CN115703836A - 基于全人源及鼠源单链抗体的靶向bcma的嵌合抗原受体及其用途 - Google Patents
基于全人源及鼠源单链抗体的靶向bcma的嵌合抗原受体及其用途 Download PDFInfo
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Abstract
本发明涉及靶向BCMA的单链抗体和基于此的嵌合抗原受体以及它们的应用。本发明提供了与BCMA特异性结合的全人源和鼠源单链抗体。所述的嵌合抗原受体包含依次连接的抗BCMA全人源或鼠源单链抗体、人CD8α铰链区、人CD8α跨膜区、人41BB胞内区和人CD3ζ胞内区。进一步的,提供了一种基于抗BCMA全人源或鼠源单链抗体的CAR‑T细胞,能够特异地与BCMA结合并有效杀伤表达BCMA的B淋巴细胞系恶性肿瘤细胞。
Description
发明领域
本发明属于抗体和嵌合抗原受体领域,具体涉及靶向BCMA胞外段的抗体和嵌合抗原受体及其用途。
发明背景
多发性骨髓瘤是一种恶性浆细胞疾病,表现为骨髓浆细胞恶性克隆性增生,分泌单克隆免疫球蛋白或其片段(M蛋白),导致骨骼、肾脏等相关靶器官或组织损伤,常见临床表现为骨痛、贫血、肾功能不全、感染等[N Engl J Med,2011.364(11):1046-60]。目前多发性骨髓瘤为血液系统第二大恶性肿瘤,占血液系统恶性肿瘤的10%,多发病于男性,其发病率随着年龄的增长逐年增高,近几年更是有年轻化的趋势[CA CancerJ Clin,2014.64(1):9-29]。B细胞成熟抗原(B-cell maturation antigen,BCMA),又称CD269,由184个氨基酸残基组成,其胞内区含80个氨基酸残基,胞外区序列很短,只有一个糖类识别结构域,为B细胞表面分子。BCMA属于缺少信号肽的I型跨膜信号蛋白,是肿瘤坏死因子受体家族(TNFR)一员,它可分别与B细胞激活因子BAFF或增殖诱导配体(aproliferation induced ligand,APRIL)两种配体相结合[Curr Opin Struct Biol,2004.14(2):154-60]。在正常组织中,BCMA表达于成熟B细胞和浆细胞表面,BCMA基因剔除小鼠免疫系统表现正常,有正常的脾结构,B淋巴细胞的发育正常,但浆细胞数量明显减少,证明BCMA在维持浆细胞的存活中起了重要的作用,其机制主要包括BCMABAFF蛋白结合,并上调抗凋亡基因Bcl-2,Mcl-1及Bclw等,维持细胞生长[J Exp Med,2004.199(1):91-8]。同样地,该机制也在骨髓瘤细胞中发挥了功能,对骨髓瘤细胞的恶性增生起了重要的促进作用[Blood,2004.103(8):3148-57]。研究表明,BCMA普遍表达于多发性骨髓瘤细胞系,在多发性骨髓瘤患者中的检测也得到了一致性的结果[Blood,2004.103(2):689-94]。Kochenderfer等在已有报道的基础上,又联合应用Q-PCR、流式细胞术和免疫组化方法深入研究了BCMA的表达特征,确认BCMA在成熟B细胞、浆细胞之外的正常人体组织无表达,且在CD34+造血细胞中也无表达[Clin CancerRes,2013.19(8):2048-60]。结合BCMA表达特征与CD19的高度相似性,以及抗CD19 CAR-T细胞治疗的成功进展,提示我们BCMA可以作为CAR-T细胞的靶点之一用于多发性骨髓瘤的细胞免疫治疗。嵌合抗原受体-T细胞(Chimeric Antigen Receptor-T cell,CAR-T)是指经基因修饰后,能以MHC非限制性方式识别特定目的抗原,并且持续活化扩增的T细胞。2012年国际细胞治疗协会年会中指出生物免疫细胞治疗已经成为手术、放疗、化疗外的第四种治疗肿瘤的手段,并将成为未来肿瘤治疗必选手段。CAR-T细胞回输治疗是当前肿瘤治疗中最明确有效的免疫治疗形式。大量研究表明,CAR-T细胞可以有效的识别肿瘤抗原,引起特异性的抗肿瘤免疫应答,显著改善患者的生存状况。嵌合抗原受体(CAR)是CAR-T的核心部件,赋予T细胞HLA非依赖的方式识别肿瘤抗原的能力,这使得经过CAR改造的T细胞相较于天然T细胞表面受体TCR能够识别更广泛的目标。CAR的基础设计中包括一个肿瘤相关抗原(tumor-associatedantigen,TAA)结合区(通常来源于单克隆抗体抗原结合区域的scFv段),一个胞外铰链区,一个跨膜区和一个胞内信号区。目标抗原的选择对于CAR的特异性、有效性以及基因改造T细胞自身的安全性来讲都是关键的决定因素。
随着CAR-T技术的不断发展,目前CAR-T主要可划分为四代。第一代CAR-T细胞由胞外结合区-单链抗体(single chain fragment variable,scFv)、跨膜区(transmembraneregion,TM)和胞内信号区-免疫受体酪氨酸活化基序(immunoreceptor tyrosine basedactivation motif,ITAM)组成,其中嵌合抗原受体各部分按如下形式连接:scFv-TM-CD3ζ。
第一代CAR虽然能够看到一些特异性的细胞毒性,但2006年对其进行临床试验总结的时候却发现疗效差强人意。究其原因是因为第一代CAR-T细胞在病人体内很快就会耗竭,其持久性很差,以至于CAR-T细胞还没有来得及接触到大量的肿瘤细胞时就已经凋亡了该种CAR-T细胞可以激发抗肿瘤的细胞毒性效应,但是细胞因子分泌比较少,但其在体内的存活期较短不能激发持久的抗肿瘤效应[Cancer Res,2007.67(22):11029-11036]。
第二代CAR-T细胞优化CAR设计,T细胞活化信号区仍然是研究的热点。T细胞的完全活化有赖于双信号和细胞因子的作用。其中第一信号为特异性信号,由TCR识别抗原递呈细胞表面的抗原肽-MHC复合物所启动;第二信号为协同刺激信号。早在1998年就出现了第二代CAR[J Immunol,1998.161(6):2791-7]。第2代CAR在胞内信号肽区添加了一个协同刺激分子,即把协同刺激信号组装到CAR里面,能够更好的为CAR-T细胞提供活化信号,这样CAR识别肿瘤细胞后能够同时活化协同刺激分子和胞内信号,实现双重活化,能明显提高T细胞增殖分泌能力和抗肿瘤效应。第一个被详细研究的T细胞共刺激信号受体是CD28,它能够与靶细胞表面的B7家族成员结合。CD28的共刺激能够促进T细胞的增殖,IL-2的合成和表达以及增强T细胞抵抗凋亡的能力。随后又出现了CD134(OX40)和41BB(4-1BB)等共刺激分子,以提高T细胞的细胞毒性、增殖活性,维持T细胞应答,延长T细胞存活时间等。这样的第二代CAR在随后的临床试验中产生了意想不到的效果,从2010年起基于第二代CAR的临床报道屡次引发震动,特别是对于复发性、难治性的ALL病人,其完全缓解率高达90%以上。
第三代CAR信号肽区整合2个以上的协同刺激分子,可使T细胞持续活化增殖,细胞因子持续分泌,T细胞杀伤肿瘤细胞的能力更加显著,即新一代的CAR可获得更强的抗肿瘤应答[Mol Ther,2005.12(5):933-941]。最典型的就是在CD28刺激因子的作用下又加了一个41BB的刺激因子。
第四代的CAR-T细胞则加入了细胞因子或共刺激配体,例如四代CAR可以产生IL-12,其能够调节免疫微环境-增加T细胞的激活,同时激活固有免疫细胞使其发挥作用来清除靶抗原阴性的癌细胞,从而达到双向调节的作用[Expert Opin Biol Ther,2015.1(8):1145-54]。
CAR-T细胞的一大优点是它们是活性药物,一旦输入,生理机制会调控T细胞的平衡、记忆形成和抗原驱动的扩增。然而,这种治疗尚未完善,T细胞会脱靶而攻击其他的组织,或扩增量过高,超出治疗所需。鉴于CAR-T细胞已被纳入标准治疗范围,设计病人或药物可控的启动或关闭机制来调控CAR-T细胞的存在是非常有用的。由于技术原因,关闭机制更易应用于T细胞。作为其中之一,iCas9系统正在临床研究当中。细胞在表达iCas9时,使用小分子化合物可诱导iCas9前体分子形成二聚体,激活凋亡途径,从而实现清除细胞的目的。在移植物抗宿主病中,小分子AP1903已被用于诱导iCas9二聚体和清除T细胞,表明了这种方法的可行性[Clin Cancer Res,2016.22(8):1875-84]。
另外,还可利用临床上已经使用的清除性抗体,使CAR-T细胞同时表达这些抗体针对的蛋白,如tEGFR,在治疗相关的毒性反应产生或是治疗已经完成后,通过给予抗体药物清除相应的CAR-T细胞[Sci Transl Med,2015.7:275ra22]。
2015年9月,Carl June研究小组在新英格兰杂志发表了使用CD19分子靶向CAR-T细胞疗法成功治疗1例复发难治多发性骨髓瘤(MM)患者的文章[NEJM,2015.373(11):1040-7]。虽然多发性骨髓瘤作为B细胞系肿瘤通常不表达CD19,因此CD19不作为多发性骨髓瘤免疫治疗的靶标。有报道指出微量的具有耐药性及疾病复发特性的多发性骨髓瘤克隆具有B细胞表型(即CD19阳性)。在明确BCMA可作为CAR-T细胞的靶点后,美国国家癌症研究院Kochenderfer等成功构建了抗BCMA CAR-T细胞,并在临床前研究表明该CAR-T细胞特异性地识别BCMA,并在被BCMA激活后大量扩增、分泌细胞因子并发挥杀伤功能,在小鼠成瘤模型中也具有抗肿瘤效应[Clin Cancer Res,2013.19(8):2048-60]。2014年美国国家癌症研究院开展抗BCMACAR-T细胞治疗多发性骨髓瘤的I期临床研究,针对现今标准治疗方案无反应的多发性骨髓瘤患者,验证抗BCMA CAR-T细胞的临床安全性和有效性(ClinicalTrials.gov Identifier:NCT02215967)。在2015年12月初的第57届美国血液年会上,美国国家癌症研究院医学肿瘤科Syed Abbas Ali教授团队报告了多发性骨髓瘤患者CAR-T细胞治疗I期临床试验结果。该研究共纳入了12例3线以上化疗失败的难治复发多发性骨髓瘤患者,有的患者骨髓中骨髓瘤细胞≥50%。这些患者输入BCMA CAR-T细胞后,1例患者完全缓解,3例患者部分缓解,其余均病情稳定,由此第一次证明抗BCMA CAR-T细胞疗法对多发性骨髓瘤有效,且无重大副作用,被评为ASH年度最具影响力的临床研究之一[Late-BreakingAbstracts,大会摘要号:LAB-1]。目前,艾森布拉姆宾夕法尼亚大学艾布拉姆森癌症中心也已注册了抗BCMA CAR-T细胞治疗多发性骨髓瘤的I期临床试验,并在紧锣密鼓的开展研究中(ClinicalTrials.gov Identifier:NCT02546167)。
发明概述
利用基于噬菌体展示技术的人源天然抗体库技术,获取了多个人源抗体作为嵌合抗原受体T细胞表面的靶向性分子。还利用基于噬菌体展示技术的鼠源免疫抗体库技术,进行了类似的工作。提供了基于抗BCMA单链抗体(例如scFv)(包括鼠源的和人源的)(特别是HK10)构建的抗BCMA嵌合抗原受体,其包括抗BCMA结合区、人CD8α铰链区、人CD8α跨膜区、人41BB胞内区和人CD3ζ胞内区。表达此嵌合抗原受体(特别是基于HK10)的T细胞具有特异杀伤BCMA阳性的肿瘤细胞的能力,且在IFNγ分泌和CD107a表达方面较表达基于C11D5.3克隆的嵌合抗原受体的T细胞更佳。表达此嵌合抗原受体的T细胞具有较优的临床治疗效果。除了特异的肿瘤细胞的杀伤能力、较优的IFNγ分泌和CD107a表达能力,当携带该嵌合抗原受体(特别是基于HK10)的T细胞应用于临床实验时,由于全人源抗体scFv的应用,可将免疫原性降到最低,避免了携带嵌合抗原受体的T细胞的清除,可能会延长携带嵌合抗原受体的T细胞的存续并提高疗效。
在一个方面,本发明涉及一种特异性结合人B细胞成熟抗原(BCMA)的抗体或抗原结合片段,其特征在于包含重链可变域和轻链可变域,所述包含重链可变域和轻链可变域:
(1)SEQ ID NO:1所示重链CDR1、SEQ ID NO:2所示重链CDR2、SEQ ID NO:3所示重链CDR3、SEQ ID NO:4所示轻链CDR1、SEQ ID NO:5所示轻链CDR2和SEQ ID NO:6所示轻链CDR3;
(2)SEQ ID NO:7所示重链CDR1、SEQ ID NO:8所示重链CDR2、SEQ ID NO:9所示重链CDR3、SEQ ID NO:10所示轻链CDR1、SEQ ID NO:11所示轻链CDR2和SEQ ID NO:12所示轻链CDR3;
(3)SEQ ID NO:13所示重链CDR1、SEQ ID NO:14所示重链CDR2、SEQ ID NO:15所示重链CDR3、SEQ ID NO:16所示轻链CDR1、SEQ ID NO:17所示轻链CDR2和SEQ ID NO:18所示轻链CDR3;
(4)SEQ ID NO:19所示重链CDR1、SEQ ID NO:20所示重链CDR2、SEQ ID NO:21所示重链CDR3、SEQ ID NO:22所示轻链CDR1、SEQ ID NO:23所示轻链CDR2和SEQ ID NO:24所示轻链CDR3;或
(5)SEQ ID NO:25所示重链CDR1、SEQ ID NO:26所示重链CDR2、SEQ ID NO:27所示重链CDR3、SEQ ID NO:28所示轻链CDR1、SEQ ID NO:29所示轻链CDR2和SEQ ID NO:30所示轻链CDR3。
优选地,所述抗体或抗原结合片段包含SEQ ID NO:1所示重链CDR1、SEQ ID NO:2所示重链CDR2、SEQ ID NO:3所示重链CDR3、SEQ ID NO:4所示轻链CDR1、SEQ ID NO:5所示轻链CDR2和SEQ ID NO:6所示轻链CDR3。
在本发明的一个实施方案中,所述抗体或抗原结合片段为嵌合的或人源的。
在另一个方面,本发明涉及一种特异性结合人B细胞成熟抗原(BCMA)的抗体或抗原结合片段,其特征在于包含重链可变域和轻链可变域,所述重链可变域和轻链可变域包含:
(1)SEQ ID NO:31所示重链CDR1、SEQ ID NO:32所示重链CDR2、SEQ ID NO:33所示重链CDR3、SEQ ID NO:34所示轻链CDR1、SEQ ID NO:35所示轻链CDR2和SEQ ID NO:36所示轻链CDR3;
(2)SEQ ID NO:37所示重链CDR1、SEQ ID NO:38所示重链CDR2、SEQ ID NO:39所示重链CDR3、SEQ ID NO:40所示轻链CDR1、SEQ ID NO:41所示轻链CDR2和SEQ ID NO:42所示轻链CDR3;
(3)SEQ ID NO:43所示重链CDR1、SEQ ID NO:44所示重链CDR2、SEQ ID NO:45所示重链CDR3、SEQ ID NO:46所示轻链CDR1、SEQ ID NO:47所示轻链CDR2和SEQ ID NO:48所示轻链CDR3;
(4)SEQ ID NO:49所示重链CDR1、SEQ ID NO:50所示重链CDR2、SEQ ID NO:51所示重链CDR3、SEQ ID NO:52所示轻链CDR1、SEQ ID NO:53所示轻链CDR2和SEQ ID NO:54所示轻链CDR3;或
(5)SEQ ID NO:55所示重链CDR1、SEQ ID NO:56所示重链CDR2、SEQ ID NO:57所示重链CDR3、SEQ ID NO:58所示轻链CDR1、SEQ ID NO:59所示轻链CDR2和SEQ ID NO:60所示轻链CDR3。
在本发明的一个实施方案中,所述抗体或抗原结合片段为鼠源的、嵌合的或人源化的。
在本发明的一个实施方案中,所述抗体或抗原结合片段特异性结合人B细胞成熟抗原(BCMA)的胞外域。
在本发明的一个实施方案中,所述抗体或抗原结合片段为scFv、Fab或完整抗体。在本发明的一个实施方案中,所述抗体或抗原结合片段的重链是IgG的,特别是IgG1的。在本发明的一个实施方案中,所述抗体或抗原结合片段的轻链是卡帕(κ)或拉姆达(λ)的,特别是卡帕的。
在又一个方面,本发明涉及一种或多种多核苷酸,其特征在于编码依照本发明的抗体或抗原结合片段。
在又一个方面,本发明涉及一种载体,其特征在于包含依照本发明的多核苷酸。在本发明的一个实施方案中,所述载体为克隆载体或表达载体,特别是质粒载体。
在又一个方面,本发明涉及一种宿主细胞,其特征在于包含依照本发明的多核苷酸或依照本发明的载体。在本发明的一个实施方案中,所述宿主细胞为原核细胞,特别是大肠杆菌细胞。在本发明的另一个实施方案中,所述宿主细胞为真核细胞,特别是中国仓鼠卵巢细胞。
在又一个方面,本发明涉及一种生成抗体或抗原结合片段的方法,其特征在于在抗体或抗原结合片段表达的条件下培养依照本发明的宿主细胞。
在又一个方面,本发明涉及一种药物组合物,其特征在于包含依照本发明的抗体或抗原结合片段,和一种或多种药学可接受载剂。
在又一个方面,本发明涉及一种嵌合抗原受体,其特征在于包含胞外区、跨膜区和胞内区,其中所述胞外区包含抗原结合区,所述抗原结合区包含重链可变域和轻链可变域,所述重链可变域和轻链可变域包含:
(1)SEQ ID NO:1所示重链CDR1、SEQ ID NO:2所示重链CDR2、SEQ ID NO:3所示重链CDR3、SEQ ID NO:4所示轻链CDR1、SEQ ID NO:5所示轻链CDR2和SEQ ID NO:6所示轻链CDR3;
(2)SEQ ID NO:7所示重链CDR1、SEQ ID NO:8所示重链CDR2、SEQ ID NO:9所示重链CDR3、SEQ ID NO:10所示轻链CDR1、SEQ ID NO:11所示轻链CDR2和SEQ ID NO:12所示轻链CDR3;
(3)SEQ ID NO:13所示重链CDR1、SEQ ID NO:14所示重链CDR2、SEQ ID NO:15所示重链CDR3、SEQ ID NO:16所示轻链CDR1、SEQ ID NO:17所示轻链CDR2和SEQ ID NO:18所示轻链CDR3;
(4)SEQ ID NO:19所示重链CDR1、SEQ ID NO:20所示重链CDR2、SEQ ID NO:21所示重链CDR3、SEQ ID NO:22所示轻链CDR1、SEQ ID NO:23所示轻链CDR2和SEQ ID NO:24所示轻链CDR3;
(5)SEQ ID NO:25所示重链CDR1、SEQ ID NO:26所示重链CDR2、SEQ ID NO:27所示重链CDR3、SEQ ID NO:28所示轻链CDR1、SEQ ID NO:29所示轻链CDR2和SEQ ID NO:30所示轻链CDR3;
(6)SEQ ID NO:31所示重链CDR1、SEQ ID NO:32所示重链CDR2、SEQ ID NO:33所示重链CDR3、SEQ ID NO:34所示轻链CDR1、SEQ ID NO:35所示轻链CDR2和SEQ ID NO:36所示轻链CDR3;
(7)SEQ ID NO:37所示重链CDR1、SEQ ID NO:38所示重链CDR2、SEQ ID NO:39所示重链CDR3、SEQ ID NO:40所示轻链CDR1、SEQ ID NO:41所示轻链CDR2和SEQ ID NO:42所示轻链CDR3;
(8)SEQ ID NO:43所示重链CDR1、SEQ ID NO:44所示重链CDR2、SEQ ID NO:45所示重链CDR3、SEQ ID NO:46所示轻链CDR1、SEQ ID NO:47所示轻链CDR2和SEQ ID NO:48所示轻链CDR3;
(9)SEQ ID NO:49所示重链CDR1、SEQ ID NO:50所示重链CDR2、SEQ ID NO:51所示重链CDR3、SEQ ID NO:52所示轻链CDR1、SEQ ID NO:53所示轻链CDR2和SEQ ID NO:54所示轻链CDR3;或
(10)SEQ ID NO:55所示重链CDR1、SEQ ID NO:56所示重链CDR2、SEQ ID NO:57所示重链CDR3、SEQ ID NO:58所示轻链CDR1、SEQ ID NO:59所示轻链CDR2和SEQ ID NO:60所示轻链CDR3。
在本发明的一个实施方案中,所述抗原结合区为scFv或Fab。
在本发明的一个实施方案中,所述胞外区还包含铰链区。在本发明的一个实施方案中,所述铰链区包含人CD8α铰链区。在本发明的一个实施方案中,所述人CD8α铰链区具有SEQ ID NO:63所示氨基酸序列。
在本发明的一个实施方案中,所述跨膜区包含人CD8α跨膜区。在本发明的一个实施方案中,所述人CD8α跨膜区具有SEQ ID NO:65所示氨基酸序列。
在本发明的一个实施方案中,所述胞内区包含一个或多个信号传导区。在本发明的一个实施方案中,所述胞内区包含人41BB胞内区和/或人CD3ζ胞内区。在本发明的一个实施方案中,所述人41BB胞内区具有SEQ ID NO:67所示氨基酸序列和/或所述人CD3ζ胞内区具有SEQ ID NO:69所示氨基酸序列。
在又一个方面,本发明涉及一种多肽,其特征在于包含信号肽和依照本发明的嵌合抗原受体。在本发明的一个实施方案中,所述信号肽是CD8α信号肽。在本发明的一个实施方案中,所述CD8α信号肽具有SEQ ID NO:61所示氨基酸序列。
在又一个方面,本发明涉及一种多核苷酸,其特征在于编码依照本发明的嵌合抗原受体或依照本发明的多肽。
在又一个方面,本发明涉及一种载体,其特征在于包含依照本发明的多核苷酸。在本发明的一个实施方案中,所述载体为克隆载体或表达载体。在本发明的一个实施方案中,所述载体为病毒载体。
在又一个方面,本发明涉及一种改造的免疫效应细胞,其特征在于表达依照本发明的嵌合抗原受体的多肽,或者包含编码依照本发明的嵌合抗原受体或的多肽的多核苷酸。在本发明的一个实施方案中,所述改造的免疫效应细胞选自T淋巴细胞、NK细胞、多能干细胞或胚胎干细胞培养分化的免疫细胞,特别是T淋巴细胞。
在又一个方面,本发明涉及一种改造免疫效应细胞的方法,其特征在于用依照本发明的载体(特别是病毒载体)感染免疫效应细胞。在本发明的一个实施方案中,所述免疫效应细胞为T淋巴细胞。
在又一个方面,本发明涉及依照本发明的抗体或抗原结合片段、嵌合抗原受体、多肽、多核苷酸、载体、或改造的免疫效应细胞在制备用于治疗癌症的药物中的用途。在又一个方面,本发明涉及依照本发明的抗体或抗原结合片段、嵌合抗原受体、多肽、多核苷酸、载体、或改造的免疫效应细胞在制备用于在具有癌症的患者中刺激免疫功能的药物中的用途。在又一个方面,本发明涉及一种治疗癌症的方法,其包括对具有该癌症的患者施用依照本发明的抗体或抗原结合片段、嵌合抗原受体、多肽、多核苷酸、载体、或改造的免疫效应细胞。在又一个方面,本发明涉及一种在具有癌症的患者中刺激免疫功能的方法,其包括对该患者施用依照本发明的抗体或抗原结合片段、嵌合抗原受体、多肽、多核苷酸、载体、或改造的免疫效应细胞。在本发明的一个实施方案中,所述癌症是B细胞相关癌症,特别是多发性骨髓瘤。在本发明的一个实施方案中,所述免疫功能是IFN-γ分泌和/或CD107a表达
附图简述
图1显示抗BCMA CAR-T对靶细胞的杀伤。
图2显示抗BCMA CAR-T CD3阳性细胞的IFN-γ及CD107a表达。
图3显示抗BCMA CAR-T CD3阳性细胞的IFN-γ表达。
图4显示抗BCMA CAR-T CD3阳性细胞的CD107a表达。
图5显示本发明抗体的重链CDR氨基酸序列(依照IMGT系统)。
图6显示本发明抗体的轻链CDR氨基酸序列(依照IMGT系统)。
发明详述
除非另有定义,本文中所使用的技术和科学术语具有与本发明所属领域普通技术人员通常的理解相同的含义。
除非另有说明,本发明的实施将采用分子生物学、微生物学、细胞生物学、生物化学和免疫学的常规技术。这些技术都在本领域的技术范围内且在文献中有充分说明。
应当理解,本文中所描述的“包含”的实施方案包括“由……组成”和/或“实质上由……组成”的实施方案。
I.抗BCMA抗体
本发明的一个方面提供特异性结合BCMA(诸如人BCMA,特别是人BCMA的胞外域)的抗BCMA抗体。在一些实施方案中,本发明的抗BCMA抗体是单克隆抗体。
B细胞成熟抗原(BCMA),也称为CD269或TNFRSF17,是肿瘤坏死因子受体超家族成员。BCMA几乎排他性地在浆细胞和多发性骨髓瘤细胞中表达。BCMA可以是针对多发性骨髓瘤的免疫治疗剂的合适肿瘤抗原靶标。
在一些实施方案中,本发明的抗BCMA抗体是全长抗体。术语“全长抗体”、“完整抗体”和“全抗体”在本文中可互换使用,指与抗体片段相比,基本上完整形式的抗体。术语“抗体”和“免疫球蛋白”在本文中可互换使用。基本的4链抗体单元是由两条相同的轻(L)链和两条相同的重(H)链组成的异源四聚体糖蛋白。来自任何脊椎动物物种的L链可根据其恒定区的氨基酸序列归为两种明显不同的型,称为卡帕(κ)和拉姆达(λ)。可根据重链恒定区的氨基酸序列,将抗体归为不同的五类:IgA、IgD、IgE、IgG和IgM,它们分别具有称为α、δ、ε、γ和μ的重链。可将IgG和IgA类进一步分为亚类,例如IgG1、IgG2(包括IgG2A和IgG2B)、IgG3、IgG4、IgA1和IgA2。就IgG而言,4链单元通常为约150,000道尔顿。每条H链在N端具有可变域(VH),然后是每条γ链的三个恒定域(CH)。每条L链在N端具有可变域(VL),然后是另一端的恒定域(CL)。
在一些实施方案中,本发明的抗BCMA抗体是IgG的,特别是IgG1的。在一些实施方案中,本发明的抗BCMA抗体是卡帕的。
在一些实施方案中,本发明的抗BCMA抗体是抗体片段。术语“抗体片段”包含完整抗体的部分,优选完整抗体的抗原结合区和/或可变区。抗体片段的实例包括Fab、Fab'、Fab'-SH、F(ab')2、Fv和scFv片段;双体;线性抗体;单链抗体;单域抗体;以及从抗体片段形成的多特异性抗体。术语“scFv”是包含连接成单个多肽链的VH和VL域的抗体片段。优选地,scFv还包含VH和VL域之间的多肽接头。术语“Fab”由整个L链以及H链的可变域(VH)和第一恒定域(CH1)组成。
在一些实施方案中,本发明的抗BCMA抗体是抗原结合片段,其包含亲本抗体的重链可变域和轻链可变域,例如scFv或Fab。抗体片段可通过多种技术来制备,包括但不限于完整抗体的蛋白水解消化,以及由重组宿主细胞产生。
在一些实施方案中,本发明的抗BCMA抗体是鼠源的、嵌合的、人源化的或人源的。
在“嵌合”抗体中,重链和/或轻链的一部分与来源于特定物种或属于特定抗体类或亚类的抗体中的对应序列相同或同源,而重链和/或轻链的其余部分与来源于另一个物种或属于另一个抗体类或亚类的抗体中的对应序列相同或同源,只要它们表现出所需的生物学活性即可。在一些实施方案中,本发明的嵌合抗体包含鼠可变区和人恒定区。
非人(例如鼠源)抗体的“人源化”形式是含有来源于非人抗体的最小序列的嵌合抗体。在一些实施方案中,人源化抗体是其中受体抗体的CDR(或HVR)残基被具有所需特异性、亲和力和/或能力的非人物种(供体抗体)诸如小鼠、大鼠、兔或非人灵长类动物的CDR(或HVR)残基替换的人抗体(受体抗体)。在一些情况下,人抗体的框架(“FR”)残基被相应的非人残基替换。此外,人源化抗体可包含受体抗体中或供体抗体中均不存在的残基。可以进行这些修饰以进一步完善抗体性能,诸如结合亲和力。
“人抗体”是具有对应于人产生的抗体的氨基酸序列和/或使用制备人抗体的任何技术来制备的抗体。人抗体的此定义明确排除包含非人抗原结合残基的人源化抗体。人抗体可使用本领域已知的多种技术来产生。人抗体可通过将免疫原施用于转基因动物来制备,所述转基因动物已被修饰为响应于抗原激发而产生此类抗体,但其内源性基因座已失能。也可通过人来源的噬菌体展示文库来产生人抗体。免疫来源的文库为免疫原提供了高亲和力抗体,而不需要构建杂交瘤。或者,可以克隆未暴露的库,从而在无需任何免疫的情况下,得到针对多种非自体抗原和自体抗原的抗体。
在一些实施方案中,本发明的抗BCMA抗体或抗原结合片段包含图5所示重链CDR。在一些实施方案中,本发明的抗BCMA抗体或抗原结合片段包含图6所示轻链CDR。
在一些实施方案中,本发明涵盖与本文所述的抗BCMA抗体中的任一者结合相同BCMA表位的抗体。在一些实施方案中,本发明涵盖与本文所述的抗BCMA抗体中的任一者竞争结合BCMA的抗体。在一些实施方案中,竞争测定法可用于鉴定与本文所述的抗BCMA抗体中的任一者结合相同BCMA表位的抗体或与本文所述的抗BCMA抗体中的任一者竞争结合BCMA的抗体。在一些实施方案中,若一种抗体将另一种抗体对抗原的结合阻断50%或更多,则认为两种抗体结合相同的表位。
本发明的一个方面提供一种或多种多核苷酸,其特征在于编码依照本发明的抗BCMA抗体。本发明的一个方面提供一种载体,其特征在于包含依照本发明的多核苷酸。在一个实施方案中,所述载体为克隆载体或表达载体,特别是质粒载体。本发明的一个方面提供一种宿主细胞,其特征在于包含依照本发明的多核苷酸或依照本发明的载体。在一个实施方案中,所述宿主细胞为原核细胞,特别是大肠杆菌细胞。在另一个实施方案中,所述宿主细胞为真核细胞,特别是中国仓鼠卵巢细胞。本发明的一个方面提供一种生成抗BCMA抗体的方法,其特征在于在抗体表达的条件下培养依照本发明的宿主细胞。
II.嵌合抗原受体
本发明的一个方面提供靶向BCMA的嵌合抗原受体(CAR)。嵌合抗原受体一般由胞外区、跨膜区和胞内区构成。胞外区包含抗原结合区,和任选的铰链区。胞内区包含一个或多个信号传导区,包括共刺激信号传导区。在细胞中表达时,嵌合抗原受体的多肽还可以包含信号肽。
信号肽
在细胞中表达时,本发明的嵌合抗原受体的多肽可以包含多肽的N端处的信号肽(也称为信号序列)。一般而言,信号肽是使多肽靶向细胞中的所需部位的肽序列。在一些实施方案中,信号肽使多肽靶向细胞的分泌通路,并且将允许多肽整合和锚定至脂双层。
在一些实施方案中,本发明中使用的信号肽来源于CD8α。在一些实施方案中,CD8α信号肽包含SEQ ID NO:61的氨基酸序列。在一些实施方案中,CD8α信号肽由SEQ ID NO:62的核酸序列编码。
抗原结合区
本发明的嵌合抗原受体包含靶向BCMA的抗原结合区。抗原结合区可以是单价的或多价的(例如二价的)。抗原结合区还可以是单特异性的或多特异性的(例如双特异性的)。双特异性可以是针对BCMA和另一种抗原,也可以是针对BCMA的两种不同表位。
在一些实施方案中,本发明中使用的抗原结合区是上文描述的抗BCMA抗体或抗原结合片段,特别是scFv形式的。
铰链区
任选地,本发明的嵌合抗原受体包含位于胞外抗原结合区和跨膜区之间的铰链区。铰链区是通常在蛋白质的两个域之间存在的氨基酸区段,并且可以允许蛋白质的柔性和两个域的彼此相对运动。
铰链区可以是天然存在的蛋白质的铰链区或其部分。抗体(诸如IgG、IgA、IgM、IgE或IgD抗体)的铰链区也可用于本文所述的嵌合抗原受体。非天然存在的肽也可用作本文所述的嵌合抗原受体的铰链区。在一些实施方案中,铰链区是肽接头。
在一些实施方案中,本发明中使用的铰链区来源于CD8α。在一些实施方案中,CD8α铰链区包含SEQ ID NO:63的氨基酸序列。在一些实施方案中,CD8α铰链区由SEQ ID NO:64的核酸序列编码。
跨膜区
本发明的嵌合抗体受体包含跨膜区。跨膜区可以形成α螺旋、多于一个α螺旋的复合物、β桶或能够跨域细胞磷脂双层的任何其它稳定结构。跨膜区可以是天然或合成来源的。跨膜区可源自T细胞受体、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、KIRDS2、OX40、CD2、CD27、LFA-1(CD11a、CD18)、ICOS(CD278)、4-1BB(CD137)、GITR、CD40、BAFFR、HVEM(LIGHTR)、SLAMF7、NKp80(KLRF1)、CD160、CD19、IL-2Rβ、IL-2Rγ、IL-7Ra、ITGA1、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDlld、ITGAE、CD103、ITGAL、CD11a、LFA-1、ITGAM、CDllb、ITGAX、CD11c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、TNFR2、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CDIOO(SEMA4D)、SLAMF6(NTB-A、Lyl08)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、PAG/Cbp、NKp44、NKp30、NKp46、NKG2D和/或NKG2C的α、β或ζ链。
在一些实施方案中,本发明中使用的跨膜区来源于CD8α。在一些实施方案中,CD8α跨膜区包含SEQ ID NO:65的氨基酸序列。在一些实施方案中,CD8跨膜区由SEQ ID NO:66的核酸序列编码。
胞内区
本发明的嵌合抗原受体包含胞内区。胞内区包含一个或多个信号传导区,包括共刺激信号传导区。
胞内信号传导区负责表达嵌合抗原受体的免疫效应细胞的至少一种正常效应子功能的活化。例如,T细胞的效应子功能可以是细胞裂解活性或辅助活性,包括细胞因子的分泌。虽然通常可以利用整个胞内信号传导区,但是在很多情况下,使用整个链是不必要的。就使用胞内信号传导区的截短部分而言,只要其转导效应子功能信号,就可以使用这种截短部分代替完整链。因此,胞内信号传导区包括足以转导效应子功能信号的胞内信号传导区的任何截短形式。在一些实施方案中,信号传导区来源于CD3ζ、FcRγ(FCER1G)、FcRβ(FcεRib)、CD3γ、CD3δ、CD3ε、CD5、CD22、CD79a、CD79b和CD66d。
在一些实施方案中,本发明中使用的信号传导区来源于CD3ζ。在一些实施方案中,CD3ζ信号传导区包含SEQ ID NO:69的氨基酸序列。在一些实施方案中,CD3ζ信号传导区由SEQ ID NO:70的核酸序列编码。
在一些实施方案中,本发明的嵌合抗原受体的胞内区还包含一个或多个共刺激信号传导区。在抗原特异性信号的刺激以外,很多免疫效应细胞还需要共刺激来促进细胞增殖、分化和存活,以及活化细胞的效应子功能。“共刺激信号传导区”可以是共刺激分子的胞质部分。术语“共刺激分子”是指免疫细胞(诸如T细胞)上的关联结合伴侣,该关联结合伴侣与共刺激配体特异性结合,从而由免疫细胞介导共刺激响应,诸如但不限于增殖和存活。共刺激信号传导区可源自B7/CD28家族成员(例如B7-1/CD80、B7-2/CD86、B7-H1/PD-L1、B7-H2、B7-H3、B7-H4、B7-H6、B7-H7、BTLA/CD272、CD28、CTLA-4、Gi24/VISTA/B7-H5、ICOS/CD278、PD-1、PD-L2/B7-DC和PDCD6);TNF超家族成员(例如4-1BB/TNFSF9/CD137、4-1BB配体/TNFSF9、BAFF/BLyS/TNFSF13B、BAFF R/TNFRSF13C、CD27/TNFRSF7、CD27配体/TNFSF7、CD30/TNFRSF8、CD30配体/TNFSF8、CD40/TNFRSF5、CD40/TNFSF5、CD40配体/TNFSF5、DR3/TNFRSF25、GITR/TNFRSF18、GITR配体/TNFSF18、HVEM/TNFRSF14、LIGHT/TNFSF14、淋巴毒素-α/TNF-β、OX40/TNFRSF4、OX40配体/TNFSF4、RELT/TNFRSF19L、TACI/TNFRSF13B、TL1A/TNFSF15、TNF-α和TNF RII/TNFRSF1B);SLAM家族成员(例如,2B4/CD244/SLAMF4、BLAME/SLAMF8、CD2、CD2F-10/SLAMF9、CD48/SLAMF2、CD58/LFA-3、CD84/SLAMF5、CD229/SLAMF3、CRACC/SLAMF7、NTB-A/SLAMF6和SLAM/CD150);以及任何其它共刺激分子,诸如CD2、CD7、CD53、CD82/Kai-1、CD90/Thy1、CD96、CD160、CD200、CD300a/LMIR1、HLAI类、HLA-DR、Ikaros、整合素α4/CD49d、整合素α4β1、整合素α4β7/LPAM-1、LAG-3、TCL1A、TCL1B、CRTAM、DAP12、Dectin-1/CLEC7A、DPPIV/CD26、EphB6、TIM-1/KIM-1/HAVCR、TIM-4、TSLP、TSLP R、淋巴细胞功能相关抗原-1(LFA-1)和NKG2C。
在一些实施方案中,本发明中使用的共刺激信号传导区来源于4-1BB。在一些实施方案中,4-1BB共刺激信号传导区包含SEQ ID NO:67的氨基酸序列。在一些实施方案中,4-1BB共刺激信号传导区由SEQ ID NO:68的核酸序列编码。
在一些实施方案中,本发明的嵌合抗原受体的胞内区包含以N端至C端方向连接的上文所述4-1BB共刺激信号传导区和上文所述CD3ζ信号传导区。
本发明的一个方面提供一种多核苷酸,其特征在于编码依照本发明的嵌合抗原受体或的多肽。本发明的一个方面提供一种载体,其特征在于包含依照本发明的多核苷酸。在一个实施方案中,所述载体为克隆载体或表达载体。在一个实施方案中,所述载体为病毒载体。
III.经改造的免疫效应细胞
本发明的一个方面提供经改造,包含或表达本发明的靶向BCMA的嵌合抗原受体的细胞,诸如免疫效应细胞。在一些实施方案中,所述免疫效应细胞是T细胞、NK细胞、外周血单个核细胞(PBMC)、造血干细胞、多能干细胞或胚胎干细胞培养分化的细胞(例如免疫细胞)。在一些实施方案中,所述免疫效应细胞是自体的。在一些实施方案中,所述免疫效应细胞是同种异体的。
载体
本发明的一个方面提供用于克隆和表达本发明的靶向BCMA的嵌合抗原受体的载体。在一些实施方案中,载体适于在真核细胞(诸如哺乳动物细胞)中复制和整合。在一些实施方案中,载体是病毒载体。病毒载体的实例包括但不限于腺病毒载体、腺相关病毒载体、慢病毒载体、逆转录病毒载体、牛痘载体、单纯疱疹病毒载体及其衍生物。
已经开发了许多基于病毒的系统用于向哺乳动物细胞进行基因转移。在一些实施方案中,使用慢病毒载体。在一些实施方案中,使用自失活慢病毒载体。例如,携带嵌合抗原受体编码序列的自失活慢病毒载体可以使用本领域已知的方案包装。所得的慢病毒载体可用于使用本领域已知的方法转导哺乳动物细胞(诸如原代人T细胞)。来源于慢病毒的载体是实现长期基因转移的合适工具,因为它们允许转基因的长期、稳定整合以及它们在子代细胞中的繁殖。慢病毒载体也具有低免疫原性,并且可以转导非增殖性细胞。
免疫效应细胞
“免疫效应细胞”是可执行免疫效应子功能的免疫细胞。在一些实施方案中,免疫效应细胞表达至少FcγRIII并执行ADCC效应子功能。介导ADCC的免疫效应细胞的实例包括外周血单个核细胞(PBMC)、天然杀伤(NK)细胞、单核细胞、细胞毒性T细胞、中性粒细胞和嗜酸性粒细胞。
在一些实施方案中,免疫效应细胞是T细胞。在一些实施方案中,T细胞是CD4+/CD8-、CD4-/CD8+、CD4+/CD8+、CD4-/CD8-或它们的组合。在一些实施方案中,T细胞在表达嵌合抗原受体并结合至靶细胞时产生IL-2、IFN和/或TNF。在一些实施方案中,CD8+ T细胞在表达嵌合抗原受体并结合至靶细胞时裂解抗原特异性靶细胞。
通过将嵌合抗原受体引入免疫效应细胞(诸如T细胞)来制备经改造的免疫效应细胞。在一些实施方案中,通过转染包含编码嵌合抗原受体的序列的核酸或载体来将嵌合抗原受体引入免疫效应细胞。在一些实施方案中,通过将蛋白质插入细胞膜,同时使细胞通过微流控系统来将嵌合抗原受体引入免疫效应细胞。
将核酸或载体引入哺乳动物细胞的方法是本领域已知的。所述载体可以通过物理、化学或生物方法转入免疫效应细胞。用于将载体引入免疫效应细胞的物理方法包括磷酸钙沉淀、脂质体转染、粒子轰击、显微注射、电穿孔等等。用于将核酸或载体引入免疫效应细胞的化学手段包括胶体分散体系,诸如大分子复合物、纳米胶囊、微球体、珠粒和基于脂质的体系(包括水包油乳液、胶束、混合胶束和脂质体)。用作体外递送媒介物的示例性胶体体系是脂质体(例如人工膜囊泡)。用于将核酸或载体引入免疫效应细胞的生物方法包括使用DNA和RNA载体。病毒载体已成为将基因插入哺乳动物,例如人细胞的最广泛使用的方法。
在一些实施方案中,转导的或转染的免疫效应细胞在引入核酸或载体之后离体繁殖。在一些实施方案中,进一步评估或筛选转导的或转染的免疫效应细胞以选择经改造的免疫效应细胞。
1.T细胞的来源
在T细胞的扩增和遗传修饰之前,从个体获得T细胞的来源。T细胞可以从许多来源获得,包括外周血单个核细胞、骨髓、淋巴结组织、脐带血、胸腺组织、来自感染部位的组织、腹水、胸腔积液、脾脏组织和肿瘤。
2.T细胞的活化和扩增
无论在使用本文所述的嵌合抗原受体进行T细胞的遗传修饰之前还是之后,通常均可使用本领域已知的方法活化和扩增T细胞。
一般而言,T细胞可通过接触表面来扩增,该表面附接有刺激CD3/TCR复合物相关信号的试剂和刺激T细胞表面上的共刺激分子的配体。具体而言,可以通过接触抗CD3抗体或其抗原结合片段或固定在表面上的抗CD2抗体,或通过接触与钙离子载体组合的蛋白激酶C活化剂(例如苔藓抑素)。对于T细胞表面上辅助分子的共刺激,使用结合辅助分子的配体。例如,T细胞群可以在适于刺激T细胞增殖的条件下接触抗CD3抗体和抗CD28抗体。为了刺激CD4+ T细胞或CD8+ T细胞的增殖,使用抗CD3抗体和抗CD28抗体。
在一些实施方案中,T细胞的主要刺激信号和共刺激信号可以由不同的方案提供。例如,提供每种信号的试剂可以处于溶液中或与表面结合。当试剂与表面结合时,可以与相同的表面(即,以“顺式”形式)或分开的表面(即,以“反式”形式)结合。或者,一种试剂可以与表面结合,而另一种试剂处于溶液中。在一个实施方案中,提供共刺激信号的试剂与细胞表面结合,而提供主要活化信号的试剂处于溶液中或与表面结合。在某些实施方案中,两种试剂都可以处于溶液中。在另一个实施方案中,所述试剂可以为可溶形式,然后与表面交联。
在一些实施方案中,T细胞与试剂涂覆的珠粒组合,随后分离珠粒和细胞,然后培养细胞。在一个替代实施方案中,在培养之前,试剂涂覆的珠粒和细胞不是分开的,而是一起培养的。在另一个实施方案中,首先通过施加力(诸如磁力)来浓缩珠粒和细胞,使得细胞表面标记物的连接增加,从而诱导细胞刺激。
适于T细胞培养的条件包括适当的培养基(例如极限必需培养基或RPMI培养基1640),所述培养基可以含有增殖和生存必需的因子,包括血清(例如胎牛血清或人血清)、白介素-2(IL-2)、胰岛素、IFN-γ、IL-4、IL-7、GM-CSF、IL-10、IL-12、IL-15、TGFβ和TNF-α或技术人员已知的用于细胞生长的任何其它添加剂。用于细胞生长的其它添加剂包括但不限于表面活性剂、人血浆蛋白粉(plasmanate)和还原剂(诸如N-乙酰半胱氨酸和2-巯基乙醇)。培养基可包括添加了氨基酸、丙酮酸钠和维生素的RPMI 1640、AIM-V、DMEM、MEM、α-MEM、F-12、X-Vivo 15和X-Vivo 20,这些培养基是无血清的或补充有适量的血清(或血浆)或一组确定的激素,和/或一定量足够T细胞生长和扩增的细胞因子。仅在实验培养物中,而不是在要输注给受试者的细胞培养物中包括抗生素(例如青霉素和链霉素)。将细胞维持在支持生长所需的条件下,例如适当的温度(例如37℃)和大气(例如空气加上5%CO2)。已经暴露于不同刺激时间的T细胞可以表现出不同的特性。例如,典型的血液或单采血液成分术的外周血单核细胞产物具有辅助T细胞群(TH,CD4+),所述辅助T细胞群大于细胞毒性或抑制T细胞群(TC,CD8)。通过刺激CD3和CD28受体来离体扩增T细胞在约第8-9天之前产生主要由TH细胞组成的T细胞群,而在约第8-9天之后,T细胞群包含逐渐增加的TC细胞群。因此,根据治疗目的,用主要包含TH细胞的T细胞群输注受试者可为有利的。类似地,若已分离TC细胞的抗原特异性子集,则使该子集扩增至更大的程度可为有益的。
此外,除了CD4和CD8标记物之外,其它表型标记物也显著不同,但在很大程度上,在细胞扩增过程中可再现。因此,这种可再现性使得能够针对特定目的定制活化T细胞产物。
如本文所用,表述“细胞”、“细胞系”和“细胞培养物”可互换使用,并且全部这些名称均包括子代。应当理解,由于有意或无意突变,所有子代在DNA含量上可能不严格相同。包括与在初始转化的细胞中筛选的细胞具有相同功能或生物学活性的变体子代。
术语“宿主细胞”、“宿主细胞系”和“宿主细胞培养物”可互换使用,并且是指已经引入外源性核酸的细胞,包括这些细胞的子代。宿主细胞包括“转化子”和“转化的细胞”,其包括原代转化细胞以及由此来源的子代,而不考虑传代次数。子代在核酸含量上与亲代细胞可能不完全相同,但可能含有突变。本文包括与在初始转化的细胞中筛选或选择的细胞具有相同功能或生物学活性的突变子代。
IV.诊断和检测方法和用途
本发明的一个方面提供用于检测生物样品中BCMA的方法。术语“检测”涵盖定量或定性检测。本发明的一个方面提供用于诊断癌症的方法。在一个实施方案中,所述癌症包括但不限于B细胞相关癌症,特别是多发性骨髓瘤。在一个实施方案中,所述癌症包括但不限于血液恶性肿瘤和实体肿瘤,特别是多发性骨髓瘤。
在一些实施方案中,所述方法包括在允许抗BCMA抗体结合BCMA的条件下使生物样品接触本文所述的抗BCMA抗体,以及检测抗BCMA抗体和BCMA之间是否形成复合物,其中复合物的形成指示生物样品中存在BCMA或产生生物样品的受试者具有癌症。这种方法可以是体外的或体内的。
在一个实施方案中,提供了标记的抗BCMA抗体或抗原结合片段。标记包括但不限于直接检测的标记或部分(诸如荧光标记、发色团标记、电子密度标记、化学发光标记和放射性标记)以及间接检测的标记或部分(例如通过酶促反应或分子相互作用,例如酶与底物、受体与配体)。
V.治疗方法和用途
本发明的一个方面提供用于治疗癌症的方法,或用于在具有癌症的患者中刺激免疫功能的方法。在一个实施方案中,所述方法包括施用本发明的一种或多种抗体或抗原结合片段。在一个实施方案中,所述方法包括施用编码本发明的一种或多种抗体或抗原结合片段的多核苷酸。在一个实施方案中,所述方法包括改造免疫效应细胞以表达本发明的一种或多种嵌合抗原受体。在一个实施方案中,所述方法包括施用本发明的一种或多种改造的免疫效应细胞。在一个实施方案中,所述方法是细胞免疫疗法。
在一个实施方案中,所述癌症包括但不限于B细胞相关癌症,特别是多发性骨髓瘤。在一个实施方案中,所述癌症包括但不限于血液恶性肿瘤和实体肿瘤,特别是多发性骨髓瘤。
施用可以以任何简便的方式,包括通过注射、吸入、输注、植入或移植来进行。施用可以是动脉内、皮下、皮内、瘤内、结内、髓内、肌肉内、静脉内或腹膜内。在一些实施方案中,施用是全身的或局部的。用于免疫疗法的输注技术是本领域已知的。
根据具体的用途,本发明的药物的剂量和浓度可以变化。适当的剂量的确定完全在普通技术人员的技能范围内。
在一些实施方案中,药物组合物单次施用。在一些实施方案中,药物组合物多次施用,诸如2次、3次、4次、5次、6次或更多次。在一些实施方案中,药物组合物每周一次、2周一次、3周一次、4周一次、每个月一次、每2个月一次、每3个月一次、每4个月一次、每6个月一次或每年一次施用。
在一些实施方案中,剂量可以通过一次或多次分开给药或通过连续输注施用。在一些实施方案中,药物组合物以分开给药,诸如分2次、3次、4次、5次或更多次施用。在一些实施方案中,分开剂量在约一周内施用。在一些实施方案中,剂量是等分的。
通过常规技术和测定可易于监控治疗的进程。针对特定患者的最佳剂量和治疗方案,可由医学领域的技术人员通过监测患者的体征并相应地调整治疗而容易地确定。
在一些实施方案中,药物组合物的量能够有效地在个体中引起客观临床响应。在一些实施方案中,药物组合物的量能够有效地在个体中引起疾病缓解(部分或完全)。在一些实施方案中,药物组合物的量能够有效地预防个体中癌症的复发或疾病进展。在一些实施方案中,药物组合物的量能够有效地延长个体的存活期(诸如无疾病存活期)。在一些实施方案中,药物组合物能够有效地改善个体的生命质量。在一些实施方案中,药物组合物的量能够有效地抑制实体或淋巴肿瘤生长或减小实体或淋巴肿瘤的大小。在一些实施方案中,药物组合物的量能够有效地抑制个体中的肿瘤转移。
VI.药物组合物
本发明的一个方面提供药物组合物,其包含本发明的一种或多种抗体或抗原结合片段、嵌合抗原受体或改造的免疫效应细胞,以及一种或多种药学上可接受的载剂。
药物组合物可以通过使具有所需纯度的活性药剂与任选的药学上可接受的载剂混合以冻干制剂或水溶液的形式制备。药学上可接受的载剂在所用的剂量和浓度下对接受者是无毒的,并且包括缓冲剂、抗氧化剂、防腐剂、等渗剂、稳定剂、表面活性剂、等。
为了使药物组合物可用于体内施用,它们必须是无菌的。可以通过无菌过滤膜过滤使药物组合物无菌。
药物组合物可以含有待治疗的具体适应症所需的多于一种活性药剂,优选地具有不会不利地互相影响的互补活性的那些。或者或此外,药物组合物还可包含细胞毒性剂、化学治疗剂、细胞因子、免疫抑制剂或生长抑制剂。此类分子以对于预期目的有效的量适当地联合存在。
VII.试剂盒和制品
本发明的一个方面提供试剂盒和制品,其包含本发明的一种或多种抗体或抗原结合片段、嵌合抗原受体或经改造的免疫效应细胞。
试剂盒或制品可包括容器以及容器上或与容器相关的标签或包装插页。合适的容器包括例如瓶、小瓶、注射器等。容器可以由多种材料(诸如玻璃或塑料)形成。标签或包装插页包括使用说明书,指通常在产品的商业包装中包括的说明,其含有关于使用这些产品的适应症、用法、用量、施用、禁忌症和/或警告的信息。另外,试剂盒或制品还可以包括从商业和使用者观点来看所需的其它材料,包括稀释剂、过滤器、针和注射器。
以举例说明方式而不是限制方式提供以下实施例来作为本发明的纯粹示例,不应视为以任何方式限制本发明。
实施例
实施例1:重组人B细胞成熟抗原(BCMA)胞外域与人IgG1 Fc区的融合蛋白(BCMA-huIgG1 Fc)的表达载体构建与真核表达
1.重组BCMA胞外域的基因合成及BCMA-huIgG1 Fc融合蛋白的表达载体构建
通过化学合成的方式合成人B细胞成熟抗原(BCMA)(NCBI accession No.NP_001183.2)的第1位甲硫氨酸至第54位丙氨酸区间的基因序列,该基因序列编码SEQ ID NO:71所示的氨基酸序列。通过化学合成的方式合成人IgG1重链恒定区(UniProtKB/Swiss-Prot accession No.P01857.1)的第99位谷氨酸至第330位赖氨酸氨酸区间的基因序列,该基因序列编码SEQ ID NO:73所示的氨基酸序列。化学合成含融合蛋白信号肽(具有SEQ IDNO:75所示的氨基酸序列)基因序列的引物用于表达载体构建。通过分子克隆,将BCMA基因片段与人IgG1 Fc基因片段进行拼接。拼接产物用TaKaRa无缝克隆试剂盒克隆到pCDNA3.1(Thermo)中。
2.重组BCMA-huIgG1 Fc融合蛋白的表达与纯化
以此表达载体转染293T细胞(ATCC)5天后,收集培养上清,用AKTA explorer 100(GE)纯化重组BCMA-huIgG1 Fc融合蛋白。由于糖基化修饰等原因,重组BCMA-huIgG1 Fc融合蛋白经还原SDS-PAGE电泳后通过考马斯亮蓝染色显示其大小约40k道尔顿左右。
实施例2:抗人BCMA鼠源抗体C11D5.3可变区与人IgG1/κ恒定区嵌合抗体表达载体构建与真核表达
1.C11D5.3鼠源抗体可变区基因的获取及C11D5.3鼠-人嵌合抗体的表达载体构建
通过化学合成的方式合成C11D5.3抗体轻重链可变区基因,C11D5.3抗体轻链可变区具有SEQ ID NO:77所示的氨基酸序列,C11D5.3抗体重链可变区具有SEQ ID NO:79所示的氨基酸序列。以重链可变区基因为模板,PCR扩增重链可变区片段,扩增产物用TaKaRa无缝克隆试剂盒克隆到含信号肽和人IgG1重链恒定区基因的pFUSEss-CHIg-hG1(invivogen)中。以轻链可变区基因为模板,PCR扩增轻链可变区片段,扩增产物用TaKaRa无缝克隆试剂盒克隆到含信号肽和人卡帕轻链恒定区基因的pFUSE2ss-CLIg-hK(invivogen)中。
2.C11D5.3嵌合抗体的表达与纯化
以此双质粒1:1比例共转染293T细胞(ATCC)5天后,收集培养上清,用AKTAexplorer 100(GE)纯化C11D5.3嵌合抗体。C11D5.3嵌合抗体经非还原SDS-PAGE电泳后通过考马斯亮蓝染色显示其大小约150k道尔顿左右。
实施例3:ELISA检测重组人BCMA与C11D5.3嵌合抗体结合
利用酶联免疫吸附测定(ELISA)来检测重组人BCMA与C11D5.3嵌合抗体结合,ELISA实验具体操作如下:微孔板中加入上文制备的BCMA-huIgG1 Fc融合蛋白100ng/孔,4℃包被过夜。PBS清洗三遍,加入1%BSA/PBS,200uL/孔,37℃封闭1小时。加入100ng/孔C11D5.3嵌合抗体,37℃结合1小时。PBST清洗三遍,加入HRP-山羊抗人IgG(Fab特异性的)37℃结合1小时。PBST清洗三遍,加入100uL/孔TMB显色液,37℃显色10分钟,加入100uL/孔ELISA终止液,酶标仪读取OD450数值。OD450数值可反映C11D5.3嵌合抗体与重组人BCMA的结合情况。
实施例4:抗人BCMA全人源抗体的制备
1.构建大容量人源天然抗体噬菌体文库
1.1收集人外周血细胞资源及cDNA获取
收集来源于自愿捐赠的不同个体的人外周血细胞,以Trizol RNA提取试剂盒(Invitrogen)从上述外周血细胞中提取总RNA。
以所述RNA为模板,使用SuperScriptTM IV First-Strand Synthesis System(Invitrogen)试剂盒合成第一链cDNA。
1.2抗体基因扩增
以所述cDNA为模板,使用重链可变域上游引物(含SfiI酶切位点)和重链恒定域CH1下游引物(含SfiI酶切位点)进行PCR扩增重链可变域和CH1恒定域基因,使用卡帕和拉姆达链的可变域上游引物(含NheI酶切位点)和恒定域下游引物引物(含SalI酶切位点)进行PCR扩增卡帕和拉姆达链的可变域和恒定域基因。在50uL反应体系中,分别加入25uLphusion master mix(Thermo),上游引物2.5uL(25pmol),下游引物2.5uL(25pmol),1.5uLDMSO,0.5uL cDNA和18uL ddH2O。按以下程序进行PCR反应:98℃预变性1分钟后进入温度循环,98℃变性30秒,58℃退火30秒,72℃延伸1.5分钟,循环32次,72℃最终延伸10分钟。使用DNA胶回收试剂盒(Invitrogen)回收扩增得到的重链可变域和CH1恒定域基因和卡帕或拉姆达链的可变域和恒定域基因。
1.3构建人源天然抗体文库
利用SfiI酶酶切上述重链可变域和CH1恒定域基因,利用NheI酶(NEB)和SalI酶(NEB)酶切上述卡帕和拉姆达链的可变域和恒定域基因。使用DNA胶回收试剂盒回收已酶切的基因片段。
制备足量经改造的pComb3XTT噬菌粒(美国Scripps研究所),其中:轻链可变域和恒定域基因序列的5’侧删除SfiI酶切位点,引入NheI酶切位点,轻链可变域和恒定域基因序列的3’侧引入SalI酶切位点。重链可变域和恒定域基因序列的5’侧引入SfiI酶切位点。删除原噬菌粒的琥珀终止密码子。
利用NheI酶和SalI酶对该载体进行酶切,使用DNA胶回收试剂盒回收酶切载体。利用DNAT4连接酶(NEB)将酶切后的噬菌粒载体与上述酶切后的卡帕和拉姆达链的可变域和恒定域基因进行过夜连接反应。利用质粒DNA纯化试剂盒(Invitrogen)对连接产物进行纯化。将含重组轻链的载体通过电转化导入TG1感受态(Lucigen)中,将含重组轻链噬菌粒载体的大肠杆菌的培养扩增,并利用质粒抽提试剂盒(Invitrogen)提取足量的含重组轻链的噬菌粒载体。利用SfiI酶酶切含重组轻链的噬菌粒载体,使用DNA胶回收试剂盒回收酶切噬菌粒载体。利用DNA T4连接酶将上述酶切后的噬菌粒载体与上述已酶切的重链可变域和CH1恒定域基因进行过夜连接反应。利用质粒DNA纯化试剂盒对连接产物进行纯化。利用电转仪(Bio-Rad)将含重组轻链和重组重链的载体电转化导入SS320感受态中。取出10ul电转化后的细菌通过合理的稀释并在含有四环素和氨苄青霉素的平板上划线,以此计数并统计噬菌体抗体文库的大小。剩余的电转化后的细菌加入含5ug/mL四环素、100ug/mL氨苄青霉素和2%葡萄糖的2xYT培养基,置于加热培养箱培养。培养结束后在4℃以4000G离心10分钟,在沉淀菌中补充适量甘油储存于-80℃作为抗体菌种库。通过多次电转化积累获得大容量人源天然抗体噬菌体文库。
2.抗体噬菌体文库的筛选与鉴定
2.1 BCMA-huIgG1 Fc融合蛋白的生物素化
应用EZ-Link Sulfo-NHS-LC-Biotin(Thermo)提供的标准操作程序对BCMA-huIgG1 Fc融合蛋白进行随机生物素化。用ELISA方法验证生物素化的BCMA-huIgG1 Fc融合蛋白与C11D5.3嵌合抗体的结合活性。
2.2生物淘选
以BCMA-huIgG1 Fc融合蛋白为目标蛋白应用生物淘选对上述人源天然抗体文库进行生物淘选获得与BCMA-huIgG1 Fc融合蛋白(尤其是人B细胞成熟抗原(BCMA)胞外域)结合的抗体。将抗体菌种库复苏并生长至对数期后应用M13KO7辅助噬菌体(NEB)挽救抗体文库,离心后用含有氨苄青霉素和卡那霉素的2xYT培养基重悬并在30℃过夜扩增。PEG/NaCl沉淀噬菌体,用甘油/PBST溶解噬菌体沉淀获得天然库噬菌体悬液。酪蛋白(Thermo)封闭的噬菌体投入酪蛋白封闭的生物素化的PD1-huIgG1 Fc融合蛋白(PD1部分含有NCBIaccession No.NP_005009.2的第25位至第167位氨基酸区间,如SEQ ID NO:81所示,huIgG1Fc部分与用于构建BCMA-huIgG1 Fc融合蛋白的huIgG1 Fc部分的区别仅在于不含第99位谷氨酸)和酪蛋白封闭的Dynabeads M-270链霉亲合素(Thermo)共孵育体系中,收集上清噬菌体悬液。进一步,将收集到的噬菌体悬液投入酪蛋白封闭的生物素化的BCMA-huIgG1 Fc融合蛋白和酪蛋白封闭的Dynabeads M-270链霉亲合素共孵育体系中,用PBST清洗磁珠去除无法与BCMA-huIgG1 Fc融合蛋白结合的噬菌体。用100mM三乙胺(Thermo)洗脱与磁珠结合的噬菌体后用1M Tris-HCl(pH=6.4)中和。留取10ul洗脱的噬菌体溶液用于测定输出噬菌体总量,剩余噬菌体溶液用于感染对数增长的SS320,过夜扩增后视为下一轮淘选使用的抗体文库。生物淘选共执行三轮,BCMA-huIgG1 Fc抗原浓度以100nM为起始,每一轮筛选抗原浓度以3倍梯度降低。
2.3 BCMA胞外域特异性结合克隆的筛选
将第三轮生物淘选结束后获得的抗体文库进行稀释涂布于含有四环素和氨苄青霉素的平板上获得单克隆,挑选单克隆在深孔板中过夜培养。次日利用-20℃冰箱对深孔板进行反复三次冻融,离心上清用于后续ELISA反应。ELISA反应利用山羊抗人IgG(Fab特异性的)过夜包被,依次加入离心上清,BCMA-huIgG1 Fc融合蛋白和链霉亲合素-HRP进行阳性克隆筛选。该筛选步骤重复两次独立实验以保证数据准确。
为排除与huIgG1 Fc区结合的克隆,执行以下ELISA反应:利用山羊抗人IgG(Fab特异性的)过夜包被,依次加入离心上清,PD1-huIgG1 Fc融合蛋白和链霉亲合素-HRP进行huIgG1 Fc区结合阳性克隆筛选。该筛选步骤重复两次独立实验以保证数据准确。
由以上两个步骤挑选出BCMA胞外域特异性结合克隆。
2.4利用解离速率常数koff进行亲和力排序
利用Octet K2(ForteBio)分子互作分析仪对上述步骤筛选到的BCMA胞外段特异结合克隆的冻融上清进行分析。将生物素化的BCMA-huIgG1 Fc融合蛋白固化在SA探针(ForteBio)上,以冻融上清作为分析物,进行亲和力测定。分析步骤中只选取解离曲线计算koff数值,以koff数值为参考依据由小至大进行排序。优选的,克隆HK10、HA08、HD10、HA05和HD07等克隆koff排序位列前五。
实施例5:抗人BCMA鼠源抗体的制备
1.免疫动物
将2mg/mL的BCMA-huIgG1 Fc融合蛋白作为抗原与等体积的完全弗氏佐剂(Sigma-Aldrich)混合乳化,取5只6周大雌性Balb/c小鼠(上海南方模式动物研究中心)进行皮下免疫。在初次免疫后,每十天时间进行一次加强免疫,共执行四次皮下免疫,第五次免疫时直接用BCMA-huIgG1 Fc融合蛋白进行脾脏冲击免疫。
2.血清效价检测
每次加强免疫前尾静脉取血50uL,离心去除细胞,保留血清。ELISA微孔板中加入重组BCMA 50ng/孔,4℃包被过夜。PBS清洗三遍,加入1%BSA/PBS,200uL/孔,37℃封闭1小时。加入梯度稀释的小鼠血清,37℃结合1小时。PBST清洗三遍,加入HRP-山羊抗小鼠IgG 37℃结合1小时。PBST清洗三遍,加入100uL/孔TMB显色液,37℃显色10分钟,加入100uL/孔ELISA终止液,酶标仪读取OD450数值。
3.构建免疫文库
3.1小鼠脾细胞总cDNA获取
利用BCMA-huIgG1 Fc融合蛋白直接进行腹腔注射方式进行冲击免疫,四天后处死小鼠,取脾脏。用细胞筛网(BD)研磨整个脾脏,获取脾脏细胞。用PBS冲洗两遍后,1000g离心10分钟,获取脾脏细胞。使用Trizol RNA提取试剂盒抽提总RNA。
以所述RNA为模板,使用SuperScriptTM IV First-Strand Synthesis System试剂盒合成第一链cDNA。
3.2抗体基因扩增与轻重链拼接
以所述cDNA为模板,使用重链可变域上游引物和下游引物(VH-F、VH-R)PCR扩增重链可变域基因,使用轻链可变域上游引物和下游引物引物(VK-F、VK-R)PCR扩增卡帕链可变域基因。在50uL反应体系中,分别加入25uL phusion master mix,上游引物2.5uL(25pmol),下游引物2.5uL(25pmol),1.5uL DMSO,0.5uL cDNA和18uL ddH2O。按以下程序进行PCR反应:98℃预变性1分钟后进入温度循环,98℃变性30秒,58℃退火30秒,72℃延伸1分钟,循环30次,72℃最终延伸10分钟。
使用DNA胶回收试剂盒回收扩增得到的VH基因和VK基因。将等量的VH基因和VK基因混合后为模板,利用上游引物scFv-F和下游引物scFv-R通过重叠PCR扩增scFv基因。在50uL反应体系中,分别加入25uLphusion master mix,上游引物2.5uL(25pmol),下游引物2.5uL(25pmol),1.5uL DMSO,0.5uL cDNA和18uL ddH2O。按以下程序进行PCR反应:98℃预变性1分钟后进入温度循环,98℃变性30秒,58℃退火30秒,72℃延伸1分钟,循环30次,72℃最终延伸10分钟。
使用DNA胶回收试剂盒回收扩增得到的scFv基因片段。
3.3构建免疫文库
分别使用SfiI DNA内切酶消化scFv基因片段和pcomb3XTT载体(美国Scripps研究所)。在50uL反应体系中,分别加入SfiI 2uL,10x缓冲液5uL,DNA 3ug,加ddH2O至50uL。充分混匀后,50℃孵育3小时。
使用DNA胶回收试剂盒回收酶切后的scFv基因片段和pcomb3X载体。使用T4连接酶环化酶切后的scFv基因片段和酶切后的pcomb3X载体。在50uL反应体系中,分别加入T4连接酶1uL,10x缓冲液5uL,scFv基因100ng,pComb3X载体500ng,加ddH2O至50uL。充分混匀后,4℃孵育16小时。取少量产物通过琼脂糖凝胶电泳验证连接效率。
将10uL上述连接环化产物加入自制的TG1电转化感受态中,然后使用电转仪进行电击转化。取出10ul电转化后的细菌通过合理的稀释并在含有氨苄青霉素的平板上划线,以此计数并统计噬菌体抗体文库的大小。剩余的电转化后的细菌加入含100ug/mL氨苄青霉素和2%葡萄糖的2xYT培养基,置于加热培养箱培养。培养结束后在4℃以4000G离心10分钟,在沉淀菌中补充适量甘油储存于-80℃作为抗体菌种库。通过多次电转化积累获得scFv免疫文库。
4.鼠源免疫抗体噬菌体文库的筛选与鉴定
4.1 BCMA-huIgG1 Fc融合蛋白的生物素化
应用EZ-Link Sulfo-NHS-LC-Biotin提供的标准操作程序对BCMA-huIgG1 Fc融合蛋白进行随机生物素化。用ELISA方法验证生物素化的BCMA-huIgG1 Fc融合蛋白与C11D5.3嵌合抗体的结合活性。
4.2生物淘选
以BCMA-huIgG1 Fc融合蛋白为目标蛋白应用生物淘选对上述鼠源免疫抗体文库进行生物淘选获得与BCMA-huIgG1 Fc融合蛋白(尤其是人B细胞成熟抗原(BCMA)胞外域)结合的抗体。将抗体菌种库复苏并生长至对数期后应用M13KO7辅助噬菌体挽救抗体文库,离心后用含有氨苄青霉素和卡那霉素的2xYT培养基重悬并在30℃过夜扩增。PEG/NaCl沉淀噬菌体,用甘油/PBST溶解噬菌体沉淀获得免疫库噬菌体悬液。酪蛋白封闭的噬菌体投入酪蛋白封闭的生物素化的PD1-huIgG1 Fc融合蛋白和酪蛋白封闭的Dynabeads M-270链霉亲合素共孵育体系中,收集上清噬菌体悬液。进一步,将收集到的噬菌体悬液投入酪蛋白封闭的生物素化的BCMA-huIgG1 Fc融合蛋白和酪蛋白封闭的Dynabeads M-270链霉亲合素共孵育体系中,用PBST清洗磁珠去除无法与BCMA-huIgG1 Fc融合蛋白结合的噬菌体。用100mM三乙胺洗脱与磁珠结合的噬菌体后用1M Tris-HCl(pH=6.4)中和。留取10ul洗脱的噬菌体溶液用于测定输出噬菌体总量,剩余噬菌体溶液用于感染对数增长的TG1,过夜扩增后视为下一轮淘选使用的抗体文库。生物淘选共执行两轮,BCMA-huIgG1 Fc抗原浓度分别为50nM和5nM。
4.3 BCMA胞外域特异性结合克隆的筛选
将第二轮生物淘选结束后获得的抗体文库进行稀释涂布于含有氨苄青霉素的平板上获得单克隆,挑选单克隆在深孔板中过夜培养。次日利用-20℃冰箱对深孔板进行反复三次冻融,离心上清用于后续ELISA反应。ELISA反应利用山羊抗人IgG(Fab特异性的)过夜包被,依次加入离心上清,生物素化的BCMA-huIgG1 Fc融合蛋白和链霉亲合素-HRP进行阳性克隆筛选。该筛选步骤重复两次独立实验以保证数据准确。
为排除与huIgG1 Fc区结合的克隆,执行以下ELISA反应。利用山羊抗人IgG(Fab特异性的)过夜包被,依次加入离心上清,生物素化的PD1-huIgG1 Fc融合蛋白和链霉亲合素-HRP进行huIgG1区结合阳性克隆筛选。该筛选步骤重复两次独立实验以保证数据准确。
由以上两个步骤挑选出BCMA胞外域特异性结合克隆。
4.4利用解离速率常数koff进行亲和力排序
利用Octet K2分子互作分析仪对上述步骤筛选到BCMA胞外段特异结合克隆的冻融上清进行分析。将生物素化的BCMA-huIgG1 Fc融合蛋白固化在SA探针上,以冻融上清作为分析物,进行亲和力测定。分析步骤中只选取解离曲线计算koff数值,以koff数值为参考依据由小至大进行排序。优选的,克隆MC12、MB09、MB11、MA04和MD07等克隆koff排序位列前五。
实施例6:抗人BCMA嵌合抗原受体-T细胞的制备和嵌合抗原受体阳性率测定
1.含CAR元件的慢病毒包装主质粒制备
选取MB09、MC12、MD07和HK10克隆以及C11D5.3克隆的抗体序列构建嵌合抗原受体。通过分子克隆构建从N末端至C末端包含有以下结构的CAR元件慢病毒包装主质粒:CD8α信号肽,scFv抗体,CD8α铰链区,CD8α跨膜区,41BB胞质区和CD3z胞质区。挑选测序正确的克隆,接种菌液至300ml 2YT培养基中,过夜摇菌,按照NucleoBond Xtra Maxi EF试剂盒说明书完成大提质粒。
2.慢病毒包装
用阳离子聚合物PEI包装含慢病毒,流程如下:分别用无血清DMEM稀释PEI和慢病毒包装质粒(慢病毒主质粒、RRE-SIV、REV、VSVG);然后将PEI/DMEM加入质粒/DMEM混合物,涡旋震荡混匀,在室温下静置15分钟;将质粒-PEI复合物加入预先铺板的293T细胞(中国科学院细胞库)。转染后16h换液,在48h后收集病毒上清,0.45um滤器过滤,留存部分原液,其余浓缩30倍。
3.病毒滴度测定
3.1生物滴度测定
病毒液的生物滴度指的是每毫升中含有的具有感染能力的病毒颗粒数。
取24孔培养板,每孔加入梯度稀释的病毒原液,感染体积起始量为1ml,三倍倍比,五个梯度稀释,体积不足1ml,用培养基补足1ml。后每孔中添加100μl含1x105个293T细胞的细胞悬液(含polybrene(Santa Cruz),终浓度为8μg/ml),3天后采用流式细胞术对细胞的感染效率进行检测,第一步染色采用生物素-山羊抗小鼠Fab(或生物素-山羊抗人IgGFab),第二步染色采用PE-链霉亲合素标记供试品细胞,以未感染的同步培养293T细胞作为阴性对照组(293T)。滴度计算公式为:滴度(TU/ml)=感染细胞数x流式检测CAR表达比例/病毒液体积。滴度应不低于1x105TU/ml。
生物滴度测定结果为:含MB09抗体的慢病毒原液生物滴度为24.6x106TU/ml,含MC12抗体的慢病毒原液生物滴度为3.06x106TU/ml,含MD07抗体的慢病毒原液生物滴度为2.10x106TU/ml,含HK10抗体的慢病毒原液生物滴度为8.82x106TU/ml,含C11D5.3抗体的慢病毒原液生物滴度为2.65x106TU/ml。
3.2物理滴度测定
病毒液的物理滴度测定的是病毒液中病毒的颗粒数,包括具有感染能力的病毒颗粒和不具感染能力的缺陷病毒颗粒。已知慢病毒遗传物质为两条单链的RNA基因组,物理滴度检测以病毒液中CAR基因拷贝数为评价指标,理论上两个CAR基因拷贝数对应一个病毒颗粒。
具体的,本实验以慢病毒基因的41BB序列为扩增对象来确定慢病毒物理滴度。首先将病毒上清去DNA处理,然后利用41BB特异性荧光定量PCR引物进行一步法RT-PCR(TaKaRa),测定41BB基因的拷贝数以确定慢病毒基因组拷贝数。
物理滴度检测结果为:含MB09抗体的慢病毒原液物理滴度为4.65x106拷贝/ul,含MC12抗体的慢病毒原液物理滴度为5.99x106拷贝/ul,含MD07抗体的慢病毒原液物理滴度为6.89x106拷贝/ul,含HK10抗体的慢病毒原液物理滴度为3.21x106拷贝/ul,含C11D5.3抗体的慢病毒原液物理滴度为4.26x106拷贝/ul。
4.嵌合抗原受体-T细胞的制备和嵌合抗原受体阳性率测定
4.1 CD3+ T细胞分离与活化
用Ficcol分离液(天津灏洋)分离获得较纯的CD3+ T细胞,用含5%AB血清X-VIVO(LONZA)培养基调整细胞密度为1x106/mL。将细胞以1ml/孔接种到预先用抗人50ng/ml CD3抗体(北京同立海元)和50ng/ml CD28抗体(北京同立海元),再加入100IU/ml的IL2(北京双鹭),刺激培养48小时后病毒感染。
4.2病毒原液感染与培养
将活化后的T细胞调整为5x105/mL,在24孔板中分别加入1ml T细胞和1ml病毒原液,每孔加1ulpolybrene,32℃,2500rpm,离心1.5h。弃去上清液,每孔加入1ml T细胞培养基(含IL-250IU/ml)。将培养板置于37℃,5%CO2培养箱中培养。感染后24h,转至6孔板,每天观察细胞的密度,适时补加含IL-2 50IU/ml的T细胞培养液,使T细胞的密度维持在5x105/ml左右,使细胞扩增。
4.3 CAR阳性率检测
病毒感染72h后检测CAR阳性率。针对含MB09、MC12、MD07、C11D5.3克隆的嵌合抗原受体组和阴性对照组选用生物素-山羊抗小鼠IgG F(ab')2片段作为一抗孵育慢病毒感染后的细胞。针对含HK10克隆的嵌合抗原受体组和阴性对照组,以生物素-山羊抗人IgG F(ab')2片段作为一抗孵育慢病毒感染后的细胞。此后加入Brilliant Violet 421TM链霉亲合素(BioLegend)二抗孵育细胞后上机检测,5个CAR-T阳性率基本一致,都在80%左右。
实施例7:抗人BCMA嵌合抗原受体-T细胞的功能验证
1.靶细胞构建
1.1慢病毒的包装
通过化学合成的方式,合成以内部核糖体进入位点(IRES)串联的萤光素酶和绿色荧光蛋白基因。通过分子克隆构建慢病毒包装主质粒(PCCL-LUC-GFP)并包装慢病毒。
1.2 K562-LUC-GFP和L363-LUC-GFP靶细胞构建
用相应慢病毒分别转染K562(不表达BCMA,中国科学院细胞库)和L363(表达BCMA,中国科学院细胞库)后以绿色荧光蛋白作为标记筛选出萤光素酶和绿色荧光蛋白高表达的K562-LUC-GFP靶细胞和L363-LUC-GFP靶细胞。
2.抗人BCMA嵌合抗原受体-T细胞杀伤实验
CAR-T杀伤实验通过检测CAR-T细胞体外对靶细胞的杀伤效果来评估CAR-T细胞的体外功能。以不同效靶比(3x104个靶细胞与1.5x105个效应细胞以及3x104个靶细胞和6x104个效应细胞)将T细胞分别与K562-LUC-GFP靶细胞和L363-LUC-GFP靶细胞共同培养,同时设置靶细胞和未转染CAR元件T细胞混合的阴性对照组。18小时后在培养体系中加入萤光素酶反应底物,检测荧光值,通过以下公式计算杀伤效率:杀伤效率=(1-实验孔荧光值/对照孔荧光值)x100%。实验分组及结果见下表。
细胞杀伤实验中,5个CAR-T及阴性对照T细胞对K562基本无功能。MB09、MC12、HK10克隆对L363功能良好,与阳性对照克隆C11D5.3相比数值差异小,但MD07克隆功能微弱。结果显示于图1。
3.抗人BCMA嵌合抗原受体-T细胞IFN-γ分泌和CD107a表达分析
将效应细胞(CAR-T及未转染CAR元件的阴性对照T细胞)与靶细胞(效应细胞和靶细胞均为3x105)共孵育后,流式检测其IFN-γ和CD107a表达情况来评价CAR-T细胞在受到靶细胞刺激后的体外效应功能。实验分组如表所示,将效应细胞和靶细胞混合置于37℃,5%CO2培养箱中共孵育4小时后,检测各组样品中分泌IFN-γ及表达CD107a的细胞占CD3+细胞数的比例,实验分组及结果见下表。
组别 | CAR-T克隆号 | 靶细胞 | CD3+IFN-γ+ | CD3+CD107a+ |
1 | MB09 | K562 | 1.30% | 0.91% |
2 | MC12 | K562 | 2.51% | 0.78% |
3 | MD07 | K562 | 7.97% | 6.83% |
4 | C11D5.3 | K562 | 2.45% | 0.82% |
5 | HK10 | K562 | 2.54% | 0.83% |
6 | NT | K562 | 1.33% | 0.68% |
7 | MB09 | L363 | 19.30% | 26.90% |
8 | MC12 | L363 | 18.90% | 25.00% |
9 | MD07 | L363 | 11.60% | 7.25% |
10 | C11D5.3 | L363 | 24.80% | 34.00% |
11 | HK10 | L363 | 34.40% | 44.60% |
12 | NT | L363 | 2.45% | 0.50% |
CAR-T细胞与靶细胞共孵育后,MD07克隆对K562和L363有非特异刺激,CD3阳性细胞都有IFN-γ和CD107a表达。其余CAR-T及阴性对照T细胞对K562无功能。HK10对L363的功能比阳性对照克隆C11D5.3强,MB09、MC12略弱于对照。结果显示于图2-4。
序列表
<110> 上海恒润达生生物科技股份有限公司
<120> 基于全人源及鼠源单链抗体的靶向BCMA的嵌合抗原受体及其用途
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ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 360
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 420
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 480
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 540
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 600
aggtggcagc aggggaacgt cttctcatgc tccgtgctgc atgaggctct gcacaaccac 660
tacacgcaga agagcctctc cctgtctccg ggtaaa 696
<210> 75
<211> 20
<212> PRT
<213> Artificial
<400> 75
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly
20
<210> 76
<211> 60
<212> DNA
<213> Artificial
<400> 76
atggagacag acacactcct gctatgggta ctgctgctct gggttccagg atctaccggt 60
<210> 77
<211> 111
<212> PRT
<213> Artificial
<400> 77
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
100 105 110
<210> 78
<211> 333
<212> DNA
<213> Artificial
<400> 78
gacatcgttt tgacacaatc tcctgcgtca ttggccatga gtctcgggaa gcgcgcaaca 60
atatcctgtc gcgccagtga atctgtgtct gtgataggag cgcacttgat ccattggtat 120
cagcagaaac ctggacaacc tcccaagctg ctcatctacc tcgccagtaa ccttgaaaca 180
ggagtacctg ctcggttttc aggttccggg tcagggacgg atttcacttt gactatcgac 240
ccagttgagg aagacgacgt agccatatat agctgcctgc agtctcggat cttcccgcgc 300
acgttcgggg gaggaactaa gctggagatt aag 333
<210> 79
<211> 117
<212> PRT
<213> Artificial
<400> 79
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
115
<210> 80
<211> 351
<212> DNA
<213> Artificial
<400> 80
caaatccaac tggttcagtc cggtccagaa ctgaaaaagc cgggggagac ggtgaaaatc 60
tcctgtaagg cctcaggtta taccttcacc gattacagca tcaattgggt aaagcgggct 120
ccagggaaag gtctgaaatg gatgggttgg atcaacacag aaacccgaga accagcctat 180
gcttacgact ttcgaggtcg attcgctttt tccttggaaa cttccgcaag cacagcctat 240
ctgcaaatca acaatctcaa gtacgaagat acggccacgt atttttgtgc cctggattac 300
agctatgcaa tggattactg gggtcagggg acgtctgtta cagtttctag t 351
<210> 81
<211> 143
<212> PRT
<213> Artificial
<400> 81
Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr Phe Ser Pro Ala
1 5 10 15
Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe Thr Cys Ser Phe
20 25 30
Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr Arg Met Ser Pro
35 40 45
Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu Asp Arg Ser Gln
50 55 60
Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu Pro Asn Gly Arg
65 70 75 80
Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn Asp Ser Gly Thr
85 90 95
Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala Gln Ile Lys Glu
100 105 110
Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg Ala Glu Val Pro
115 120 125
Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly Gln Phe Gln
130 135 140
<210> 82
<211> 429
<212> DNA
<213> Artificial
<400> 82
ttagactccc cagacaggcc ctggaacccc cccaccttct ccccagccct gctcgtggtg 60
accgaagggg acaacgccac cttcacctgc agcttctcca acacatcgga gagcttcgtg 120
ctaaactggt accgcatgag ccccagcaac cagacggaca agctggccgc cttccccgag 180
gaccgcagcc agcccggcca ggactgccgc ttccgtgtca cacaactgcc caacgggcgt 240
gacttccaca tgagcgtggt cagggcccgg cgcaatgaca gcggcaccta cctctgtggg 300
gccatctccc tggcccccaa ggcgcagatc aaagagagcc tgcgggcaga gctcagggtg 360
acagagagaa gggcagaagt gcccacagcc caccccagcc cctcacccag gccagccggc 420
cagttccaa 429
Claims (10)
1.一种特异性结合人B细胞成熟抗原(BCMA)的抗体或抗原结合片段,其特征在于包含重链可变域和轻链可变域,所述包含重链可变域和轻链可变域:
(1)SEQ ID NO:1所示重链CDR1、SEQ ID NO:2所示重链CDR2、SEQ ID NO:3所示重链CDR3、SEQ ID NO:4所示轻链CDR1、SEQ ID NO:5所示轻链CDR2和SEQ ID NO:6所示轻链CDR3;
(2)SEQ ID NO:7所示重链CDR1、SEQ ID NO:8所示重链CDR2、SEQ ID NO:9所示重链CDR3、SEQ ID NO:10所示轻链CDR1、SEQ ID NO:11所示轻链CDR2和SEQ ID NO:12所示轻链CDR3;
(3)SEQ ID NO:13所示重链CDR1、SEQ ID NO:14所示重链CDR2、SEQ ID NO:15所示重链CDR3、SEQ ID NO:16所示轻链CDR1、SEQ ID NO:17所示轻链CDR2和SEQ ID NO:18所示轻链CDR3;
(4)SEQ ID NO:19所示重链CDR1、SEQ ID NO:20所示重链CDR2、SEQ ID NO:21所示重链CDR3、SEQ ID NO:22所示轻链CDR1、SEQ ID NO:23所示轻链CDR2和SEQ ID NO:24所示轻链CDR3;或
(5)SEQ ID NO:25所示重链CDR1、SEQ ID NO:26所示重链CDR2、SEQ ID NO:27所示重链CDR3、SEQ ID NO:28所示轻链CDR1、SEQ ID NO:29所示轻链CDR2和SEQ ID NO:30所示轻链CDR3。
2.一种特异性结合人B细胞成熟抗原(BCMA)的抗体或抗原结合片段,其特征在于包含重链可变域和轻链可变域,所述重链可变域和轻链可变域包含:
(1)SEQ ID NO:31所示重链CDR1、SEQ ID NO:32所示重链CDR2、SEQ ID NO:33所示重链CDR3、SEQ ID NO:34所示轻链CDR1、SEQ ID NO:35所示轻链CDR2和SEQ ID NO:36所示轻链CDR3;
(2)SEQ ID NO:37所示重链CDR1、SEQ ID NO:38所示重链CDR2、SEQ ID NO:39所示重链CDR3、SEQ ID NO:40所示轻链CDR1、SEQ ID NO:41所示轻链CDR2和SEQ ID NO:42所示轻链CDR3;
(3)SEQ ID NO:43所示重链CDR1、SEQ ID NO:44所示重链CDR2、SEQ ID NO:45所示重链CDR3、SEQ ID NO:46所示轻链CDR1、SEQ ID NO:47所示轻链CDR2和SEQ ID NO:48所示轻链CDR3;
(4)SEQ ID NO:49所示重链CDR1、SEQ ID NO:50所示重链CDR2、SEQ ID NO:51所示重链CDR3、SEQ ID NO:52所示轻链CDR1、SEQ ID NO:53所示轻链CDR2和SEQ ID NO:54所示轻链CDR3;或
(5)SEQ ID NO:55所示重链CDR1、SEQ ID NO:56所示重链CDR2、SEQ ID NO:57所示重链CDR3、SEQ ID NO:58所示轻链CDR1、SEQ ID NO:59所示轻链CDR2和SEQ ID NO:60所示轻链CDR3。
3.一种嵌合抗原受体,其特征在于包含胞外区、跨膜区和胞内区,其中所述胞外区包含抗原结合区,所述抗原结合区包含重链可变域和轻链可变域,所述重链可变域和轻链可变域包含:
(1)SEQ ID NO:1所示重链CDR1、SEQ ID NO:2所示重链CDR2、SEQ ID NO:3所示重链CDR3、SEQ ID NO:4所示轻链CDR1、SEQ ID NO:5所示轻链CDR2和SEQ ID NO:6所示轻链CDR3;
(2)SEQ ID NO:7所示重链CDR1、SEQ ID NO:8所示重链CDR2、SEQ ID NO:9所示重链CDR3、SEQ ID NO:10所示轻链CDR1、SEQ ID NO:11所示轻链CDR2和SEQ ID NO:12所示轻链CDR3;
(3)SEQ ID NO:13所示重链CDR1、SEQ ID NO:14所示重链CDR2、SEQ ID NO:15所示重链CDR3、SEQ ID NO:16所示轻链CDR1、SEQ ID NO:17所示轻链CDR2和SEQ ID NO:18所示轻链CDR3;
(4)SEQ ID NO:19所示重链CDR1、SEQ ID NO:20所示重链CDR2、SEQ ID NO:21所示重链CDR3、SEQ ID NO:22所示轻链CDR1、SEQ ID NO:23所示轻链CDR2和SEQ ID NO:24所示轻链CDR3;
(5)SEQ ID NO:25所示重链CDR1、SEQ ID NO:26所示重链CDR2、SEQ ID NO:27所示重链CDR3、SEQ ID NO:28所示轻链CDR1、SEQ ID NO:29所示轻链CDR2和SEQ ID NO:30所示轻链CDR3;
(6)SEQ ID NO:31所示重链CDR1、SEQ ID NO:32所示重链CDR2、SEQ ID NO:33所示重链CDR3、SEQ ID NO:34所示轻链CDR1、SEQ ID NO:35所示轻链CDR2和SEQ ID NO:36所示轻链CDR3;
(7)SEQ ID NO:37所示重链CDR1、SEQ ID NO:38所示重链CDR2、SEQ ID NO:39所示重链CDR3、SEQ ID NO:40所示轻链CDR1、SEQ ID NO:41所示轻链CDR2和SEQ ID NO:42所示轻链CDR3;
(8)SEQ ID NO:43所示重链CDR1、SEQ ID NO:44所示重链CDR2、SEQ ID NO:45所示重链CDR3、SEQ ID NO:46所示轻链CDR1、SEQ ID NO:47所示轻链CDR2和SEQ ID NO:48所示轻链CDR3;
(9)SEQ ID NO:49所示重链CDR1、SEQ ID NO:50所示重链CDR2、SEQ ID NO:51所示重链CDR3、SEQ ID NO:52所示轻链CDR1、SEQ ID NO:53所示轻链CDR2和SEQ ID NO:54所示轻链CDR3;或
(10)SEQ ID NO:55所示重链CDR1、SEQ ID NO:56所示重链CDR2、SEQ ID NO:57所示重链CDR3、SEQ ID NO:58所示轻链CDR1、SEQ ID NO:59所示轻链CDR2和SEQ ID NO:60所示轻链CDR3。
4.依照权利要求3所述的嵌合抗原受体,其中所述胞外区还包含具有SEQ ID NO:63所示氨基酸序列的铰链区。
5.依照权利要求3或4所述的嵌合抗原受体,其中所述跨膜区具有SEQ ID NO:65所示氨基酸序列。
6.依照权利要求3至5中任一项所述的嵌合抗原受体,其中所述胞内区具有SEQ ID NO:67所示氨基酸序列和/或SEQ ID NO:69所示氨基酸序列。
7.一种多核苷酸,其特征在于编码依照权利要求1或2所述的抗体或抗原结合片段或依照权利要求3至6中任一项所述的嵌合抗原受体。
8.一种改造的免疫效应细胞,其特征在于表达依照权利要求3至6中任一项所述的嵌合抗原受体,或者包含编码依照权利要求3至6中任一项所述的嵌合抗原受体的多核苷酸。
9.依照权利要求1或2所述的抗体或抗原结合片段、依照权利要求3至6中任一项所述的嵌合抗原受体、依照权利要求7所述的多核苷酸、或依照权利要求8所述的改造的免疫效应细胞在制备用于治疗癌症的药物中的用途。
10.依照权利要求1或2所述的抗体或抗原结合片段、依照权利要求3至6中任一项所述的嵌合抗原受体、依照权利要求7所述的多核苷酸、或依照权利要求8所述的改造的免疫效应细胞在制备用于在具有癌症的患者中刺激免疫功能的药物中的用途。
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