CN117396513A - 治疗癌症的联合疗法 - Google Patents
治疗癌症的联合疗法 Download PDFInfo
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Abstract
本文公开了用于治疗癌症的方法和材料。本公开进一步提供了使用一个或多个抗原结合蛋白(例如抗B细胞成熟抗原(BCMA)抗原结合蛋白)和一个或多个T细胞衔接器来治疗患有癌症的受试者的方法和材料。
Description
相关申请
本申请要求享有2021年5月28日提交的美国临时申请号63/194,547的优先权,其公开内容通过引用整体并入本文。
序列表
本申请含有已经以ASCII格式通过电子方式提交并且在此通过引用其整体并入本文的序列表。所述ASCII副本创建于2022年5月13日,命名为SEQUENCE_LISTING_009442.00184_ST25.txt,大小为60千字节。
技术领域
本公开涉及用于治疗癌症的方法和材料。例如,本公开提供了使用一个或多个抗体-药物缀合物(ADC)和一个或多个T细胞衔接器来治疗患有癌症的哺乳动物(例如,人)的方法和材料。本公开还提供了使用一个或多个抗原结合蛋白(例如抗B细胞成熟抗原(BCMA)抗原结合蛋白)和一个或多个T细胞衔接器来治疗患有癌症的受试者的方法和材料。
背景技术
多发性骨髓瘤(MM)是一种无法治愈的恶性肿瘤,占所有癌症的1%,占所有血液系统恶性肿瘤的10%。多种药物和联合治疗已被评估并发现可有效治疗多发性骨髓瘤(National Comprehensive Cancer Network,2016;Moreau,San Miguel et al.,2017)。然而,这些患者中的大多数(如果不是全部)不可避免地会复发(Richardson,Barlogie etal.,2003;Richardson,Barlogie et al.,2006;Jagannath,Barlogie et al.,2008)。
目前,免疫治疗领域仍然需要替代的或改进的组合物和方法以更有效地治疗自身免疫性疾病和癌症。
发明概述
本公开提供了用于治疗癌症的方法和材料。例如,本公开提供了使用一个或多个分子的方法和材料,其中每种分子包括:(i)具有针对BCMA多肽的结合特异性的抗BCMA抗原结合蛋白或ADC以及一个或多个用于治疗患有癌症的受试者的T细胞衔接器。在一些情况下,可以向哺乳动物(例如,人,如患有癌症的人)施用本文公开的组合治疗,其包括(a)具有针对BCMA多肽的结合特异性的抗BCMA抗原结合蛋白或ADC,和(b)一个或多个T细胞衔接器。
本文公开了包含抗BCMA抗原结合蛋白和T细胞衔接器的组合。在一些情况下,T细胞衔接器与CD3结合。在一些情况下,抗BCMA抗原结合蛋白包含抗体。在一些情况下,抗体是单克隆抗体。在一些情况下,单克隆抗体是IgG1。在一些情况下,抗体是无岩藻糖基化的。在一些实施方案中,抗体是岩藻糖基化的。在一些实施方案中,抗体是唾液酸化的。在一些实施方案中,抗体是糖基化的。在一些实施方案中,抗体是糖基化的。在一些实施方案中,抗体是半乳糖基化的。在一些情况下,抗BCMA抗原结合蛋白是人的、人源化的或嵌合的。在一些情况下,该抗BCMA抗原结合蛋白包括含有SEQ ID NO:1中列出的氨基酸序列的CDRH1;含有SEQ ID NO:2中列出的氨基酸序列的CDRH2;含有SEQ ID NO:3中列出的氨基酸序列的CDRH3;含有SEQ ID NO:4中列出的氨基酸序列的CDRL1;含有SEQ ID NO:5中列出的氨基酸序列的CDRL2;以及含有SEQ ID NO:6中列出的氨基酸序列的CDRL3。在一些情况下,抗BCMA抗原结合蛋白包括含有SEQ ID NO:7中列出的氨基酸序列的重链可变区(VH);以及含有SEQID NO:8中列出的氨基酸序列的轻链可变区(VL)。在一些情况下,抗BCMA抗原结合蛋白包含含有SEQ ID NO:9中列出的氨基酸序列的重链(H)和含有SEQ ID NO:10中列出的氨基酸序列的轻链(L)。在一些情况下,抗BCMA抗原结合蛋白是免疫缀合物。在一些情况下,抗BCMA抗原结合蛋白是包含与细胞毒素缀合的抗体的免疫缀合物。在一些情况下,细胞毒素是MMAE或MMAF。在一些情况下,细胞毒素是MMAF。在一些实施方案中,细胞毒素是AFP、MMAF、MMAE、AEB、AEVB或澳瑞他汀E。在一些实施方案中,细胞毒素是紫杉醇、多西他赛、CC-1065、SN-38、拓扑替康、吗啉代-阿霉素、根霉素、氰基吗啉代-阿霉素、海兔毒素-10、棘霉素、combretatstatin、卡奇霉素(calicheamicin)或纺锤菌素。在一些实施方案中,细胞毒素是奥瑞他汀、美登木素生物碱(maytansinoid)或卡奇霉素。在一些实施方案中,细胞毒素是长春新碱、长春花碱、长春地辛、长春瑞滨、VP-16、喜树碱、埃坡霉素A、埃坡霉素B、诺考达唑、秋水仙碱、colcimid、雌莫司汀、西马多丁、圆皮海绵内酯(discodermolide)、美登醇、美登素、DM1、DM2、DM3、DM4或五加素(eleutherobin)。在一些情况下,抗BCMA抗原结合蛋白是贝兰他单抗莫福汀(belantamab mafodotin)。在一些情况下,贝兰他单抗莫福汀以至少约0.5mg/kg、0.95mg/kg、1.0mg/kg、1.25mg/kg、1.4mg/kg、1.7mg/kg、1.9mg/kg、2.5mg/kg、或3.4mg/kg的剂量存在于组合中。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是0.95mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是1.0mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是1.4mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是1.9mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是1.92mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是2.5mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是3.4mg/kg。在一些实施方案中,每周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每2周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每3周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每4周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每5周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每6周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,在第一次施用后,治疗有效剂量的抗BCMA抗原结合蛋白的剂量逐步降低至本文所述的较低剂量。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量的3.4mg/kg剂量逐步降低至1.9mg/kg剂量、1.4mg/kg或更少。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量的2.5mg/kg剂量逐步降低至1.9mg/kg剂量、1.4mg/kg或更少。在一些实施方案中,在第1天、第8天以及此后每3-12周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些情况下,T细胞衔接器是双特异性T细胞衔接器。在一些情况下,T细胞衔接器选自下组:Cevostamab、Talquetamab、Teclistimab、PF-3135、TNB-383B、REGN5458、博纳吐单抗(Blinatumomab)和索利托单抗(Solitomab)。在一些情况下,T细胞衔接器是抗FcRH5 T细胞衔接器。在一些情况下,T细胞衔接器是Cevostamab。在一些实施方案中,T细胞衔接器包含SEQ ID NO:11、12、13和14中列出的序列。在一些情况下,组合包含至少约1.5mg、2mg、3mg、3.6mg、10mg、15mg、20mg、90mg或132mg Cevostamab。在一些情况下,T细胞衔接器是抗GPRC5D T细胞衔接器。在一些情况下,T细胞衔接器是Talquetamab。在一些情况下,T细胞接合物是抗BCMA T细胞衔接器。在一些情况下,T细胞衔接器选自下组:Teclistimab、PF-3135、TNB-383B和REGN5458。在一些情况下,T细胞衔接器选自下组:CC-93269、AMG701、JNJ-7957和GBR1342。在一些情况下,T细胞衔接器不结合ICOS。在某些情况下,T细胞衔接器不结合CD38。在一些情况下,组合包含药学上可接受的载体。在一些情况下,组合还包含辅助剂。
本文公开了治疗癌症的方法。在一些情况下,该方法包括治疗对其有需要的受试者中的癌症,包括向受试者施用治疗有效剂量的本文公开的组合。在一些情况下,癌症选自下组:多发性骨髓瘤、慢性淋巴细胞白血病、华氏巨球蛋白血症和非霍奇金淋巴瘤。在某些情况下,癌症是多发性骨髓瘤。在一些情况下,癌症是复发性和/或难治性多发性骨髓瘤。在一些情况下,受试者已接受至少一种先前的癌症治疗。在一些情况下,至少约每1-60天一次向受试者施用治疗有效剂量的组合。在一些情况下,至少约每21天一次向受试者施用治疗有效剂量的组合。在一些情况下,至少约每8天一次向受试者施用治疗有效剂量的组合。在一些情况下,与单独施用治疗有效量的抗BCMA抗原结合蛋白相比,施用治疗有效剂量的组合降低了眼毒性。在一些情况下,抗BCMA抗原结合蛋白是贝兰他单抗莫福汀。在一些情况下,眼毒性是以下中的至少一种:角膜上皮变化、干眼、刺激、发红、视力模糊、干眼、畏光或视力变化。在一些情况下,眼毒性通过以下方法中的至少一种来测量:最佳矫正视力、明显屈光的记录以及用于获得最佳矫正视力的方法、当前眼镜处方(如果适用)、眼压测量、眼前节(裂隙灯)检查,包括角膜荧光素染色和晶状体检查、散瞳眼底镜检查或眼表疾病指数(OSDI)。在一些情况下,本文公开的抗BCMA抗原结合蛋白以至少约0.5mg/kg、0.95mg/kg、1.25mg/kg、1.4mg/kg、1.7mg/kg、1.9mg/kg、1.92mg/kg、2.5mg/kg或3.4mg/kg的剂量施用于受试者。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是0.95mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是1.0mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是1.4mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是1.9mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是1.92mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是2.5mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是3.4mg/kg。在一些实施方案中,每周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每2周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每3周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每4周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每5周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每6周、7周、8周、9周、10周、11周或12周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,在第一次施用后,治疗有效剂量的抗BCMA抗原结合蛋白的剂量逐步降低至本文所述的较低剂量。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量的3.4mg/kg剂量逐步降低至1.9mg/kg剂量、1.4mg/kg或更少。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量的2.5mg/kg剂量逐步降低至1.9mg/kg剂量、1.4mg/kg或更少。在一些实施方案中,在第1天、第8天以及此后每3-12周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。
本文公开了用于药物的制备。在一些情况下,本文公开了用于制造用于治疗癌症的药物的组合。本文公开了本文公开的组合用于治疗癌症的用途。
本文公开了试剂盒。在一些情况下,本文公开的试剂盒用于治疗癌症。在一些情况下,本文公开的试剂盒包含本文公开的组合和用于治疗癌症的说明书。
本文公开了预填充注射器或自动注射器装置。在一些情况下,本文公开的预填充注射器或自动注射器装置包含本文公开的组合。
除非另外定义,否则本文中使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同含义。尽管与本文描述的那些类似或等同的方法和材料可用于实践本发明,但合适的方法和材料描述如下。本文提及的所有出版物、专利申请、专利和其他参考文献均通过引用整体并入。另外,材料、方法和实施例仅是说明性的而非旨在限制性的。
本发明的一个或多个实施方案的细节在下面的描述中阐述。本发明的其他特征、目的和优点将从说明书和权利要求中是明显的。
发明详述
组合
本公开提供了用于治疗癌症的方法和材料。在一些情况下,本文公开了用于治疗癌症或其他B细胞介导的疾病或病症的包含抗BCMA抗原结合蛋白和T细胞衔接器的组合。
本文描述的术语“组合”是指至少两种治疗剂。如本文所用,术语“治疗剂”应理解为是指在组织、系统、动物、哺乳动物、人或其他受试者中产生理想效果的物质。在一个实施方案中,组合可以含有另外的治疗剂,例如另外的癌症治疗剂。在一个实施方案中,另外的癌症治疗剂是免疫调节酰亚胺药物(IMiD),例如沙利度胺、来那度胺、泊马度胺、阿普斯特或其他沙利度胺类似物。在一些实施方案中,另外的癌症治疗剂可以是卡非佐米、达雷木单抗、伊沙妥昔单抗、伊沙佐米、马佐米、奥普佐米或其药学上可接受的盐。在一些实施方案中,另外的癌症治疗剂是PD-1抑制剂。在一些情况下,PD-1抑制剂选自下组:PDR001、纳武单抗、派姆单抗、Pidilizumab、MEDI0680、REGN2810、TSR-042、PF-06801591和AMP-224。在一些情况下,PD-1抑制剂是Jemperli。在一些实施方案中,另外的癌症治疗剂是PD-L1抑制剂。在一些情况下,PD-L1抑制剂选自下组:FAZ053、阿特珠单抗、Avelumab、Durvalumab和BMS-93655。在一些实施方案中,另外的癌症治疗剂是CTLA-4抑制剂。在一些情况下,CTLA-4抑制剂是Ipilimumab或Tremelimumab。在一些情况下,另外的癌症治疗剂是TIM-3抑制剂。在一些情况下,TIM-3抑制剂是MGB453或TSR-022。在一些实施方案中,另外的癌症治疗剂是LAG-3抑制剂。在一些情况下,LAG-3抑制剂选自下组:LAG525、BMS-986016和TSR-033。在一些实施方案中,另外的癌症治疗剂是mTOR抑制剂。在某些情况下,mTOR抑制剂是RAD001或雷帕霉素。
本公开的组合的施用可优于单独的治疗剂,因为当与单独施用单一治疗剂相比时,组合可以提供一个或多个以下改进的性质:i)比活性最强的单一药物更强的抗癌作用,ii)协同或高度协同的抗癌活性,iii)提供增强的抗癌活性和减少的副作用的给药方案,iv)毒性作用的降低,v)治疗窗口的增加,或vi)一种或两种治疗剂的生物利用度增加。
本文描述的组合可以是药物组合物的形式。“药物组合物”含有本文所述的组合,以及一个或多个药学上可接受的载体、稀释剂或赋形剂。一个或多个载体、一个或多个稀释剂或一个或多个赋形剂在与制剂的其他成分相容、能够进行药物配制且对其接受者无害的意义上必须是可接受的。在一个实施方案中,组合中的每种治疗剂单独配制为其自身的药物组合物,并且施用每种药物组合物以治疗癌症。在该实施方案中,每种药物组合物可以具有相同或不同的载体、稀释剂或赋形剂。例如,在一个实施方案中,第一药物组合物含有对BCMA多肽具有结合特异性的抗BCMA抗原结合蛋白或ADC,第二药物组合物含有一个或多个T细胞衔接器,并且第一和第二药物组合物均被施用来治疗癌症。在另一个实施方案中,组合中的每种治疗剂一起配制为单一药物组合物并施用以治疗癌症。例如,在一个实施方案中,单一药物组合物含有对BCMA多肽具有结合特异性的抗BCMA抗原结合蛋白或ADC和一个或多个T细胞衔接器,并且作为单一药物组合物施用以治疗癌症。
抗BCMA抗原结合蛋白
本文使用的术语“抗BCMA抗原结合蛋白”是指能够与BCMA结合的抗体和其他蛋白质构建体,如结构域。术语“BCMA结合蛋白”和“抗BCMA抗原结合蛋白”在本文中可互换使用。
本文所述的抗BCMA抗原结合蛋白可以结合人BCMA,该人BCMA包括例如含有GenBank登录号Q02223.2的氨基酸序列的人BCMA,或编码与其具有至少90%同源性或至少90%同一性的人BCMA的基因。
示例性抗BCMA抗原结合蛋白及其制备方法公开于国际公布号WO2012/163805中,其通过引用整体并入本文。另外的示例性抗BCMA抗原结合蛋白包括在以下中描述的那些:WO2016/014789、WO2016/090320、WO2016/090327、WO2016/020332、WO2016/079177、WO2014/122143、WO2014/122144、WO2017/021450、WO2016/014565、WO2014/068079、WO2015/166649、WO2015/158671、WO2015/052536、WO2014/140248、WO2013/072415、WO2013/072406、WO2014/089335、US2017/165373、WO2013/154760、WO2018/201051和WO2017/051068,其中每一个都通过引用整体并入本文。
本文使用的术语“抗原结合蛋白”是指能够结合抗原的抗体和其他蛋白质构建体,如结构域。
术语“抗体”在本文中以最广泛的含义使用,是指具有免疫球蛋白样结构域(例如IgG、IgM、IgA、IgD或IgE)的分子,并且包括单克隆、重组、多克隆、嵌合、人、人源化、多特异性抗体,包括双特异性抗体和异源缀合抗体;单可变结构域(例如,结构域抗体(DAB))、抗原结合抗体片段、Fab、F(ab')2、Fv、二硫键连接的Fv、单链Fv、二硫键连接的scFv、双抗体、TANDABS等,以及上述任意的修改版本(有关替代“抗体”形式的摘要,参见Holliger和Hudson,Nature Biotechnology,2005,Vol 23,No.9,1126-1136)。
在一些实施方案中,本文公开的BCMA结合蛋白可以源自大鼠、小鼠、灵长类动物(例如食蟹猴、旧世界猴或类人猿)或人。BCMA结合蛋白可以是人抗体、人源化抗体或嵌合抗体。BCMA结合蛋白可包含恒定区,其可以是任何同种型或亚类。恒定区可以是IgG同种型,例如IgGl、IgG2、IgG3、IgG4或其变体。BCMA结合蛋白恒定区可以是IgG1。
术语“完全的”、“全部的”或“完整的”抗体在本文中可互换使用,是指异四聚体糖蛋白。完整的抗体由通过共价二硫键连接的两条相同的重链(HC)和两条相同的轻链(LC)组成。这种H2L2结构折叠形成三个功能域,包括两个称为‘Fab’片段的抗原结合片段和一个‘Fc’可结晶片段。Fab片段由氨基末端的可变结构域(重链可变区(VH)或轻链可变区(VL))以及羧基末端的恒定结构域(CH1(重链)和CL(轻链))组成。Fc片段由成对的CH2和CH3区域二聚化形成的两个结构域组成。Fc可以通过与免疫细胞上的受体结合或通过结合C1q(经典补体途径的第一组分)来引发效应功能。五类抗体IgM、IgA、IgG、IgE和IgD由不同的重链氨基酸序列定义,分别称为μ、α、γ、ε和δ,每条重链可以与K或λ轻链配对。血清中的大多数抗体属于IgG类,人IgG有四种同种型(IgG1、IgG2、IgG3和IgG4),其序列主要在铰链区不同。
如本文所用,“约”是指加或减10%。
可以使用多种方法获得完全人抗体,例如使用基于酵母的文库或可以产生人抗体库的转基因动物(例如小鼠)。可以使用基于FACS(荧光激活细胞分选)的方法或通过使用标记抗原捕获在珠粒上来选择在其表面上呈递与感兴趣的抗原结合的人抗体的酵母。可以用感兴趣的抗原和使用B细胞分选技术分离的抗原特异性人抗体对经过修饰以表达人免疫球蛋白基因的转基因动物进行免疫。然后可以对使用这些技术产生的人抗体的理想特性进行表征,如亲和力、开发性和选择性。
在一些方面,可以使用替代抗体形式。替代抗体形式包括替代支架,其中BCMA抗体的一个或多个CDR可排列在合适的非免疫球蛋白支架或骨架上,如亲和体、SpA支架、LDL受体A类结构域、avimer(参见,例如,美国专利申请公开号2005/0053973,2005/0089932,2005/0164301)或EGF结构域。
术语“结构域”是指折叠的多肽结构,其独立于多肽的其余部分保留其三级结构。一般而言,结构域负责多肽的离散功能特性,并且在许多情况下可以添加、去除或转移至其他多肽,而不损失蛋白质和/或结构域的其余部分的功能。
术语“单可变结构域”是指包含抗体可变结构域的序列特点的折叠多肽结构域。因此,它包括完整的抗体可变结构域如VH、VHH和VL以及修饰的抗体可变结构域,例如,其中一个或多个环被不具有抗体可变结构域特征的序列、或被截短的或包含N-或C-端延伸的抗体可变结构域以及保留至少全长结构域的结合活性和特异性的可变结构域的折叠片段所取代。单个可变结构域可以独立于不同的可变区或结构域结合抗原或表位。“结构域抗体”或“DAB”可以被认为与“单可变结构域”相同。单可变结构域可以是人单可变结构域,但也包括来自其他物种的单可变结构域,如啮齿动物(例如,如WO 00/29004A1中公开的)、护士鲨和骆驼科动物VHH DAB。骆驼科动物VHH是源自骆驼、美洲驼、羊驼、单峰骆驼和原驼等物种的免疫球蛋白单可变结构域多肽,其产生天然缺乏轻链的重链抗体。此类VHH结构域可根据本领域可用的标准技术人源化,并且此类结构域被认为是“单可变结构域”。如本文所用,VH包括骆驼科动物VHH结构域。
抗原结合片段、BCMA结合蛋白片段、功能片段、生物活性片段或免疫有效片段可以包含部分重链或轻链可变序列。片段长度为至少5、6、8或10个氨基酸。或者,片段的长度为至少15、至少20、至少50、至少75或至少100个氨基酸。
抗原结合片段可以通过在非抗体蛋白支架上排列一个或多个CDR来提供。如本文所用,“蛋白支架”包括但不限于免疫球蛋白(Ig)支架,例如IgG支架,其可以是四链或二链抗体,或者可以仅包含抗体的Fc区,或者可以包含来自抗体的一个或多个恒定区,该恒定区可以是人类或灵长类动物起源的,或者可以是人类和灵长类动物恒定区的人工嵌合体。
蛋白支架可以是Ig支架,例如IgG或IgA支架。IgG支架可以包含抗体的一些或全部结构域(即CH1、CH2、CH3、VH、VL)。本文公开的抗原结合蛋白可包含选自IgGl、IgG2、IgG3、IgG4或IgG4PE的IgG支架。例如,支架可以是IgG1。支架可以由抗体的Fc区组成或包含抗体的Fc区,或者是其一部分。
蛋白支架可以是选自下组的支架的衍生物:TLA-4、脂质运载蛋白、蛋白质A衍生分子如蛋白质A的Z结构域(Affibody,SpA)、A结构域(Avimer/Maxibody);热休克蛋白如GroEl和GroES;转铁蛋白(trans-body);锚蛋白重复蛋白(DARPin);肽适体;C型凝集素结构域(Tetranectin);人γ-晶状体蛋白和人泛素(affilis);PDZ结构域;人蛋白酶抑制剂的蝎毒素kunitz型结构域;和纤连蛋白/adnectin;它经过蛋白质工程以获得与除天然配体以外的抗原的结合。
“抗原结合位点”是指抗原结合蛋白上能够特异性结合抗原的位点,这可以是单个可变结构域,或其可以是成对的VH/VL结构域,如可以在标准抗体上发现的那样。单链Fv(ScFv)结构域也可以提供抗原结合位点。
术语多特异性抗原结合蛋白是指包含至少两个不同抗原结合位点的抗原结合蛋白。这些抗原结合位点中的每一个都能够结合不同的表位,该表位可以在相同的抗原或不同的抗原上呈现。多特异性抗原结合蛋白可以对多于一种抗原具有特异性,例如两种抗原、或三种抗原、或四种抗原。
Labrijn等人2019年以及Brinkmann和Kontermann 2017年的综述全面描述了双特异性抗体的分类和形式。双特异性抗体通常可分为具有对称或不对称的结构。双特异性可以具有Fc或可以是基于片段的(缺少Fc)。基于片段的双特异性抗体将多个抗原结合抗体片段组合在一个没有Fc区的分子中,例如Fab-scFv、Fab-scFv2、正交Fab-Fab、Fab-Fv、串联scFc(例如BiTE和BiKE分子)、Diabody、DART、TandAb、scDiabody、串联dAb等。
对称形式在单个多肽链或单个HL对中组合了多种结合特异性,包括基于片段的形式和抗体片段与常规抗体分子融合的形式的Fc融合蛋白。对称形式的实例可包括DVD-Ig、TVD-Ig、CODV-Ig、(scFv)4-Fc、IgG-(scFv)2、四价DART-Fc、F(ab)4CrossMab、IgG-HC-scFv、IgG-LC-scFv、mAb-dAb等。
不对称形式在三条(如果使用共同的重链或轻链)或四条多肽链(例如Triomab、不对称重组技术免疫球蛋白(ART-Ig)、CrossMab、Biclonics共同轻链、ZW1共同轻链、DuoBody和杵臼(KiH)、DuetMab、κλbody、Xmab、YBODY、HET-mAb、HET-Fab、DART-Fc、SEEDbody、小鼠/大鼠嵌合IgG)的共表达期间,通过强制正确的HL链配对和/或促进H链异源二聚化,尽可能地保留天然抗体的天然结构。
双特异性形式还包括与非Ig支架融合的抗体,如Affimab、Fynomab、Zybodies和Anticalin-IgG融合物、ImmTAC。
在一些实施方案中,本文所述的抗原结合蛋白是多特异性抗原结合蛋白。
本文使用的术语“嵌合抗原受体”(“CAR”)是指由胞外抗原结合结构域(其通常衍生自单克隆抗体或其片段,例如scFv形式的VH结构域和VL结构域)、任选的间隔区、跨膜区和一个或多个细胞内效应结构域组成的工程化受体。CAR也被称为嵌合T细胞受体或嵌合免疫受体(CIR)。CAR通过基因导入造血细胞(如T细胞)以重定向T细胞对理想细胞表面抗原的特异性,从而产生CAR-T疗法。在一些实施方案中,CAR包含本文公开的抗BCMA抗原结合蛋白。
本文所用的术语“间隔区”是指具有将跨膜结构域连接至靶标结合结构域的功能的寡肽或多肽。该区域也可称为“铰链区”或“柄区”。间隔物的尺寸可以根据靶标表位的位置而变化,为了在CAR:靶标结合时保持设定的距离(例如14nm)。
本文使用的术语“跨膜结构域”是指穿过细胞膜的CAR分子的部分。
本文使用的术语“胞内效应结构域”(也称为“信号传导结构域”)是指CAR中负责抗原结合结构域与靶标结合后的胞内信号传导的结构域。胞内效应结构域负责激活表达CAR的免疫细胞的至少一种正常效应功能。例如,T细胞的效应功能可以是溶细胞活性或辅助活性,包括细胞因子的分泌。
本领域技术人员应当理解,可以将本文公开的VH和/或VL结构域,例如,以scFv的形式,掺入CAR-T疗法。
亲和力(Affinity)也称为“结合亲和力”,是在单个相互作用位点,即一个分子(如本公开的BCMA结合蛋白)与另一个分子(如其靶抗原)在单个结合位点的结合强度。抗原结合蛋白与其靶标的结合亲和力可以通过平衡方法(例如酶联免疫吸附测定(ELISA)或放射免疫测定(RIA))或动力学(例如BIACORE分析)来测定。
亲合力(Avidity)也称为功能亲和力,是多个相互作用位点处结合的累积强度,例如,两个分子(或更多,例如,在双特异性或多特异性分子的情况下)在多个位点相互结合的强度的总和,例如,考虑到相互作用的价。
在一个实施方案中,本文公开的抗原结合蛋白-抗原相互作用的平衡解离常数(KD)为100nM或更小、10nM或更小、2nM或更小、或者1nM或更小。或者,KD可以在5和10nM之间;或1到2nM之间。KD可以在1pM和500pM之间;或500pM至1nM之间。技术人员将理解,KD数值越小,结合越强。KD的倒数(即1/KD)是单位为M-1的平衡结合常数(KA)。技术人员将理解,KA数值越大,结合越强。
解离速率常数(kd)或“解离速率”描述了抗原结合蛋白复合物的稳定性,即复合物每秒衰变的分数。例如,0.01s-1的kd相当于每秒1%的复合物衰变。在一个实施方案中,解离速率常数(kd)为1x10-3s-1或更小、1x10-4s-1或更小、1x10-5s-1或更小、或者1x10-6s-1或更小。kd可以在1x10-5 s-1和1x10-4 s-1之间;或在1x10-4 s-1和1x10-3 s-1之间。在一些实施方案中,本文公开的抗原结合蛋白的kd为2.06x10-4s-1或更小、1.58x10-4s-1或更小、1.7x10-4s-1或更小、或者5.68x10-4s-1或更少、6.78x10-4 s-1或更少、8.26x10-4 s-1或更少、5.15x10-4s-1或更少、或者5.68x10-4 s-1或更少。
结合速率常数(ka)或“结合速率”描述了抗原结合蛋白复合物形成的速率。在一个实施方案中,结合速率常数(ka)为6.49x106 M-1s-1、4.65x106 M-1s-1、3.27x106 M-1s-1、8.28x106 M-1s-1、1.47x107 M-1s-1、1.10x107 M-1s-1、5.90x106M-1s-1。
对于本领域技术人员来说显而易见的是,术语“衍生的”不仅意在限定其是材料的物理起源的意义上的来源,而且意在限定结构上与该材料相同但并非源自参考来源的材料。
“分离的”意指将诸如BCMA结合蛋白的分子从其可能在自然界中发现的环境中移取。例如,分子可以从自然界中通常存在的物质中纯化出来。例如,就含有BCMA结合蛋白的培养基而言,BCMA结合蛋白可以纯化至至少95%、96%、97%、98%或99%或更高。本文公开的BCMA结合蛋白和抗体可以是分离的BCMA结合蛋白和抗体。
“CDR”被定义为抗原结合蛋白的互补决定区氨基酸序列。这些是免疫球蛋白重链和轻链的高变区。免疫球蛋白的可变部分中有三个重链和三个轻链CDR(或CDR区)。因此,本文使用的“CDR”是指所有三个重链CDR、所有三个轻链CDR、所有重链和轻链CDR、或至少两个CDR。
在整个本说明书中,可变结构域序列中的氨基酸残基和全长抗原结合序列内的可变结构域区域,例如,在抗体重链序列或抗体轻链序列内,根据Kabat编号惯例进行编号。类似地,实例中使用的术语“CDR”、“CDRL1”、“CDRL2”、“CDRL3”、“CDRH1”、“CDRH2”、“CDRH3”遵循Kabat编号惯例。欲了解更多信息,请参见Kabat等人,Sequences of Proteins ofImmunological Interest,4th Ed.,U.S.Department of Health and Human Services,National Institutes of Health(1987)。
变体
对于本领域技术人员来说显而易见的是,对于可变结构域序列和全长抗体序列中的氨基酸残基存在替代的编号惯例。CDR序列也有替代的编号惯例,例如Chothia等人(1989)Nature 342:877-883中列出的那些。例如,BCMA结合蛋白的结构和蛋白质折叠可能意味着其他残基被认为是CDR序列的一部分且将被技术人员理解为如此。
技术人员可用的CDR序列的其他编号惯例包括“AbM”(巴斯大学)和“Contact”(伦敦大学学院)方法。可以使用Kabat、Chothia、AbM和Contact方法中的至少两种来确定最小重叠区域,以提供“最小结合单元”。最小结合单元可以是CDR的子部分。
下面的表1代表了对每个CDR或结合单元使用每种编号惯例的一种定义。表1中使用Kabat编号方案对可变结构域氨基酸序列进行编号。应该注意的是,一些CDR定义可能会根据所使用的个别出版物而有所不同。
表1
相应地,提供了BCMA结合蛋白,其包含以下CDR中的任一个或组合:SEQ ID NO:1的CDRH1、SEQ ID NO:2的CDRH2、SEQ ID NO:3的CDRH3、SEQ ID NO:4的CDRL1、SEQ ID NO:5的CDRL2、SEQ ID NO:6的CDRL3。CDR可通过至少一个氨基酸取代、缺失或添加进行修饰,其中变体抗原结合蛋白基本上保留未修饰的蛋白的生物学特性,如与抗原的结合。
表2.抗BCMA抗原结合蛋白的示例性CDR序列。
序列 | SEQ ID NO | |
VH CDR1 | NYWMH | 1 |
VH CDR2 | ATYRGHSDTYYNQKFKG | 2 |
VH CDR3 | GAIYDGYDVLDN | 3 |
VL CDR1 | SASQDISNYLN | 4 |
VL CDR2 | YTSNLHS | 5 |
VL CDR3 | QQYRKLPWT | 6 |
应当理解,CDR H1、H2、H3、L1、L2、L3中的每一个可以以任何排列或组合单独修饰或与任何其他CDR组合被修饰。在一个实施方案中,通过取代、缺失或添加最多至3个氨基酸,例如1或2个氨基酸,例如1个氨基酸来修饰CDR。通常,修饰是取代,特别是保守取代,例如如下表3中所示。
表3:取代
侧链 | 成员 |
疏水的 | Met,Ala,Val,Leu,Ile |
中性亲水的 | Cys,Ser,Thr |
酸性的 | Asp,Glu |
碱性的 | Asn,Gln,His,Lys,Arg |
影响链定向的残基 | Gly,Pro |
芳香族的 | Trp,Tyr,Phe |
例如,在变体CDR中,包含CDR作为替代定义如Kabat或Chothia的一部分的侧翼残基可以被保守氨基酸残基取代。
本文公开的VH或VL(或HC或LC)序列可以是具有最多至10个氨基酸取代、添加或缺失的变体序列。例如,变体序列可具有最多至9、8、7、6、5、4、3、2或1个氨基酸取代、添加或缺失。序列变异可以排除一个或多个或全部CDR,例如CDR与VH或VL(或HC或LC)序列相同并且变异是在VH或VL(或HC或LC)序列的剩余部分中,使得CDR序列固定且完整。
或者,重链可变区可与本文所述的抗体的氨基酸序列具有75%或更大、80%或更大、85%或更大、90%或更大、95%或更大、98%或更大、99%或更大或100%同一性;并且轻链可变区可与本文所述的抗体的氨基酸序列具有75%或更大、80%或更大、85%或更大、90%或更大、95%或更大、98%或更大、99%或更大、或100%同一性。
本文公开的抗体的重链可变区或氨基酸序列可以是变体,其可含有30、25、20、15、10、9、8、7、6、5、4、3、2或1个氨基酸替换、插入或缺失。本文公开的抗体或氨基酸序列的轻链可变区可以是变体,其可含有30、25、20、15、10、9、8、7、6、5、4、3、2或1个氨基酸替换、插入或缺失。
本文使用的术语“表位”是指与抗原结合蛋白的特定结合结构域接触的抗原部分,也称为互补位。表位可以是线性的或构象/不连续的。构象或不连续表位包含被其他序列分开的氨基酸残基,即,不在通过多肽链的三级折叠组装的抗原的一级序列中的连续序列中。尽管残基可能来自多肽链的不同区域,但它们在抗原的三维结构中紧密接近。在多聚体抗原的情况下,构象或不连续表位可以包括来自不同肽链的残基。包含在表位内的特定残基可通过计算机建模程序或通过本领域已知的方法(如X射线晶体学)获得的三维结构来确定。表位作图可以使用本领域技术人员已知的,如出版物中所述的各种技术进行,例如Methods in Molecular Biology‘Epitope Mapping Protocols’,Mike Schutkowski andUlrich Reineke(volume 524,2009)and Johan Rockberg and Johan Nilvebrant(volume1785,2018)。示例性方法包括基于肽的方法,如肽扫描,其中使用如ELISA的技术或通过体外展示肽或蛋白质突变体(例如噬菌体)的大文库来筛选一系列重叠肽用于结合。详细的表位信息可以通过包括X射线晶体学、溶液核磁共振(NMR)光谱学和冷冻电子显微镜(cryo-EM)的结构技术来确定。诱变,如丙氨酸扫描,是一种有效的方法,通过结合丢失分析用于表位作图。另一种方法是氢/氘交换(HDX)结合蛋白质水解和液相色谱质谱(LC-MS)分析来表征不连续或构象表位。
同一性百分比
查询核酸序列和目标核酸序列之间的“同一性百分比”是在使用合适的算法或软件(如BLASTN,FASTA,ClustalW,MUSCLE,MAFFT,EMBOSS Needle,T-Coffee和DNASTARLasergene)进行成对整体序列比对后,在查询序列的整个长度上,用合适的算法或软件(如BLASTN、FASTA、DNASTAR Lasergene、GeneDoc、Bioedit、EMBOSS Needle或EMBOSSinfoalign)计算的表示为百分比的“同一性”值。重要的是,查询核酸序列可以通过本文的一项或多项权利要求中鉴定的核酸序列来描述。
查询氨基酸序列和目标氨基酸序列之间的“同一性百分比”是在使用合适的算法/软件(例如BLASTP、FASTA、ClustalW、MUSCLE、MAFFT、EMBOSS Needle、T-Coffee和DNASTARLasergene)进行成对整体序列比对后,在查询序列的整个长度上,用合适的算法或软件(如BLASTP、FASTA、DNASTAR Lasergene、GeneDoc、Bioedit、EMBOSS Needle或EMBOSSinfoalign)计算的表示为百分比的“同一性”值。重要的是,查询氨基酸序列可以通过本文的一项或多项权利要求中鉴定的氨基酸序列来描述。
查询序列可以与目标序列100%相同,或者与目标序列相比,其可以包括最高至一定整数数量的氨基酸或核苷酸改变,使得%同一性小于100%。例如,查询序列与目标序列至少50、60、70、75、80、85、90、95、96、97、98或99%相同。此类改变包括至少一个氨基酸缺失、取代(包括保守性和非保守性取代)或插入,并且其中所述改变可以发生在查询序列的氨基末端或羧基末端位置处或这些末端位置之间的任意处,单独地散布在查询序列中的氨基酸或核苷酸之间或者散布在查询序列内的一个或多个连续组中。
可以在包括CDR的查询序列的整个长度上确定%同一性。或者,%同一性可以排除一个或多个或所有CDR,例如所有CDR与目标序列100%相同且%同一性变异在查询序列的剩余部分中,例如框架序列,这使得CDR序列固定且完整。在一些实施方案中,本文公开的抗BCMA结合蛋白包含与本文公开的序列至少约50、60、70、75、80、85、90、95、96、97、98或99%同一性的序列。
修饰
术语“肽”、“多肽”和“蛋白质”各自指包含两个或更多个氨基酸残基的分子。肽可以是单体的或聚合的。
Fc工程方法可应用于修饰抗体的功能或药代动力学特性。可以通过在Fc区进行突变来改变效应功能,这些突变增加或减少与C1q或Fcγ受体的结合并分别修饰CDC或ADCC活性。还可以对抗体的糖基化模式进行修饰以改变效应功能。抗体的体内半衰期可以通过进行影响Fc与FcRn(新生儿Fc受体)结合的突变来改变。
本文使用的术语“效应功能”是指抗体介导的效应中的一个或多个,包括抗体依赖性细胞介导的细胞毒性(ADCC)、抗体介导的补体激活包括补体依赖性细胞毒性(CDC)、补体依赖性细胞介导的吞噬作用(CDCP)、抗体依赖性补体介导的细胞裂解作用(ADCML)和Fc介导的吞噬作用或抗体依赖性细胞吞噬作用(ADCP)。
抗原结合蛋白或抗体的Fc区与各种Fc受体(FcR),包括FcγRI(CD64)、FcγRII(CD32)、FcγRIII(CD16)、FcRn、C1q和II型Fc受体之间的相互作用被认为介导抗原结合蛋白或抗体的效应功能。显著的生物效应可以是效应功能的结果。通常,介导效应功能的能力需要抗原结合蛋白或抗体与抗原的结合,且并非所有抗原结合蛋白或抗体都会介导每种效应功能。
效应功能可以通过多种方式进行评估,包括,例如,评估经由FcγRIII通过自然杀伤(NK)细胞介导的或经由FcγRI通过单核细胞/巨噬细胞介导的包被至靶细胞的抗体的ADCC效应功能,或评估经由C1q通过补体级联介导的包被至靶细胞的抗体的CDC效应功能。例如,可以在自然杀伤细胞测定中评估本发明的抗原结合蛋白的ADCC效应功能。此类测定的实例可以在Shields等人,2001,The Journal of Biological Chemistry,Vol.276,p.6591-6604;Chappel等人,1993,The Journal of Biological Chemistry,Vol 268,p.25124-25131;Lazar等人,2006,2006,PNAS,103;4005-4010中找到。
确定CDC功能的测定的实例包括J Imm Meth,1995,184:29-38中描述的那些。
可以评估突变对效应功能(例如,FcRn结合、FcγR和C1q结合、CDC、ADCML、ADCC、ADCP)的影响,例如,如Grevys等人,J Immunol.2015Jun 1;194(11):5497–5508,或Tam等人,Antibodies 2017,6(3);Monnet等人,2014mAbs,6:2,422-436中所描述的。
在本说明书的全文中,抗体序列或全长抗原结合蛋白序列中的Fc区中的氨基酸残基根据EU索引编号惯例进行编号。
含有特定突变的人IgG1恒定区已被证明增强与Fc受体的结合。在一些情况下,这些突变也被证明增强如下文描述的效应功能,例如ADCC和CDC。本发明的抗原结合蛋白可以包括任何以下突变。
增强的CDC:Fc工程可用于增强基于补体的效应功能。例如(参考IgG1),K326W/E333S;S267E/H268F/S324T;和IgG1/IgG3交叉亚类可增加C1q结合;E345R(Diebolder等人,Science 2014;343:1260-1293)和E345R/E430G/S440Y产生预形成的IgG六聚体(Wang等人,Protein Cell.2018Jan;9(1):63–73)。
增强的ADCC:Fc工程可用于增强ADCC。例如(参考IgG1),F243L/R292P/Y300L/V305I/P396L;S239D/I332E;和S298A/E333A/K334A增加FcγRIIIa结合;S239D/I332E/A330L增加FcγRIIIa结合并减少FcγRIIb结合;G236A/S239D/I332E提高与FcγRIIa的结合,提高FcγRIIa/FcγRIIb结合比(激活/抑制比),以及增强巨噬细胞对抗体包被的靶细胞的吞噬作用。不对称Fc(其中一条重链含有L234Y/L235Q/G236W/S239M/H268D/D270E/S298A突变,且相对重链中含有D270E/K326D/A330M/K334E)增加对FcγRIIIaF158(亲和力较低的等位基因)和FcγRIIIaV158(亲和力较高的等位基因)的亲和力,而不增加对抑制性FcγRIIb的结合亲和力(Mimoto等人,2013)。
增强的ADCP:Fc工程可用于增强ADCP。例如(参考IgG1),G236A/S239D/I332E增加FcγRIIa结合并增加FcγRIIIa结合(RichardsJ等人,Mol.CancerTher.2008;7:2517-2527)。
增加的共结合(co-engagemen):Fc工程可用于增加与FcR的共结合。例如(参考IgG1),S267E/L328F增加FcγRIIb结合;N325S/L328F增加FcγRIIa结合并减少FcγRIIIa结合(Wang等人2018)。
糖基化
本发明的抗原结合蛋白可以包含具有改变的糖基化特征的重链恒定区,使得抗原结合蛋白具有增强的效应功能,例如,增强的ADCC、增强的CDC,或都增强的ADCC和CDC。产生具有改变的糖基化特征的抗原结合蛋白的合适方法的实例描述于WO2003011878、WO2006014679和EP1229125中,所有这些都可以应用于本发明的抗原结合蛋白。
IgG1抗体N297上的Fc聚糖部分上α1,6最内的岩藻糖残基的缺乏增强了对FcγRIIIA的亲和力。因此,无岩藻糖基化或低岩藻糖基化的单克隆抗体可具有增加的治疗功效(Shields et al.,J Biol Chem.2002,277(30):26733-40和Monnet et al.,2014,mAbs,6:2,422-436)。
Potelligent
本公开还提供了产生根据本发明的抗原结合蛋白的方法,该方法包括以下步骤:
a)培养包含表达载体的重组宿主细胞,该表达载体包含如本文所述的分离的核酸,其中编码α-1,6-岩藻糖基转移酶的FUT8基因已在重组宿主细胞中失活;和
b)回收抗原结合蛋白。
此类用于产生抗原结合蛋白的方法可以例如使用从BioWa,Inc.(Princeton,NJ)获得的POTELLIGENT技术系统来进行,其中缺乏FUT8基因的功能性拷贝的CHOK1SV细胞产生具有增强的ADCC活性的单克隆抗体,该ADCC活性相对于如US7214775、US6946292、WO0061739和WO0231240中描述的在具有功能性FUT8基因的细胞中产生的相同单克隆抗体的活性增加,所有这些文献均通过引用并入本文。本领域普通技术人员还将认识到其他适当的系统。
在本公开的一个实施方案中,抗原结合蛋白在FUT8基因已失活的宿主细胞中产生。在本发明的一个实施方案中,抗原结合蛋白在-/-FUT8宿主细胞中产生。在本发明的一个实施方案中,抗原结合蛋白在Asn297(IgGl)处无岩藻糖基化。
在一些实施方案中,可能需要修饰本文公开的抗原结合蛋白的效应功能,例如,以增强ADCC或CDC、半衰期等。在一个实施方案中,抗原结合蛋白可以是Fc失能的。实现Fc失能的一种方法包括重链恒定区位置235和237(EU索引编号)处的丙氨酸残基的取代。或者,抗原结合蛋白可以是Fc启用的并且不包含位置235和237处的丙氨酸取代。抗原结合蛋白可以在人体内或在鼠类动物模型体内具有至少6小时、至少1天、至少2天、至少3天、至少4天、至少5天、至少7天或至少9天的半衰期。
抗体的Fc效应部分的突变变化可用于改变FcRn和抗体之间相互作用的亲和力以调节抗体周转。抗体在体内的半衰期可以延长。这可能对患者群体有益,因为由于在较长时间内维持体内IC50,可以实现最大剂量量和最大给药频率。
在一些实施方案中,包含恒定区的抗原结合蛋白可具有降低的ADCC和/或补体激活或效应功能。恒定结构域可包含IgG2或IgG4同种型的天然失能恒定区或突变的IgG1恒定结构域。合适的修饰实例描述于EP0307434中。实现Fc失能的一种方法包括重链恒定区位置235和237(EU索引编号)处的丙氨酸残基的取代,即L235A和G237A(通常称为“LAGA”突变)。另一个实例包括在位置234和235(EU索引编号)处用丙氨酸取代,即L234A和L235A(通常称为“LALA”突变)。在一些实施方案中,本文公开的抗原结合蛋白的Fc效应功能已使用LAGA突变而失能。
降低效应功能的另外的改变和突变包括:(除非另有说明,否则参考IgG1):糖基化的N297A或N297Q或N297G;L235E;IgG4:F234A/L235A;和嵌合IgG2/IgG4。IgG2:H268Q/V309L/A330S/P331S和IgG2:V234A/G237A/P238S/H268A/V309L/A330S/P331S可以减少FcγR和C1q结合(Wang等人,2018andUS8,961,967)。
其他降低效应功能的突变包括L234F/L235E/P331S;使用来自人的IgG2的CH1和铰链区以及来自人IgG4的CH2和CH3区建立的嵌合抗体;IgG2m4,基于具有源自IgG4的四个关键氨基酸残基变化(H268Q、V309L、A330S和P331S)的IgG2同种型;IgG2σ,其含有V234A/G237A/P238S/H268A/V309L/A330S/P331S取代,以消除与Fcγ受体和C1q补体蛋白的亲和力;IgG2m4(H268Q/V309L/A330S/P331S,更改为IgG4);IgG4(S228P/L234A/L235A);huIgG1L234A/L235A(AA);huIgG4S228P/L234A/L235A;IgG1σ(L234A/L235A/G237A/P238S/H268A/A330S/P331S);IgG4σ1(S228P/F234A/L235A/G237A/P238S);和IgG4σ2(S228P/F234A/L235A/G236/G237A/P238S)(Tam等人,Antibodies2017,6(3))。
在一些实施方案中,本文公开的抗原结合蛋白可包含选自突变的恒定结构域的一个或多个修饰,使得抗体具有增强的效应功能/ADCC和/或补体激活。合适的修饰实例描述于Shields et al.J.Biol.Chem(2001)276:6591-6604,Lazar et al.PNAS(2006)103:4005-4010和US6737056、WO2004063351和WO2004029207。抗原结合蛋白可包含具有改变的糖基化特征的恒定结构域,使得抗原结合蛋白具有增强的效应功能/ADCC和/或补体激活。产生具有改变的糖基化特征的抗原结合蛋白的合适方法的实例描述于WO2003/011878、WO2006/014679和EP1229125中。
半衰期
半衰期是指抗原结合蛋白的血清浓度达到其原始值一半所需的时间。蛋白质的血清半衰期可以根据Kim et al.,1994,Eur.J.of Immuno.24:542-548描述的方法通过药代动力学研究来测量。根据该方法,将放射性标记的蛋白质静脉内注射到小鼠中,并且定期测量其血浆浓度作为时间的函数,例如在注射后约3分钟至约72小时。用于药代动力学分析和确定分子半衰期的其他方法是那些本领域技术人员所熟悉的。
本发明的抗原结合蛋白可具有增加恒定结构域或其片段对FcRn的亲和力的氨基酸修饰。增加治疗性和诊断性IgG抗体和其他生物活性分子的半衰期(即血清半衰期)有很多好处,包括减少这些分子的给药量和/或频率。在一个实施方案中,本发明的抗原结合蛋白包含具有一个或多个以下氨基酸修饰的IgG恒定结构域的全部或一部分(FcRn结合部分)。
例如,参考IgG1,M252Y/S254T/T256E(通常称为“YTE”突变)和M428L/N434S(通常称为“LS”突变)增加了pH6.0下的FcRn结合(Wang等人,2018)。
T250Q/M428L、V259I/V308F/M428L、N434A和T307A/E380A/N434A突变(参考IgG1和Kabat编号)也可以提高半衰期(Monnet等人)。
半衰期和FcRn结合还可以通过引入H433K和N434F突变(通常称为“HN”或“NHance”突变)(参考IgG1)来延长(WO2006/130834)。
WO00/42072公开了包含具有改变的FcRn结合亲和力的变体Fc区的多肽,该多肽在氨基酸位置238、252、253、254、255、256、265、272、286、288、303、305、307、309、311、312、317、340、356、360、362、376、378、380、386、388、400、413、415、424、433、434、435、436、439以及Fc区的447(欧盟索引编号)中的任一处或多处包含氨基酸修饰。
WO02/060919公开了修饰的IgG,其包含相对于野生型IgG恒定结构域含有一个或多个氨基酸修饰的IgG恒定结构域,其中修饰的IgG与具有野生型IgG恒定区的半衰期相比具有增加的半衰期,并且其中一个或多个氨基酸修饰处于位置251、253、255、285-290、308-314、385-389和428-435中的一个或多个处。
Shields et al.(2001,J Biol Chem;276:6591-604)使用丙氨酸扫描诱变来改变人IgGl抗体的Fc区中的残基,然后评估与人FcRn的结合。当改变为丙氨酸时,有效废除与FcRn结合的位置包括I253、S254、H435和Y436。其他位置显示出不太明显的结合减少,如下:E233-G236、R255、K288、L309、S415和H433。当改变为丙氨酸时,几个氨基酸位置表现出FcRn结合的改善;其中值得注意的是P238、T256、E272、V305、T307、Q311、D312、K317、D376、E380、E382、S424和N434。许多其他氨基酸位置在FcRn结合方面表现出轻微改善(D265、N286、V303、K360、Q362和A378)或没有变化(S239、K246、K248、D249、M252、E258、T260、S267、H268、S269、D270、K274、N276、Y278、D280、V282、E283、H285、T289、K290、R292、E293、E294、Q295、Y296、N297、S298、R301、N315、E318、K320、K322、S324、K326、A327、P329、P331、E333、K334、T335、S337、K338、K340、Q342、R344、E345、Q345、Q347、R356、M358、T359、K360、N361、Y373、S375、S383、N384、Q386、E388、N389、N390、K392、L398、S400、D401、K414、R416、Q418、Q419、N421、V422、E430、T437、K439、S440、S442、S444和K447)。
发现组合变体在改善FcRn结合方面具有最显著的效果。在pH6.0下,相对于天然IgG1,与E380A的2倍和N434A的3.5倍相比,E380A/N434A变体显示出超过8倍的更好的与FcRn的结合。添加T307A后,与天然IgG1相比,结合提高了12倍。在一个实施方案中,本发明的抗原结合蛋白包含E380A/N434A突变并且具有增加的与FcRn的结合。
Dall’Acqua et al.(2002,J Immunol.;169:5171-80)描述了针对小鼠FcRn的人IgG1铰链-Fc片段噬菌体展示文库的随机诱变和筛选。他们公开了位置251、252、254-256、308、309、311、312、314、385-387、389、428、433、434和436的随机诱变。当取代位于横跨Fc-FcRn界面的条带中的残基(M252、S254、T256、H433、N434和Y436)以及在较小程度上取代外围残基(例如V308、L309、Q311、G385、Q386、P387和N389)时,IgG1-人FcRn复合物稳定性发生重大改善。通过组合M252Y/S254T/T256E(“YTE”)和H433K/N434F/Y436H突变获得对人FcRn具有最高亲和力的变体,并且相对于野生型IgG1,亲和力增加了57倍。与野生型IgG1相比,这种突变的人IgG1的体内行为在食蟹猴中表现出血清半衰期近4倍的增加。
因此,本发明提供了具有与FcRn的优化结合的抗原结合蛋白。在一个优选的实施方案中,抗原结合蛋白在所述抗原结合蛋白的Fc区中包含至少一个氨基酸修饰,其中所述修饰位于选自下组的氨基酸位置处:Fc区的226、227、228、230、231、233、234、239、241、243、246、250、252、256、259、264、265、267、269、270、276、284、285、288、289、290、291、292、294、297、298、299、301、302、303、305、307、308、309、311、315、317、320、322、325、327、330、332、334、335、338、340、342、343、345、347、350、352、354、355、356、359、360、361、362、369、370、371、375、378、380、382、384、385、386、387、389、390、392、393、394、395、396、397、398、399、400、401、403、404、408、411、412、414、415、416、418、419、420、421、422、424、426、428、433、434、438、439、440、443、444、445、446和447。
另外,各种出版物描述了获得具有修饰的半衰期的生理活性分子的方法,通过将FcRn结合多肽引入分子中(WO97/43316、US5869046、US5747035、WO96/32478和WO91/14438)或通过将分子与FcRn结合亲和力被保留但对其他Fc受体的亲和力已极大降低的抗体进行融合(WO99/43713),或与抗体的FcRn结合结构域融合(WO00/09560、US4703039)。
在pH6.0下的筛选中鉴定出FcRn亲和力增强的Fc变体可提高抗体细胞毒性和半衰期。所选择的IgG变体可以作为低岩藻糖基化分子生产。产生的变体在hFcRn小鼠中显示出增加的血清持久性,以及保守的增强的ADCC(Monnet等人)。示例性变体包括(参考IgG1和Kabat编号):P230T/V303A/K322R/N389T/F404L/N434S;P228R/N434S;Q311R/K334R/Q342E/N434Y;C226G/Q386R/N434Y;T307P/N389T/N434Y;P230S/N434S;P230T/V305A/T307A/A378V/L398P/N434S;P23OT/P387S/N434S;P230Q/E269D/N434S;N276S/A378V/N434S;T307A/N315D/A330V/382V/N389T/N434Y;T256N/A378V/S383N/N434Y;N315D/A330V/N361D/A387V/N434Y;V259I/N315D/M428L/N434Y;P230S/N315D/M428L/N434Y;F241L/V264E/T307P/A378V/H433R;T250A/N389K/N434Y;V305A/N315D/A330V/P395A/N434Y;V264E/Q386R/P396L/N434S/K439R;E294del/T307P/N434Y(其中“del”表示缺失)。
抗体药物缀合物
还提供了包含缀合至一个或多个药物的根据本发明的抗原结合蛋白的免疫缀合物(可互换地称为“抗体-药物缀合物”、“ADC”或“抗原结合蛋白-药物缀合物”),所述药物例如为细胞毒性剂,例如化疗剂、免疫治疗剂、生长抑制剂、毒素(例如蛋白质毒素,如细菌、真菌、植物或动物来源的酶促活性毒素或其片段)、抗病毒剂、放射性同位素(即放射性缀合物)、抗生素或小干扰RNA(siRNA)。
免疫缀合物已在癌症治疗中用于细胞毒性剂的局部递送,细胞毒性剂即杀死或抑制细胞生长或增殖的药物(Lambert,J.(2005)Curr.Opinion in Pharmacology 5:543-549;Wu et al.(2005)Nature Biotechnology 23(9):1137-1146;Payne,G.(2003)i 3:207-212;Syrigos and Epenetos(1999)Anticancer Research 19:605-614;Niculescu-Duvaz and Springer(1997)Adv.Drug Deliv.Rev.26:151-172;U.S.Pat.No.4,975,278)。免疫缀合物尤其允许将药物部分靶向递送至肿瘤,并在其中进行细胞内积累,其中未缀合药物的全身施用可能会对正常细胞产生不可接受的毒性水平(Tsuchikama and An,Protein and Cell,(2018)9:33–46)。免疫缀合物可以选择性地将强效细胞毒性有效负载递送至靶癌细胞,从而导致与传统化疗相比提高的疗效、降低的全身毒性,以及更好的药代动力学(PK)/药效学(PD)和生物分布(Tsuchikama and An 2018;Beck A.et al(2017)NatureRev.Drug Disc.16:315-337)。
据报道,多克隆抗体和单克隆抗体都可用于这些策略(Rowland et al.,(1986)Cancer Immunol.Immunother.21:183-87)。这些方法中使用的药物包括道诺霉素、阿霉素、甲氨蝶呤和长春地辛(Rowland et al.,(1986)同上)。抗体-毒素缀合物中使用的毒素包括细菌毒素例如白喉毒素、植物毒素例如蓖麻毒素、小分子毒素例如格尔德霉素(Mandler etal(2000)J.Nat.Cancer Inst.92(19):1573-1581;Mandler et al(2000)Bioorganic&Med.Chem.Letters 10:1025-1028;Mandler et al(2002)Bioconjugate Chem.13:786-791),美登木素生物碱(EP 1391213;Liu et al.,(1996)Proc.Natl.Acad.Sci.USA 93:8618-8623)和卡奇霉素(Lode et al(1998)Cancer Res.58:2928;Hinman et al(1993)Cancer Res.53:3336-3342)。
在某些实施方案中,免疫缀合物包含抗原结合蛋白,例如抗体,和药物,例如毒素,例如化疗剂。药物可以被修饰(例如,通过标准合成化学)以允许其化学附着(例如,含有反应柄以允许其化学附着)至将药物连接至抗原结合蛋白的接头的反应性末端。
免疫缀合物的药物组分
本文描述了可用于产生免疫缀合物的药物,例如化疗剂。可以使用的酶促活性毒素及其片段包括白喉A链、白喉毒素的非结合活性片段、外毒素A链(来自铜绿假单胞菌)、蓖麻毒素A链、相思豆毒素A链、modeccin A链、α-八叠球菌素、油桐蛋白、石竹素蛋白、美洲商陆蛋白(PAPI、PAPII和PAP-S)、苦瓜抑制剂、麻疯树毒蛋白、巴豆素、肥皂草抑制剂、白树毒素、mitogellin、局限曲菌素、酚霉素、伊诺霉素和单端孢霉烯(tricothecene)。参见,例如1993年10月28日公布的WO93/21232。
除了毒素之外,放射性材料(例如放射性核苷酸)也可以用作ADC中的药物。多种放射性核苷酸可用于生产放射性缀合抗体。实例包括212Bi、131I、131In、90Y和186Re。
本发明的抗原结合蛋白(例如抗体)还可以缀合至一个或多个毒素,包括但不限于卡奇霉素、美登木素生物碱、海兔毒素、澳瑞他汀、单端孢霉烯和CC1065,以及这些毒素的具有毒素活性的衍生物。合适的细胞毒性剂包括但不限于澳瑞他汀,包括多缬氨酸-缬氨酸-多拉异亮氨酸-多拉脯氨酸-苯丙氨酸(MMAF)和单甲基澳瑞他汀E(MMAE)以及MMAE的酯形式、DNA小沟结合剂、DNA小沟烷化剂、烯二炔、lexitropsin、倍癌霉素、紫杉烷(例如紫杉醇和多西他赛)、嘌呤霉素、海兔毒素、美登木素生物碱和长春花生物碱。具体的细胞毒性剂包括拓扑替康、吗啉代-阿霉素、根霉素、氰基吗啉代-阿霉素、海兔毒素-10、棘霉素、combretatstatin、卡奇霉素、美登素、DM-1、DM-4和纺锤菌素。其他合适的细胞毒性剂包括抗微管蛋白剂,例如澳瑞他汀、长春花生物碱、鬼臼毒素、紫杉烷、浆果赤霉素衍生物、cryptophysin、美登木素生物碱、康普瑞汀或海兔毒素。抗微管蛋白剂包括二甲基缬氨酸-缬氨酸-多拉异亮氨酸-多拉脯氨酸-苯丙氨酸-对苯二胺(AFP)、MMAF、MMAE、澳瑞他汀E、长春新碱、长春花碱、长春地辛、长春瑞滨、VP-16、喜树碱、紫杉醇、多西他赛、埃博霉素A、埃博霉素B、诺考达唑、秋水仙碱、colcimid、雌莫司汀、西马多丁、圆皮海绵内酯、美登素、DM-1、DM-4和五加素。
抗体药物缀合物可以通过将抗微管蛋白剂单甲基澳瑞他汀E(MMAE)或单甲基澳瑞他汀F(MMAF)缀合至抗原结合蛋白(例如抗体)来产生。就MMAE而言,接头可由硫醇反应性马来酰亚胺、己酰基间隔基、二肽缬氨酸-瓜氨酸或对氨基苄氧基羰基(一种自消解断裂基团)组成。对于MMAF,可以使用蛋白酶抗性马来酰亚胺己酰基接头。缀合过程导致药物-抗体附着的异质性,与每个抗体分子结合的药物数量(摩尔比[MR])和附着位点都不同。最常见的种类是MR=4的材料;MR为0、2、6和8的材料不太常见。总体平均药物与抗体的MR为约4。
澳瑞他汀和海兔毒素
在一些实施方案中,免疫缀合物包含与海兔毒素或海兔毒素肽类似物或衍生物、澳瑞他汀(美国专利号5,635,483;5,780,588)缀合的抗原结合蛋白(例如抗体)。海兔毒素和澳瑞他汀已被证明可干扰微管动力学、GTP水解以及细胞核和细胞分裂(Woyke et al.(2001)Antimicrob.Agents and Chemother.45(12):3580-3584),并具有抗癌作用(美国专利号5,663,149)和抗真菌活性(Pettit et al.(1998)Antimicrob.Agents Chemother.42:2961-2965)。海兔毒素或澳瑞他汀(海兔毒素的五肽衍生物)药物部分可以通过肽药物部分的N(氨基)末端或C(羧基)末端连接至抗体(WO02/088172)。
示例性澳瑞他汀实施方案包括N-末端连接的单甲基澳瑞他汀药物部分DE和DF,其公开于"Monomethylvaline Compounds Capable of Conjugation to Ligands",美国专利号7,498,298中。如本文所用,缩写“MMAE”是指单甲基澳瑞他汀E。如本文所用,缩写“MMAF”是指多缬氨酸-缬氨酸-多拉异亮氨酸-多拉脯氨酸-苯丙氨酸。
通常,基于肽的药物部分可以通过在两个或更多个氨基酸和/或肽片段之间形成肽键来制备。此类肽键可以根据例如液相合成方法(参见E.Schroder and K.Lubke,"ThePeptides,"volume 1,pp 76-136,1965,Academic Press)来制备,该方法在肽化学领域是众所周知的。澳瑞他汀/海兔毒素药物部分可以根据以下中的方法制备:美国专利号5,635,483;美国专利号5,780,588;Pettit et al.(1989)J.Am.Chem.Soc.111:5463-5465;Pettitet al.(1998)Anti-Cancer Drug Design 13:243-277;Pettit,G.R.,et al.Synthesis,1996,719-725;和Pettit et al.(1996)J.Chem.Soc.Perkin Trans.15:859-863。还参见Doronina(2003)Nat Biotechnol 21(7):778-784;"Monomethylvaline CompoundsCapable of Conjugation to Ligands,"美国专利号7,498,298(公开了例如接头和制备与接头缀合的单甲基缬氨酸化合物(例如MMAE和MMAF)的方法)。充当细胞毒剂的生物活性有机化合物,特别是五肽,公开于美国专利号6,884,869;7,498,298;7,098,308;7,256,257;和7,423,116。
美登素和美登木素生物碱
美登木素生物碱是有丝分裂抑制剂,通过抑制微管蛋白聚合起作用。美登素首先从东非灌木Maytenus serrata中分离出来(美国专利号3,896,111)。随后,发现某些微生物也产生美登木素生物碱,例如美登醇和C-3美登醇酯(美国专利号4,151,042)。高细胞毒性的美登木素生物碱药物可以由微生物如放线菌发酵产生的安丝菌素前体制备。分离安丝菌素的方法描述于美国专利号6,573,074中。合成的美登醇及其衍生物和类似物公开于例如美国专利号4,137,230;4,248,870;4,256,746;4,260,608;4,265,814;4,294,757;4,307,016;4,308,268;4,308,269;4,309,428;4,313,946;4,315,929;4,317,821;4,322,348;4,331,598;4,361,650;4,364,866;4,424,219;4,450,254;4,362,663;和4,371,533中。
抗体-美登木素生物碱缀合物通过将抗原结合蛋白(例如抗体)与美登木素生物碱分子化学连接而制备,而不显著降低抗体或美登木素生物碱分子的生物活性。参见例如,美国专利号5,208,020。每个抗体分子平均缀合3-4个美登木素生物碱分子,已显示出增强靶细胞的细胞毒性功效,而不会对抗体的功能或溶解度产生负面影响,但是即使是一分子毒素/抗体也有望相比于裸抗体的使用增强细胞毒性。美登木素生物碱是本领域熟知的并且可以通过已知技术合成或从天然来源分离。合适的美登木素生物碱公开于例如美国专利号5,208,020以及上文提到的其他专利和非专利出版物中。美登木素生物碱是美登醇和在美登醇分子的芳环或其他位置进行修饰的美登醇类似物,例如各种美登醇酯。用于制备与抗体连接的美登木素生物碱的方法公开于例如美国专利号6,570,024和6,884,874中。
卡奇霉素
卡奇霉素家族抗生素能够在亚皮摩尔浓度下产生双链DNA断裂。对于卡奇霉素家族缀合物的制备,参见例如美国专利号5,712,374、5,714,586、5,739,116、5,767,285、5,770,701、5,770,710、5,773,001和5,877,296。可以使用的卡奇霉素的结构类似物包括但不限于1I、2I、3I、N-乙酰基1I、PSAG和I1(Hinman et al.,Cancer Research 53:3336-3342(1993),Lode et al.,Cancer Research 58:2925-2928(1998)和上述美国专利)。另一种可以与抗体缀合的抗肿瘤药物是QFA,它是一种抗叶酸剂。卡奇霉素和QFA均具有细胞内作用位点,并且不易穿过质膜。因此,这些药剂通过抗体介导的内化的细胞摄取极大增强了它们的细胞毒性作用。
其他细胞毒性剂
可以与抗原结合蛋白(例如抗体)缀合的其他细胞毒性剂,例如抗肿瘤剂,包括BCNU、链脲佐菌素(streptozoicin)、长春新碱和5-氟尿嘧啶,描述于美国专利号5,053,394和5,770,710中的统称为LL-E33288复合物的药剂家族,以及埃斯培拉霉素(美国专利号5,877,296)。
可以使用的酶促活性毒素及其片段包括白喉A链、白喉毒素的非结合活性片段、外毒素A链(来自铜绿假单胞菌)、蓖麻毒素A链、相思豆毒素A链、modeccin A链、α-八叠球菌素、油桐蛋白、石竹素蛋白、美洲商陆蛋白(PAPI、PAPII和PAP-S)、苦瓜抑制剂、麻疯树毒蛋白、巴豆素、肥皂草抑制剂、白树毒素、mitogellin、局限曲菌素、酚霉素、伊诺霉素和单端孢霉烯。参见例如1993年10月28日公开的WO 93/21232。
本发明还考虑了在抗原结合蛋白(例如抗体)和具有核酸溶解活性的化合物(例如核糖核酸酶或DNA核酸内切酶如脱氧核糖核酸酶;DNase)之间形成的免疫缀合物。
为了选择性破坏肿瘤,抗原结合蛋白(例如抗体)可以包含高放射性原子。多种放射性同位素可用于生产放射性缀合抗体。实例包括At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212和Lu的放射性同位素。当缀合物用于检测时,它可以包含用于闪烁法研究的放射性原子,例如tc99m或I123,或用于核磁共振(NMR)成像(也称为磁共振成像,mri)的自旋标记物,例如碘-123、碘-131、铟-111、氟-19、碳-13、氮-15、氧-17、钆、锰或铁。
放射性标记或其他标记可以以已知的方式掺入缀合物中。例如,肽可以是生物合成的,或者可以使用合适的氨基酸前体(包括例如代替氢的氟-19)通过化学氨基酸合成来合成。诸如tc99m或I123、Re186、Re188和In111等标记可以通过肽中的半胱氨酸残基附着。Yttrium-90可以通过赖氨酸残基附着。IODOGEN方法(Fraker et al.(1978)Biochem.Biophys.Res.Commun.80:49-57)可用于掺入碘-123。"Monoclonal Antibodiesin Immunoscintigraphy"(Chatal,CRC Press 1989)详细描述了其他方法。
在一些情况下,本文公开的抗BCMA抗原结合蛋白是包含根据本文所述的公开内容的抗原结合蛋白的免疫缀合物,包括但不限于缀合至一个或多个细胞毒性剂(例如化疗剂)、药物、生长抑制剂、毒素(例如蛋白质毒素、细菌、真菌、植物或动物来源的酶活性毒素或其片段)或放射性同位素(即放射性缀合物)的抗体。在一些情况下,抗BCMA抗原结合蛋白缀合至毒素例如澳瑞他汀,例如单甲基澳瑞他汀E(MMAE)或单甲基澳瑞他汀F(MMAF)。在一些实施方案中,抗BCMA抗原结合蛋白缀合至AFP、MMAF、MMAE、AEB、AEVB或澳瑞他汀E。在一些实施方案中,抗BCMA抗原结合蛋白缀合至紫杉醇、多西他赛、CC-1065、SN-38、拓扑替康、吗啉代-阿霉素、根霉素、氰基吗啉代-阿霉素、海兔毒素-10、棘霉素、combretatstatin、卡奇霉素或纺锤菌素。在一些实施方案中,抗BCMA抗原结合蛋白缀合至澳瑞他汀、美登木素生物碱或卡奇霉素。在一些实施方案中,抗BCMA抗原结合蛋白缀合至AFP、MMAP、MMAE、AEB、AEVB、澳瑞他汀E、长春新碱、长春花碱、长春地辛、长春瑞滨、VP-16、喜树碱、紫杉醇、多西他赛、埃博霉素A、埃博霉素B、诺考达唑、秋水仙碱、colcimid、雌莫司汀、西马多丁、圆皮海绵内酯、美登醇、美登素、DM1、DM2、DM3、DM4或五加素。
在一些情况下,缀合至毒素的抗BCMA抗原结合蛋白可包括重链,该重链具有包含、基本上组成为或组成为SEQ ID NO:1中列出的氨基酸序列的VHCDR1,包含、基本上组成为或组成为SEQ ID NO:2中列出的氨基酸序列的VHCDR2,以及包含、基本上组成为或组成为SEQID NO:3中列出的氨基酸序列的VHCDR3。例如,与本文描述的毒素缀合的抗BCMA抗原结合蛋白可以包括重链可变区,该重链可变区包括SEQ ID NO:7中列出的氨基酸序列。在一些情况下,与本文所述的毒素缀合的抗BCMA抗原结合蛋白可包括包含SEQ ID NO:9中列出的氨基酸序列的重链。
在一些情况下,缀合至毒素的抗BCMA抗原结合蛋白可包括轻链,该轻链具有包含、基本上组成为或组成为SEQ ID NO:4中列出的氨基酸序列的VLCDR1,包含、基本上组成为或组成为SEQ ID NO:5中列出的氨基酸序列的VLCDR2,以及包含、基本上组成为或组成为SEQID NO:6中列出的氨基酸序列的VLCDR3。缀合至本文所述毒素的抗BCMA抗原结合蛋白可包括轻链可变区,该轻链可变区包括SEQ ID NO:8中列出的氨基酸序列。在一些情况下,与本文所述的毒素缀合的抗BCMA抗原结合蛋白可包括SEQ ID NO:10中列出的氨基酸序列的轻链。
在一些情况下,缀合至毒素的抗BCMA抗原结合蛋白可包括重链,该重链具有包含SEQ ID NO:1中列出的氨基酸序列的VHCDR1、包含SEQ ID NO:2中列出的氨基酸序列的VHCDR2和包含SEQ ID NO:3中列出的氨基酸序列的VHCDR3,并且可以包括轻链,该轻链具有包含SEQ ID NO:4中列出的氨基酸序列的VLCDR1、包含SEQ ID NO:5中列出的氨基酸序列VLCDR2和包含SEQ ID NO:6中列出的氨基酸序列VLCDR3。例如,缀合至毒素的抗BCMA抗原结合蛋白可包括含有SEQ ID NO:7中列出的氨基酸序列的重链可变区,并且可包括含有SEQID NO:8中列出的氨基酸序列的轻链可变区。在一些情况下,与本文所述的毒素缀合的抗BCMA抗原结合蛋白可以包括包含SEQ ID NO:9中列出的氨基酸序列的重链并且可以包括包含SEQ ID NO:10中列出的氨基酸序列的轻链。
在一些实施方案中,本文公开的抗BCMA抗原结合蛋白包含SEQ ID NO:19、23或27的重链可变区。在一些实施方案中,本文公开的抗BCMA抗原结合蛋白包含SEQ ID NO:20、24或28的轻链可变区。在一些实施方案中,本文公开的抗BCMA抗原结合蛋白包含SEQ ID NO:21、25、30或32的重链区。本文公开的抗原结合蛋白包含SEQ ID NO:22、26、31或33的轻链区。在一些实施方案中,本文公开的抗BCMA抗原结合蛋白包含SEQ ID NO:19的重链可变区和SEQ ID NO:20的轻链可变区、SEQ ID NO:23的重链可变区和SEQ ID NO:24的轻链可变区、或SEQ ID NO:27的重链可变区和SEQ ID NO:28的轻链可变区。在一些实施方案中,本文公开的抗BCMA抗原结合蛋白包含SEQ ID NO:21的重链区和SEQ ID NO:22的轻链、SEQ IDNO:25的重链区和SEQ ID NO:26的轻链、SEQ ID NO:30的重链区和SEQ ID NO:31的轻链、或SEQ ID NO:32的重链区和SEQ ID NO:33的轻链。在一些实施方案中,本文公开的抗BCMA抗原结合蛋白是包含SEQ ID NO:29的scFV-fc。
在一些情况下,抗BCMA抗原结合蛋白是具有以下通用结构的免疫缀合物:
ABP-((接头)n-Ctx)m
其中
ABP是抗原结合蛋白
接头不存在或者是任何可切割或不可切割的接头
Ctx是本文描述的任何细胞毒性剂
n为0、1、2或3,并且
m为1、2、3、4、5、6、7、8、9或10。
示例性接头包括6-马来酰亚胺己酰基(MC)、马来酰亚胺丙酰基(MP)、缬氨酸-瓜氨酸(val-cit)、丙氨酸-苯丙氨酸(ala-phe)、对氨基苄氧基羰基(PAB)、N-琥珀酰亚胺基4-(2-吡啶基硫代)戊酸酯(SPP)、N-琥珀酰亚胺基4-(N-马来酰亚胺甲基)环己烷-1羧酸酯(SMCC)和N-琥珀酰亚胺基(4-碘代-乙酰基)氨基苯甲酸酯(SIAB)。
在一些情况下,抗BCMA抗原结合蛋白是含有连接至MMAE或MMAF的单克隆抗体的免疫缀合物。在另一个实施方案中,抗BCMA抗原结合蛋白是含有通过MC接头连接至MMAE或MMAF的单克隆抗体的免疫缀合物,如以下结构所示:
在一些情况下,抗BCMA抗原结合蛋白是抗体belantamab。在另一个实施方案中,抗BCMA抗原结合蛋白是免疫缀合物贝兰他单抗莫福汀。
在一些情况下,本公开的缀合抗体(抗体-药物缀合物或ADC)是强效的抗癌剂,被设计为允许高效的细胞毒性剂特异性靶向肿瘤细胞,同时不伤害健康组织。尽管使用了肿瘤特异性抗体,但新出现的ADC临床数据表明,在ADC达到最佳治疗剂量之前,不良事件经常发生。因此,尽管这些ADC在临床前肿瘤模型中具有高活性,但它们在临床中的治疗窗口很窄,而且给药方案似乎受到无法总是根据临床前模型的数据进行预测的剂量限制性毒性的阻碍。
可以联合起来协同增强治疗功效而不恶化安全特征的疗法将是癌症患者治疗中的重大进步,特别是在治疗新兴不良事件(例如眼毒性)的发生率和严重性方面。
从根本上说,与可以增强剂量功效的药物的组合,导致明显更高的总体响应率(ORR),同时具有最佳的获益-风险特征,这将导致用这种抗原结合蛋白治疗的患者的管理中的范式转移。
病症
在一些情况下,本文公开的组合治疗B细胞病症。B细胞病症可分为B细胞发育/免疫球蛋白生产的缺陷(免疫缺陷)和过度/不受控制的增殖(淋巴瘤、白血病)。如本文所用,B细胞病症指两种类型的疾病,并且提供了用抗原结合蛋白治疗B细胞病症的方法。
癌症并且特别是B细胞介导的或浆细胞介导的疾病或抗体介导的疾病或病症的实例包括多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、滤泡性淋巴瘤(FL)、弥漫性大B细胞淋巴瘤(DLBCL)、非分泌性多发性骨髓瘤、冒烟型多发性骨髓瘤、意义未明的单克隆丙种球蛋白病(MGUS)、孤立性浆细胞瘤(骨,髓外)、淋巴浆细胞淋巴瘤(LPL)、华氏巨球蛋白血症、浆细胞白血病、重链病、系统性红斑狼疮(SLE)、POEMS综合征/骨硬化性骨髓瘤、I型和II型冷球蛋白血症、轻链沉积病、Goodpasture综合征、特发性血小板减少性紫癜(ITP)、急性肾小球肾炎、天疱疮和类天疱疮病症、以及获得性大疱性表皮松解症;或任何非霍奇金淋巴瘤B细胞白血病(NHL)和霍奇金淋巴瘤(HL)。在一些情况下,疾病或病症选自多发性骨髓瘤(MM)、非霍奇金淋巴瘤B细胞白血病(NHL)、滤泡性淋巴瘤(FL)和弥漫性大B细胞淋巴瘤(DLBCL)。在某些情况下,疾病是多发性骨髓瘤或非霍奇金淋巴瘤B细胞白血病(NHL)。在某些情况下,疾病是多发性骨髓瘤。
在一些情况下,癌症可以是造血(或血液的或血液学的或血液相关的)癌症,例如源自血细胞或免疫细胞的癌症,其可被称为“液体肿瘤”。在一些情况下,癌症是B细胞相关癌症,特别是表达BCMA的癌症。在一些情况下,癌症是白血病,例如慢性髓细胞白血病、急性髓细胞白血病、慢性淋巴细胞白血病和急性淋巴细胞白血病。在另一种情况下,癌症是淋巴瘤,例如非霍奇金淋巴瘤、霍奇金淋巴瘤等。在另一种情况下,癌症是浆细胞恶性肿瘤,例如多发性骨髓瘤和华氏巨球蛋白血症。在一些实施方案中,本文公开的组合治疗AL淀粉样变性。
在一些情况下,癌症是多发性骨髓瘤。在一些情况下,癌症是复发性和/或难治性多发性骨髓瘤。在一些情况下,患有复发性和/或难治性多发性骨髓瘤的患者先前已用至少一种、至少两种、至少三种或至少四种治疗剂治疗以治疗多发性骨髓瘤。
先前治疗
在一些情况下,本文描述的受试者在用本文描述的组合治疗之前可以已经具有0、1、2、3或4或更多线的先前治疗。在另一个实施方案中,受试者可患有复发性和/或难治性多发性骨髓瘤,并且在用本文所述的组合治疗之前已经具有0、1、2、3或4或更多线的先前治疗。在另一个实施方案中,受试者先前已用至少3个前线治疗,该前线治疗可包括以下:免疫调节药物(IMiD)、蛋白酶体抑制剂(PI)和抗CD38治疗(例如,达雷木单抗)或其组合。治疗线可由国际骨髓瘤研讨会(IMWG)的共识小组定义[Rajkumar,2011]。
在一些情况下,受试者在用本文所述的组合治疗之前可以已经具有0、1、2、3或4或更多线的先前治疗,其中一个或多个前线治疗不成功。在一些情况下,与前线治疗相关的不良事件迫使前线治疗中止。当可如本文所述治疗的哺乳动物(例如,人)是在如本文所述治疗之前已经具有0、1、2、3、或4或更多线的先前治疗的哺乳动物时,前线治疗可以是任何适当的治疗。例如,在如本文所述进行治疗之前已经具有0、1、2、3或4或更多线的先前治疗的哺乳动物,可以先前已经用免疫调节药物(IMiD)、蛋白酶体抑制剂(PI)、抗CD38治疗或其组合进行治疗。
在一些情况下,具有前线治疗的受试者可患有复发的、复发性和/或难治性的癌症。在一些情况下,癌症可以是原发性癌症。在一些情况下,癌症可以是转移性癌症。在一些情况下,癌症可以是化疗抗性的癌症。在一些情况下,癌症可以是B细胞癌症(例如白血病和淋巴瘤)。可以如本文所述治疗的癌症的实例包括但不限于多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、慢性髓细胞白血病、急性髓细胞白血病、急性淋巴细胞白血病、滤泡性淋巴瘤(FL)、弥漫性大B-细胞淋巴瘤(DLBCL)、非分泌性多发性骨髓瘤、冒烟性多发性骨髓瘤、意义未明的单克隆丙种球蛋白病(MGUS)、孤立性浆细胞瘤(例如骨孤立性浆细胞瘤和髓外孤立性浆细胞瘤)、淋巴浆细胞淋巴瘤(LPL)、华氏巨球蛋白血症、浆细胞白血病、重链病、系统性红斑狼疮(SLE)、POEMS综合征、骨硬化性骨髓瘤、I型和II型冷球蛋白血症、轻链沉积病、Goodpasture综合征、特发性血小板减少性紫癜(ITP)、急性肾小球肾炎、天疱疮和类天疱疮症状、获得性大疱性表皮松解症、非霍奇金淋巴瘤、B细胞白血病和霍奇金淋巴瘤。
使用声明
在一些情况下,本文公开的组合可用于治疗BCMA抗原结合蛋白指示的疾病或病症,例如癌症。此类治疗可包括:(i)对BCMA多肽具有结合特异性的抗BCMA抗原结合蛋白或ADC和(ii)一个或多个T细胞衔接器。在一些情况下,可以向哺乳动物(例如,人,如患有癌症的人)施用:(i)包含对BCMA多肽具有结合特异性的抗BCMA抗原结合蛋白或ADC的多肽和(ii)一个或多个T细胞衔接器。在一些情况下,本文公开的组合将ADC的细胞毒性剂靶向表达BCMA多肽(例如,在细胞表面上表达BCMA多肽)的细胞(例如,癌细胞)并刺激(例如,诱导或增强)针对表达癌症相关抗原的细胞(例如癌细胞)的免疫反应。在一些情况下,BCMA抗原结合蛋白和T细胞衔接器可以结合至同一癌细胞。在一些情况下,抗BCMA抗原结合蛋白和T细胞衔接器可以结合至不同的癌细胞。在一些情况下,抗BCMA抗原结合蛋白和T细胞衔接器可以与相同或不同的癌细胞相互作用。
在一些情况下,本文公开的组合用于治疗受试者。术语“个体”、“受试者”和“患者”在本文中可互换使用。受试者通常是人类。受试者还可以是哺乳动物,例如小鼠、大鼠或灵长类动物(例如狨猴或猴子)。受试者可以是非人类动物。待治疗的受试者可以是农场动物,例如牛或公牛、绵羊、猪、牛、山羊或马或可以是家畜如狗或猫。动物可以是任何年龄的动物,或者是成熟的成年动物。在一些实施方案中,治疗可以是治疗性的、预防的或预防性的。受试者可以是需要其的个体。需要治疗的受试者可包括已经患有医学疾病的个体以及将来可能患上该疾病的个体。
因此,本文所述的组合物可用于预防的或预防性的治疗。在这种情况下,将本文所述的组合物施用于个体以预防或延迟疾病的一个或多个方面或症状的发作。受试者可以是无症状的。受试者可具有该疾病的遗传倾向。在一些实施方案中,将本文公开的组合的预防有效量施用于这样的个体。在一些实施方案中,预防有效量是预防或延迟本文所述疾病的一个或多个方面或症状发生的量。
本文公开的组合也可用于治疗方法中。术语“治疗”涵盖疾病的至少一个方面或症状的减轻、减少或预防。例如,本文公开的组合可用于改善或减少本文所述疾病的一个或多个方面或症状。
在一些情况下,本文描述的组合以治疗的、预防的或预防性的治疗的有效量使用。在一些情况下,本文所述的组合的治疗有效量是有效改善或减少疾病的一个或多个方面或症状的量。在一些情况下,本文公开的组合还可以对受试者的健康具有普遍有益的影响,例如它可以增加受试者的预期寿命。
本文描述的组合不需要导致完全治愈或根除疾病的每种症状或表现以构成可行的治疗性治疗。如相关领域所认识到的,用作治疗剂的药物可以降低给定疾病状态的严重性,但不需要消除疾病的每种表现才被视为有用的治疗剂。类似地,为了构成可行的预防剂,预防性施用的治疗不需要完全有效地预防疾病的发作。简单地减少疾病的影响(例如,通过减少其症状的数量或严重程度,或通过提高另一种治疗的有效性,或通过产生另一种有益效果),或降低疾病会发生的可能性(例如通过延迟疾病发作)或恶化就足够了。
在一些情况下,本文提供的材料和方法可用于减少或消除患有癌症的哺乳动物(例如,人)体内存在的癌细胞数量。例如,可以向需要其的哺乳动物(例如,患有癌症的哺乳动物)施用抗BCMA抗原结合蛋白和T细胞衔接器,以使患有癌症的哺乳动物体内存在的癌细胞数量(例如,从患有癌症的哺乳动物获得的样品中存在的癌细胞数量)减少例如至少约10%、20%、30%、40%、50%、60%、70%、80%、90%、95%或更多百分比。在一些情况下,从患有癌症的哺乳动物获得的样品中不存在癌细胞。例如,可以向需要其的哺乳动物(例如,患有癌症的哺乳动物)施用抗BCMA抗原结合蛋白和T细胞衔接器,以使患有癌症的哺乳动物体内存在的一个或多个肿瘤的大小(例如,体积)减小例如至少约10%、20%、30%、40%、50%、60%、70%、80%、90%、95%或更多百分比。在一些情况下,可以监测正在治疗的哺乳动物体内存在的癌细胞数量。可以使用任何适当的方法来确定哺乳动物体内存在的癌细胞数量是否减少。例如,成像技术可用于评估哺乳动物体内存在的癌细胞数量。
在一些情况下,本文提供的材料和方法可用于改善患有癌症的哺乳动物(例如,人)的存活率。例如,可以向需要其的哺乳动物(例如患有癌症的哺乳动物)施用抗BCMA抗原结合蛋白和T细胞衔接器以改善哺乳动物的存活率。例如,本文所述的材料和方法可用于将患有癌症的哺乳动物的存活提高例如至少约10%、20%、30%、40%、50%、60%、70%、80%、90%、95%或更多百分比。例如,本文描述的材料和方法可用于将患有癌症的哺乳动物的存活率提高例如至少约3个月(例如,至少约3个月、至少约6个月、至少约8个月、至少约10个月、至少约1年、至少约1.5年、至少约2年、至少约2.5年、至少约3年、至少约4年、至少约5年或更多)。
在一些情况下,本文提供的材料和方法可用于治疗患有癌症的哺乳动物(例如,人),使得该哺乳动物可以经历最小的、减少的或没有副作用。例如,当施用本文公开的组合(例如抗BCMA抗原结合蛋白和T细胞衔接器)时,与患有癌症并且单独施用抗BCMA抗原结合蛋白或单独施用T细胞衔接器的哺乳动物相比,哺乳动物可以经历最小的、减少的或没有副作用。患有癌症的哺乳动物可经历的副作用的实例包括但不限于选自以下的一个或多个副作用:视力或眼睛变化,例如眼部检查的发现(角膜病)、视力下降或视力模糊、恶心、低血细胞计数、发烧、输液相关反应、疲倦、肾或肝功能血液检测变化、血小板减少、眼毒性(例如角膜上皮变化、干眼、刺激、发红、视力模糊、干眼、畏光和视力变化)。
在一些情况下,提供了包含抗BCMA抗原结合蛋白和T细胞衔接器的组合,其用于预防和/或减少患有癌症例如多发性骨髓瘤的患者的眼毒性。在一个实施方案中,当与单独用抗BCMA抗原结合蛋白治疗(单一疗法)的患者相比时,预防或减少了眼毒性。在一些实施方案中,与单独用抗BCMA抗原结合蛋白的治疗相比,本文公开的组合,例如抗BCMA抗原结合蛋白和T细胞衔接器,减少/减缓Snellen视力从基线下降1行。在一些实施方案中,与单独用抗BCMA抗原结合蛋白的治疗相比,本文公开的组合,例如抗BCMA抗原结合蛋白和T细胞衔接器,减少/减缓Snellen视力从基线下降2或3行。在一些实施方案中,与单独用抗BCMA抗原结合蛋白的治疗相比,本文公开的组合,例如抗BCMA抗原结合蛋白和T细胞衔接器,减少/减缓Snellen视力从基线下降超过3行。在一些实施方案中,与单独用抗BCMA抗原结合蛋白的治疗相比,本文公开的组合,例如抗BCMA抗原结合蛋白和T细胞衔接器,减少/减缓Snellen视力从基线的变化。在一些实施方案中,与单独用抗BCMA抗原结合蛋白的治疗相比,本文公开的组合,例如抗BCMA抗原结合蛋白和T细胞衔接器,减少/减缓logMAR(最小分辨率角的对数)单位从基线的下降。在一些实施方案中,与单独使用抗BCMA抗原结合蛋白的治疗相比,本文公开的组合,例如抗BCMA抗原结合蛋白和T细胞衔接器,减少/减缓或预防受试者的轻度浅表角膜病、中度浅表角膜病、重度浅表角膜病或角膜上皮缺陷的发展。在一些实施方案中,与单独用抗BCMA抗原结合蛋白的治疗相比,本文公开的组合,例如抗BCMA抗原结合蛋白和T细胞衔接器,预防受试者的轻度浅表角膜病、中度浅表角膜病、重度浅表角膜病或角膜上皮缺陷。
“眼毒性”是指治疗剂对眼组织的任何意外暴露。眼毒性可包括:角膜上皮变化、干眼、刺激、发红、视力模糊、干眼、畏光和/或视力变化。
眼科检查可由眼科医生或验光师进行。眼科检查可包括以下中的一项或多项:
1.最佳矫正视力,
2.主觉验光的记录以及用于获得最佳矫正视力的方法,
3.当前的眼镜处方(如果适用),
4.眼压测量,
5.眼前节(裂隙灯)检查,包括角膜荧光素染色和晶状体检查,
6.散瞳眼底镜检查,和/或
7.眼表疾病指数(OSDI),其是用于评估潜在的眼部视力变化对功能和健康相关生活质量的影响的视觉功能问卷。
上述方法是本领域技术人员已知并熟练的。眼科检查可以在治疗之前、期间和/或之后进行。
在本公开的一个方面,提供了在需要其的受试者中治疗癌症的方法,包括施用治疗有效剂量的根据本公开抗BCMA抗原结合蛋白和T细胞衔接器。
T细胞衔接器
本文公开了包含(i)包含对BCMA多肽具有结合特异性的抗BCMA抗原结合蛋白或ADC的多肽和(ii)一个或多个T细胞衔接器的组合。本文公开的T细胞衔接器可以针对T细胞和肿瘤相关抗原。任何合适的T细胞衔接器可用于治疗患有本文所述的癌症的哺乳动物(例如,人)。在一些情况下,T细胞衔接器可以是双特异性T细胞衔接器(BiTE)。在一些情况下,本文所述的T细胞衔接器是结合CD3和BCMA(CD3xBCMA)的双特异性T细胞衔接器。在一些情况下,本文所述的T细胞衔接器是结合CD3和GPRC5D(CD3xGPRC5D)的双特异性T细胞衔接器。在一些情况下,本文所述的T细胞衔接器是结合CD3和FcRH5(CD3xFcRH5)的双特异性T细胞衔接器。在一些情况下,T细胞衔接器可以是检查点抑制性T细胞衔接器(CiTE)。在一些情况下,T细胞衔接器可以是同时多重相互作用T细胞衔接器(SMITE)。在一些情况下,T细胞衔接器可以是三特异性杀伤衔接器(TriKE)。在一些实施方案中,本文公开的T细胞衔接器结合BCMA。在一些实施方案中,本文公开的T细胞衔接器结合GPRC5D。在一些实施方案中,本文公开的T细胞衔接器结合FcRH5。在一些实施方案中,本文公开的T细胞衔接器结合CD38。在一些实施方案中,本文公开的T细胞衔接器不结合BCMA。在一些实施方案中,本文公开的T细胞衔接器不结合GPRC5D。在一些实施方案中,本文公开的T细胞衔接器不结合FcRH5。在一些实施方案中,本文公开的T细胞衔接器不结合CD38。
在一些情况下,本文公开的T细胞衔接器结合人CD3。在一些情况下,CD3是活化T细胞抗原。本文使用的“活化T细胞抗原”可以指在T淋巴细胞、特别是细胞毒性T淋巴细胞表面上表达的抗原决定簇,其能够在与抗原结合分子相互作用时诱导T细胞激活。具体地,抗原结合分子与活化T细胞抗原的相互作用可以通过触发T细胞受体复合物的信号级联放大来诱导T细胞激活。在一些情况下,本文公开的T细胞衔接器能够诱导T细胞激活。本文使用的“T细胞激活”可以指T淋巴细胞、特别是细胞毒性T淋巴细胞的一个或多个选自以下的细胞应答:增殖、分化、细胞因子分泌、细胞毒性效应分子释放、细胞毒性活性和活化标记物的表达。在一些情况下,本文公开的T细胞衔接器是双特异性的。在一些情况下,本文公开的T细胞接合器结合人肿瘤细胞上表达的至少一个表面分子。在一些情况下,本文公开的T细胞衔接器结合BCMA、CD19、CD20、CD30、CD33、CD38、CD44、CD123、CD138、CEA、CLEC12A、CS-1、EGFR、EGFRvIII、EPCAM、DLL3、LGR5、MSLN、FOLR1、FOLR3、HER2、HM1.24、MCSP、PSMA或其组合。
可用于治疗患有本文所述癌症的哺乳动物的T细胞衔接器的实例可包括但不限于cevostamab、talquetamab、Teclistimab、PF-3135、TNB-383B、REGN5458、博纳吐单抗、索利托单抗、sibrotuzumab、fresolimumab、defactinib AZD4547或其组合。在一些情况下,本文公开的组合包含Teclistimab、PF-3135、TNB-383B、REGN5458或其组合。在一些情况下,本文公开的组合包含CC-93269、AMG701、JNJ-7957、GBR1342或其组合。在一些情况下,本文公开的组合包含Talquetamab。在一些情况下,本文公开的组合包含Cevostamab。在一些情况下,本文公开的组合物包含至少约1mg、1.5mg、2mg、3mg、3.6mg、10mg、15mg、20mg、90mg或132mgCevostamab。
Cevostamab是双特异性T细胞衔接器抗体,其由两个单链可变片段(scFv)组成,一个直接针对肿瘤相关抗原Fc受体样蛋白5(FCRH5;CD307;FCRL5;IRTA2;BXMAS1),另一个直接针对T淋巴细胞上存在的CD3抗原。在一些情况下,在施用cevostamab后,双特异性抗体与细胞毒性T淋巴细胞(CTL)上的CD3抗原和表达FCRH5的肿瘤细胞上存在的FCRH5结合。在一些情况下,这会激活CTL并使CTL与表达FCRH5的肿瘤细胞交联,从而导致CTL介导的表达FCRH5的肿瘤细胞死亡。在一些情况下,FCRH5(一种免疫受体易位相关蛋白/Fc受体同源物(IRTA/FCRH)家族成员和B细胞谱系标记物)在骨髓瘤细胞上过表达。
在一些实施方案中,T细胞衔接器包含对FCRL5特异性的scFv并且包含与SEQ IDNO:11中列出的氨基酸序列具有至少80%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的重链可变区。在一些实施方案中,T细胞衔接器包含对FCRL5特异性的scFv并且包含与SEQ ID NO:12中列出的氨基酸序列具有至少80%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的轻链可变区。在一些实施方案中,T细胞衔接器包含对FCRL5特异性的scFv并且包含具有SEQ ID NO:11中列出的氨基酸序列的重链可变区。在一些实施方案中,T细胞衔接器包含对FCRL5特异性的scFv并且包含具有SEQ ID NO:12中列出的氨基酸序列的轻链可变区。在一些实施方案中,T细胞衔接器包含对CD3特异性的活化T细胞抗原结合scFv并且包含与SEQ ID NO:13中列出的氨基酸序列具有至少80%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的重链可变区。在一些实施方案中,T细胞衔接器包含对CD3特异性的活化T细胞抗原结合scFv并且包含与SEQ ID NO:14中列出的氨基酸序列具有至少80%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的轻链可变区。在一些实施方案中,T细胞衔接器包含对CD3特异性的活化T细胞抗原结合scFv并且包含具有SEQ ID NO:13中列出的氨基酸序列的重链可变区。在一些实施方案中,T细胞衔接器包含对CD3特异性的活化T细胞抗原结合scFv并且包含具有SEQ ID NO:14中列出的氨基酸序列的轻链可变区。在一些实施方案中,T细胞衔接器包含SEQ ID NO:11、12、13和14中列出的序列。在一些实施方案中,T细胞衔接器包含与SEQ ID NO:15和17中列出的重链具有至少80%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列。在一些实施方案中,T细胞衔接器包含与SEQ ID NO:16和18中列出的轻链具有至少80%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列。在一些实施方案中,T细胞衔接器包含SEQ ID NO:15和17中列出的重链的氨基酸序列;以及SEQ ID NO:16和18中列出的轻链。
表4:示例性T细胞衔接器序列。
Talquetamab是针对人CD3和人G蛋白偶联受体家族C组5成员D(GPRC5D)(一种肿瘤相关抗原)的双特异性人源化单克隆抗体。在一些情况下,施用后,Talquetamab与T细胞上的CD3和某些肿瘤细胞上表达的GPRC5D结合。在一些情况下,这会导致T细胞和肿瘤细胞交联,并诱导针对表达GPRC5D的肿瘤细胞的有效细胞毒性T淋巴细胞(CTL)反应。在一些情况下,GPRC5D在某些肿瘤(例如多发性骨髓瘤)上过表达,而在正常健康细胞上最低限度表达,并在肿瘤细胞增殖中发挥关键作用。
博纳吐单抗是重组单链抗CD19/抗CD3双特异性单克隆抗体。博纳吐单抗拥有两个抗原识别位点,一个针对CD3复合物,一个针对CD19(一种在B细胞表面过表达的肿瘤相关抗原)。在一些情况下,博纳吐单抗将表达CD19的肿瘤B细胞与细胞毒性T淋巴细胞(CTL)和辅助T淋巴细胞(HTL)结合在一起,导致CTL和HTL介导的表达CD19的B淋巴细胞死亡。
索利托单抗是针对CD3和上皮细胞粘附分子(EpCAM)的重组双特异性单克隆抗体。在一些情况下,索利托单抗附着于表达CD3的T淋巴细胞和表达EpCAM的肿瘤细胞,从而选择性地交联肿瘤和T淋巴细胞。在一些情况下,这会导致细胞毒性T淋巴细胞(CTL)募集至T淋巴细胞/肿瘤细胞聚集体,以及CTL介导的表达EpCAM的肿瘤细胞死亡。
REGN5458是人双特异性T细胞衔接器抗体,由两个单链可变片段(scFv)组成:一个直接针对BCMA,另一个直接针对T淋巴细胞上表达的CD3抗原。在一些情况下,施用后,抗BCMA/抗CD3 REGN5458与细胞毒性T淋巴细胞(CTL)上的CD3和表达BCMA的肿瘤细胞上的BCMA结合。在一些情况下,这激活了CTL并将其重定向至表达BCMA的肿瘤细胞,从而导致CTL介导的对表达BCMA的肿瘤细胞的杀伤。
TNB-383B是针对肿瘤相关抗原BCMA和T淋巴细胞上的CD3抗原的双特异性抗体。TNB-383B由一个臂上按顺序排列的两个抗BCMA部分、一个单一的抗CD3臂和一个沉默的IgG4 Fc组成。在一些情况下,在施用抗BCMA/抗CD3 T细胞衔接双特异性抗体TNB-383B后,该双特异性抗体与细胞毒性T淋巴细胞(CTL)上的CD3和表达BCMA的肿瘤细胞上存在的BCMA结合。在一些情况下,这激活了CTL并将其重定向至表达BCMA的肿瘤细胞,从而导致CTL介导的表达BCMA的肿瘤细胞死亡。
剂量
在一些情况下,本文提供了用于治疗癌症的包含治疗有效剂量的抗BCMA抗原结合蛋白和T细胞衔接器的组合,该抗BCMA抗原结合蛋白包含根据SEQ ID NO:1的CDRH1;根据SEQ ID NO:2的CDRH2;根据SEQ ID NO:3的CDRH3;根据SEQ ID NO:4的CDRL1;根据SEQ IDNO:5的CDRL2;和根据SEQ ID NO:6的CDRL3。
在一些情况下,本文提供了用于治疗癌症的包含治疗有效剂量的抗BCMA抗原结合蛋白和T细胞衔接器的组合,该抗BCMA抗原结合蛋白包含根据SEQ ID NO:7的重链可变区(VH)和根据SEQ ID NO:8的轻链可变区(VL)。
在一些情况下,本文提供了用于治疗癌症的包含治疗有效剂量的抗BCMA抗原结合蛋白和T细胞衔接器的组合,该抗BCMA抗原结合蛋白包含根据SEQ ID NO:9的重链(H)和根据SEQ ID NO:10的轻链(L)。
在一些实施方案中,本文公开的抗BCMA抗原结合蛋白包含SEQ ID NO:19、23或27的重链可变区。在一些实施方案中,本文公开的抗BCMA抗原结合蛋白包含SEQ ID NO:20、24或28的轻链可变区。在一些实施方案中,本文公开的抗BCMA抗原结合蛋白包含SEQ ID NO:21、25、30或32的重链区。本文公开的抗原结合蛋白包含SEQ ID NO:22、26、31或33的轻链区。在一些实施方案中,本文公开的抗BCMA抗原结合蛋白包含SEQ ID NO:19的重链可变区和SEQ ID NO:20的轻链可变区、SEQ ID NO:23的重链可变区和SEQ ID NO:24的轻链可变区、或SEQ ID NO:27的重链可变区和SEQ ID NO:28的轻链可变区。在一些实施方案中,本文公开的抗BCMA抗原结合蛋白包含SEQ ID NO:21的重链区和SEQ ID NO:22的轻链、SEQ IDNO:25的重链区和SEQ ID NO:26的轻链、SEQ ID NO:30的重链区和SEQ ID NO:31的轻链、或SEQ ID NO:32的重链区和SEQ ID NO:33的轻链。在一些实施方案中,本文公开的抗BCMA抗原结合蛋白是包含SEQ ID NO:29的scFV-fc。
在一些情况下,本文公开的组合当在药物制剂中时以单位剂量形式存在。在一些实施方案中,剂量方案将由医学专业和/或临床因素确定。正如医学领域所熟知的,任何一名患者的剂量取决于许多因素,包括患者的体型、体表面积、年龄、待施用的组合、性别、施用时间和途径、一般健康状况和其他同时施用的药物。示例性剂量可以根据接受治疗的个体的体型和健康状况以及接受治疗的状况而变化。
本文所述的抗BCMA抗原结合蛋白的合适剂量可以根据患者的体重计算,例如合适的剂量可以在约0.1mg/kg至约20mg/kg的范围内,例如约1mg/kg至约20mg/kg,例如约10mg/kg至约20mg/kg或例如约1mg/kg至约15mg/kg,例如约10mg/kg至约15mg/kg。
在一些情况下,抗BCMA抗原结合蛋白的治疗有效剂量在约0.03mg/kg至约4.6mg/kg的范围内。在另一个实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是0.03mg/kg、0.06mg/kg、0.12mg/kg、0.24mg/kg、0.48mg/kg、0.96mg/kg、1.92mg/kg、2.5mg/kg、3.4mg/kg或4.6mg/kg。在又一个实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是1.9mg/kg、2.5mg/kg或3.4mg/kg。
在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是0.95mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是1.0mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是1.4mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是1.9mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是1.92mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是2.5mg/kg。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量是3.4mg/kg。在一些实施方案中,每周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每2周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每3周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每4周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每5周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,每6周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。在一些实施方案中,在第一次施用后,治疗有效剂量的抗BCMA抗原结合蛋白的剂量逐步降低至本文所述的较低剂量。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量的3.4mg/kg剂量逐步降低至1.9mg/kg剂量、1.4mg/kg或更少。在一些实施方案中,抗BCMA抗原结合蛋白的治疗有效剂量的2.5mg/kg剂量逐步降低至1.9mg/kg剂量、1.4mg/kg或更少。在一些实施方案中,在第1天、第8天以及此后每3-12周向受试者施用治疗有效剂量的抗BCMA抗原结合蛋白。
本文所述的T细胞衔接器的合适剂量可以根据患者的体重计算,例如合适的剂量可以在约0.1mg/kg至约30mg/kg的范围内,例如约5mg/kg至约20mg/kg,或例如约10mg/kg至约20mg/kg。
在一些情况下,T细胞衔接器的治疗有效剂量为约5mg/kg、约6mg/kg、约7mg/kg、约8mg/kg、约9mg/kg、约10mg/kg、约11mg/kg、约12mg/kg、约13mg/kg、约14mg/kg、约15mg/kg、约16mg/kg、约17mg/kg、约18mg/kg、约19mg/kg,或约20mg/kg。
一方面,提供了用于治疗癌症的包含贝兰他单抗莫福汀和T细胞衔接器的组合,其中贝兰他单抗莫福汀以至少约0.5mg/kg、0.95mg/kg、1mg/kg、1.4mg/kg、1.9mg/kg、1.92mg/kg、2.5mg/kg或3.4mg/kg施用,并且T细胞衔接器(例如Cevostamab)以至少约2mg、3mg、3.6mg、10mg、15mg、20mg、50mg、100mg或150mg施用。
一方面,提供了用于治疗癌症的包含贝兰他单抗莫福汀和T细胞衔接器的组合,其中贝兰他单抗莫福汀以0.5mg/kg、0.95mg/kg、1mg/kg、1.4mg/kg、1.9mg/kg、1.92mg/kg、2.5mg/kg或3.4mg/kg在21天周期的第1天施用,并且T细胞衔接器(例如Cevostamab)以2mg、3mg、3.6mg、10mg、15mg、20mg、50mg、100mg或150mg在21天周期的第1天施用。
一方面,提供了用于治疗癌症的包含贝兰他单抗莫福汀和T细胞接合剂的组合,其中贝兰他单抗莫福汀以0.5mg/kg、0.95mg/kg、1mg/kg、1.4mg/kg、1.9mg/kg、1.92mg/kg、2.5mg/kg或3.4mg/kg在21天周期的第1天施用,并且T细胞衔接器(例如Cevostamab)以2mg、3mg、3.6mg、10mg、15mg、20mg、50mg、100mg或150mg在8天周期的第1天施用。
一方面,提供了用于治疗癌症的包含贝兰他单抗莫福汀和T细胞衔接器的组合,其中贝兰他单抗莫福汀以0.5mg/kg、0.95mg/kg、1mg/kg、1.4mg/kg、1.9mg/kg、1.92mg/kg、2.5mg/kg或3.4mg/kg在21天周期的第1天施用,并且T细胞衔接器(例如Cevostamab)以2mg、3mg、3.6mg、10mg、15mg、20mg、50mg、100mg或150mg在15天周期的第1天施用。
一方面,提供了用于治疗癌症的包含贝兰他单抗莫福汀和T细胞衔接器的组合,其中贝兰他单抗莫福汀以0.5mg/kg、0.95mg/kg、1mg/kg、1.4mg/kg、1.9mg/kg、1.94mg/kg、2.5mg/kg或3.4mg/kg施用,并且一半剂量在21天周期的第1天施用,一半剂量在21天周期的第8天施用;并且T细胞衔接器(例如Cevostamab)以2mg、3mg、3.6mg、10mg、15mg、20mg、50mg、100mg或150mg施用。
一方面,提供了用于治疗多发性骨髓瘤的包含贝兰他单抗莫福汀和T细胞衔接器的组合,其中贝兰他单抗莫福汀以0.5mg/kg、0.95mg/kg、1mg/kg、1.4mg/kg、1.9mg/kg、1.92mg/kg、2.5mg/kg或3.4mg/kg施用,并且T细胞衔接器(例如Cevostamab)以2mg、3mg、3.6mg、10mg、15mg、20mg、50mg、100mg或150mg施用。
一方面,提供了用于治疗多发性骨髓瘤的包含贝兰他单抗莫福汀和T细胞衔接器的组合,其中贝兰他单抗莫福汀以0.5mg/kg、0.95mg/kg、1mg/kg、1.4mg/kg、1.9mg/kg、1.92mg/kg、2.5mg/kg或3.4mg/kg施用,并且一半剂量在21天周期的第1天施用,一半剂量在21天周期的第8天施用;并且T细胞衔接器(例如Cevostamab)以2mg、3mg、3.6mg、10mg、15mg、20mg、50mg、100mg或150mg在21天周期的第1-7天施用。
在一些情况下,受试者之前接受过至少一种癌症治疗。在一些情况下,至少约每1-60天一次向受试者施用治疗有效剂量的组合。在一些情况下,至少约每21天一次向受试者施用治疗有效剂量的组合物。在一些情况下,至少约每8天一次向受试者施用治疗有效剂量的组合物。
施用途径
在一些情况下,(i)包含对BCMA多肽具有结合特异性的抗BCMA抗原结合蛋白或ADC的多肽和(ii)一个或多个T细胞衔接器可以同时向哺乳动物施用(例如,在单一组合物中)。在一些情况下,(i)包含对BCMA多肽具有结合特异性的抗BCMA抗原结合蛋白或ADC的多肽和(ii)一个或多个T细胞衔接器可以单独向受试者施用。当单独施用时,这可以同时发生或以任何顺序相继发生(通过相同或不同的施用途径)。这种按顺序的施用可以在时间上接近或在时间上久远。对组合或其药物组合物的治疗剂和进一步的治疗活性剂的剂量以及相对施用时间进行选择,以实现理想的组合治疗效果。
在一些实施方案中,剂量单次或多次施用,例如每天、每周、每两周或每月、每小时施用,或在所治疗的疾病或病症复发、恶化或进展后施用。在一些实施方案中,剂量的施用可以通过在约2至约24小时、例如约2至约12小时、或约2至约6小时的时间内缓慢连续输注。
在一些实施方案中,本文公开的药物组合物包含用于肠胃外、透皮、腔内、动脉内、鞘内和/或鼻内施用或通过直接注射到组织中的组合。在一些实施方案中,通过输注或注射将药物组合物施用于患者。在一个实施方案中,提供了用于静脉内施用的包含BCMA结合蛋白和T细胞衔接器的药物组合物。在一些实施方案中,提供了用于皮下施用的包含BCMA结合蛋白和T细胞衔接器的药物组合物。在一些实施方案中,本文所述的药物组合物经动脉、皮下、皮内、瘤内、结内、髓内、肌内、静脉内(i.v.)注射、静脉内(i.v.)输注或腹膜内施用于受试者。在一些实施方案中,通过皮内或皮下注射将组合施用于受试者。
在一个实施方案中,组合的一个或多个治疗剂静脉内施用。在另一个实施方案中,组合的一个或多个治疗剂瘤内施用。在另一个实施方案中,组合的一个或多个治疗剂经口施用。在另一个实施方案中,组合的一个或多个治疗剂全身施用,例如静脉内,以及组合的一个或多个其它治疗剂瘤内施用。在另一个实施方案中,本文公开的组合的所有治疗剂均全身施用,例如静脉内施用。在一个替代实施方案中,本文描述的组合的所有治疗剂均瘤内施用。在任意实施方案中,例如在该段落中,本公开的治疗剂作为一个或多个药物组合物施用。
药物组合物
在一些实施方案中,通过本身已知的用于施用于受试者的药学上可接受的组合物的制备方法来制备药物组合物,使得有效量的BCMA结合蛋白+T细胞衔接器与药学上可接受的载体组合在混合物中。合适的载体描述于例如Remington's Pharmaceutical Sciences(Remington's Pharmaceutical Sciences,20thed.,Mack Publishing Company,Easton,Pa.,USA,2000)中。在此基础上,组合物可包括但不限于,与一个或多个药学上可接受的载体或稀释剂结合的物质的溶液,并且包含在具有合适pH且与生理液体等渗的缓冲溶液中。在一些实施方案中,本文公开的药物组合物是酸性的。在一些实施方案中,本文公开的药物组合物是碱性的。在一些实施方案中,药物组合物可具有约1、1.5、2、2.5、3、3.5、4、4.5、5、5.5、6、6.5、7、7.5、8、8.5、9、9.5、10、10.5、11、11.5、12、12.5、13、13.5或约14的pH。
在一些实施方案中,合适的药学上可接受的载体包括基本上化学惰性且无毒的组合物,其不干扰药物组合物的生物活性的有效性。合适的药物载体的实例包括但不限于水、盐水溶液、甘油溶液、N-(1(2,3-二油烯基氧基)丙基)N,N,N-三甲基氯化铵(DOTMA)、二油酰磷脂酰乙醇胺(DOPE)和脂质体。在一些实施方案中,此类组合物含有治疗有效量的本文公开的BCMA结合蛋白和T细胞衔接器,以及适量的载体,以便提供用于直接施用于受试者的形式。
药物组合物可包括但不限于冻干粉末或水性或非水性无菌注射溶液或悬浮液,其还可包含抗氧化剂、缓冲剂、抑菌剂和使组合物与预期接受者的组织或血液基本上相容的溶质。可以存在于此类组合物中的其他组分包括例如水、表面活性剂(例如吐温)、醇、防腐剂、多元醇、甘油和植物油。临时注射溶液和悬浮液可以由无菌粉末、颗粒、片剂或浓缩溶液或悬浮液制备。
本文公开的药物组合物可以配制成多种形式并通过多种不同的方式施用。药物制剂可以按需要以含有常规可接受的载体、佐剂和载剂的形式经口、直肠或肠胃外施用。本文使用的术语“肠胃外”包括皮下、静脉内、肌内或胸骨内注射和输注技术。施用包括注射或输注,包括动脉内、心内、脑室内、皮内、十二指肠内、髓内、肌内、骨内、腹膜内、鞘内、血管内、静脉内、玻璃体内、硬膜外和皮下、吸入、经皮、经粘膜、舌下、颊和局部(包括表皮、真皮、灌肠、滴眼剂、滴耳剂、鼻内、阴道)施用。在一些示例性实施方案中,施用途径是通过注射,例如肌内、静脉内、皮下或腹膜内注射。
液体制剂可包括口服制剂、静脉内制剂、鼻内制剂、眼部制剂、耳部制剂、气雾剂等。在某些实施方案中,施用多种制剂的组合。在某些实施方案中,组合物被配制用于延长释放曲线。
本公开的药物组合物可以与其他疗法或治疗组合施用。在一些实施方案中,对受试者的治疗可以是手术、放射、化疗、营养方案、身体活动、免疫疗法、药物组合物、细胞移植、血液融合或其任意组合。在一些情况下,将本文公开的组合与一个或多个用于治疗癌症的另外的药剂/疗法一起施用于患有癌症的哺乳动物。用于治疗癌症的另外的药剂/疗法的实例包括但不限于手术、放射疗法、化学疗法、靶向疗法(例如单克隆抗体疗法)、激素疗法、血管生成抑制剂、免疫抑制剂、检查点阻断疗法(例如抗PD-1抗体疗法、抗PD-L1抗体疗法和/或抗CTLA4抗体疗法)、骨髓移植。
在一些实施方案中,本文公开的组合/制剂是稳定的。在一些实施方案中,“稳定”制剂是其中的组合在储存后基本上保留其物理和/或化学稳定性和/或生物活性的制剂。用于测量蛋白质稳定性的各种分析技术在本领域中是可用的并且在例如以下文献中进行了综述:Peptide and Protein Drug Delivery,247-301,Vincent Lee Ed.,Marcel Dekker,Inc.,New York,N.Y.,Pubs(1991)和Jones,A.Adv.Drug Delivery Rev.10:29-90(1993)。可以在选定的温度下、选定的时间段内测量稳定性。在一些实施方案中,制剂在环境温度或40℃下稳定至少1个月和/或在2-8℃下稳定至少1至2年。在一些实施方案中,制剂在冷冻(例如至-70℃)和解冻后是稳定的。在一些实施方案中,如通过颜色和/或透明度的目视检查观察到的或通过UV光散射(测量可见聚集体)或尺寸排阻色谱(SEC)测量的,蛋白质在聚集、沉淀和/或变性方面表现出很少甚至没有变化,则该蛋白质在制剂中“保持其物理稳定性”。SEC测量的可溶性聚集体不一定是可见聚集体的前体。在一些实施方案中,如果给定时间的化学稳定性是蛋白质被认为保留其生物活性,则蛋白质在制剂中“保留其化学稳定性”。化学降解的种类可能具有生物活性但化学不稳定。化学稳定性可以通过检测和定量蛋白质的化学改变形式来评估。化学改变可涉及尺寸修饰(例如剪切),可以使用例如SEC、SDS-PAGE和/或基质辅助激光解吸电离/飞行时间质谱分析(MALDI/TOFMS)来评估。其他类型的化学变化包括电荷变化(例如由于脱酰胺作用而发生),可以通过例如离子交换色谱法来评估。
在一些实施方案中,如果BCMA结合蛋白在给定时间的生物活性在该药物制剂制备时如在抗原结合测定中确定的所表现出的生物活性的约10%(在测定的误差内)内,则BCMA结合蛋白在药物制剂中“保留其生物活性”。在一些实施方案中,如果T细胞衔接器在给定时间的生物活性在药物制剂制备时如在抗原结合测定中确定的所表现出的生物活性的约10%(在测定的误差内)内,则T细胞衔接器在药物制剂中“保留其生物活性”。
在一些实施方案中,本文公开的缓冲液是指通过其酸碱缀合物组分抵抗pH变化的缓冲溶液。在一些实施方案中,缓冲液可以是磷酸盐、柠檬酸盐和其他有机酸。在一些实施方案中,缓冲液选自下组:乙酸钠、碳酸钠、柠檬酸盐、双甘氨肽、组氨酸、甘氨酸、赖氨酸、精氨酸、磷酸二氢钠、磷酸氢二钠、磷酸钠、柠檬酸钠、硼酸钠、三(羟甲基)-氨基甲烷、二甘氨酸、三甘氨酸、苹果酸、琥珀酸、马来酸、富马酸、酒石酸、天冬氨酸或其混合物。本文公开的组合物可包含抗氧化剂,包括抗坏血酸和/或甲硫氨酸。在一些实施方案中,本文公开的组合物包含防腐剂。在一些实施方案中,防腐剂是例如可以包含在制剂中以大幅减少其中的微生物(包括细菌)作用从而有利于例如多用途制剂的生产的化合物。潜在防腐剂的实例包括十八烷基二甲基苄基氯化铵;氯化六甲铵;苯扎氯铵、苄索氯铵;苯酚、丁醇或苯甲醇;对羟基苯甲酸烷基酯,例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(少于约10个残基)多肽;蛋白质,例如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,例如聚乙烯吡咯烷酮;氨基酸,例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,例如EDTA;糖类,例如蔗糖、甘露醇、海藻糖或山梨醇;成盐反离子,例如钠;金属复合物(例如,锌-蛋白质复合物);和/或非离子表面活性剂,例如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。
在一些实施方案中,本文公开的组合还可包含化疗剂、细胞毒性剂、细胞因子、生长抑制剂、抗激素剂和/或心脏保护剂。此类分子以有效用于预期目的量适当存在于组合中。
在一些实施方案中,本文公开的组合被制备成缓释制剂。缓释制剂的合适实例包括含有该组合或其部分的固体疏水性聚合物的半渗透性基质,该基质为成形制品的形式,例如,薄膜或微胶囊。缓释基质的实例包括聚酯、水凝胶(例如,聚(2-羟乙基-甲基丙烯酸酯)或聚(乙烯醇))、聚丙交酯、L-谷氨酸和γ乙基-L-谷氨酸的共聚物、不可降解的乙烯-乙酸乙烯酯、可降解的乳酸-乙醇酸共聚物,如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林组成的注射微球)和聚-D-(-)-3-羟基丁酸。
在一些实施方案中,本文公开了包含BCMA结合蛋白和T细胞衔接器的药物组合物,其以1mg/ml至500mg/ml的浓度存在,并且其中该药物组合物具有2.0至10.0的pH。药物组合物还可包含缓冲系统、一个或多个防腐剂、一个或多个张度剂、一个或多个螯合剂、稳定剂和表面活性剂。在一些实施方案中,药物组合物是水性制剂,例如包含水的制剂。这种制剂通常是溶液或悬浮液。在进一步的实施方案中,药物制剂是水溶液。在一些实施方案中,水性制剂是包含至少50%w/w水的制剂。在一些实施方案中,水溶液被定义为包含至少50%w/w水的溶液。在一些实施方案中,药物组合物是包含本文所述的组合的稳定液体水性药物制剂。
药物组合物还可以包含另外的稳定剂,其可以进一步增强治疗活性组合的稳定性。稳定剂可以包括但不限于甲硫氨酸和EDTA,其保护多肽免遭甲硫氨酸氧化,以及非离子表面活性剂,其保护多肽免于与冻融作用或机械剪切相关的聚集。在一些实施方案中,药物组合物还可包含表面活性剂。表面活性剂可选自洗涤剂、乙氧基化蓖麻油、聚乙二醇化甘油酯、乙酰化单甘油酯、脱水山梨糖醇脂肪酸酯、聚氧丙烯-聚氧乙烯嵌段聚合物(例如泊洛沙姆如PLURONIC F68、泊洛沙姆188和407、TritonX-100)、聚氧乙烯脱水山梨糖醇脂肪酸酯、聚氧乙烯和聚乙烯衍生物例如烷基化和烷氧基化衍生物(吐温,例如吐温-20、吐温-40、吐温-80和Brij-35)、单甘油酯或其乙氧基化衍生物、双甘油酯或其聚氧乙烯衍生物、醇、甘油、凝集素和磷脂(例如磷脂酰丝氨酸、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰肌醇、二磷脂酰甘油和鞘磷脂)、磷脂衍生物(例如二棕榈酰磷脂酸)和溶血磷脂(例如棕榈酰溶血磷脂酰-L-丝氨酸和乙醇胺、胆碱、丝氨酸或苏氨酸的1-酰基-sn-甘油-3-磷酸酯)以及烷基、烷氧基(烷基酯)、烷氧基(烷基醚)-溶血磷脂酰和磷脂酰胆碱的衍生物,例如溶血磷脂酰胆碱的月桂酰和肉豆蔻酰衍生物、二棕榈酰磷脂酰胆碱和极性头基的修饰,即胆碱、乙醇胺、磷脂酸、丝氨酸、苏氨酸、甘油、肌醇和带正电的DODAC、DOTMA、DCP、BISHOP、溶血磷脂酰丝氨酸和溶血磷脂酰苏氨酸,甘油磷脂(例如脑磷脂)、甘油糖脂(例如半乳糖苷)、鞘糖脂(例如神经酰胺、神经节苷脂)、十二烷基磷酸胆碱、鸡蛋溶血卵磷脂、夫西地酸衍生物(例如牛磺二氢夫西地酸钠等)、长链脂肪酸及其盐C6-C12(例如,油酸和辛酸),酰基肉碱和衍生物,包含赖氨酸、精氨酸或组氨酸与中性或酸性氨基酸的任意组合的二肽的N-酰化衍生物,包含中性氨基酸和两个带电氨基酸的任意组合的三肽的N-酰化衍生物,DSS(多库酯钠,CAS登记号[577-11-7])、多库酯钙、CAS登记号[128-49-4])、多库酯钾、CAS登记号[7491-09-0])、SDS(十二烷基硫酸钠或月桂基硫酸钠)、辛酸钠、胆酸或其衍生物、胆汁酸及其盐以及甘氨酸或牛磺酸缀合物、熊去氧胆酸、胆酸钠、脱氧胆酸钠、牛磺胆酸钠、甘胆酸钠、N-十六烷基-N,N-二甲基-3-铵基-1-丙磺酸内盐、阴离子(烷基-芳基-磺酸盐)单价表面活性剂、两性离子表面活性剂(例如,N-烷基-N,N-二甲基铵基-1-丙烷磺酸盐、3-胆酰氨基-1-丙基二甲基铵基-1-丙烷磺酸盐、阳离子表面活性剂(季铵基)(例如,鲸蜡基-三甲基溴化铵、氯化十六烷基吡啶)、非离子表面活性剂(例如,十二烷基β-D-吡喃葡萄糖苷)、泊洛沙胺(例如,Tetronic's),它们是由环氧丙烷和环氧乙烷顺序加成至乙二胺而衍生的四官能嵌段共聚物,或表面活性剂可以选自咪唑啉衍生物或其混合物。
试剂盒
还提供了包含药物组合物以及使用说明的试剂盒套件。为了方便起见,试剂盒套件可以包含预定量的试剂以及使用说明。
在一些实施方案中,本文公开了包含本文公开的BCMA结合蛋白和T细胞衔接器的试剂盒。试剂盒可包括多个注射器、安瓿、箔片包或泡壳包装,每个包含单个单位剂量的本文所述的试剂盒组分。试剂盒的容器可以是密封的、防水的(例如,对于湿气或蒸发的变化是不可渗透的)和/或不透光的。试剂盒可以包括适合于组分施用的装置,例如注射器、吸入器、移液管、镊子、量匙、滴管(例如滴眼管(eye dropper))、拭子(例如棉签或木拭子)或任何这样的递送装置。在一些实施方案中,装置可以是医疗植入装置,例如,被包装用于手术插入。本文公开的试剂盒可包含使得方法得以实施的一个或多个试剂或仪器。
除了上述组分之外,试剂盒中还可以提供使用说明。这些说明可以多种形式存在于试剂盒中,例如在合适的介质或基质上(例如,其上打印有信息的一张或多张纸)、在试剂盒的包装中、在药品说明书中等的印刷信息。在一些实施方案中,使用说明可以提供在计算机可读介质(例如,跳盘/拇指驱动器、CD等)上,其上已经记录了信息,或者提供在网站地址,其可以通过互联网访问网站上的信息而使用。
装置
本公开的另一方面提供了预填充注射器或自动注射器装置,其包含本文所述的BCMA抗原结合蛋白、T细胞衔接器或组合。在一些实施方案中,储存在容器、预填充注射器、注射器或自动注射器装置中的组合含有本文公开的BCMA抗原结合蛋白和T细胞衔接器。
实施例
实施例1:治疗癌症
受试者将被鉴定为患有癌症。将向受试者施用包含(a)抗BCMA抗原结合蛋白或抗BCMA ADC和(b)T细胞衔接器的组合。
实施例2:治疗癌症
受试者将被鉴定为患有癌症。将向受试者施用在独立的组合物中将被共同施用的(a)抗BCMA抗原结合蛋白或抗BCMA ADC和(b)T细胞衔接器。例如,将向患有癌症的受试者共同施用包含一个或多个对BCMA多肽具有结合特异性的ADC的第一组合物和包含一个或多个T细胞衔接器的第二组合物。
实施例3:治疗癌症
受试者将被鉴定为患有癌症。将向受试者施用在独立的组合物中将被单独施用的(a)抗BCMA抗原结合蛋白或抗BCMA ADC和(b)T细胞衔接器。例如,将分别向患有癌症的受试者施用包含一个或多个对BCMA多肽具有结合特异性的ADC的第一组合物和包含一个或多个T细胞衔接器的第二组合物。
实施例4:治疗癌症
受试者将被鉴定为患有癌症。将向受试者施用包含贝兰他单抗莫福汀和cevostamab的组合。
其他实施方案
应当理解,虽然已经结合其详细描述描述了本发明,但是前面的描述旨在说明而不是限制本发明的范围,本发明的范围由所附权利要求的范围限定。其他方面、优点和修改在以下权利要求的范围内。
实施方案:
1.组合,其包含:
a.抗BCMA抗原结合蛋白;和
b.与CD3结合的T细胞衔接器。
2.实施方案1的组合,其中所述抗BCMA抗原结合蛋白包含抗体。
3.实施方案2的组合,其中所述抗体是单克隆抗体。
4.实施方案3所述的组合,其中所述单克隆抗体是IgG1。
5.实施方案2-4中任一项的组合,其中所述抗体是无岩藻糖基化的。
6.实施方案1-5中任一项的组合,其中所述抗BCMA抗原结合蛋白是人的、人源化的或嵌合的。
7.实施方案1-6中任一项的组合,其中所述抗BCMA抗原结合蛋白包含含有SEQ IDNO:1中列出的氨基酸序列的CDRH1;含有SEQ ID NO:2中列出的氨基酸序列的CDRH2;含有SEQ ID NO:3中列出的氨基酸序列的CDRH3;含有SEQ ID NO:4中列出的氨基酸序列的CDRL1;含有SEQ ID NO:5中列出的氨基酸序列的CDRL2;和含有SEQ ID NO:6中列出的氨基酸序列的CDRL3。
8.实施方案1-7中任一项的组合,其中所述抗BCMA抗原结合蛋白包含含有SEQ IDNO:7中列出的氨基酸序列的重链可变区(VH);和含有SEQ ID NO:8中列出的氨基酸序列的轻链可变区(VL)。
9.实施方案1-8中任一项的组合,其中所述抗BCMA抗原结合蛋白包含含有SEQ IDNO:9中列出的氨基酸序列的重链(H);和含有SEQ ID NO:10中列出的氨基酸序列的轻链(L)。
10.实施方案1-9中任一项的组合,其中所述抗BCMA抗原结合蛋白是免疫缀合物。
11.实施方案1-10中任一项的组合,其中所述抗BCMA抗原结合蛋白是包含缀合至细胞毒素的抗体的免疫缀合物。
12.实施方案11的组合,其中所述细胞毒素是MMAE或MMAF。
13.实施方案12的组合,其中所述细胞毒素是MMAF。
14.实施方案11的组合,其中所述细胞毒素是紫杉醇、多西他赛、CC-1065、SN-38、拓扑替康、吗啉代-阿霉素、根霉素、氰基吗啉代-阿霉素、海兔毒素-10、棘霉素、combretatstatin、卡奇霉素、纺锤菌素、澳瑞他汀、美登木素生物碱、卡奇霉素、AFP、MMAP、MMAE、AEB、AEVB、长春新碱、长春花碱、长春地辛、长春瑞滨、VP-16、喜树碱、埃博霉素A、埃博霉素B、诺考达唑、秋水仙碱、colcimid、雌莫司汀、西马多丁、圆皮海绵内酯、美登醇、美登素、DM1、DM2、DM3、DM4或五加素。
15.实施方案1-14中任一项的组合,其中所述抗BCMA抗原结合蛋白是贝兰他单抗莫福汀。
16.实施方案15的组合,其中所述组合包含至少约0.5mg/kg、0.95mg/kg、1mg/kg、1.4mg/kg、1.9mg/kg、1.92mg/kg、2.5mg/kg或约3.4mg/kg贝兰他单抗莫福汀。
17.实施方案1-16中任一项的组合,其中所述T细胞衔接器是双特异性T细胞衔接器。
18.实施方案1-17中任一项的组合,其中所述T细胞衔接器选自Cevostamab、Talquetamab、Teclistimab、PF-3135、TNB-383B、REGN5458、博纳吐单抗和索利托单抗。
19.实施方案1-17中任一项的组合,其中所述T细胞衔接器是抗FcRH5 T细胞衔接器。
20.实施方案19的组合,其中所述T细胞衔接器是Cevostamab。
21.实施方案19的组合,其中所述组合包含至少约1.5mg、2mg、3mg、3.6mg、10mg、15mg、20mg、90mg或132mg Cevostamab。
22.实施方案1-17中任一项的组合,其中所述T细胞衔接器是抗GPRC5D T细胞衔接器。
23.实施方案22的组合,其中所述T细胞衔接器是Talquetamab。
24.实施方案1-17中任一项的组合,其中所述T细胞衔接器是抗BCMA T细胞衔接器。
25.实施方案1-17中任一项的组合,其中所述T细胞衔接器选自Teclistimab、PF-3135、TNB-383B和REGN5458。
26.实施方案1-17中任一项的组合,其中所述T细胞衔接器选自CC-93269、AMG701、JNJ-7957和GBR1342。
27.实施方案1-17中任一项的组合,其中所述T细胞衔接器不结合ICOS。
28.实施方案1-17中任一项的组合,其中所述T细胞衔接器不结合CD38。
29.实施方案1-28中任一项的组合,其中所述组合包含药学上可接受的载体。
30.实施方案1-29中任一项的组合,其中所述组合进一步包含佐剂。
31.治疗需要其的受试者中的癌症的方法,包括向所述受试者施用治疗有效剂量的实施方案1-30中任一项的组合。
32.治疗需要其的受试者中的癌症的方法,包括向所述受试者施用治疗有效剂量的实施方案1-30中任一项的组合,其中所述抗BCMA抗原结合蛋白的剂量在第一次施用后逐步降低至较低剂量。
33.实施方案31或32的方法,其中所述癌症选自多发性骨髓瘤、慢性淋巴细胞白血病、华氏巨球蛋白血症和非霍奇金淋巴瘤。
34.实施方案31-33中任一项的方法,其中所述癌症是多发性骨髓瘤。
35.实施方案31或32的方法,其中所述癌症是复发性和/或难治性多发性骨髓瘤。
36.实施方案31-35中任一项的方法,其中所述受试者已接受至少一种先前的癌症治疗。
37.实施方案31-36中任一项的方法,其中每21天至少约一次向所述受试者施用所述治疗有效剂量。
38.实施方案31-37中任一项的方法,其中与单独施用治疗有效剂量的抗BCMA抗原结合蛋白相比,施用治疗有效剂量的所述组合治疗降低了眼毒性。
39.实施方案38的方法,其中所述抗BCMA抗原结合蛋白是贝兰他单抗莫福汀。
40.实施方案38或39的方法,其中所述眼毒性是以下中的至少一种:角膜上皮变化、干眼、刺激、发红、视力模糊、干眼、畏光或视力变化。
41.实施方案38-40中任一项的方法,其中所述眼毒性通过以下方法中的至少一种来测量:最佳矫正视力,明显屈光的记录以及用于获得最佳矫正视力的方法,当前眼镜处方(如果适用),眼压测量,眼前节(裂隙灯)检查,包括角膜荧光素染色和晶状体检查,散瞳眼底镜检查或眼表疾病指数(OSDI)。
42.实施方案31-41中任一项的方法,其中所述抗BCMA抗原结合蛋白以至少约0.5mg/kg、0.95mg/kg、1.25mg/kg、1.4mg/kg、1.7mg/kg、1.9mg/kg、1.92mg/kg、2.5mg/kg或3.4mg/kg的剂量施用于所述受试者。
43.实施方案1-30中任一项的组合,其用于制造用于治疗癌症的药物。
44.实施方案1-30中任一项的组合,其用于治疗癌症。
45.用于治疗癌症的试剂盒,包含:
a.实施方案1-30中任一项的组合;和
b.用于治疗癌症的说明。
46.预填充注射器或自动注射器装置,包括实施方案1-30中任一项的组合。
序列表
SEQ ID NO:1:CDRH1
NYWMH
SEQ ID NO:2:CDRH2
ATYRGHSDTYYNQKFKG
SEQ ID NO:3:CDRH3
GAIYDGYDVLDN
SEQ ID NO:4:CDRL1
SASQDISNYLN
SEQ ID NO:5:CDRL2
YTSNLHS
SEQ ID NO:6:CDRL3
QQYRKLPWT
SEQ ID NO:7:重链可变区
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSS
SED ID NO:8:轻链可变区
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKR
SEQ ID NO:9:重链区
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:10:轻链区
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:11:FCRL5靶标:重链可变区
EVQLVESGPGLVKPSETLSLTCTVSGFSLTRFGVHWVRQPPGKGLEWLGVIWRGGSTDYNAAFVSRLTISKDNSKNQVSLKLSSVTAADTAVYYCSNHYYGSSDYALDNWGQGTLVTVSS
SEQ ID NO:12:FCRL5靶标:轻链可变区
DIQMTQSPSSLSASVGDRVTITCKASQDVRNLVVWFQQKPGKAPKLLIYSGSYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYSPPYTFGQGTKVEIK
SEQ ID NO:13:CD3靶标:重链可变区
EVQLVQSGAEVKKPGASVKVSCKASGFTFTSYYIHWVRQAPGQGLEWIGWIYPENDNTKYNEKFKDRVTITADTSTSTAYLELSSLRSEDTAVYYCARDGYSRYYFDYWGQGTLVTVSS
SEQ ID NO:14:CD3靶标:轻链可变区
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSRTRKNYLAWYQQKPGQSPKLLIYWTSTRKSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCKQSFILRTFGQGTKVEIK
SEQ ID NO:15:FCRL5靶标:重链
EVQLVESGPGLVKPSETLSLTCTVSGFSLTRFGVHWVRQPPGKGLEWLGVIWRGGSTDYNAAFVSRLTISKDNSKNQVSLKLSSVTAADTAVYYCSNHYYGSSDYALDNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWlNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:16:FCRL5靶标:轻链
DIQMTQSPSSLSASVGDRVTITCKASQDVRNLVVWFQQKPGKAPKLLIYSGSYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYSPPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:17:CD3靶标:重链
EVQLVQSGAEVKKPGASVKVSCKASGFTFTSYYIHWVRQAPGQGLEWIGWIYPENDNTKYNEKFKDRVTITADTSTSTAYLELSSLRSEDTAVYYCARDGYSRYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:18:CD3靶标:轻链
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSRTRKNYLAWYQQKPGQSPKLLIYWTSTRKSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCKQSFILRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:19:BQ76重链可变区
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKVAPYFAPFDYWGQGTLVTVSS
SEQ ID NO:20:BQ76轻链可变区
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGNPPLYTFGQGTKVEIK
SEQ ID NO:21:BQ76重链可变区
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKVAPYFAPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGX,其中X是K或不存在
SEQ ID NO:22:BQ76轻链可变区
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGNPPLYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:23:BU76重链可变区
QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWINTETREPAYAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDYWGQGTSVTVSS
SEQ ID NO:24:BU76轻链可变区
DIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIHWYQQKPGQPPTLLIQLASNVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLEIK
SEQ ID NO:25:BU76重链区
QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWINTETREPAYAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGX,其中X是K或不存在
SEQ ID NO:26:BU76轻链区
DIVLTQSPASLAMSLGKRATISCRASESVSVIGAHLIHWYQQKPGQPPKLLIYLASNLETGVPARFSGSGSGTDFTLTIDPVEEDDVAIYSCLQSRIFPRTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:27:EE11重链可变区
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKVLGWFDYWGQGTLVTVSS
SEQ ID NO:28:EE11轻链可变区
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGYPPDFTFGQGTKVEIK
SEQ ID NO:29:EE11 scFV-Fc
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKVLGWFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGYPPDFTFGQGTKVEIKGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGX,其中X是K或不存在
SEQ ID NO:30:EM90重链
EVQLVESGGGLVKPGGSLRLSCAASGFTFSNSGMIWVRQAPGKGLEWVGHIRSKTDGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTTGGSGSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGX,其中X是K或不存在
SEQ ID NO:31:EM90轻链
QAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQEKPGQAFRGLIGGTNKRAPGTPARFSGSLLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
SEQ ID NO:32:FP31重链可变区
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAIGGSGGSLPYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYWPMDIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCEVECPECPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCEVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:33:FP31轻链可变区
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLMYDASIRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYQSWPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
序列表
<110> 葛兰素史密斯克莱知识产权发展有限公司
<120> 治疗癌症的联合疗法
<130> 009442_00184
<140> 63/194,547
<141> 2021-05-21
<160> 33
<170> PatentIn 版本 3.5
<210> 1
<211> 5
<212> PRT
<213> 人工的
<220>
<223> CDRH1
<400> 1
Asn Tyr Trp Met His
1 5
<210> 2
<211> 17
<212> PRT
<213> 人工的
<220>
<223> CDRH2
<400> 2
Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 3
<211> 12
<212> PRT
<213> 人工的
<220>
<223> CDRH3
<400> 3
Gly Ala Ile Tyr Asp Gly Tyr Asp Val Leu Asp Asn
1 5 10
<210> 4
<211> 11
<212> PRT
<213> 人工的
<220>
<223> CDRL1
<400> 4
Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 5
<211> 7
<212> PRT
<213> 人工的
<220>
<223> CDRL2
<400> 5
Tyr Thr Ser Asn Leu His Ser
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工的
<220>
<223> CDRL3
<400> 6
Gln Gln Tyr Arg Lys Leu Pro Trp Thr
1 5
<210> 7
<211> 121
<212> PRT
<213> 人工的
<220>
<223> 重链可变区
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asn Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Tyr Asp Gly Tyr Asp Val Leu Asp Asn Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 8
<211> 108
<212> PRT
<213> 人工的
<220> 轻链可变区
<400> 8
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Asn Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Lys Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 9
<211> 451
<212> PRT
<213> 人工的
<220>
<223> 重链区
<400> 9
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asn Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Tyr Asp Gly Tyr Asp Val Leu Asp Asn Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 10
<211> 214
<212> PRT
<213> 人工的
<220>
<223> 轻链区
<400> 10
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Asn Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Lys Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 11
<211> 120
<212> PRT
<213> 人工的
<220>
<223> FCRL5 靶标: 重链可变区
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Arg Phe
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Val
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ser
85 90 95
Asn His Tyr Tyr Gly Ser Ser Asp Tyr Ala Leu Asp Asn Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 12
<211> 107
<212> PRT
<213> 人工的
<220>
<223> FCRL5 靶标: 轻链可变区
<400> 12
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Asn Leu
20 25 30
Val Val Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Ser Pro Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 13
<211> 119
<212> PRT
<213> 人工的
<220>
<223> CD3 靶标: 重链可变区
<400> 13
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Ser Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Glu Asn Asp Asn Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 14
<211> 112
<212> PRT
<213> 人工的
<220>
<223> CD3 靶标: 轻链可变区
<400> 14
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 15
<211> 450
<212> PRT
<213> 人工的
<220>
<223> FCRL5 靶标: 重链
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Arg Phe
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Val
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ser
85 90 95
Asn His Tyr Tyr Gly Ser Ser Asp Tyr Ala Leu Asp Asn Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 16
<211> 214
<212> PRT
<213> 人工的
<220>
<223> FCRL5 靶标: 轻链
<400> 16
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Asn Leu
20 25 30
Val Val Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Ser Pro Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 17
<211> 449
<212> PRT
<213> 人工的
<220>
<223> CD3 靶标: 重链
<400> 17
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Ser Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Glu Asn Asp Asn Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 18
<211> 219
<212> PRT
<213> 人工的
<220>
<223> CD3 靶标: 轻链
<400> 18
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 19
<211> 119
<212> PRT
<213> 人工的
<220>
<223> BQ76 重链可变区
<400> 19
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ala Pro Tyr Phe Ala Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 20
<211> 109
<212> PRT
<213> 人工的
<220>
<223> BQ76 轻链可变区
<400> 20
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Asn Pro Pro
85 90 95
Leu Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 21
<211> 449
<212> PRT
<213> 人工的
<220>
<223> BQ76 重链区,其中 Xaa 为 K 或不存在
<220>
<221> 混杂特征
<222> (449)..(449)
<223> Xaa 为 K 或不存在
<400> 21
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ala Pro Tyr Phe Ala Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Xaa
<210> 22
<211> 216
<212> PRT
<213> 人工的
<220>
<223> BQ76 轻链区
<400> 22
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Asn Pro Pro
85 90 95
Leu Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
115 120 125
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
130 135 140
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
145 150 155 160
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
165 170 175
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
180 185 190
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
195 200 205
Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 23
<211> 111
<212> PRT
<213> 人工的
<220>
<223> BU76 重链可变区域
<400> 23
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly
1 5 10 15
Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu
20 25 30
Gly Ser His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg
85 90 95
Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 24
<211> 111
<212> PRT
<213> 人工的
<220>
<223> BU76 重链区
<400> 24
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly
1 5 10 15
Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu
20 25 30
Gly Ser His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg
85 90 95
Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 25
<211> 447
<212> PRT
<213> 人工的
<220>
<223> BU76 重链区,其中 Xaa 为 K 或不存在
<220>
<221> 混杂特征
<222> (447)..(447)
<223> Xaa 为 K 或不存在
<400> 25
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Ile Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp Phe
50 55 60
Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Xaa
435 440 445
<210> 26
<211> 218
<212> PRT
<213> 人工的
<220>
<223> BU76 轻链区
<400> 26
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Met Ser Leu Gly
1 5 10 15
Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Ser Val Ile
20 25 30
Gly Ala His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Thr Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Glu Asp Asp Val Ala Ile Tyr Ser Cys Leu Gln Ser Arg
85 90 95
Ile Phe Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 27
<211> 116
<212> PRT
<213> 人工的
<220>
<223> EE11 重链可变区
<400> 27
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 28
<211> 109
<212> PRT
<213> 人工的
<220>
<223> EE11 轻链可变区
<400> 28
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Pro Pro
85 90 95
Asp Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 29
<211> 477
<212> PRT
<213> 人工的
<220>
<223> EE11 scFV_Fc,其中 Xaa 为 K 或不存在
<220>
<221> 混杂特征
<222> (477)..(477)
<223> Xaa 为 K 或不存在
<400> 29
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro
130 135 140
Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg
145 150 155 160
Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala
180 185 190
Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr
210 215 220
Cys Gln Gln Tyr Gly Tyr Pro Pro Asp Phe Thr Phe Gly Gln Gly Thr
225 230 235 240
Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys
245 250 255
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
260 265 270
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
275 280 285
Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro Glu Val Lys
290 295 300
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
305 310 315 320
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
325 330 335
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
340 345 350
Val Ser Asn Lys Ala Leu Ala Ala Pro Ile Glu Lys Thr Ile Ser Lys
355 360 365
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys
370 375 380
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys
385 390 395 400
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
405 410 415
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
420 425 430
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
435 440 445
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
450 455 460
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Xaa
465 470 475
<210> 30
<211> 449
<212> PRT
<213> 人工的
<220>
<223> EM90 重链,其中 Xaa 为 K 或不存在
<220>
<221> 混杂特征
<222> (449)..(449)
<223> Xaa 为 K 或不存在
<400> 30
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ser
20 25 30
Gly Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly His Ile Arg Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Thr Gly Gly Ser Gly Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Xaa
<210> 31
<211> 215
<212> PRT
<213> 人工的
<220>
<223> EM90 轻链
<400> 31
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Gly Gln Ala Phe Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro
100 105 110
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu
115 120 125
Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro
130 135 140
Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala
145 150 155 160
Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala
165 170 175
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg
180 185 190
Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr
195 200 205
Val Ala Pro Thr Glu Cys Ser
210 215
<210> 32
<211> 441
<212> PRT
<213> 人工的
<220>
<223> FP31 重链区
<400> 32
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Gly Gly Ser Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly
180 185 190
Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Thr Val Glu Arg Lys Cys Glu Val Glu Cys Pro Glu Cys
210 215 220
Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
245 250 255
Val Val Ala Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
260 265 270
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
275 280 285
Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
305 310 315 320
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
325 330 335
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
340 345 350
Thr Lys Asn Gln Val Ser Leu Thr Cys Glu Val Lys Gly Phe Tyr Pro
355 360 365
Ser Asp Ile Ser Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
370 375 380
Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
385 390 395 400
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
405 410 415
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
420 425 430
Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 33
<211> 215
<212> PRT
<213> 人工的
<220>
<223> FP31 轻链区
<400> 33
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
Claims (45)
1.组合,其包含:
a.抗BCMA抗原结合蛋白;和
b.与CD3结合的T细胞衔接器。
2.权利要求1所述的组合,其中所述抗BCMA抗原结合蛋白包含抗体。
3.权利要求2所述的组合,其中所述抗体是单克隆抗体。
4.权利要求3所述的组合,其中所述单克隆抗体是IgG1。
5.权利要求2-4中任一项所述的组合,其中所述抗体是无岩藻糖基化的。
6.权利要求1-5中任一项所述的组合,其中所述抗BCMA抗原结合蛋白是人的、人源化的或嵌合的。
7.权利要求1-6中任一项所述的组合,其中所述抗BCMA抗原结合蛋白包含含有SEQ IDNO:1中列出的氨基酸序列的CDRH1;含有SEQ ID NO:2中列出的氨基酸序列的CDRH2;含有SEQ ID NO:3中列出的氨基酸序列的CDRH3;含有SEQ ID NO:4中列出的氨基酸序列的CDRL1;含有SEQ ID NO:5中列出的氨基酸序列的CDRL2;和含有SEQ ID NO:6中列出的氨基酸序列的CDRL3。
8.权利要求1-7中任一项所述的组合,其中所述抗BCMA抗原结合蛋白包含含有SEQ IDNO:7中列出的氨基酸序列的重链可变区(VH);和含有SEQ ID NO:8中列出的氨基酸序列的轻链可变区(VL)。
9.权利要求1-8中任一项所述的组合,其中所述抗BCMA抗原结合蛋白包含含有SEQ IDNO:9中列出的氨基酸序列的重链(H)和含有SEQ ID NO:10中列出的氨基酸序列的轻链(L)。
10.权利要求1-9中任一项所述的组合,其中所述抗BCMA抗原结合蛋白是免疫缀合物。
11.权利要求1-10中任一项所述的组合,其中所述抗BCMA抗原结合蛋白是包含缀合至细胞毒素的抗体的免疫缀合物。
12.权利要求11所述的组合,其中所述细胞毒素是MMAE或MMAF。
13.权利要求12所述的组合,其中所述细胞毒素是MMAF。
14.权利要求1-13中任一项所述的组合,其中所述抗BCMA抗原结合蛋白是贝兰他单抗莫福汀(belantamab mafodotin)。
15.权利要求14所述的组合,其中所述组合包含至少约0.5mg/kg、0.95mg/kg、1mg/kg、1.4mg/kg、1.9mg/kg、1.92mg/kg、2.5mg/kg或约3.4mg/kg贝兰他单抗莫福汀。
16.权利要求1-15中任一项所述的组合,其中所述T细胞衔接器是双特异性T细胞衔接器。
17.权利要求1-16中任一项所述的组合,其中所述T细胞衔接器选自Cevostamab、Talquetamab、Teclistimab、PF-3135、TNB-383B、REGN5458、博纳吐单抗(Blinatumomab)和索利托单抗(Solitomab)。
18.权利要求1-16中任一项所述的组合,其中所述T细胞衔接器是抗FcRH5 T细胞衔接器。
19.权利要求18所述的组合,其中所述T细胞衔接器是Cevostamab。
20.权利要求18或19所述的组合,其中所述组合包含至少约1.5mg、2mg、3mg、3.6mg、10mg、15mg、20mg、90mg或132mg Cevostamab。
21.权利要求1-16中任一项所述的组合,其中所述T细胞衔接器是抗GPRC5D T细胞衔接器。
22.权利要求21所述的组合,其中所述T细胞衔接器是Talquetamab。
23.权利要求1-16中任一项所述的组合,其中所述T细胞衔接器是抗BCMA T细胞衔接器。
24.权利要求1-16中任一项所述的组合,其中所述T细胞衔接器选自Teclistimab、PF-3135、TNB-383B和REGN5458。
25.权利要求1-16中任一项所述的组合,其中所述T细胞衔接器选自CC-93269、AMG701、AMG420、JNJ-7957和GBR1342。
26.权利要求1-16中任一项所述的组合,其中所述T细胞衔接器不结合ICOS。
27.权利要求1-16中任一项所述的组合,其中所述T细胞衔接器不结合CD38。
28.权利要求1-27中任一项所述的组合,其中所述组合包含药学上可接受的载体。
29.权利要求1-28中任一项所述的组合,其中所述组合进一步包含佐剂。
30.治疗需要其的受试者中的癌症的方法,包括向所述受试者施用治疗有效剂量的权利要求1-29中任一项所述的组合。
31.治疗需要其的受试者中的癌症的方法,包括向受试者施用治疗有效剂量的实施方案1-29中任一项所述的组合,其中所述抗BCMA抗原结合蛋白的剂量在第一次施用后逐步降低至较低剂量。
32.权利要求30或31所述的方法,其中所述癌症选自多发性骨髓瘤、慢性淋巴细胞白血病、华氏巨球蛋白血症和非霍奇金淋巴瘤。
33.权利要求30-32中任一项所述的方法,其中所述癌症是多发性骨髓瘤。
34.权利要求30或31所述的方法,其中所述癌症是复发性和/或难治性多发性骨髓瘤。
35.权利要求30-34中任一项所述的方法,其中所述受试者已接受至少一种先前的癌症治疗。
36.权利要求30-35中任一项所述的方法,其中每21天至少约一次向所述受试者施用所述治疗有效剂量。
37.权利要求30-36中任一项所述的方法,其中与单独施用治疗有效剂量的所述抗BCMA抗原结合蛋白相比,施用治疗有效剂量的所述组合治疗降低了眼毒性。
38.权利要求37所述的方法,其中所述抗BCMA抗原结合蛋白是贝兰他单抗莫福汀。
39.权利要求37或38所述的方法,其中所述眼毒性是以下中的至少一种:角膜上皮变化、干眼、刺激、发红、视力模糊、干眼、畏光或视力变化。
40.权利要求37-39中任一项所述的方法,其中所述眼毒性通过以下方法中的至少一种来测量:最佳矫正视力,明显屈光的记录以及用于获得最佳矫正视力的方法,当前眼镜处方(如果适用),眼压测量,眼前节(裂隙灯)检查,包括角膜荧光素染色和晶状体检查,散瞳眼底镜检查或眼表疾病指数(OSDI)。
41.权利要求30-40中任一项所述的方法,其中所述抗BCMA抗原结合蛋白以至少约0.5mg/kg、0.95mg/kg、1mg/kg、1.25mg/kg、1.4mg/kg、1.7mg/kg、1.9mg/kg、1.92mg/kg、2.5mg/kg或3.4mg/kg的剂量施用于所述受试者。
42.权利要求1-29中任一项所述的组合,其用于制造用于治疗癌症的药物。
43.权利要求1-29中任一项所述的组合,其用于治疗癌症。
44.用于治疗癌症的试剂盒,包含:
a.权利要求1-29中任一项所述的组合;和
b.用于治疗癌症的说明。
45.预填充注射器或自动注射器装置,包括权利要求1-29中任一项所述的组合。
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2022
- 2022-05-26 EP EP22740439.9A patent/EP4347656A1/en active Pending
- 2022-05-26 JP JP2023573231A patent/JP2024521187A/ja active Pending
- 2022-05-26 CA CA3220227A patent/CA3220227A1/en active Pending
- 2022-05-26 WO PCT/GB2022/051348 patent/WO2022248870A1/en active Application Filing
- 2022-05-26 BR BR112023024804A patent/BR112023024804A2/pt unknown
- 2022-05-26 CN CN202280038099.7A patent/CN117396513A/zh active Pending
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JP2024521187A (ja) | 2024-05-28 |
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CA3220227A1 (en) | 2022-12-01 |
EP4347656A1 (en) | 2024-04-10 |
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