100111A1 (en) | 2017-11-21 | 2019-05-31 | Monash University | Methods of treating and diagnosing conditions |
| US12405275B2 (en) | 2018-03-13 | 2025-09-02 | Amgen Inc. | Methods for the preparation of trypsin-resistant polypeptides for mass spectrometric analysis |
| SG11202101824VA (en) | 2018-10-15 | 2021-03-30 | Amgen Inc | Platform assembly process for drug delivery device |
| KR20250127186A (en) | 2018-10-15 | 2025-08-26 | 암젠 인크 | Drug delivery device having damping mechanism |
| AU2020286889A1 (en) | 2019-06-04 | 2022-01-20 | Jiangsu Hengrui Medicine Co., Ltd. | Antibody capable of binding to thymic stromal lymphopoietin and use thereof |
| US20220289833A1 (en) | 2019-09-04 | 2022-09-15 | Biosion Inc. | Antibodies binding tslp and uses thereof |
| CN112876564B (en) | 2019-11-29 | 2022-07-15 | 康诺亚生物医药科技（成都）有限公司 | Development and application of TSLP (TSLP-related disease treatment agent) |
| CA3155759A1 (en) | 2019-12-13 | 2021-06-17 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Anti-tslp antibody and uses thereof |
| TW202140550A (en) | 2020-01-29 | 2021-11-01 | 瑞士商諾華公司 | Methods of treating an inflammatory or obstructive airway disease using anti-tslp antibody |
| CN111171150B (en) | 2020-02-05 | 2020-12-08 | 北京智仁美博生物科技有限公司 | Anti-human TSLP antibodies and uses thereof |
| CN111196850B (en) | 2020-02-07 | 2020-10-30 | 北京汇智和源生物技术有限公司 | Human thymic stromal lymphopoietin monoclonal antibody and application thereof |
| UY39089A (en)* | 2020-02-18 | 2021-08-31 | Amgen Inc | FORMULATIONS OF HUMAN ANTI-TSLP ANTIBODIES AND METHODS OF USE OF THE SAME |
| CN114437212B (en) | 2020-11-06 | 2023-03-14 | 上海麦济生物技术有限公司 | Anti-human thymic stromal lymphopoietin antibody and preparation method and application thereof |
| TW202229339A (en) | 2020-12-03 | 2022-08-01 | 大陸商江蘇恒瑞醫藥股份有限公司 | Antibody binding to thymic stromal lymphopoietin and application thereof |
| EP4257604A4 (en) | 2020-12-03 | 2024-11-13 | Jiangsu Hengrui Pharmaceuticals Co., Ltd. | PHARMACEUTICAL COMPOSITION CONTAINING ANTI-TSLP ANTIBODY AND USE THEREOF |
| CN113501878B (en) | 2021-02-03 | 2022-12-02 | 北京智仁美博生物科技有限公司 | Antibodies against human TSLP and uses thereof |
| WO2022166739A1 (en) | 2021-02-04 | 2022-08-11 | Staidson (Beijing) Biopharmaceuticals Co., Ltd. | Antibodies specifically recognizing thymic stromal lymphopoietin and uses thereof |
| CN114853888B (en) | 2021-02-05 | 2023-11-03 | 上海洛启生物医药技术有限公司 | anti-TSLP nanobody and application thereof |
| CN119367534A (en) | 2021-03-03 | 2025-01-28 | 正大天晴药业集团股份有限公司 | Pharmaceutical composition containing anti-TSLP antibody |
| TW202304980A (en) | 2021-04-23 | 2023-02-01 | 美商安進公司 | Modified anti-tslp antibodies |
| TW202308690A (en) | 2021-04-23 | 2023-03-01 | 美商安進公司 | Anti-tslp antibody compositions and uses thereof |
| CN115433275A (en) | 2021-06-02 | 2022-12-06 | 启愈生物技术(上海)有限公司 | Anti-thymic stromal lymphopoietin (TSLP) antibody and use thereof |
| WO2023070948A1 (en) | 2021-11-01 | 2023-05-04 | 江苏荃信生物医药股份有限公司 | Preparation method for concentrated solution containing anti-human thymic stromal lymphopoietin (tslp) monoclonal antibody, and liquid preparation |
| CN117209604B (en) | 2021-12-02 | 2024-03-22 | 北京东方百泰生物科技股份有限公司 | An anti-TSLP monoclonal antibody, its antigen-binding fragment and its application |
| EP4453030A1 (en) | 2021-12-24 | 2024-10-30 | Inmagene Pte. Ltd. | Novel anti-tslp antibodies |
| Publication number | Publication date |
|---|---|
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| Publication | Publication Date | Title |
|---|---|---|
| US20250032608A1 (en) | Treatment of asthma with anti-tsl p antibody | |
| RU2713406C2 (en) | Methods of treating or preventing asthma by administering il-4r antagonist | |
| EP2152290B1 (en) | Methods for administering anti-il-5 antibodies | |
| EP2627673B1 (en) | Therapies for improving pulmonary function | |
| US20230081261A1 (en) | Formulations of human anti-tslp antibodies and methods of using the same | |
| US20210000949A1 (en) | Methods for treating or preventing asthma by administering an il-33 antagonist | |
| US20230073888A1 (en) | Treatment of atopic dermatitis with anti-tslp antibody | |
| JP2007506681A (en) | Treatment of respiratory diseases with anti-IL-2 receptor antibodies | |
| TW202509066A (en) | Treatment of corticosteroid dependent asthma with anti-tslp antibody | |
| TW202134273A (en) | Methods for treating copd by administering an il-33 antagonist | |
| WO2025147632A1 (en) | Treatment of chronic obstructive pulmonary disease with anti-tslp antibody | |
| TW202448501A (en) | Treatment of chronic rhinosinusitis with anti-tslp antibody | |
| HK1188603B (en) | Therapies for improving pulmonary function | |
| HK1188603A (en) | Therapies for improving pulmonary function |