CN116829161A - 嵌合抗原受体t细胞及方法 - Google Patents
嵌合抗原受体t细胞及方法 Download PDFInfo
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Abstract
对于癌症等增殖性疾病的免疫治疗,需要新的替代方案。这一需要可以通过提供具有胞外结构域的嵌合抗原受体来解决,该胞外结构域包含识别癌细胞相关蛋白Lgr5的结合域;跨膜结构域;以及激活细胞功能的胞内信号结构域。这种CART细胞可用于杀死癌细胞,治疗或预防受试者的癌症。
Description
优先权声明
本申请要求澳大利亚临时申请2020904256的优先权,其全部内容并入本文。
技术领域
本发明涉及嵌合抗原T细胞受体、表达嵌合抗原T细胞受体的免疫细胞、包含嵌合抗原T-细胞受体的药物组合物、使用嵌合抗原-T细胞受体和携带所述T细胞受体的T细胞的方法,以用于预防和/或治疗诸如癌症的增殖性疾病。
背景技术
以下对本发明背景的讨论旨在促进对本发明的理解。然而,应当理解的是,该讨论并不是承认或承认所提及的任何材料在本说明书的任何一项权利要求的优先权日是公开的、已知的或公知常识的一部分。
免疫系统通过防止一系列机会性微生物感染和防止异常细胞生长(如肿瘤细胞或肿瘤前细胞)来主动维持受试者身体的完整性。由于免疫系统的特异性和有效性,已经有许多尝试操纵适应性免疫系统来特异性靶向肿瘤细胞。这些技术统称为免疫肿瘤学。
免疫肿瘤学包括许多不同的技术,包括抗体的使用、癌症抗原疫苗接种、细胞因子治疗和过继性T细胞转移。也许最常用的免疫肿瘤学形式是开发针对肿瘤相关抗原的特异性单克隆抗体。抗体表现出一系列特征,使其成为免疫肿瘤学的绝佳选择。在一个个体(人)内,估计可以产生至多1011至1012个独特的抗体,每个抗体具有不同的抗原特异性和亲和力。因此,几乎可以产生针对任何表面抗原的抗体。此外,使用永生化杂交瘤细胞系可以容易地在体外重组产生抗体。这意味着它们可以大量生产。此外,抗体可以配制(例如冷冻干燥)以在长时间内保持稳定,从而允许容易的储存和分发。最后,抗体的剂量可以很容易地控制,以提高反应性,或者在出现副作用时减少副作用。
抗体可用于通过抗体依赖性细胞毒性(ADCC)直接靶向细胞杀伤,其中抗体与靶标的结合指导抗体结合细胞的裂解。或者,抗体可用于抑制癌细胞上表达的受体和信号分子的功能。
由于上述特性,抗体在免疫肿瘤学中越来越受欢迎。然而,它们确实有一些局限性。例如,抗体的大小降低了它们进入实体瘤内细胞的能力,而实体瘤内的细胞通常血管化较差。此外,癌细胞会定期进行适应,以表达低水平或无目标抗原。因此,抗体通常会延长癌症感染者的生存期,而不是治愈患者。
最近,科学家和医生开始探索利用适应性免疫系统的细胞臂(cellular arm)来治疗癌症。例如,被称为肿瘤浸润白细胞(TIL)的T细胞已经从切除的肿瘤中分离出来。这些TILS可以基于对个体肿瘤相关抗原的反应性选择性地扩增,并给予患者。在某些情况下,当给予额外治疗时,这些TIL会导致患者完全缓解(NIH(2018)“New approach toimmunotherapy leads to complete response in breast cancer patientunresponsive to other treatments”)。当其他一线治疗失败时,细胞治疗的成功可能归因于T细胞主动浸润肿瘤并诱导和协调免疫系统其他部分反应的能力。
然而,这些细胞治疗的成功率变化很大,治疗在很大程度上依赖于单个肿瘤独特抗原特性的表征,以及对少数与这些独特抗原反应的TIL的鉴定。这导致了极高的成本,产生TIL的时间框架很长,在某些情况下,无法分离和扩增适当的TIL。
因此,对于癌症等增殖性疾病的免疫治疗,需要新的替代方案。
发明内容
本发明部分是基于识别肿瘤相关抗原Lgr5的嵌合抗原受体(CAR)T细胞的开发。
富含亮氨酸重复序列的G蛋白偶联受体5(Lgr5)是一种受体,当与同源配体结合时,激活Wnt信号传导。Lgr5已被确定为癌症干细胞的标记物,其信号增强与癌症的发展和复发有关。
因此,本发明提供了一种嵌合抗原受体,包含:胞外结构域,其包括识别Lgr5的结合域;跨膜结构域;以及激活细胞功能的胞内信号结构域,或由它们组成。
嵌合抗原受体(CAR)是人工构建的蛋白质,在细胞表面表达后可诱导抗原特异性细胞反应。CAR利用胞内部分,当这些部分被激活时,会在宿主胞内引起信号级联。嵌合抗原受体还包括胞外结构域,所述胞外结构域具有决定CAR抗原特异性的结合域。因此,CAR可以被设计为模拟抗原受体(如T细胞受体)的功能,但具有可定制的抗原特异性和可定制的胞内信号传导。然而,与T细胞受体不同,CAR可以被设计为独立于主要组织相容性(MHC)分子(如人类白细胞抗原(HLA))而被激活,并且根据胞内部分的设计,独立于额外或外源性共刺激。
因此,当在适当的宿主细胞如T细胞中表达时,本发明的CAR可以诱导细胞活性,这可以导致表达Lgr5的细胞被杀死。因此,本发明的CAR可用于杀死或诱导杀死表达Lgr5的细胞。
Lgr5包括螺旋管(solenoid)蛋白结构域,其包含17个富含亮氨酸的重复序列,所述重复序列形成具有凸表面和凹配体结合表面的马蹄形。在一些实施方案中,CAR的结合域识别Lgr5的凸面上的表位。在一些实施方案中,表位在Lgr5的富含亮氨酸的重复序列6至9内。
包括结合Lgr5结合部分(例如CDR)的抗体已经生成。其中包括18G7H6A3(BNC101)、18G7H6A1和18G7.1。因此,在一些实施方案中,结合域包括选自18G7H6A3、18G7H6A1或18G7.1的抗体的至少一个结合部分。
如本领域所理解的,抗体包括由可变重(VH)链和可变轻(VL)链定义的可变区。这些可变区中的每一个都包括由三个互补决定区(CDR)间隔的四个框架区,从而产生总共六个CDR。然而,抗体的单链可以特异性地结合表位。主要可变重链可用于形成单结构域抗体(sdAb)。此外,可以产生单链可变片段(scFv)融合蛋白,其中可变重链和轻链通过融合肽(融合接头)融合在一起。或者,已知为Fab(片段抗原结合)的抗体的结合片段可以通过抗体的酶促消化产生,以从Fab片段中分离Fc片段。消化可以在铰链区从抗体产生两个Fab,或者在铰链下方产生F(ab)2,所述F(ab)2包括通过抗体二硫键连接的抗体的两个Fab区。
因此,在一些实施方案中,本发明的CAR的结合域是单结构域抗体,所述抗体包括与结合Lgr5的抗体的VH或VL链相同的序列,或与结合Lgr5的抗体Fab片段相同的序列,或与包含结合Lgr5的抗体的VH和VL区的单链可变片段(scFv)相同的序列。
在一些实施方案中,CAR的结合域至少包括结合Lgr5的抗体的可变重链。然而,单结构域抗体形式的可变轻链也可以特异性结合抗原。因此,在一些实施方案中,结合域至少包括结合Lgr5的抗体的可变轻链。
如所公开的,每个可变链包括三个CDR。因此,在一些实施方案中,CAR的结合域包括:重链CDR1,其具有SEQ ID No.37中所示氨基酸序列或具有SEQ ID No.37中所示的具有1、2或3个氨基酸修饰的氨基酸序列;和重链CDR2,其具有SEQ ID No.38中所示氨基酸序列,或具有SEQ ID No.38中所示的具有1、2或3个氨基酸修饰的氨基酸序列;以及重链CDR3,其具有SEQ ID No.39中所示氨基酸序列,或具有SEQ ID No.39中所示的具有1、2或3个氨基酸修饰的氨基酸序列。在一些实施方案中,结合域包括与SEQ ID No.37、SEQ ID No.38和SEQID No.39相同的氨基酸序列。
在一些实施方案中,CAR的结合域包括:轻链CDR1,其具有SEQ ID No.40中所示氨基酸序列或具有SEQ ID No.40中所示的具有1、2或3个氨基酸修饰的氨基酸序列;和轻链CDR2,其具有SEQ ID No.41中所示氨基酸序列,或具有SEQ ID No.41中所示的具有1、2或3个氨基酸修饰的氨基酸序列;以及轻链CDR3,其具有SEQ ID No.42所示氨基酸序列或具有SEQ ID No.42所示具有1、2或3个氨基酸修饰的氨基酸序列。
在一些实施方案中,其中结合域是单链可变片段,可变重(VH)链的C端连接到可变轻(VL)链条的N端。在一些可选实施方案中,单链可变片段包括连接到VH链的N端的VL链的C端。在这些实施方案的优选形式中,VH链包括:具有SEQ ID No.37序列的CDR1、具有SEQ IDNo.38序列的CDR2和具有SEQ ID No.39序列的CDR3,VL链包括:具有SEQ ID No.40序列的CDR1、具有SEQ ID No.41序列的CDR2和具有SEQ ID No.42序列的CDR3,并且其中每个CDR可以具有1、2或3个氨基酸修饰。
在一些实施方案中,结合域包括具有SEQ ID No.95的重链CDR1,以及SEQ IDNo.38、39或96中所述的任何重链CDR2或CDR3。在一些实施方案中,结合域包括具有SEQ IDNo.96的重链CDR3,以及SEQ ID No.37、95或38中所述的任何重链CDR1或CDR2。
在一些实施方案中,CAR的结合域包括SEQ ID No.49和/或SEQ ID No.50,或其与SEQ ID No.49或50具有至少80%序列同一性的变体。在一些实施方案中,结合域的序列与SEQ ID No.49或50具有至少90%的序列同一性。在一些实施方案中,结合域的序列与SEQID No.49或50具有至少95%的序列同一性。
在一些实施方案中,VL和VH通过融合结构域连接,该融合结构域包含SEQ IDNo.98的序列或由其组成。因此,在一些实施方案中,所述结合域包括SEQ ID No.53或SEQID No.54,或其与SEQ ID No.53或54具有至少80%序列同一性的变体。在一些实施方案中,结合域的序列与SEQ ID No.53或54具有至少90%的序列同一性。
CAR的抗原识别结构域可以直接连接到跨膜结构域。然而,在抗原识别结构域和跨膜结构域之间提供接头结构域可能是有利的。CAR T细胞已经被设计和生产出在不包含接头结构域的情况下具有这种功能,因此,在这种情况下,接头结构域可能对CAR的功能不是必需的。
然而,一些CAR在缺乏接头结构域的情况下不能发挥作用,或者可能不能发挥最佳作用。因此,在CAR的一些实施方案中,胞外结构域包含将结合域连接到跨膜结构域的接头结构域。
接头结构域的长度可以改变CAR和表达CAR的T细胞的功能。在CAR的一些实施方案中,接头结构域的长度为至少12个氨基酸。在一些实施方案中,接头结构域的长度为或至少为约12个氨基酸。在一些实施方案中,接头结构域的长度为或至少为119个氨基酸。在一些实施方案中,接头结构域的长度为或至少为约119个氨基酸。在一些实施方案中,接头结构域的长度为或至少为229个氨基酸。在一些实施方案中,接头结构域的长度为或至少为约229个氨基酸。在一些实施方案中,接头结构域的长度为12个氨基酸至229个氨基酸。在一些实施方案中,接头结构域的长度为约12个氨基酸至约229个氨基酸。在一些实施方案中,接头结构域的长度为119个氨基酸至229个氨基酸。在一些实施方案中,接头结构域的长度为约119个氨基酸至约229个氨基酸。
一系列肽序列可用于提供CAR的接头结构域。在本发明的一些实施方案中,接头结构域包含与免疫球蛋白铰链如IgG4铰链的序列相同的氨基酸序列。在一些实施方案中,接头包括与IgG4铰链的修饰版本相同的序列。在一些实施方案中,IgG4铰链的修饰版本包括1、2或3个氨基酸修饰,优选1个氨基酸修饰。
在一些实施方案中,接头结构域包含与免疫球蛋白的CH3区域的序列相同的氨基酸序列,例如IgG4的CH3区。在一些实施方案中,接头结构域包含与免疫球蛋白的CH2区域的序列相同的氨基酸序列,例如IgG4的CH2区。在一些实施方案中,接头结构域包含铰链区、CH3区和/或CH2区的组合。
在一些实施方案中,接头结构域包含或由选自SEQ ID No.55、SEQ ID No.56或SEQID No.57的序列或其功能变体组成。
一旦表达CAR的T细胞识别其同源抗原,CAR的胞内信号结构域就发出T细胞激活的信号。因此,CAR的胞内信号可以影响细胞激活的类型和幅度。
在一些实施方案中,胞内信号结构域包含具有与活化受体的信号传导部分相同的氨基酸序列的部分。在一些实施方案中,活化受体是CD3共受体复合物或Fc受体的成员。特别设想的信号结构域包含与CD3-ζ(CD3ζ)的至少一个信号传导部分或FcεRI或FcγRI的信号传导部分相同的氨基酸序列。
在一些实施方案中,CAR的胞内信号结构域包含具有与共刺激受体的信号传导部分相同的氨基酸序列的部分。在一些实施方案中,共刺激受体选自CD27、CD28、CD30、CD40、DAP10、OX40、4-1BB(CD137)和ICOS。在一些实施方案中,共刺激受体是4-1BB。
在一些实施方案中,胞内结构域包含与CD3-ζ(CD3ζ)的至少一个信号传导部分相同的氨基酸序列和与4-1BB的信号传导部分相同的氨基酸序列,或其功能变体。
在一些实施方案中,胞内结构域包含与SEQ ID No.58和/或SEQ ID No.59相同的氨基酸序列或其功能变体。
在一些实施方案中,CAR包括或由选自SEQ ID No.60、61、62、63、64或65的氨基酸序列或其功能变体组成。在一些优选实施方案中,CAR包括或由选自SEQ ID No.62、63、64或65的氨基酸序列或其功能变体组成。
进一步提供了编码上述CAR的核酸分子或包括该核酸分子的核酸构建体。在一些实施方案中,核酸构建体是载体。在一些实施方案中,核酸分子在核酸构建体中的表达在转录控制序列的控制下。在一些实施方案中,转录控制序列是组成型启动子。在一些实施方案中,启动子选自:猴病毒40(SV40)、巨细胞病毒(CMV)、P-肌动蛋白、泛素C(UBC)、延伸因子-1α(EF1A)、磷酸甘油酸激酶(PGK)和CMV早期增强子/鸡β肌动蛋白(CAGG)。在一些实施方案中,启动子是CMV启动子。
本发明的核酸或核酸构建体可用于制备遗传修饰的细胞,或用于制备病毒载体,或用于制备药物,或用于遗传修饰细胞的方法,或制备药物的病毒载体。
因此,本文还提供了一种病毒载体,其包括编码和/或表达本文所述CAR的核酸分子或核酸构建体。在一些实施方案中,病毒载体是慢病毒。
在一些实施方案中,病毒载体用于制备遗传修饰细胞的方法。在一些实施方案中,病毒载体用于制备用于治疗癌症或用于杀死表达或异常表达Lgr5的细胞的药物。
本发明进一步提供了一种细胞或遗传修饰的细胞,其包括本文所述的嵌合抗原受体,或本文所述核酸分子或构建体,或核酸分子或结构体的基因组整合形式。
在一些实施方案中,遗传修饰的细胞是白细胞、外周血单核细胞(PBMC)、淋巴细胞、T细胞、自然杀伤细胞或自然杀伤T细胞。
在一些实施方案中,T细胞是CD4+T细胞或CD8+T细胞。
本申请还提供了一种杀死表达或异常表达Lgr5的靶细胞的方法,该方法包括将靶细胞暴露于表达CAR的细胞或转基因细胞,其中CAR靶向Lgr5。在一些实施方案中,CAR包括本文描述的特征中的任何一个或多个。
在一些实施方案中,所述细胞或遗传修饰的细胞是靶细胞的自体细胞。在一些实施方案中,所述细胞或遗传修饰的细胞与靶细胞是同种异体的。在一些实施方案中,靶细胞在受试者的身体内。在一些实施方案中,靶细胞是癌细胞。
在杀死靶细胞的方法的一些实施方案中,该方法还包括在将靶细胞暴露于表达嵌合抗原受体的细胞或基因修饰的细胞之前分析靶细胞上Lgr5的表面表达。在一些实施方案中,其中靶细胞是癌细胞,将Lgr5在癌细胞上的表面表达与可比较的非癌细胞进行比较,以确定异常表达。
本发明还提供了一种预防或治疗患有癌症的患者的方法,所述方法包括将患者暴露于CAR,其中所述CAR靶向Lgr5。优选地,CAR在细胞或遗传修饰的细胞中表达,例如本文所述的那些细胞。因此,在一些实施方案中,预防或治疗患有癌症的患者的方法包括将患者暴露于如本文所述的包含或表达CAR的细胞。在一些实施方案中,细胞是患者自身的。在一些实施方案中,该细胞与患者是同种异体的。在一些实施方案中,预防或治疗患者中癌症的方法还包括识别患者中是否存在癌症干细胞。
在用于杀死癌细胞或预防或治疗癌症的方法的一些实施方案中,癌细胞选自以下一种或多种:乳腺癌细胞、胰腺癌细胞、前列腺癌细胞、结肠癌细胞、结肠直肠癌细胞、胃肠道癌细胞、肺癌细胞(NSCLC)、淋巴瘤癌细胞、卵巢癌细胞或B细胞淋巴瘤癌细胞。在一些实施方案中,癌细胞选自以下一种或多种;大肠癌细胞、B细胞淋巴瘤癌细胞或卵巢癌细胞。在一些实施方案中,癌症是结肠癌、结肠直肠癌或另一种胃肠道癌。在一些实施方案中,癌症是转移性的或是复发性癌症。
进一步提供了一种药物组合物,其包括本文所述的CAR、核酸、载体或遗传修饰的细胞以及药学上可接受的载体、赋形剂或稀释剂。在一些实施方案中,所述药物组合物包括细胞因子。
附图说明
尽管任何其他形式都可能落入本发明的范围内,但现在将参考附图,仅以示例的方式描述本发明的优选实施例,其中:
图1是抗体18G7.1、18G7H6A1的重链和轻链的CDR与本文举例说明的嵌合抗原受体的实施方案的比对。
图2是抗体18G7.1和18G7H6A1的可变重链和轻链区域与本文举例说明的嵌合抗原受体的实施方案的可变重链和轻链的比对。CDR由方框表示。
图3是根据本发明实施方案的嵌合抗原受体(CAR)的示意图,其示出了长度为12(4a)、119(4b)和229(4c)个氨基酸的三个不同接头结构域。
图4A和4B是示出了根据本发明的CAR的结合域的两个实施方案的示意图。具体说明了两种针对Lgr5的scFv融合蛋白,其包括通过融合结构域连接的抗体可变重(VH)和可变轻(VL)链。
图5A和5B是淋巴细胞的流式细胞术直方图(基于前向散射和侧向散射门控),并对CD4+、CD8+和EGFR表达进行染色(作为CAR表达的替代标记),图5A显示了用CNA3002、CNA3003和CNA3004以及未转染的T细胞转导后5天的CAR表达。图5B显示了用CNA3102、CNA3103和CNA3104以及未转染的T细胞转导后5天的CAR表达。
图6A和6B是淋巴细胞的流式细胞术直方图(基于前向散射和侧向散射门控),并对CD4+、CD8+和EGFR表达进行染色(作为CAR表达的标志物)。图6A显示了用CNA3002、CNA3003和CNA3004以及未转染的T细胞转导后15天的CAR表达。图6B显示了用CNA3102、CNA3103和CNA3104以及未转染的T细胞转导后15天的CAR表达。
图7是野生型CHO细胞和过表达Lgr5的CHO细胞中Lgr5表达的流式细胞术直方图,Lgr5未染色并用抗Lgr5抗体BNC101染色。
图8A和8B说明了CAR转导的T细胞在裂解表达Lgr5的靶标中的功效。具体而言,图8A说明了细胞毒性(杀伤)测定,表明用CNA3002、CNA3004、CNA3102、CNA3103和CNA3104中的一种转导的T细胞可以以10:1、3:1和1:1的靶细胞与效应细胞比率有效裂解过表达Lgr5的CHO细胞,而未转染的T细胞仅最低限度地裂解相同的靶细胞。图8B说明了相同的转导T细胞仅对不过表达Lgr5的CHO细胞产生最小的杀伤作用。
图9A至9G说明了CNA3002、CNA3003、CNA3004、CNA3102、CNA3103和CNA3104在杀死一系列癌细胞系方面的功效。检测的癌细胞系包括:(9A)LoVo细胞(转移性结肠上皮细胞癌症);(9B)LIM1215细胞(结肠上皮细胞癌);(9C)Raji细胞(伯基特淋巴瘤);(9D)Namalwa细胞(伯基特淋巴瘤);(9E)OVCAR3(卵巢癌);(9F)SHY-5Y-SY(神经母细胞瘤);和(9G)BE(2)-M17(神经母细胞瘤)。这些检测使用效应CAR T细胞进行,靶向癌细胞(E:T)的比率为10:1、3:1和1:1
图10A和10B说明了重复图9A和9B中所示的杀伤试验的结果,但效应细胞与靶细胞(E:T)的比例为10:1至1:30。
图11说明了CNA3002、CNA3004、CNA3102、CNA3103和CNA3104在以10:1和1:1的效应物与靶细胞(E:T)比率杀死原发性卵巢癌细胞方面的功效。
图12A至12C说明了Lgr5阻断抗体在CAR T细胞介导的LoVo靶细胞杀伤中的作用。这些图具体说明了CNA3002、CNA3004、CNA3102、CNA3103和CNA3104在以10:1和1:30的效应物与靶细胞(E:T)比率杀死原发性卵巢癌细胞方面的功效。
图13A说明了CNA3004、CNA3102、CNA3103和CNA3104在癌症小鼠异种移植模型中的体内疗效(通过肿瘤生长测定)。
图14A和14B显示了癌症小鼠异种移植模型中的生存时间(14A)和无瘤天数(14B)。
具体实施方式
富含亮氨酸重复序列的G蛋白偶联受体5(Lgr5)是GPCR的A类红蛋白样家族的一种七跨膜蛋白。Lgr5与其配体R-Spondin结合时,与Wnt受体Frizzled和LPR5/6相互作用,增强Wnt/β-连环蛋白信号传导(Carmon,K.S.等人,PNAS.,2011;108,11452-7)。
当Lgr5被激活时,β-连环蛋白在细胞的胞质溶胶中积累,并转移到细胞核,在细胞核中激活原癌基因,包括c-myc、周期素D1(cyclinD1)和免死蛋白(survivin)。在正常条件下,Lgr5对胚胎发育以及成体干细胞的细胞可塑性、增殖和分化至关重要。因此,Lgr5是几种组织中成人干细胞的标志物,所述组织包括乳腺组织、小肠和大肠以及毛囊(Xu,L等人,stem CellRes Ther.,2019;10:219)。
值得注意的是,Lgr5在各种癌症类型中被确定为上调,所述癌症类型包括腺癌、基底细胞癌、胶质母细胞瘤、肝细胞癌、大肠癌、胰腺癌症、B细胞恶性肿瘤、非小细胞肺癌(NSCLC)和卵巢癌症(Tanese K,等人,Am JPathol.2008;173(3):835–43;Carmon,K.S.等人,Proc NatlAcad Sci USA.,2011;108,11452–7;Jiang XM,等人,Proc Natl Acad SciUSA.2013;110(31):12649–54;Gao等人,Transl Cancer Res.,2019;8(1):203-211和McClanahan T,等人,CancerBiol Ther.2006;5(4):419–26)。
研究表明,癌症中Lgr5的上调主要刺激癌症干细胞的增殖和更新,并促进癌症的迁移和肿瘤的形成。Lgr5还被证明可以促进乳腺癌上皮细胞向间质细胞的转化(Yang L等,Stem Cells.2015;33(10):2913–24.)。因此,Lgr5在癌症转移和继发肿瘤形成中起着重要作用,并在癌症干细胞(CSC)上表达。
本发明的部分前提是,发明人认识到,表达针对Lgr5嵌合抗原受体的细胞会杀死表达Lgr5的细胞,因此可以为癌症患者提供替代治疗。
因此,本发明提供了一种嵌合抗原受体,其包括:胞外结构域,所述结构域包含识别Lgr5的结合域;跨膜结构域;以及激活细胞功能的胞内信号结构域,或由它们组成。
在整个说明书中,本发明的CAR构建体(统称为CNA-CAR家族构建体)将被称为CNA30xx或CNA31xx,后缀“xx”是序列号(即02、03或04)。因此,本文举例说明的六个CNA是CNA3002、CNA3003、CNA3004、CNA3102、CNA3103和CNA3104。前缀CNA30xx是指在结合区中具有可变轻链和可变重链的第一取向的CAR,而CNA31xx具有相反取向。序列号(“xx”)指的是不同的接头长度。
嵌合抗原受体(CAR)是人工构建的蛋白质,在细胞表面表达后可诱导抗原特异性细胞反应。在其最基本的形式中,CAR至少包括三个结构域。第一结构域是特异性识别抗原的胞外抗原识别结构域,或更具体地识别抗原的一个或多个表位部分。第二结构域是能够诱导或参与诱导胞内信号通路的胞内信号结构域。第三结构域是穿过质膜并桥接胞外抗原识别结构域和胞内信号结构域的跨膜结构域。
前两个结构域的组合决定了CAR的抗原特异性和CAR诱导所需细胞反应的能力,后者也依赖于CAR的宿主细胞。例如,在T辅助细胞中表达并具有包含CD3激活结构域的信号结构域的CAR的激活,一旦被其同源抗原激活,就可能诱导CD4+T辅助细胞分泌一系列细胞因子。在另一个例子中,当在CD8+细胞毒性T细胞中表达时,相同的CAR—一旦被表达同源抗原的细胞激活—可能诱导细胞毒素的释放,最终导致抗原表达细胞的凋亡诱导。
第三结构域(跨膜结构域)可以包含CAR的信号结构域的一部分,或者可以与之相关。跨膜结构域通常是一个或多个疏水螺旋,其跨越细胞的脂质双层并将CAR嵌入细胞膜内。当与细胞结合时,CAR的跨膜结构域可以是CAR表达模式中的一个决定因素。例如,使用与CD3共受体相关的跨膜结构域可以允许CAR在幼稚T细胞中表达,而使用来自CD4共受体的跨膜域可以指导CAR在辅助T细胞中的表达。CD8共受体跨膜结构域的使用可以直接在细胞毒性T淋巴细胞(CTL)中表达,而CD28跨膜结构区可以允许在CTL和T辅助细胞中表达,并且可以帮助稳定CAR。
嵌合抗原受体的另一组分或部分可以是接头结构域。接头结构域从跨膜结构域的胞外侧跨越到抗原识别结构域,从而将抗原识别结构区连接到跨膜结构区。通常,在本领域中,接头结构域被认为是可选结构域,因为一些CAR在没有接头结构域的情况下发挥作用。
结合域
在整个说明书中使用的术语“识别”(相对于Lgr5)是指结合域与Lgr5的期望表位或Lgr5分子的任何部分结合的能力。优选地,这种识别是选择性的,因为结合域仅或主要结合Lgr5。在一些实施方案中,结合域可以直接结合Lgr5或其表位。在一些实施方案中,抗原识别结构域可以与Lgr5的加工形式结合。在本文中使用的术语“加工形式”是指通常由于胞内加工而被截短或消化的Lgr5形式,包括主要组织相容性复合物(如人类白细胞抗原)上存在的Lgr5形式和表位。
CAR结合域可以是能够识别Lgr5或其表位的任何合适的结构域。在整个说明书中使用的术语“结合域”是指CAR中为Lgr5提供CAR特异性的部分。在本发明的上下文中,结合域仅包括CAR的胞外区域(或胞外结构域)的一部分。
富含亮氨酸重复序列的G蛋白偶联受体5(SEQ ID No.1–Uniprot登录号O75473,NCBI登录号NP_003658.1和NM_003667.2–也称为其同义词GPR49、GPR67、FEX和GPR HG38)是一种长度为907个氨基酸的膜结合受体。Lgr5由561个氨基酸的胞外结构域组成,包括21个氨基酸的信号结构域和来自氨基酸67-446的至多17个富含亮氨酸的重复序列。富含亮氨酸的重复序列形成弓形结构,所述弓形结构具有胞外结构域中的凸面和与RSPO1和RNF43相互作用的凹面(Kumar K.等人,Protein Sci.2014;23(5):551-65Chen P.等人Genes Dev.,2013;27(12):1345-50)。Lgr5还包括21个氨基酸的7个跨膜螺旋结构域和84个氨基酸的细胞质尾部。胞外结构域的最C端区域包含一个跨越481-552的铰链结构域。
因此,在一些实施方案中,结合域识别残基22-561之间的表位。在一些实施方案中,结合域识别Lgr5的凸面上的Lgr5表位。在一些实施方案中,结合域识别残基67-446之间的表位。
CAR的结合域可以包括一系列的结合分子。这些包括抗体(包括非常规抗体,如重链抗体)、抗体片段和蛋白质结合支架。
在一些实施方案中,抗原结合域包括识别Lgr5的抗体的结合部分。在一些实施方案中,结合域包括结合Lgr5的抗体的可变重链。在一些实施方案中,结合域包括结合Lgr5的抗体的可变轻链。
识别Lgr5的抗体为本领域已知抗体,包括抗Lgr5抗体,可从以下公司获得:Huabio(ET1608-18)、LifeSpan BioSciences(LS-A1236)、mybiosource(MBS856950、MBS7113118和MBS9604330)、Novus Biologicals(NLS1236)、Biorbyt(orb137136和orb137177)、ProSci(23-394)、BioVision(A1007-100)、Cusabio(CSB-PA012906LA01HU)、StressMarqBiosciences Inc(SPC-764)、Biolegend(373803和373804)、R&D systems(MAB8240)、Bioss(bsm-52412R)、Biorad(AHP2742)、G0Biosciences(ITA3755)、RayBiotech(144-10545-50)、AtlasAntibodies(HPA012530)、OriGene Technologies(TA890013)、Elabscience(E-AB-63432)、GeneTex(GTX71143)、St John’s Laboratory(STJ112563)、ThermoFisher(MA5-32978和MA5-32979)、NSJ Bioreagents(F48166)、Acam(ab219107)、Abnova(PAB30456和PAB2591)、Miltenyi Biotec(130-111-390)、Sino Biological(100687-T04)、Abbexa Ltd(abx019126)、MBL International(MC-1236和MC-1235)、BosterBio(M00239)、SignalwayAntibody(21659和C44974)、Wuhan Fine Biotech(FNab04765)、Merck(HPA012530)、Leading Biology(AMM03069G)、Neuromics(RA25071)、Antibody Research Corporation(111302)、Bon Opus Biosciences(BA111499)、Creative Diagnostics(L640)和CreativeBiolabs(NAB-1650-VHH)。在US20190248889A1中公开了进一步的抗Lgr5抗体(抗体GEN89.Lgr5.1-12和抗体GEN89.Lgr5.26-1)。
在一些实施方案中,抗体是人源化抗体。在优选的实施方案中,识别Lgr5的抗体是18G7H6A3或18G7H6A1(BNC101),如WO2015153916–标题:Humanized antibodies that bindlgr5和WO2018232164A1–标题:Antibody drug conjugates that bind lgr5(其全部公开内容以其整体并入本文)中所述。因此,在一些实施方案中,本发明的CAR的结合域包括抗体18G7H6A1或18G7H6A3的结合部分。
使用氢-氘交换质谱法对抗体18G7H6A1和18G7H6A3与Lgr5相互作用的表位作图(参见Morris,1996“Epitope Mapping Protocols,”inMethods in MolecularBiologyvol.66;Humana Press,Totowa,N.J.)鉴定了关键表位残基为Lgr5的T175、E176、Q180、R183、S186、A187、Q189、D247、E248、T251、R254、S257、N258和K260(SEQ ID No.1)。这些残基在富含亮氨酸的重复序列6至9的凸面内。因此,在一些实施方案中,CAR的结合域识别Lgr5的富含亮氨酸的重复序列6-9内的表位。在一些实施方案中,CAR的结合域识别Lgr5的一个或多个表位残基T175、E176、Q180、R183、S186、A187、Q189、D247、E248、T251、R254、S257、N258和K260。
抗体18G7H6A3或18G7H6A1是鼠抗体18G7.1的人源化和亲和成熟版本。通过进行丙氨酸扫描诱变,将重链CDR1、轻链CDR1和CDR3中的单个残基突变为丙氨酸,转染到HEK 293细胞中,并通过流式细胞术测定所得条件培养基的LGR5抗原结合活性。对重链CDR3进行饱和诱变,其中CDR3中的每个残基都突变为除该位置原始氨基酸自身外的19个天然存在的氨基酸中的每一个。将每个突变体转染到HEK 293细胞中,并通过流式细胞术测定所得条件培养基的LGR5抗原结合活性。可在重链和轻链的CD2序列上使用类似的诱变。
图1说明了18G7.1、18G7H6A1的CDR区与本发明的本发明CAR构建体的CDR的比对。可以看出,在18G7.1和本发明的CAR构建体之间的重链CDR1中,至多三个氨基酸残基是不同的。
此外,图2说明了CAR的18G7.1、18G7H6A1和CNA3xxx家族的重链可变区的比对(没有前导序列)。可以看出,本发明的重链可变区不同于18G7H6A1,在位置101处有Y到L的取代(见图2)。CNA3xxx CAR的重链CDR3区(SEQ ID No.39)和抗体18G7H6A1的重链CDR3区(SEQID No.96)的比较表明,这种修饰在重链的CDR3区内(见图1)。
如图1所示,18G7.1、18G7H6A1和CNA3xxx CARs的轻链CDR3区显示18G7.1在位置4包括N到A的突变(参见SEQ ID No.97)。
在一些实施方案中,结合域包括:重链CDR1,其具有SEQ ID No.37中所示氨基酸序列或具有SEQ ID No.37中所示的具有至多1、2或3个氨基酸修饰的氨基酸序列,或重链CDR2,其具有SEQ ID No.38中所示氨基酸序列或具有SEQ ID No.38中所示的具有至多1、2或3个氨基酸修饰的氨基酸序列,和重链CDR3,其具有SEQ ID No.39中所示氨基酸序列,或具有SEQ ID No.39中所示的具有至多1、2或3个氨基酸修改的氨基酸序列。
在一些实施方案中,结合域包括:具有SEQ ID No.37、38和39中所示氨基酸序列的重链CDR1、CDR2和CDR3。
在一些实施方案中,结合域包括具有SEQ ID No.95的重链CDR1,以及SEQ IDNo.38、39或96中所述的任何重链CDR2或CDR3。
在一些实施方案中,结合域包括具有SEQ ID No.96的重链CDR3,以及SEQ IDNo.37、95或38中所述的任何重链CDR1或CDR2。
在一些实施方案中,结合域包括:轻链CDR1,其具有SEQ ID No.40所示氨基酸序列或具有SEQ ID No.40所示的具有至多1、2或3个氨基酸修饰的氨基酸序列,轻链CDR2,其具有SEQ ID No.41所示氨基酸序列或具有SEQ ID No.41所示的具有至多1、2或3个氨基酸修饰的氨基酸序列,以及轻链CDR3,其具有SEQ ID No.42中所示氨基酸序列或具有SEQ IDNo.42中所示的具有至多1、2或3种氨基酸修饰的氨基酸序列。
在一些实施方案中,结合域包括:具有SEQ ID No.40、41和42中所示氨基酸序列的轻链CDR1、CDR2和CDR3。
在一些实施方案中,结合域包括具有SEQ ID No.97中所示氨基酸序列的轻链CDR3,以及具有SEQ ID No.41和42的CDR1和CDR2。
抗体和抗体片段
如上所述,CAR的结合域可包含抗体或抗体的结合部分,或衍生自抗体。抗体是具有示例性多样性的蛋白质结合分子,在单个个体中可能有至多1011至1012个独特分子,个体之间的遗传变异允许进一步的多样性。体内抗体多样性是由V(D)J连接中一系列基因的随机重组驱动的。
抗体的结合主要由重链和轻链的三个高变区决定,称为互补决定区(CDR)1、2和3。因此,每个成熟抗体具有六个CDR(可变重(VH)链CDR1、CDR2和CDR3以及可变轻(VL)链CDR1、CDR1和CDR3)。这些高变区形成三维抗原结合口袋,抗体的结合特异性由CDR(主要是CDR3)中的特定氨基酸序列决定。
特异性分析物的抗体可以从商业上获得,也可以通过本领域已知的方法产生。例如,特异性分析品的抗体可以使用Howard和Kaser(Making and usingAntibodies:aPractical Handbook,CRC Press,2007)公开的方法制备。
受试者体内产生的抗体的特异性、亲合力(avidity)和亲和力(affinity)可以通过体外过程如亲和力成熟来修饰(参见例如;Fujino Y.等人,Biochem Biophys ResComm.,2012;428(3):395-400;Li,B.等人MAbs.2014;6(2):pp.437-45以及Ho M和PastanI,“In vitro Antibody Affinity Maturation Targeting GermlineHotspots”,MethodMol Biol.,2009;525:293-xiv)。这些技术包括(但不限于)定点诱变和PCR驱动的诱变、噬菌体文库开发和亲和筛选。例如,与A/G-G-C/T-A/T(RGYW)和AG-C/T(AGY)序列(参照编码免疫球蛋白DNA)定义的热点位置相邻的突变可能会改变产生的抗体的亲和力。或者,可以使用诸如体外扫描饱和诱变的过程(Chen,G等人Protein Eng-Des Sel.,1999;(12)4:346-356)来用每个其他可能的突变取代CDR区域内的每个修饰。然后评估每个变体的抗原亲和力和特异性。因此,体内衍生的抗体或其结合片段可以被进一步修饰,以产生不同但线性相关的抗体。因此,术语“抗体”(及其片段)包括体内衍生的抗体和体外衍生的分子,这些抗体和分子经历了修饰CDR结合位点的突变过程,使得它们与体内产生的抗体相比具有独特的序列。此外,抗体的结合部分,特别是CDR,可以使用本领域已知的技术进行亲和成熟和突变。
抗体一词还包括由骆驼、鲨鱼和大颚鱼等物种产生的非常规抗体。因此,术语抗体包括重链抗体,包括骆驼抗体、IgNARs和可变淋巴细胞受体(VLR)。此外,这些可以被片段化为它们的结合部分(例如VNARs—IgNARs的单一结合部分),或者重组整合到融合蛋白中。本领域已知用于产生和适应这种非常规抗体的方法,例如参见Nuttall,S.,MethodsMol.Biol,2012;911:pp.27-36和Vincke C.等人,Methods Mol.Biol.2012;907:pp.145-76。
可以产生结合Lgr5的特异性鉴定的表位区域的抗体。此外,这种抗体可以是亲和力成熟的,以优化持久的亲和力和亲合力。因此,在一些实施方案中,结合域包括与结合Lgr5的抗体的一个或多个结合区相同的序列,或者包括与结合Lgr5的结合区的亲和力成熟形式相对应的序列。虽然亲和力成熟的结合区可以与原始抗体结合区显著不同,但在优选形式中,亲和力成熟形式的结合区与结合Lgr5的抗体具有80%、85%、90%、95%、97%、98%或99%或更高的序列同一性。因此,CAR的结合域可以包含与结合Lgr5的抗体具有80%、85%、90%、95%、97%、98%或99%或更高序列同一性的序列。
抗体结合片段
在一些实施方案中,结合域是抗体结合片段。抗体结合片段可以衍生自抗体,或者可以用与抗体或抗体片段的CDR相同的序列重组产生。事实上,这些CDR可能来自亲和力成熟的抗体,因此可能与体内衍生的抗体不相同。
抗体由四条链(两条重链和两条轻链)组成,可分为Fc(可结晶部分)和Fab(抗原结合部分)结构域。抗体的Fc部分与Fc受体和补体系统相互作用。因此,Fc部分对于抗体的免疫功能是重要的。然而,Fab部分包含抗体的结合区,并且对于抗体对所需表位的特异性是关键的。
因此,在一些实施方案中,结合域是抗体的Fab片段。Fab片段可以是单独的Fab片段(即抗体片段是在没有连接的二硫键的情况下产生的)或包含通过二硫键连接的抗体的两个Fab片段的F(ab’)2片段。这些片段通常是通过使用消化酶(例如胃蛋白酶)将抗体片段化而产生的。方法是本领域已知的,例如参见J.等人,Methods Mol Biol.2017;1535:pp.39-29。/>
抗体的每个Fab片段总共有六个CDR,VH和VL链各包含三个CDR(在由4个框架区组成的框架内)。Fab片段的恒定区可以被去除以仅留下抗体的VH和VL区。单个VH和VL链(每个仅包含三个CDR)已显示以高亲和力特异性结合。通常,单独的结合区被称为单抗体结构域(sdAb)。或者,VH和VL链可以通过接头连接,形成被称为单链可变片段(scFv,也称为双抗体)的融合蛋白。与Fab不同,scFv不是从抗体片段化的,而是通常基于抗体的CDR和框架区重组形成的。此外,sdAb也可以重组产生并形成更大的融合蛋白的结合组分,该融合蛋白也可以包括额外的部分。因此,在一些实施方案中,结合域是或包括scFv或sdAb。scFv可以包括连接在一起以形成多价scFv的多个VH和VL链,例如二价scFv或三价scFv。
因此,在一些实施方案中,结合域是单结构域抗体(sdAb),其包括与结合Lgr5的抗体的可变重链或可变轻链相同的序列,或与结合Lgr5的抗体片段抗原结合(Fab)片段相同的序列,或与包含结合Lgr5的抗体的可变重链区和可变轻链区的单链可变片段(scFv)相同的序列。
在一些实施方案中,可变重链区具有SEQ ID No.50的氨基酸序列,或具有至少80%或90%序列同一性的其变体。在一些实施方案中,可变轻链区具有SEQ ID No.49的氨基酸序列,或具有至少80%或90%序列同一性的其变体。
在一些实施方案中,结合域是单链可变片段,其包括连接到VL链的N端的VH链的C端,其中VH链包括:具有SEQ ID No.37序列的CDR1、具有SEQ ID No.38序列的CDR2和具有SEQ ID No.39序列的CDR3,并且VL链包括:具有SEQ ID No.40序列的CDR1、具有SEQ IDNo.41序列的CDR2和具有SEQ ID No.42序列的CDR3,并且其中每个CDR可以具有1、2或3个氨基酸修饰。
在一些实施方案中,结合域是单链可变片段,其包括连接到VH链的N端的VL链的C端,其中VL链包括:具有SEQ ID No.40序列的CDR1、具有SEQ ID No.41序列的CDR2和具有SEQ ID No.42序列的CDR3,并且VH链包括:具有SEQ ID No.37序列的CDR1、具有SEQ IDNo.38序列的CDR2和具有SEQ ID No.39序列的CDR3,并且其中每个CDR可以具有1、2或3个氨基酸修饰。
在一些实施方案中,可变轻链的CDR1和CDR3区包括至多1、2或3个突变。在一些实施方案中,重链的CDR1和/或CDR3区包括至多1、2或3个突变。在一些实施方案中,轻链的CDR3包括至多1个、2个或3个突变。
可变重链和可变轻链可以通过任何合适的融合结构域进行融合。在一些实施方案中,融合结构域具有SEQ ID No.98的序列。因此,在一些实施方案中,结合域包括SEQ IDNo.53或SEQ ID No.54中所示的序列。在一些实施方案中,结合域包括与SEQ ID No.53或54具有至少90%序列同一性的SEQ ID No.53或SEQ ID No.54的变体。在一些实施方案中,结合域包括与SEQ ID No.53或54具有至少80%序列同一性的SEQ ID No.53或SEQ ID No.54的变体。
含有抗体衍生序列的抗体、抗体片段或融合蛋白可以从商业上获得或通过本领域已知的方法(例如上面讨论的方法)产生。
在上述上下文中(以及在整个说明书中使用),术语“序列同一性”或“与…相同”等应解释为氨基酸或核酸序列之间的相似程度。除非通过数字百分比或范围限定,否则这些术语在默认情况下应被解释为需要功能性序列同一性。也就是说,除了不影响序列功能的冗余修饰和突变外,序列应被解释为相同。本文描述了这样的突变。
在整个说明书中,应该理解的是,术语“衍生自”不是指多肽或核苷酸本身的来源,而是指构成多肽或核苷酸的一部分的序列信息的衍生,例如结合域或胞内信号结构域的部分或全部。因此,术语“衍生自”包括合成、人工或以其他方式产生的多肽或核苷酸,这些多肽或核苷酸与它们来源的肽或核酸具有序列同一性。
蛋白质结合支架
本发明的CAR的抗原结合域可以是或可以包括蛋白质支架。蛋白质结合支架已经成为与各种分子和蛋白质结合的可行分子。蛋白质结合支架通常包括稳定的蛋白质结构(支架),其可以耐受指定结合区内氨基酸的修饰而不改变结合域的相对排列。这些蛋白质结合支架包括(但不限于):Adnectin、Affilin(Nanofitin)、亲合体、Affimer分子、Affitin、Alphabody、适配体、Anticalin、基于犰狳(armadillo)重复蛋白的支架、Avimer、设计的锚定蛋白重复蛋白(DARPin)、Fynomer、半胱氨酸结抑制剂(Inhibitor CystineKnot,ICK)支架、Kunitz结构域肽、Monobody(AdNectinsTM)和Nanofitin。
Affilin是人工产生的约20kDa的蛋白质。它们包括与人类泛素和脊椎动物γ-B结晶蛋白在结构上相关的支架,具有八种表面暴露的可操纵氨基酸,这些氨基酸可以被设计为与靶分析物特异性结合。亲和素分子可以使用定点诱变和噬菌体展示文库等技术特异性地适应于对多种分子的结合。生产和选择Affinin分子的方法是本领域已知的,例如,Lorey,S.等人,J Bio Chem.2014;289(12):pp.8493-507。
亲合体是约6kDa的蛋白质,其包含IgG同种型抗体的Z结构域的蛋白质支架,带有位于它两个α螺旋的结合域中的13个氨基酸残基中的一个或多个修饰。工程化和生产亲和体分子的方法是本领域已知的,包括Feldwisch,J.和Tolmachev,V.“Engineering ofaffibody molecules for therapy and diagnostics”,Methods in Molecular Biology(2012);899:pp103-126.。
Affimer是约12至14kDa的蛋白质,其利用衍生自胱抑素(cystatin)半胱氨酸蛋白酶抑制剂家族的蛋白质支架。Affimer除了可适用于靶特异性结合的N端序列外,还包含两个肽环区。在结合位点具有1010个氨基酸组合的Affimer可以使用噬菌体展示文库和本领域已知的技术,例如Hoffmann T.等人Protein Eng.Des.Sel.2010;23(5):pp403–13。
Affitin是66个残基(约7kDa)的蛋白质,并且使用来源于在嗜酸热硫化叶菌(Sulfolobus acidocaldarius)中发现的DNA结合蛋白Sac7d的蛋白质支架。它们很容易在体外从原核细胞培养物中产生,并含有14个结合残基,这些残基可以突变产生超过3x1012个结构变体。本领域已知用于生产Affitin的技术,包括Mouratou等人PNAS.2007;Nov 13;104(46):17983–17988。诸如表面等离子体共振之类的筛选技术可以用于识别这些分子的特异性结合。
Alphabody是大约10kDa的分子,与大多数大分子不同,它可以穿透细胞膜,因此可以与胞内和胞外分子结合。Alphaboidy的支架是基于计算设计的具有三个α螺旋(A、B和C)的螺旋状结构,这三个螺旋与自然结构不相似。A和Cα螺旋上的氨基酸可以被修饰以靶向特异性抗原。至少在US20100305304A1中描述了产生Alphabody并筛选其与靶分子结合的方法。
用于结合蛋白质的适配体包括一系列核酸(DNA、RNA和XNA)和肽,这些核酸和肽可以筛选与特定靶分子的结合。核酸适配体数据库(参见例如Nucleic Acids Research,Volume 32,Issue suppl_1,1January 2004,pp.95–100,https://doi.org/10.1093/nar/ gkh094)允许选择体外鉴定的DNA适配体。肽适配体由短氨基酸序列组成,通常嵌入稳定的蛋白质支架框架(“框架上的环”)内的环状结构中。通常,5至20个残基的肽环是选择性结合靶分子的变异性的来源。组合文库和诸如酵母双杂交筛选的技术可用于产生和筛选肽适配体。用于产生和筛选蛋白质适配体的其他技术是已知的,并在文献中描述,包括ReverdatoS.等人,Curr TopMed Chem.2015;15(12):pp1082–1101。
Anticalin是衍生自脂质运载蛋白的蛋白质结合分子。通常,与抗体相比,Anticalin与更小的分子结合。本领域公开了筛选和开发Anticalin的方法,包括Gebauer,M.和Skerra,A.,“Anticalins:small engineered binding proteins based on thelipocalin scaffold”,Methods Enzymology,503(2012),pp.157-188和Richter,A.等人FEBS Letters.2014;588(2):pp213-218。
基于犰狳重复序列蛋白的支架的特征在于一个犰狳结构域,由大约42个氨基酸的串联犰狳重复序列组成,形成由三个α-螺旋组成的重复单元的超级螺旋。保守结合域内残基的修饰允许制备一系列组合文库,其可用于选择靶特异性结合物(参见例如ParmeggianiF等人JMol Biol.2008;376(5):pp1282-304)
Avimer(也称为亲和性多聚体、大抗体(maxibody)或低密度脂蛋白受体(LDLR)结构域A)包含至少两个基于富含半胱氨酸的细胞表面受体蛋白的A结构域的连接的长30至35个氨基酸的肽。A结构域的修饰允许与同一靶标上或跨靶标的一系列表位定向结合,其中连接的肽的数量决定了每个病毒聚体的可能靶标的数量。本领域已知一系列的Avimer噬菌体展示文库,包括商业文库,例如Creative Biolabs的文库。
设计锚定蛋白重复蛋白(DARPin)是衍生自锚定蛋白的工程结合蛋白。本领域已知用于筛选和鉴定DARPin的方法,例如Stumpp MT等,Drug Discov.Drug Discov.Today2008;13(15-16):pp695-701和Pluckthurn A.,Annu.Rev.inPharmacol.Toxicol.,2015;55:pp489-511。
半胱氨酸结抑制剂(ICK)支架是一个小蛋白家族(30至50个氨基酸残基长),其形成稳定的三维结构,包括连接一系列具有高序列变异性的环的三个二硫键。胱氨酸结抑制剂包括三个作为结蛋白的家族成员;环肽和生长因子半胱氨酸结。数据库是本领域已知的,例如KNOTTIN数据库(www.dsimb.inserm.fr/KNOTTIN/),其公开了已知结蛋白和环肽的特定性质,例如它们的序列、结构和功能。此外,生产ICK和筛选结合的方法是已知的,包括Moore,S.等人,Protein Engineering forTherapeutics,PartB–Chapter 9,MethodsinEnzymology(2012),503;pp.223-251。
Monobody(也称为AdNectin商品名)利用FN3(纤维连接蛋白III型结构域)支架,该支架具有多种可操作的可变基团。连接蛋白与抗体共享抗体可变结构域和β-折叠环。单体的结合亲和力可以通过体外进化方法进行多样化和定制,如mRNA展示、噬菌体展示和酵母展示。本领域公开了筛选和生产单体的方法,包括Park SH等人,PLoSOne,2015;10(7)doi:10.1002/pro.3148and Lipovsek,D.,ProteinEng.Des.Sel.,2011;24(1-2):3-9。
接头结构域
接头结构域连接CAR的跨膜结构域和抗原识别结构域。已经形成的CAR T细胞在不包含接头结构域的情况下发挥作用,因此,在这种情况下,接头结构域通常不被认为是所有CAR功能所必需的。
在不希望被理论束缚的情况下,接头结构域可以向CAR的胞外域(胞外结构域)提供适当的分子长度,以允许抗原识别结构域识别表位,同时在表达CAR的效应细胞和靶细胞之间形成正确的免疫突触距离。此外,接头结构域可以为抗原识别结构域提供适当的灵活性,使其以正确的方式定向以识别其表位。
因此,在一些实施方案中,胞外结构域包含将结合域连接到跨膜结构域的接头结构域。在一些实施方案中,连接的结构域的长度为至少12个氨基酸。在一些实施方案中,连接的结构域的长度为至少约12个氨基酸。在一些实施方案中,连接的结构域的长度大于12个氨基酸。在一些实施方案中,连接的结构域的长度为至少119个氨基酸。在一些实施方案中,连接的结构域的长度为至少约119个氨基酸。在一些实施方案中,连接的结构域的长度大于119个氨基酸。在一些实施方案中,连接的结构域的长度为至少229个氨基酸。在一些实施方案中,连接的结构域的长度为至少约229个氨基酸。在一些实施方案中,连接的结构域的长度大于229个氨基酸。
在一些实施方案中,连接的结构域的长达119个氨基酸。在一些实施方案中,连接的结构域的长度至多为约119个氨基酸。在一些实施方案中,连接的结构域的长度为至多229个氨基酸。在一些实施方案中,连接的结构域的长度至多为约229个氨基酸。
合适的接头结构域的选择可以基于(i)降低对Fc受体(如Fcγ和FcRn受体)的结合亲和力,这使CAR表达细胞的“脱靶”激活最小化,以及(ii)通过增强抗原结合区的灵活性来优化CAR构建体的功效,减少免疫突触形成的空间约束(例如,减少空间位阻和优化突触距离)。
在一些实施方案中,接头结构域包含与来自免疫球蛋白的铰链区或来自参与T细胞突触形成的膜结合分子的铰链或胞外区相同的序列。例如,接头结构域可以包括具有与来自CD4、CD8、CD3、CD7或CD28的铰链区同源的氨基酸序列的区域。
在一些实施方案中,接头结构域包含与免疫球蛋白的一部分相同的序列。在一些实施方案中,该部分是铰链区(例如IgG4铰链区或其修饰形式)、恒定重链(CH)1区、CH2区、CH3区或CH4区中的一个或多个。在一些实施方案中,所述部分是免疫球蛋白的CH2区、CH3区或铰链区,或者与所述CH区具有至少50%、60%、70%、80%、90%、95%、98%或99%的序列同一性。在一些实施方案中,该部分是免疫球蛋白的CH2区或CH3区和铰链区。在一些实施方案中,免疫球蛋白选自IgG亚型。
在一些实施方案中,接头结构域包含与IgG1、IgG2、IgG3或IgG4-Fc区中的一个或多个的一部分具有相似性的序列,例如IgG4的IgG1铰链区和CH2或CH3区或其具有至少50%、60%、70%、80%、90%、95%、98%、99%或99.5%序列同一性的功能变体。
在一些实施方案中,接头结构域包含免疫球蛋白铰链区的全部或部分。如本领域所理解的,形成免疫球蛋白铰链区的特定区域对于不同的同种型是不同的。例如,IgA、IgD和IgG同种型免疫球蛋白在CH1和CH2区域之间具有铰链区域,而铰链区域的功能由IgE和IgM同种型免疫球蛋白中的CH2区域提供。
在本发明CAR的至少一些实施方案中,接头结构域包含与IgG4铰链序列相同的氨基酸序列,或包括与IgG4-铰链的修饰版本相同的序列,优选具有1、2或3个氨基酸修饰。
在包含结合域的一些实施方案中,所述结合域包含由连接到可变重链的N端的可变轻链的C端形成的单链可变片段,其中所述可变轻链包括或由SEQ ID No.49(或其功能变体)组成,并且所述可变重链包括或为由SEQ ID No.50(或其功能变体)构成,所述接头的长度为至少119个氨基酸,或大于119个氨基酸长度,或至少229个氨基酸长度,并且将结合域连接到跨膜结构域,并且其中接头结构域连接至可变重链的C端。
在一些实施方案中,所述结合域包含与可变重链的N端连接的可变轻链的C端,其中所述可变轻链包含具有SEQ ID No.40(CDR1-ESVDSYGNSF)、SEQ ID No.41(CDR2-LTS)和SEQ ID No.42(CDR3-QQNAEDPRT)的氨基酸序列的CDR或其功能变体,并且所述可变重链包括具有SEQ ID No.37(CDR1-GYSFTAYW)、SEQ ID No.38(CDR2-ILPGSDST)和SEQ ID No.39(CDR3-ARSGYGSSQY)的氨基酸序列的CDR或其功能变体,并且所述接头为12个氨基酸,或长度为至少12个氨基酸或长度为约12个氨基酸。在该实施方案的一些形式中,接头是至多119个氨基酸,或至多约119个氨基酸。在该实施方案的一些替代形式中,接头为至多229个氨基酸,或至多约229个氨基酸。为了避免疑问,接头长度可以是12个或更多个、12至119个、或12至229个氨基酸。
在一些实施方案中,所述结合域包含与可变重链的N端连接的可变轻链的C端,其中所述可变轻链包含具有SEQ ID No.40(CDR1)、SEQ ID No.41(CDR2)和SEQ ID No.42(CDR3)的氨基酸序列的CDR,或其功能变体,并且所述可变重链包括具有SEQ ID No.37(CDR1)、SEQ ID No.38(CDR2)和SEQ ID No.39(CDR3)的氨基酸序列的CDR或其功能变体,并且所述接头为119个氨基酸,或长度为至少119个氨基酸或长度为约119个氨基酸。在该实施方案的一些形式中,接头是至多229个氨基酸,或至多约229个氨基酸。
在一些实施方案中,所述结合域包含与可变重链的N端连接的可变轻链的C端,其中所述可变轻链包含具有SEQ ID No.40(CDR1)、SEQ ID No.41(CDR2)和SEQ ID No.42(CDR3)的氨基酸序列的CDR,或其功能变体,并且所述可变重链包括具有SEQ ID No.37(CDR1)、SEQ ID No.38(CDR2)和SEQ ID No.39(CDR3)的氨基酸序列的CDR或其功能变体,并且所述接头为229个氨基酸,或长度为至少229个氨基酸或长度为约229个氨基酸。
在一些实施方案中,所述结合域包含与可变轻链的N端连接的可变重链的C端,其中所述可变重链包含具有SEQ ID No.37(CDR1)、SEQ ID No.38(CDR2)和SEQ ID No.39(CDR3)的氨基酸序列的CDR,或其功能变体,并且可变轻链包括具有SEQ ID No.40(CDR1)、SEQ ID No.41(CDR2)和SEQ ID No.42(CDR3)的氨基酸序列的CDR,或其功能变体,并且接头为12个氨基酸,或长度为至少12个氨基酸或长度为约12个氨基酸。在该实施方案的一些形式中,接头是至多119个氨基酸,或至多约119个氨基酸。在该实施方案的一些替代形式中,接头为至多229个氨基酸,或至多约229个氨基酸。为了避免疑问,接头长度可以是12个或更多、12至119个、或12至229个氨基酸。
在一些实施方案中,结合域包括与可变轻链的N端连接的可变重链的C端,其中可变重链包括具有SEQ ID No.37(CDR1)、SEQ ID No.38(CDR2)和SEQ ID No.39(CDR3)的氨基酸序列的CDR,或其功能变体,并且可变轻链包括具有SEQ ID No.40(CDR1)、SEQ ID No.41(CDR2)和SEQ ID No.42(CDR3)的氨基酸序列的CDR,或其功能变体,并且接头为119个氨基酸,或长度为至少119个氨基酸或长度为约119个氨基酸。在该实施方案的一些形式中,接头是至多229个氨基酸,或至多约229个氨基酸。
在一些实施方案中,所述结合域包含与可变轻链的N端连接的可变重链的C端,其中所述可变重链包含具有SEQ ID No.37(CDR1)、SEQ ID No.38(CDR2)和SEQ ID No.39(CDR3)的氨基酸序列的CDR,或其功能变体,并且可变轻链包括具有SEQ ID No.40(CDR1)、SEQ ID No.41(CDR2)和SEQ ID No.42(CDR3)的氨基酸序列的CDR,或其功能变体,并且接头为229个氨基酸,或长度为至少229个氨基酸或长度为约229个氨基酸。
可结合到接头结构域中的序列的非穷尽列表在下面的表1中提供。在一些实施方案中,本发明的接头结构域可以包括表1中提供的任何一种或多种组分。在一些实施方案中,接头结构域可以由表1中提供的任何一种或多种接头组成。此外,接头结构域可以是人工合成的序列,例如多甘氨酸序列或GGGGS(Gly4Ser)序列的重复序列(例如(Gly4Ser)3)。
表1可能的接头结构域组分
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在一些实施方案中,接头结构域包含选自SEQ ID No:2-30的任何一个或多个序列中所示的序列,或其具有至少50%、60%、70%、80%、90%、95%、98%、99%或99.5%的序列同一性的功能变体或部分。
在一些实施方案中,接头结构域包含与免疫球蛋白CH3结构域、免疫球蛋白CH2结构域或CH2和CH3结构域相同的序列。在一些实施方案中,接头结构域包含与免疫球蛋白铰链区和CH3结构域或CH2结构域中的一个或多个相同的序列。在一些实施方案中,CH2和/或CH3区来自IgG抗体的IgG4亚类。
在一些实施方案中,接头结构域包含或由选自SEQ ID No.55、SEQ ID No.56或SEQID No.57的序列组成,或其具有至少50%、60%、70%、80%、90%、95%、98%、99%或99.5%序列同一性的功能变体或部分。
免疫球蛋白的铰链区、CH2和CH3区,特别是IgG同种型抗体,可以与Fc受体结合,如Fcγ受体和Fc新生儿(neonatal)受体。嵌合抗原受体的接头结构域的结合可降低受体的功效并可导致脱靶杀伤。因此,在一些实施方案中,接头结构域被设计为使得其与Fc受体结合的能力降低或没有能力。在一些实施方案中,接头结构域与免疫球蛋白相同,与其他免疫球蛋白同种型相比,其与Fc受体结合的能力降低。在一些实施方案中,嵌合抗原受体的接头结构域不包括基本上与Fc受体结合的氨基酸序列。
Fc受体与不同IgG同种型结合的能力如下表2所示。
表2Fc受体与IgG亚型的结合
IgG1 | IgG2 | IgG3 | IgG4 | |
FcγRIa(CD64) | +++ | - | ++++ | ++ |
FcγRIIaa(CD32) | +++ | ++ | ++++ | ++ |
FcγRIIba(CD32) | + | - | ++ | + |
FcγRIIIba(CD16a) | +++ | - | ++++ | - |
FcRn | +++ | +++ | +++ | +++ |
在一些实施方案中,其中接头结构域包含与免疫球蛋白的Fc区相同的部分,该部分可以被修饰以减少与Fc受体的结合。本领域已知修饰蛋白质以减少Fc受体结合的方法。Fcγ受体主要与免疫球蛋白区的下铰链区和CH2区的N端结合,而新生儿Fc受体主要与CH2区C端和CH3区N端的氨基酸结合。Fc受体与IgG抗体结合的指南见“Antibody Fc:LinkingAdaptive and Innate Immunity”Ackerman and Nimmerjahn,Elsevier Science&Technology 2014的第7章。因此,在这些区域中的修饰可以改变Fc受体与与免疫球蛋白的Fc部分具有同源性的接头结构域的结合。已显示减少Fcγ受体和FcRn结合的人IgG1突变的非穷尽示例性列表包括:E116P、L117V、L118A、删除的G119、P121A、S122A、I136A、S137A、R138A、T139A、E141A、D148A、S150A、S150A、E152A、D153A、E155A、N159A、D163A、H168A、N169A、K171A、K173A、R175A、E176A、Q178A、Y179F、N180A、S181A、R184A、V188A、T190A、L192A、Q194A、D195A、N198A、K200A、K205A、K209A、A210Q、A210S、A210G、P212A、P214A、E216A、K217A、S220A、K221A、A222T、K243A、Q245A、H251A、D259A、A261Q、E263A、E265A、V286A、S288A、K297A、S307A、E313A、H316A、N317A、H318A、Y319A(编号对应于Uniprot参考号P01857-1中规定的序列)。
跨膜和胞内结构域
CAR的跨膜结构域将胞外部分(外结构域)连接到胞内部分(胞内域),其作用主要是结构性的。因此,跨膜结构域可以由任何可以锚定和跨越细胞的脂质双层的序列组成。然而,跨膜结构域的性质可以影响其定位和表达。
在优选实施方案中,跨膜结构域与参与T细胞突触形成或T细胞信号诱导的分子序列具有同源性。在一些实施方案中,本发明的嵌合抗原受体包括跨膜结构域,其包括与CD3、CD4、CD8或CD28的跨膜结构区的全部或部分相同的序列。在一些实施方案中,跨膜结构域包含与CD8或CD28的跨膜结构区的全部或部分具有同一性的序列。在一些实施方案中,跨膜结构域与CD28的跨膜结构区的全部或部分具有序列同一性。在一些实施方案中,跨膜结构域与SEQ ID No.72或所述DNA或编码氨基酸序列的功能变体具有序列同一性。
除了抗原识别结构域、接头结构域和跨膜结构域外,本发明的嵌合抗原受体还包括胞内(内)结构域,其包括信号部分(信号结构域)。
嵌合抗原受体的胞内信号结构域可以是任何合适的结构域,其能够在抗原识别结构域识别抗原而激活CAR时诱导或参与诱导胞内信号级联。CAR的信号结构域将根据CAR激活后的预期细胞结果来具体选择。虽然有许多可能的信号结构域,但当用于免疫治疗和癌症治疗时,根据其来源的受体,信号结构域可分为两大类,即活化受体和共刺激受体(详见下文)。因此,在一些实施方案中,信号结构域包含具有与活化受体的信号传导部分或其功能变体相同的氨基酸序列的部分。在一些实施方案中,信号结构域包含具有与共刺激受体或功能变体的信号传导部分相同的氨基酸序列的部分。
如在整个说明书中使用的,当涉及活化受体或共刺激受体时,术语“部分”涉及受体的任何片段,该片段包括负责或参与在受体与其同源抗原或配体相互作用后启动/诱导胞内信号级联的序列。通过CD3启动/诱导T细胞受体(TCR)的胞内信号级联的实例概述如下。
虽然不希望被理论束缚,但TCR的胞外部分主要包括克隆型TCRα和TCRβ链(TCRα/β受体)或TCRγ和TCRδ链(TCRγδ受体)的异二聚体。这些TCR异二聚体通常缺乏固有的信号转导能力,因此它们与CD3的多个信号转导亚基(主要是CD3ζ、-γ、-δ和-ε)非共价结合。CD3的γ、δ和ε链中的每一个都具有胞内(细胞质)部分,该部分包括单个免疫受体酪氨酸基激活基序(ITAM),而CD3ζ链包括三个串联的ITAM。在MHC存在下,TCR与其同源抗原结合,并与必要的共受体如CD4或CD8结合后,启动信号传导,导致酪氨酸激酶(即Lck)磷酸化CD3链的胞内ITAM内的两个酪氨酸残基。随后,第二个酪氨酸激酶(ZAP-70自身被Lck磷酸化激活)被募集来对ITAM进行二磷酸化。因此,几个下游靶蛋白被激活,最终导致胞内构象变化、钙动员和肌动蛋白细胞骨架重组,当结合时,最终导致转录因子的激活和T细胞免疫反应的诱导。
如整个说明书中所使用的,术语“活化受体”涉及形成T细胞受体(TCR)复合物的组分或参与T细胞受体复合物形成的受体或共受体,或由于识别抗原或其他免疫原性刺激而参与免疫细胞特异性激活的受体。
这种活化受体的非限制性实例包括T细胞受体-CD3复合物(CD3ζ、-γ、-δ和-ε)、CD4共受体、CD8共受体,Fc受体或自然杀伤(NK)细胞相关活化受体如LY-49(KLRA1)、天然细胞毒性受体(NCR,优选NKp46、NKp44、NKp30或NKG2或CD94/NKG2异二聚体)的组分。因此,在本发明的CAR的一些实施方案中,信号结构域包含衍生自CD3共受体复合物(优选至少CD3-Zeta(ζ)链的信号传导部分)、CD4共受体、CD8共受体,Fc受体(FcR)的信号传导部分(优选Fcε)。
每个CD3链的特异性胞内信号转导部分在本领域是已知的。例如,CD3ζ链的胞内细胞质区跨越SEQ ID No.31中所列序列的第52至164位氨基酸,三个ITAM区跨越SEQ IDNo.31的第61至89、100至128和131至159位氨基酸。此外,CD3ε链的胞内部分跨越SEQ IDNo.32中所述序列的153至207位氨基酸,单个ITAM区跨越SEQ ID No.32的178至205位氨基酸。CD3γ链的胞内部分跨越SEQ ID No.33中所列序列的138至182位氨基酸,其中单个ITAM区跨越SEQ ID No.33的149至177位氨基酸。CD3δ的胞内部分跨越SEQ ID No.34中所述序列的127至171位氨基酸,单个ITAM区跨越SEQ ID No.34的138至166位氨基酸。
在本发明的一些实施方案中,信号结构域包含衍生自CD3或与CD3具有序列同源性的部分(优选CD3-ζ链或其一部分)。在一些实施方案中,信号结构域包含与CD3ζ(CD3-ζ)的胞内结构域的全部或部分相同的序列。在一些实施方案中,CD3-ζ共受体复合物的部分包括SEQ ID No.58中所示氨基酸序列,或其具有至少50%、60%、70%、80%、90%、95%、98%、99%或99.5%序列同一性的功能变体。
替代信号结构域包含Fc受体的胞内部分,这是本领域已知的。例如,FcεR1的胞内部跨越SEQ ID No.35中所述序列的1至59、118至130和201至244位氨基酸,或其功能变体。此外,FcγRI的胞内部分跨越SEQ ID No.36中所述序列的314至374位氨基酸或其功能变体。
活化受体部分的各种组合可用于形成CAR的跨膜(TM)和胞内(IC)部分,例如CD3ζTM和CD3ζ的IC(Landmeier S.等人,CancerRes.,2007;67:8335-43;Guest RD.等人,JImmunother.,2005,28:203-11;HombachAA.等人J Immunol.,2007;178:4650-7),the CD4TM和CD3ζIC(James SE.等人J Immunol.,2008;180:7028-38),the CD8 TM and CD3ζIC(Patel SD.等人Gene Ther.,1999;6:412-9),以及FcεRIγTM和FcεRIγIC(Haynes NM.等人J Immunol.,2001;166:182-7;AnnenkovAE.等人J Immunol.,1998;161:6604-13)。
如上所述,在本发明嵌合抗原受体的一些实施方案中,信号结构域包含具有与共刺激受体的信号传导部分相同的氨基酸序列的部分。
在整个说明书中使用的术语“共刺激受体”涉及在抗原特异性诱导活化受体时辅助免疫细胞激活的受体或共受体。如所理解的,共刺激受体不需要抗原的存在,并且不是抗原特异性的,但通常是两种信号中的一种,另一种是激活信号,其是诱导免疫细胞反应所需的。在免疫应答的背景下,共刺激受体通常通过其在抗原呈递细胞(APC)(如树突细胞或巨噬细胞)表面上表达的配体的存在而被激活。就T细胞而言,共刺激对于导致细胞活化、增殖、分化和存活是必要的(所有这些通常被称为T细胞活化),而在没有共刺激的情况下将抗原呈递给T细胞可能导致无能、克隆缺失和/或抗原特异性耐受的发展。重要的是,共刺激分子可以告知T细胞对同时遇到的抗原的反应。通常,在“阳性”共刺激分子的背景下遇到的抗原将导致T细胞的激活和旨在消除表达该抗原的细胞的细胞免疫反应。而在“阴性”共受体的情况下遇到的抗原将导致对共遭遇抗原(co-encoutered antigen)的诱导的耐受状态。
T细胞共刺激受体的非限制性实例包括CD27、CD28、CD30、CD40、DAP10、OX40、4-1BB(CD137)、ICOS。具体而言,CD27、CD28、CD30、CD40、DAP10、OX40、4-1BB(CD137)和ICOS都代表增强T细胞反应激活的“阳性”共刺激分子。因此,在本发明第一方面的一些实施方案中,信号结构域包含衍生自CD27、CD28、CD30、CD40、DAP10、OX40、4-1BB(CD137)和ICOS中的任何一种或多种的部分。
在本发明的一些实施方案中,信号结构域包含衍生自CD28、OX40或4-1BB共刺激受体的部分。在一些实施方案中,所述信号结构域包括4-1BB的一部分。在一些实施方案中,4-1BB共刺激受体的部分包括SEQ ID No.59中所示氨基酸序列或其功能变体。
共刺激受体的不同部分可单独或组合用于形成CAR的跨膜(TM)和胞内(IC)部分。组合的实例包括CD8TM和DAP10 IC或CD8TM和4-1BB IC(Marin V.等人Exp Hematol.,2007;35:1388-97)、CD28 TM和CD28IC(Wilkie S.等人J Immunol.,2008;180:4901-9;Maher J.等人Nat Biotechnol.,2002;20:70-5),以及CD8 TM和CD28 IC(MarinV.等人ExpHematol.,2007;35:1388-97)。
上述激活和共刺激受体的序列信息在各种数据库中很容易访问。例如,表3中提供了这些受体的人氨基酸、基因和mRNA序列的实施方案。
表3激活和共刺激受体序列信息汇总
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虽然表3是参考人类激活和共刺激受体提供的,但本领域技术人员应该理解,每种受体的同源和直系同源版本存在于大多数哺乳动物和脊椎动物物种中。因此,以上引用的序列仅作为可包含在本发明第一方面的CAR中的受体序列的非限制性实例提供,并且来自任何期望物种的同源和直向同源序列可用于产生适合于给定物种的CAR。
在本发明的一些实施方案中,跨膜结构域和信号结构域的一部分与同一分子共享同源性。例如,可以使用包括跨膜结构域和信号结构域的CD3的一部分。在一些实施方案中,跨膜结构域包含或由与CD28的跨膜结构区的全部或一部分相同的序列组成,并且信号结构域包含与CD28胞内结构域的全部或部分相同的序列或由其组成。
在本发明的一些实施方案中,信号结构域包含衍生自活化受体的部分和衍生自共刺激受体的部分。虽然不希望被理论束缚,但在这种情况下,CAR的抗原识别结构域对抗原的识别将同时诱导胞内激活信号和胞内共刺激信号。因此,这将模拟APC表达共刺激配体对抗原的呈递。或者,CAR可以具有信号结构域,该信号结构域包含衍生自活化受体或共刺激受体的部分。在这种替代形式中,CAR将仅诱导激活胞内信号级联或共刺激胞内信号级联。
在本发明的一些实施方案中,信号结构域包含或由与4-1BB和CD3-ζ链的胞内结构域的全部或一部分相同的序列组成。在一些实施方案中,本发明的CAR包括胞内结构域,所述胞内结构域包含SEQ ID No.59和SEQ ID No.58,或其功能变体,或由它们组成。
在一些实施方案中,CAR将具有信号结构域,所述信号结构域包含单个活化受体的一部分和多个共刺激受体的部分。在一些实施方案中,CAR将具有信号结构域,所述信号结构域包含与多个活化受体的部分相同的序列和衍生自单个共刺激受体的部分。在一些实施方案中,CAR将具有信号结构域,所述信号结构域包含与多种活化受体的部分和多种共刺激受体的部分相同的序列。在一些实施方案中,CAR将具有信号结构域,所述信号结构域包含与单个活化受体的一部分和两个共刺激受体的部分相同的序列。在一些实施方案中,CAR将具有信号结构域,所述信号结构域包含与单个活化受体的一部分和衍生自三个共刺激受体的部分相同的序列。在一些实施方案中,CAR将具有信号结构域,所述信号结构域包含与两个活化受体的部分和一个共刺激受体的部分相同的序列。在一些实施方案中,CAR将具有信号结构域,所述信号结构域包含与两个活化受体的部分和两个共刺激受体的部分相同的序列。如将理解的,活化受体和共刺激受体的数量存在进一步的变化,并且上述实施例不被认为是对本文所包括的可能组合的限制。
在本发明的一些实施方案中,跨膜结构域的序列和信号结构域的至少一部分与不同分子的部分具有序列相似性。在一些实施方案中,跨膜结构域包含或由与CD28的跨膜结构区的全部或一部分相同的序列组成,并且信号结构域包含与4-1BB和CD3-ζ链的胞内结构域的全部或部分相同的序列或者由它们组成。
嵌合抗原受体
在一些实施方案中,CAR将包括对Lgr5特异性的抗原识别结构域、对IgG4铰链区具有序列同一性的接头结构域、与CD28跨膜序列具有序列同一性的跨膜区,与4-1BB的信号传导区具有序列同一性的胞内部分和/或与CD3ζ的信号传导部分具有序列同一性的胞外部分,或所述部分、结构域或区域的功能变体。
在一些实施方案中,CAR将包括对Lgr5特异性的抗原识别结构域、与IgG4 CH3区结合的对IgG4铰链区具有序列同一性的接头结构域、与CD28跨膜序列具有序列同一性的跨膜区、与4-1BB的信号传导区具有序列同一性的胞内部分和/或与CD3ζ的信号传导部分具有序列同一性的胞外部分,或所述部分、结构域或区域的功能变体。
在一些实施方案中,CAR将包括对Lgr5特异性的抗原识别结构域、与IgG4 CH2区和IgG4 CH3区组合的与IgG4铰链区具有序列同一性的接头结构域、与CD28跨膜序列具有序列同一性的跨膜区、与4-1BB的信号传导区具有序列同一性的胞内部分和/或与CD3ζ的信号传导部分具有序列同一性的胞外部分,或所述部分、结构域或区域的功能变体。
在本发明的一些实施方案中,嵌合抗原受体包括选自SEQ ID No.60、61、62、63、64或65的氨基酸序列或其功能变体或由它们组成。在一些实施方案中,嵌合抗原受体包括选自SEQ ID No.62、63、64或65的氨基酸序列或其功能变体或由它们组成。
如本领域技术人员所理解的,可以在不偏离本发明范围的情况下对本文所述的CAR受体进行修饰。例如,关于SEQ ID No.60、61、62、63、64和65,CAR的优选功能是识别Lgr5并诱导导致表达CAR的T细胞活化的胞内信号。如本领域技术人员所理解的,可以在不显著改变CAR的特异性和/或表达CAR的细胞(如T细胞)的活化的情况下对嵌合抗原受体的氨基酸序列的部分进行变异。这种变化可以包括但不限于嵌合抗原受体的铰链区的变化、跨膜结构域的变化、以及包含嵌合抗原受体胞内结构域的活化受体和/或共刺激受体部分的变化。当进行这样的变化时,本领域的技术人员将利用所述知识和技能来达到可行的CAR。因此,这些变化的范围排除了本领域技术人员能够立即识别为导致CAR的功能被丧失的那些变化。
核酸构建和细胞的遗传修饰
本文所述的CAR可以通过本领域已知的任何方法生产,尽管优选使用重组DNA技术生产。编码嵌合受体的几个区域的核酸可以通过本领域已知的标准分子克隆技术(基因组文库筛选、PCR、引物辅助连接、定点诱变等)制备并组装成完整的编码序列。所得编码区优选插入表达载体中,并用于转化合适的表达宿主细胞系,优选T淋巴细胞细胞系,最优选自体T淋巴细胞系。
因此,本发明进一步提供核酸分子或包括核酸分子的核酸构建体,所述核酸分子包括编码上述嵌合抗原受体的核酸序列。
此外,所述核酸构建体包括表达载体,所述表达载体包括编码上述嵌合抗原受体的核酸序列。
在一些实施方案中,核酸分子包括编码SEQ ID No.60、61、62、63、64或65中所示氨基酸序列或其功能变体的核苷酸序列。
核酸分子可以包括任何聚核糖核苷酸或聚脱氧核糖核苷酸,其可以是未修饰或修饰的RNA或DNA。例如,核酸分子可以包括单链和/或双链DNA、作为单链和双链区域的混合物的DNA、单链和双链RNA、以及作为单链和双链区域的混合的RNA、包括DNA和RNA的杂交分子,所述杂交分子可以是单链的,双链或单链和双链区域的混合物。此外,核酸分子可以包括包含RNA或DNA或RNA和DNA两者的三链区。核酸分子还可以包含一个或多个修饰的碱基或出于稳定性或其他原因而修饰的DNA或RNA主链。可以对DNA和RNA进行多种修饰;因此,术语“核酸分子”包括化学、酶促或代谢修饰的形式。
在本发明的一些实施方案中,核酸分子包括SEQ ID No.66、67、68、69、70或71中所述的核苷酸序列或其功能变体。
为了消除疑问,应理解的是,SEQ ID No.66、67、68、69、70或71的功能变体包括具有一个或多个不同核酸但仍编码相同氨基酸序列的序列变体。由于遗传密码的简并性,大量的核酸可以编码任何给定的蛋白质。例如,密码子GCA、GCC、GCG和GCU都编码丙氨酸。本领域技术人员将认识到,核酸序列中的每个密码子(除了AUG和TGG之外,AUG通常是蛋氨酸的唯一密码子,TGG通常是色氨酸的唯一密码子)可以被修饰以产生功能相同的分子。因此,编码多肽的核苷酸序列的每个无义变异隐含在每个描述的序列中。
应当理解,根据本发明的核酸构建体可以进一步包含以下中的一种或多种:一个或多个宿主的复制起源;在一个或多个宿主中具有活性的选择性标记基因;和/或一个或多个转录控制序列,其中所述核酸分子的表达在转录控制序列的控制下。
如本文所用,术语“选择性标记基因”包括在其表达的细胞上赋予表型的任何基因,以促进的细胞鉴定和/或选择,所述细胞用构建体转染或转导。
“选择性标记基因”包括任何核苷酸序列,当用构建体转导的细胞表达时,这些核苷酸序列赋予细胞表型,从而促进这些转导细胞的鉴定和/或选择。编码合适的选择性标记的一系列核苷酸序列是本领域已知的(例如Mortesen,RM.和Kingston RE.Curr ProtocMol Biol,2009;Unit 9.5)。编码选择性标记的示例性核苷酸序列包括:腺苷脱氨酶(ADA)基因;胞嘧啶脱氨酶(CDA)基因;二氢叶酸还原酶(DHFR)基因;组氨酸脱氢酶(hisD)基因;嘌呤霉素-N-乙酰基转移酶(PAC)基因;胸苷激酶(TK)基因;黄嘌呤-鸟嘌呤-磷酸核糖转移酶(XGPRT)基因或抗生素抗性基因,如氨苄青霉素抗性基因、嘌呤霉素抗性基因、博来霉素耐药性基因、潮霉素抗性遗传基因、卡那霉素耐药性遗传基因和氨苄青霉素耐药性基因;荧光报告基因,例如编码绿色、红色、黄色或蓝色荧光蛋白的基因;以及基于发光的报告基因如荧光素酶基因等,其允许使用诸如荧光激活细胞分选(FACS)的技术对细胞进行光学选择。此外,在Barese,C.N.和Dunubar C.E.,Hum.Gene Ther.,2011;22(6):pp.659-68中具体讨论了T细胞的细胞选择标记。这些标记物包括新霉素(NEO)抗性基因、δNGFR(非信号NGFR)、截短的CD34和截短的非信号CD19(δCD19)。本发明的实施方案(如本文进一步描述的)利用截短形式的上皮生长因子受体(EGFRt)。已经开发了用于在体内追踪CAR T细胞的进一步技术,包括修饰的eDHFD(参见Sellmyer,M.A.等人Mol.Ther.,2020;28(1):pp.42-51)。
此外,应该注意的是,选择性标记基因可以是构建体中独特的开放阅读框,或者可以作为与另一多肽(例如CAR)的融合蛋白表达。
如上所述,核酸构建体还可以包含一个或多个转录控制序列。术语“转录控制序列”应理解为包括影响可操作连接核酸转录的任何核酸序列。转录控制序列可以包括,例如,前导序列、多腺苷酸化序列、启动子、增强子或上游激活序列,以及转录终止子。通常,转录控制序列至少包括启动子。本文使用的术语“启动子”描述了赋予、激活或增强细胞中核酸表达的任何核酸。
在一些实施方案中,至少一个转录控制序列可操作地连接到本发明第二方面的核酸分子。为了本说明书的目的,当转录控制序列能够促进、抑制或以其他方式调节核酸分子的转录时,转录控制序列被视为与给定的核酸分子“可操作地连接”。因此,在一些实施方案中,核酸分子处于转录控制序列的控制下,例如组成型启动子或诱导型启动子。
启动子可以组成性或差异性地调节可操作连接的核酸分子相对于表达发生的细胞、组织或器官的表达。因此,启动子可以包括例如组成型启动子或诱导型启动子。“组成型启动子”是指在大多数环境和生理条件下具有活性的启动子。“诱导型启动子”是指在特定环境或生理条件下具有活性的启动子。本发明考虑在感兴趣的细胞中具有活性的任何启动子的用途。因此,本领域普通技术人员将容易地确定广泛的启动子阵列。
哺乳动物组成型启动子可包括但不限于猿猴病毒40(SV40)、巨细胞病毒(CMV)、P-肌动蛋白、泛素C(UBC)、延伸因子-1α(E3A)、磷酸甘油酸激酶(PGK)和CMV早期增强子/鸡β肌动蛋白(CAGG)。
诱导型启动子可包括但不限于化学诱导型启动子和物理诱导型启动子。化学诱导型启动子包括具有由化合物如醇、抗生素、类固醇、金属离子或其他化合物调节的活性的启动子。化学诱导型启动子的实例包括:四环素调控的启动子(例如参见美国专利5,851,796和美国专利5,464,758);诸如糖皮质激素受体启动子的类固醇反应性启动子(例如参见美国专利5,512,483)、蜕皮激素受体启动剂(例如参见美国专利6,379,945)等;以及金属响应性启动子如金属硫蛋白启动子(例如参见美国专利4,940,661、美国专利4,579,821和美国专利4601978)等。
如上所述,控制序列还可以包括终止子。术语“终止子”是指转录单元末端的DNA序列,该序列发出转录终止的信号。终止子是3’-非翻译的DNA序列,通常含有聚腺苷酸信号,这有助于将聚腺苷酸序列添加到初级转录物的3’-末端。与启动子序列一样,终止子可以是在其想要使用的细胞、组织或器官中可操作的任何终止子序列。合适的终止子对于本领域技术人员来说是已知的。
如将理解的,根据本发明的核酸构建体可以进一步包括额外的序列,例如允许增强表达、细胞质或膜运输和定位信号的序列。具体的非限制性实例包括内部核糖体进入位点(IRES)、N-末端白细胞介素-2信号肽(Moot R.等人,Mol Ther Oncoloytics,2016;3:16026)、CSF2RA、IgE前导序列(WO2017147458)、流感血凝素信号序列(Quitterer,U.等人,Biochem.Biophys.Res.,2011:409(3):p.544-579)等。Owki,H.等人Eur.J.Cell Biol.,2018;97(6):422-441中提供了对信号肽的综述,其通过引用并入本文。
本发明扩展到基本上如本文所述的所有遗传构建体。这些构建体可以进一步包括用于在真核生物中维持和/或复制遗传构建体和/或将遗传构建体或其一部分整合到真核细胞基因组中的核苷酸序列。
核酸构建体可以是任何合适的形式,例如质粒、噬菌体、转座子、粘粒、染色体、载体等的形式,当与适当的控制元件结合时,其能够复制,并且能够在细胞之间转移包含在构建体内的基因序列。
因此,术语载体包括克隆和表达载体以及病毒载体。在一些实施方案中,核酸构建体是载体。在一些实施方案中,载体是病毒载体,因此本发明提供了包括编码上述CAR的核酸分子或核酸构建体的病毒载体。在一些实施方案中,所述载体是DNA载体或mRNA载体。
在至少一些实施方案中,本发明提供用于制备遗传修饰细胞的编码上述CAR的核酸分子或核酸构建体。此外,在至少一些实施方案中,本发明提供核酸分子在制备用于细胞的转化、转染或转导的载体中的用途。优选地,所述细胞是表达CD3、CD4或CD8中的一种或多种的T细胞。适合于基因修饰的细胞可以是异源的或自体的。
在一些实施方案中,细胞用于预防或治疗癌症的方法或药物的制备。因此,在一些实施方案中,本发明提供了载体在制备用于预防或治疗癌症的药物中的用途。
本领域已知将外源遗传物质(如核酸构建体)有意引入(转染/转导)到真核细胞中的方法。可以理解的是,最适合将核酸构建体引入所需宿主细胞的方法取决于许多因素,例如核酸构建体的大小、宿主细胞的类型、转染/转导的所需效率以及转染/转导细胞的最终所需或所需存活力。这种方法的非限制性实例包括:用如阳离子聚合物、磷酸钙的化学物质或如脂质体和树枝状聚合物的结构进行化学转染;非化学方法,如电穿孔(见Potter和Heller,“Transfection by Electroporation.”Curr.Prot.Mol.Bio.,ed.FrederickM.Ausubel et al.2003:Unit–9.3)、声蒸发(Wang,M等人,Sci.Reps.,2018;8:3885)、热休克或光学转染;基于颗粒的方法,如“基因枪”递送、磁感染或转染、脂质纳米颗粒或病毒转导。
本领域已知用于哺乳动物细胞的多种病毒转导技术。常见的病毒载体包括慢病毒和逆转录病毒。在Wang L等人的Proc.Natl.Acad.Sci.,2011;108:E803-12。可选病毒载体包括HSV、腺病毒和AAV(Howarth J等人,Cell.Bio.&Toxic.,2010,vol.26,issue 1,pp 1–20)。
在一些实施方案中,本发明提供慢病毒,其包含编码本文所述嵌合抗原受体的核酸。此外,本发明提供了病毒载体(优选逆转录病毒,例如慢病毒或γ逆转录病毒)在制备转基因细胞或用于预防或治疗癌症或用于杀死表达Lgr5或异常表达Lgr 5的细胞的药物中的用途。
细胞的转导可导致编码上述CAR的DNA的基因组整合。或者,DNA可以在转导的胞内瞬时表达。每一个都有积极的一面和消极的一面。基因组整合DNA在细胞复制过程中稳定表达并复制到子代细胞。这确保了强大的免疫反应和体内表达CAR的T细胞的显著增加。
或者,瞬时转导(通常通过用信使核糖核酸转导实现)导致细胞中的临时CAR表达。这通常会导致低得多的反应,但会为从业者提供更多的控制,以根据需要增加或减少“剂量”。
如上所述,在一些实施方案中,本发明提供了DNA载体或重组DNA在制备用于细胞遗传转导的病毒载体中的用途。细胞可以是任何细胞,然而下面提供了合适的实例。
核酸构建体将根据所需的转染/转导方法进行选择。在一些实施方案中,核酸构建体是病毒载体,并且将核酸构建体引入宿主细胞的方法是病毒转导。本领域已知利用病毒转导在PBMC如T细胞中引发CAR表达的方法(Parker,LL.等人Hum Gene Ther.2000;11:2377-87),更一般地利用逆转录病毒系统转导哺乳动物细胞(Cepko,C.和Pear,W.CurrProtoc Mol Biol.2001,unit 9.9),并且可以通过本领域已知的任何合适的方法转染到细胞中。
本领域已知用于细胞亚群的选择/分离的技术。这些包括荧光活化细胞分选(BasuS.等人J.Vis.Exp.2010;41:1546),利用固定在基质上的抗体的技术,例如对表达所需标记物的细胞进行免疫磁性选择的磁性细胞分离装置(Zola H.等人Blood,2005;106(9):3123-6),或微流体芯片的使用。一系列细胞标记物可用于分离免疫系统的细胞,包括(但不限于)BCR、CCR10、CD1a、CD1b、CD1c、CD1d、CD3、CD4、CD5、CD7、CD8、CD10、CD11b、CD11c、CD13、CD16、CD19、CD21、CD23、CD25、CD27、CD31、CD32、CD33、CD34、CD38、CD39、CD40、CD43、CD45、CD45RA、CD45RO、CD48、CD49d、CD49f、CD51、CD56、CD57、CD62、CD62L、CD68、CD69、CD62、CD62L、CD66b、CD68、CD69、CD73、CD78、CD79a、CD79b、CD80、CD81、CD83、CD84、CD85g、CD86、CD94、CD103 CD106、CD115、CD117、CD122、CD123、CD126、CD127、CD130、CD138、CD140a、CD140b、CD141、CD152、CD159a、CD160、CD161、CD163、CD165、CD169、CD177、CD178、CD183、CD185、CD192、CD193、CD194、CD195、CD196、CD198、CD200、CD200R、CD203c、CD205、CD206、CD207、CD209、CD212、CD217、CD218α、CD229、CD244、CD268、CD278、CD279、CD282、CD284、CD289、CD294、CD303、CD304、CD314、CD319、CD324、CD335、CD336、CXCR3、Dectin-1、Tc-epsilor R1α、Flt3、颗粒酶A、颗粒酶B、IL-9、IL-13α1、IL-21R、iNOS、KLRG1、MARCO、MHC II类、RAG、RORγT、Singlec-8、ST2、TCRα/β、TCRγ/δ、TLR4、TLR7、VEGF、ZAP70
特别值得注意的是T细胞CCR10、CD1a、CD1c、CD1d、CD2、CD3、CD4、CD5、CD7、CD8、CD9、CD10、CD11b、CD11c、CD13、CD16、CD23、CD25、CD27、CD31、CD34、CD38、CD39、CD43、CD45、CD45RA、CD45RO、CD48、CD49d、CD56、CD62、CD62L、CD68、CD69、CD73、CD79a、CD80、CD81、CD83、CD84、CD86、CD94、CD103、CD122、CD126、CD127、CD130、CD140a、CD140b、CD152、CD159a、CD160、CD161、CD165、CD178、CD183、CD185、CD192、CD193、CD194、CD195、CD196、CD198、CD200、CD200R、CD212、CD217、CD218 alpha、CD229、CD244、CD278、CD279、CD294、CD304、CD314、CXCR3、Flt3、颗粒酶A、颗粒酶B、IL-9、IL-13α1、IL-21R、KLRG1、MHC II类、RAG、RORγT、ST2、TCRα/β、TCRγ/δ、ZAP70。用于T细胞选择的特别优选的细胞标记物包括TCRγ、TCRδ、CD3、CD4和CD8。
然后可以培养分离的细胞以改变细胞活性、扩增或活化。本领域已知用于扩增和激活细胞的技术(Wang X.和Rivière I.Mol.Thera.Oncololytics.2016;3:16015)。其中包括:使用抗CD3/CD28微珠(Miltenyi Biotec或Thermofisher Scientific-根据制造商的说明书)或其他形式的固定的CD3/CD28激活抗体。然后可以在细胞因子(如IL-2、IL-12、IL-15或IL-17)存在下体外扩增活化的/基因修饰的细胞,然后冷冻保存。在Wang和Rivièra(同上)中提供了扩增CAR T细胞的方法的概述。
本发明进一步提供了一种基因修饰的细胞,所述细胞包含如上所述的嵌合抗原受体、核酸分子或核酸构建体。在一些实施方案中,遗传修饰的细胞包括核酸分子或构建体的基因组整合形式。在一些实施方案中,遗传修饰的细胞是白细胞。在一些实施方案中,遗传修饰的细胞是外周血单核细胞(PBMC)。在一些实施方案中,遗传修饰的细胞是髓细胞。在一些实施方案中,遗传修饰的细胞是单核细胞。在一些实施方案中,遗传修饰的细胞是巨噬细胞。在一些实施方案中,遗传修饰的细胞是淋巴细胞。在一些实施方案中,遗传修饰的细胞是T细胞。在一些实施方案中,遗传修饰的细胞是α-β(αβ)T细胞。在一些实施方案中,遗传修饰的细胞是γ-δ(γδ)T细胞。在一些实施方案中,遗传修饰的细胞是CD3+T细胞(例如原始CD3+T细胞或记忆CD3+T细胞)。在一些实施方案中,T细胞是CD4+T细胞(例如初始CD4+T淋巴细胞或记忆性CD4+T细胞)。在一些实施方案中,T细胞是CD8+T细胞(例如初始CD8+T淋巴细胞或记忆性CD8+T细胞)。在一些实施方案中,遗传修饰的细胞是自然杀伤细胞。在一些实施方案中,遗传修饰的细胞是自然杀伤T细胞。
嵌合抗原受体表达细胞的用途。
遗传修饰的细胞,如本文所述的CAR T细胞,可用于靶向表达Lgr5的细胞,并且(取决于细胞类型)可协助或导致表达Lgr5的细胞被杀死。在一些实施方案中,本发明提供了杀死表达Lgr5或异常表达Lgr5的细胞的方法,该方法包括将表达Lgr5的细胞暴露于具有嵌合抗原受体的遗传修饰细胞(例如上述CAR T细胞),其中嵌合抗原受体靶向Lgr5。
在一些实施方案中,遗传修饰的细胞是表达Lgr5的细胞的自体细胞。在一些实施方案中,表达或异常表达Lgr5的细胞在受试者体内。在一些实施方案中,表达或异常表达Lgr5的细胞是癌细胞。在一些实施方案中,受试者是人。
因此,本发明提供了上述转基因细胞用于预防或治疗癌症的用途。因此,本发明提供了一种预防或治疗患有癌症的患者的方法,所述方法包括将患者暴露于表达嵌合抗原受体的细胞,其中嵌合抗原受体靶向Lgr5。优选地,给患者施用表达嵌合抗原受体的细胞或基因修饰的细胞。
此外,本发明提供了一种杀死表达Lgr5的细胞的方法,所述方法包括使表达Lgr5的细胞与表达CAR的细胞接触,如上所述。在一些实施方案中,表达或异常表达Lgr5的细胞是癌细胞。
在一些实施方案中,杀死表达或异常表达Lgr5的细胞的方法以及预防或治疗患者的方法还包括分析Lgr5在靶细胞或癌细胞上的表面表达。在一些实施方案中,将靶细胞和癌细胞上Lgr5的表面表达与可比较的非癌细胞进行比较。这些可比较的细胞可以是自体的,也可以是异源的。该方法可以在体外或体内进行。
在一些实施方案中,在将靶细胞或癌细胞暴露于表达嵌合抗原受体的细胞或转基因细胞之前,对Lgr5的表面表达进行分析。
在一些实施方案中,当靶细胞是癌细胞并且与非癌细胞相比异常表达Lgr5时,执行杀死靶细胞的方法。在治疗患者癌症的方法的一些实施方案中,如果与可比较的非癌细胞相比,癌细胞过度表达Lgr5,则施用表达CAR的细胞。
在一些实施方案中,预防或治疗患者癌症的方法包括在将患者暴露于表达嵌合抗原受体的细胞或转基因细胞之前识别患者中是否存在癌症干细胞。
癌症干细胞标记物包括(但不限于):ABCB5、ALDH1A1、CD200、CD133、CD44、CD34、CD24、EpCAM和Lgr5
本领域已知使用标记物识别各种癌症类型中的癌症干细胞。其中的示例包括:乳腺癌(Ferro deF.等人,JClin Pathol,2013;66(3):187-91)、结肠癌(Munro M.等人,JClin Pathol.,2018;71(2):110和Cherciu I.等人,CurrHealth SciJ.,2014;40(3):153-161)、淋巴瘤(Kim S.等人,Korean J Hematol.,2011;46(4):211-213和Song S.等人JCancer.,2020;11(1):142-152)、胃肠道癌(Ahmad R.等人,Biochem Pharmacol.,2016;5(2):202)、肺癌(TempletonA.等人,Stem CellInvestig.,2014;1(9)和Huang Z.等人,JCancer.,2017;8(16):3190-3197)、胶质母细胞瘤(Lathia J.等人,Genes Dev.2015;29(12):1203-17)、胰腺癌(Gzil A.等人,MolBiol Rep.,2019;46:6629-45)以及肝癌(Sun J.等人,World J Gastroenterol.,2016;7(22):3547-57)。
在一些实施方案中,癌症是实体癌症。在一些实施方案中,癌症选自以下组:膀胱癌、脑癌、乳腺癌、宫颈癌、结肠癌、子宫内膜癌、上皮癌、食管癌、肺癌、口腔癌、卵巢癌、癌、肝癌、白血病、淋巴瘤、骨髓瘤、胰腺癌、前列腺癌、直肠癌、皮肤癌、胃癌、睾丸癌、甲状腺癌和舌癌。
在一些实施方案中,癌症选自:乳腺癌、胰腺癌、前列腺癌、结肠癌、大肠癌、肺癌(NSCLC)、淋巴瘤、卵巢癌、胃肠道癌或B细胞淋巴瘤。在一些实施方案中,癌症选自:结肠癌、结肠癌、B细胞淋巴瘤、卵巢癌或胃肠道癌。在一些实施方案中,所述癌症是转移性癌。在一些实施方案中,所述癌症是III期癌症或IV期癌症
。在一些实施方案中,癌症是血液学癌症。在一些实施方案中,癌症选自以下组:白血病、淋巴瘤和/或骨髓瘤。在一些实施方案中,白血病是急性淋巴细胞白血病(ALL)、急性髓细胞性白血病(AML)、慢性淋巴细胞白血病(CLL)或慢性髓细胞白血病(CML)。在一些实施方案中,淋巴瘤是霍奇金淋巴瘤或是非霍奇金淋巴瘤。在一些实施方案中,骨髓瘤是IgG、IgA、IgM、IgD或IgE。在一些实施方案中,骨髓瘤是轻链骨髓瘤或非分泌性骨髓瘤。
在一些实施方案中,当本发明的CAR在细胞毒性T淋巴细胞(CTL)中表达时,在体外诱导对表达或异常表达Lgr5的靶细胞的细胞毒性,Lgr5为至少20%、至少30%、至少40%或至少50%、或至少60%、或至少70%、或至少80%、或至少90%、或至少95%,CAR转导的CTL与靶细胞的比例为30:1或更大、10:1或更大,3:1或更大或1:1或更大。CTL主要表达CD8(即CD8+),然而CD4表达细胞的亚群已被证明具有细胞毒性特征(Takeuchi,A.和Saito,T,Front.Immunol.2017;8:art.1994)。因此,在一些实施方案中,CTL是CD8+。在一些实施方案中,CTL是CD4+。
在一些实施方案中,当本发明的嵌合抗原受体在CD4+T辅助细胞中表达时,与表达或异常表达Lgr5的靶细胞共培养时,增加IL-2、TNF-α和/或IFN-γ的产生。在一些实施方案中,该增加是统计上显著的增加。在一些实施方案中,统计上显著的增加达到0.05、0.01或0.001的P值。
本发明进一步提供如本文所述的嵌合抗原受体在免疫细胞中表达时用于治疗癌症的用途。合适的免疫细胞包括上面公开的遗传修饰细胞
本发明还提供了一种药物组合物,其包括遗传修饰细胞和一种或多种药学上可接受的载体、赋形剂或稀释剂,所述遗传修饰细胞包含如上所述的嵌合抗原受体、核酸分子或核酸构建体。
如本文所用,“载体”、“赋形剂”或“稀释剂”包括(但不限于)任何溶剂、分散介质、载体、包衣、稀释剂、抗菌剂和/或抗真菌剂、等渗剂、延迟吸收剂、缓冲液、悬浮液、胶体等。这种培养基和/或试剂用于药物活性物质的用途在本领域是众所周知的。任何与转基因细胞不相容的常规培养基或试剂都可用于药物组合物。补充活性成分也可以掺入组合物中。“药学上可接受的”是指任何在生物学上不受欢迎、或不受欢迎的反应性或毒性的材料,并且可以与表达嵌合抗原受体的遗传修饰细胞一起施用于个体,而不会引起任何不希望的生物效应或以有害的方式与其中含有它的药物组合物的任何其他组分(特别是遗传修饰细胞)相互作用。在一些实施方案中,药物组合物包括同时、协作或协同作用的另一种活性成分。在一些实施方案中,所述药物组合物包括细胞因子。
药物组合物可以配制成适合优选给药途径的多种形式。因此,一种组合物可以通过已知途径给药,包括胃肠外给药(如皮内、经皮、皮下、肌内、静脉内、腹膜内等)。药物组合物也可以通过持续或延迟释放给药。包含表达嵌合抗原受体的基因修饰细胞的药物组合物可以以任何合适的形式提供,包括但不限于溶液、悬浮液、乳液、喷雾、气溶胶或任何形式的混合物。
在一些实施方案中,药物组合物可以每周给药约一次至约五次。在一些实施方案中,所述药物组合物给药一次。在一些实施方案中,所述药物组合物被施用两次。在一些实施方案中,所述药物组合物被施用三次。在一些实施方案中,所述药物组合物被施用四次。
在一些实施方案中,药物组合物包括至少5×108个细胞。在一些实施方案中,药物组合物包括至少3×108个细胞。在一些实施方案中,药物组合物包括至少2.5×108个细胞。在一些实施方案中,药物组合物包括至少1×108个细胞。在一些实施方案中,药物组合物包括至少5×107个细胞。在一些实施方案中,药物组合物包括至少2.5×107个细胞。在一些实施方案中,药物组合物包括至少1×107个细胞。在一些实施方案中,药物组合物包括至少5×106个细胞。在一些实施方案中,药物组合物包括至少2.5×106个细胞。在一些实施方案中,药物组合物包括至少1×106个细胞。
在一些实施方案中,施用药物组合物以提供至少5×108个细胞。在一些实施方案中,施用药物组合物以提供至少3×108个细胞。在一些实施方案中,施用药物组合物以提供至少2.5×108个细胞。在一些实施方案中,施用药物组合物以提供至少1×108个细胞。在一些实施方案中,施用药物组合物以提供至少5×107个细胞。在一些实施方案中,施用药物组合物以提供至少2.5×107个细胞。在一些实施方案中,施用药物组合物以提供至少1×107个细胞。在一些实施方案中,施用药物组合物以提供至少5×106个细胞。在一些实施方案中,施用药物组合物以提供至少2.5×106个细胞。在一些实施方案中,施用药物组合物以提供至少1×106个细胞。
通常,以一定量和给药方案向受试者施用该药物组合物,可有效减少、限制癌症的进展、改善或在任何程度上解决癌症症状或临床症状。如本文所用,“改善”是指癌症症状或临床体征的范围、严重程度、频率和/或可能性的任何降低。“症状”是指疾病或患者状况的任何主观证据。“体征”或“临床体征”是指与特定情况有关的客观身体发现。在癌症的情况下,将组合物以一定量和有效的给药方案施用于受试者,以限制一个或多个肿瘤的生长,减小一个或更多肿瘤的大小、体积或重量,降低癌症的转移率或转移数量,减少癌症的增殖,或延长受试者的预期寿命。
定义和限制条件
本文中提及的核苷酸和多肽序列由序列标识符编号(SEQ ID No.)表示。序列标识符的摘要见表4。序列列表也作为说明书的一部分提供。
表4序列说明
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如本文所述,上述序列包括可能在序列中具有修饰和突变的功能变体。如本领域技术人员所理解的,“功能变体”仍然保持序列的原始蛋白质或核酸的部分或全部功能。因此,该功能变体可以例如具有一个或多个相对于上面提供的SEQ ID No.1的氨基酸插入、缺失或取代。或者,在核酸的情况下,功能变体可以包括一个或多个同义突变从而仍然编码相同的氨基酸序列,或者可以包括一种或多个非同义突变,只要编码的蛋白质是原始编码的蛋白质的功能变体即可。
例如,抗体的功能变体或抗体的结合部分可以是提供相同或相似特异性的任何变体。关于抗体,必须在其使用背景下考虑抗体的功能。例如,抗体结合部分的功能是其识别表位的能力。然而,任何抗体的整体也可以起到诱导免疫反应的作用,例如激活补体或激活效应细胞。
在一些实施方案中,功能变体或变体可包含与本文列出和列举的SEQ ID No.s中的任何一个至少50%的氨基酸序列同一性、至少55%的氨基酸序列同一性、至少60%的氨基酸序列同一性、至少65%的氨基酸序列同一性、至少70%的氨基酸序列同一性、至少75%的氨基酸序列同一性、至少80%的氨基酸序列同一性、至少85%的氨基酸序列同一性、至少90%的氨基酸序列同一性、至少91%的氨基酸序列同一性、至少92%的氨基酸序列同一性、至少93%的氨基酸序列同一性、至少94%的氨基酸序列同一性、至少95%的氨基酸序列同一性、至少96%的氨基酸序列同一性、至少97%的氨基酸序列同一性,至少98%的氨基酸序列同一性、至少99%的氨基酸序列同一性,或至少99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%或99.9%的氨基酸序列同一性。在一些实施方案中,功能变体保持原始肽/蛋白质的50%、60%、70%、80%、90%、95%、98%、99%或99.9%的功能。
如本文所用,“异常表达”涉及任何偏离可比细胞正常表达的表达。在一些实施方案中,异常表达是指表达突变形式的Lgr5或功能失调或非功能形式的Lgr5。在一些实施方案中,异常表达意味着与正常细胞相比Lgr5的过表达。在一些实施方案中,过表达是指与相当的正常细胞相比至少10%的表达升高、或至少20%的表达升高、或至少30%的表达升高、或至少40%的表达升高、或至少50%的表达升高、或至少60%的表达升高、或至少70%的表达升高、或至少80%的表达升高、或至少90%的表达升高、或至少100%的表达升高、或至少125%的表达升高、或至少150%的表达升高、或至少175%的表达升高、或至少200%的表达升高、或至少250%的表达升高、或至少300%的表达升高、或至少350%的表达升高、或至少400%的表达升高、或至少450%的表达升高、或至少500%的表达升高。
在整个说明书中,除非上下文另有要求,否则“包括(comprise)”一词或诸如“包括(comprises)”或“包括(comprising)”的变体将被理解为包含所述元素或整数或元素或整数组,而不排除任何其他元素或整数、或元素或整数组。
应进一步理解的是,诸如“包括(comprise)”之类的术语,或诸如“包括(comprises)”或“包括(comprising)”之类的变体,固有地包括在其范围内(但不限于)排除与本发明直接相关的其他元素的本发明版本。因此,诸如“由…组成”或“基本上由…组成”之类的术语可以代替诸如“包括(comprise)”、“包括(comprises)”或“包括(comprising)”之类的词汇,其效果是将本发明的范围限制为具体列举的元素。值得注意的是,在明确意图以详尽的方式考虑本发明的情况下,这种限制应被认为仅与本文公开的发明概念有关,并且可以添加落在发明概念范围之外的其他特征。此类特征或元素可包括但不限于赋形剂、制剂、添加剂、稀释剂、包装、佐剂和并置特征,这些特征或元素不应被术语排除在外,例如“由…组成”或“基本由…组成”。
当比较核酸序列时,应在由核酸长度决定或以其他方式指定的比较窗口上对序列进行比较。例如,在表4中列出的任何一个序列的全长上的至少20个残基、至少50个残基和至少75个残基、至少100个残基或至少200个残基,至少300个残基或者至少500个残基以及至少600个残基的比较窗口。与参考序列(不包括添加或缺失)相比,比较窗口可包括约20%、约18%、约16%、约14%、约12%、约9%、约8%、约6%、约4%或约2%或更少的添加或缺失,以实现两个序列的最佳比对。用于比对比较窗口的序列的最佳比对可以通过诸如程序的BLAST家族的算法的计算机化实现来进行,例如,由Altschul等人,Nucl.AcidsRes.1997;25:3389-3402。全局比对程序也可以用于对大小大致相等的相似序列进行比对。全球比对计划的例子包括NEEDLE(可在www.ebi.ac.uk/Tools/psa/emboss_needle/上获得),它是emboss包的一部分(Rice P等人,Trends Genet.,2000;16:276-277),以及GGSEARCH计划(可在fasta.bioch.virginia.edu/fasta_www2/fasta_www.cgi?rm=compare&pgm=gnw上获得),其是FASTA包的一部分(Pearson W和Lipman D,1988,Proc.Natl.Acad.Sci.USA,85:2444-2448)。这两个程序都基于Needleman-Wunsch算法,该算法用于找到两个序列沿其整个长度的最佳比对(包括空位)。序列分析的详细讨论也可以在Ausubel等人的19.3单元中找到("Current Protocols in Molecular Biology"JohnWiley&Sons Inc,Chapter 19,2003)。
术语“取代”是指用另一种氨基酸取代亲本肽或蛋白质序列中特定位置的氨基酸。可以以非保守的方式(例如,通过将属于具有特定大小或特征的一组氨基酸的氨基酸改变为属于另一组的氨基酸;例如,用疏水性氨基酸取代亲水性氨基酸)或以保守的方式进行取代以改变所得蛋白质中的氨基酸(例如,通过将属于具有特定大小或特性的一组氨基酸的氨基酸改变为属于同一组的氨基酸;例如,用亲水性氨基酸取代亲水性氨基酸)。这种保守的变化通常导致修饰的肽/蛋白质的构象和功能变化的减少。以下是各种氨基酸分组的实例:1)具有非极性R基团的氨基酸:丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸、蛋氨酸;2)极性R基团不带电的氨基酸:甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬氨酸、谷氨酰胺;3)带有带电荷的极性R基团的氨基酸(在pH6.0时带负电荷):天冬氨酸、谷氨酸;4)碱性氨基酸(pH 6.0时带正电荷):赖氨酸、精氨酸、组氨酸(pH 6.0)。另一组可能是带有苯基的氨基酸:苯丙氨酸、色氨酸和酪氨酸。
本领域技术人员将认识到,任何氨基酸都可以被化学(功能)相似的氨基酸取代,并保留多肽的功能。这种保守的氨基酸取代在本领域是众所周知的。表5和表6中的以下基团提供了一些保守的氨基酸。
表5示例性氨基酸保守取代
表6保守氨基酸组
族 | 氨基酸 |
脂肪族 | Val(V)、Leu(L)、Ile(I)、Gly(G) |
芳香族 | Phe(F)、Tyr(Y)、Trp(W) |
羟基或含硫/硒 | Ser(S)、Cys(C)、Sec(U)、Thr(T)、Met(M) |
环状 | Pro(P) |
碱性 | His(H)、Lys(K)、Arg(R) |
酸性或其酰胺 | Asp(D)、Glu(E)、Asp(D)、Gln(Q) |
术语“插入”是指在序列内部添加氨基酸。“添加”是指将氨基酸添加到序列的末端。“删除”是指从序列中删除氨基酸。
应理解,术语“修饰”或“突变”包括氨基酸序列或核酸序列的任何添加、缺失、插入或取代。
参考分子生物学的标准教科书,其中包含实施本发明所涵盖的基本技术的方法。例如,参见Green MR和Sambrook J,Molecular Cloning:A LaboratoryManual(4thedition),Cold Spring Harbor Laboratory Press,2012。
本文描述的所有方法都可以以任何合适的顺序进行,除非本文另有说明或与上下文明显矛盾。使用任何和所有示例或示例性语言(例如,“诸如”、“即”)仅旨在更好地说明示例性实施例,除非明确要求保护,否则不对所要求保护的发明的范围构成限制。说明书中的任何语言都不应被解释为将任何未要求保护的元素指示为必要的。
本文提供的描述与几个实施例有关,这些实施例可以共享共同的特性和特征。应当理解,一个实施例的一个或多个特征可以与其他实施例的另一个或更多个特征组合。此外,实施例的单个特征或特征的组合可以构成附加的实施方案。
本文中使用的主题标题仅为读者参考方便而包含,不应用于限制贯穿本申请或权利要求书的主题。主题标题不应用于解释权利要求的范围或权利要求的限制。
本领域技术人员将理解,本文所述的发明容易受到除具体描述的变化和修改之外的变化和变化的影响。应当理解,本发明包括所有这样的变化和修改。本发明还包括本说明书中单独或共同提及或指示的所有步骤、特征、组合物和化合物,以及任何两个或多个步骤或特征的任何和所有组合。
此外,应注意,如本文所用,单数形式“一个(a)”、“一个(an)”和“所述(the)”包括复数形式,除非上下文另有规定。
对于本领域技术人员来说,显而易见的是,尽管为了清楚和理解的目的在本文中详细描述了本发明,但在不脱离本说明书中公开的发明概念的范围的情况下,可以对本文中描述的实施例和方法进行各种修改和更改。
实施例
本发明在以下实施例中得到进一步说明。这些实例仅用于描述特定实施例的目的,而不旨在限制以上描述
实施例1-抗Lgr5嵌合抗原受体的设计、制备和表达。
详述根据本发明实施方案的嵌合抗原受体的设计和表达过程的示例方案如下。
CAR构建体(统称为CNA-CAR家族构建体)如图3所示制备,其由以下组成:包含前导序列2的胞外结构域1,所述前导序列2为抗体轻链前导序列(CNA30xx-SEQ ID No.85)或重链前导序列(CNA31xx-SEQ ID No.87),针对Lgr5的抗原结合域3(CNA 30xx–SEQ ID No.53和CNA31xx–SEQ ID No.54),和连接到CD28跨膜结构域5(SEQ ID No.72)的三个接头结构域4a-c(SEQ ID No.55、56和57)之一,以及包括胞内信号结构域的胞内域6,其包括4-1BB 7的信号传导部分(SEQ ID No.59)、CD3ζ链8的胞内信号部分(SEQ ID No.58)、T2A自切割位点9(SEQ ID No.79)和缺乏胞内信号结构域的EGFR受体(EGFRt)10的截短形式(SEQ IDNo.81)。因此,EGFRt的表面表达可以用作用CAR构建体测定转导效率的替代物。
如图3所示,胞外结构域1和跨膜结构域5由三个接头结构域之一连接:
4a.一种12个氨基酸的接头结构域,其包含IgG4铰链区的突变版本(SEQ IDNo.55)。这些CAR用系列后缀(xx)编号02表示;
4b.119个氨基酸的接头结构域,其包含IgG4铰链区和IgG4 CH3区(SEQ ID No.83)的突变版本,以提供具有SEQ ID No.56中所示氨基酸序列的连接结构区。具有该接头的CAR用系列后缀(xx)编号03表示;和
4c.229个氨基酸的接头结构域,其包含IgG4铰链区、IgG4 CH2区(SEQ ID No.84且具有L235D和N297Q突变)的突变版本,以提供具有SEQ ID No.57中所示氨基酸序列的连接结构区。具有该接头的CAR用序列后缀(xx)编号04和IgG4 CH3区表示。
如图4A和4B所示,胞外结构域1的抗原结合域3由两种融合蛋白中的一种组成(用前缀CNA30xx和前缀CNA31xx表示,其中后缀是上面讨论的“xx”序列号之一。具体而言,形成了两种单链变体片段(scFv)融合蛋白。它们包括由18个氨基酸的融合结构域13(SEQ IDNo.98)融合的可变重(VH)链11(SEQ ID No.50)和可变轻(VL)链12(SEQ ID No.49)。图4A显示了第一个双链结构域(CNA30xx–SEQ ID No.53),其中VL链的C端通过融合结构域13连接到VH链的N端。第二个结合域(CNA31xx–SEQ ID No.54)如图4B所示,其中VH链的C端通过融合结构域13连接到VL链的N端。如前所述,由于CAR的可变结构域顺序可能影响CAR的表面表达和活性,因此产生了两种不同的scFv取向(Burns等人,CancerRes:2010,70,3027-3033)。
因此,设计了六种不同的CAR,具有三个接头中的一个和两个结合域。这六项CAR总结如下:
·CNA3002–VL-VH-IgG4铰链(短铰链–12a.a.):氨基酸序列–Seq ID No.60。
·CNA3003–VL-VH-IgG4铰链-CH3(中等铰链–119a.a.):氨基酸序列–Seq IDNo.61。
·CNA3004–VL-VH-IgG4铰链-CH2-CH3(长铰链–229a.a.):氨基酸序列–Seq IDNo.62。
·CNA3102–VH-VL-IgG4铰链(短铰链–12a.a.):氨基酸序列–序列号63。
·CNA3103–VH-VL-IgG4铰链-CH3(中等铰链–119a.a.):氨基酸序列–Seq IDNo.64。
·CNA3104–VH-VL-IgG4铰链-CH2-CH3(长铰链–229a.a.):氨基酸序列–Seq IDNo.65。
六种CAR构建体中的每一种都是人类密码子使用优化的。编码每个成分的各个序列在下面的表7中列出。总共合成了六个CAR DNA编码序列(Seq ID No.:66、67、68、69、70和71,分别对应于CNA3002、CNA3003、CNA3004、CNA3102、CNA3103和CNA3104)。这些被合成为GeneBlockTM双链DNA片段,并使用NEB-HiFi组装反应克隆到消化的epHIV-7.2慢病毒DNA载体骨架中以提供六种载体。
表7CAR组分的蛋白质和编码DNA
实施例2-慢病毒载体的制备。
239T细胞用含有CAR的CNA家族的载体瞬时转染以产生慢病毒。
293T细胞接种在补充有5%血清的Opti-MEM GlutaMAX培养基中,并在37℃和5%CO2下孵育,使细胞粘附在烧瓶上。
通过在编码CAR的DNA质粒、病毒包装质粒、Lipofectamine 3000试剂(Invitrogen)、P3000增强子试剂和293T细胞的培养基中孵育产生用于六种不同CNA CAR的病毒。
收集上清液并旋转,以去除细胞碎片。然后过滤上清液(0.45μM),通过离心从过滤的上清液中浓缩病毒,并在-80℃下储存。
实施例3-T细胞的分离和转导。
根据制造商的方案,使用Rosettesep人T细胞富集混合物(StemCell)从全血中分离CD3+T细胞。
分离后用CD3/CD28 Dynabead(Thermo Fischer Scientific)刺激分离的CD3+T细胞1小时(37℃,5%CO2)。随后用含有CNA3002、CNA3003、CNA3004、CNA3102、CNA3103或CNA3104 CAR的病毒之一转导受刺激的细胞。使用未生产的样品作为对照。在通过磁分离去除Dynabead之前,将分离的细胞在含有聚凝胺的完整培养基中在37℃、5%CO2下培养。细胞在含有IL-21、IL-7和IL-15的完全培养基中进一步培养。细胞通过定期更换培养基来维持,并定期分裂以维持生长。
1×106个CAR转导的T细胞以及未转染的对照细胞中的每一个,在包括IL-21、IL-7和IL-15的完整培养基中,使用经照射的PBMC细胞和CD3抗体给予第二次刺激。在此期间,在用于体外细胞裂解测定(见下文)之前如上所述对细胞进行喂养和分裂,或冷冻以备后续使用。
如上所述,CAR构建体包括连接到T2A自切割肽的EGFRt。CAR构建体表达后,EGFRt从成熟嵌合抗原受体多肽上裂解,并在细胞表面上单独表达。因此,使用截短的EGFR(EGFRt)的表面表达来测定T细胞中的转导效率。
在转导后第5天(图5A和5B)和转导后第15天(图6A和6B),通过用抗CD3抗体、抗CD4抗体、反CD8抗体和抗EGFR抗体(eBiosciences)染色转导的细胞,并通过流式细胞术分析表面表达,测定CD3细胞的转导效率。
如图5A和5B所示,在转导后第5天,所有六组转导的CD3+T细胞均显示出超过90%的EGFR表达,表明相关CAR的表达。具体而言,用CNA3002 CAR构建体转导的CD3+淋巴细胞中95.3%表达EGFR,用CNA3003 CAR构建物转导的CD3+淋巴细胞中94.7%表达EGFR,用CNA3103 CAR构建体转导的CD3+淋巴细胞中95.5%表达EGFR,用CNA3104 CAR构建物转导的CD3+淋巴细胞中94.0%表达表皮生长因子受体。相比之下,只有0.21%的未转染的CD3+细胞用抗EGFR抗体染色。然而,到第15天(图6A和6B),EGFR的表达已经减少。
实施例4–CAR T细胞效应物功能。
为了评估表达抗Lgr5 CAR的T细胞的活性,进行了体外杀伤试验。
将修饰为表达FF萤光素酶的CHO细胞(对照)和过表达Lgr5并表达FF萤光素酶的CHO细胞用作模型靶细胞。图7显示了用与Alexa Fluor647缀合的抗Lgr5抗体BNC101对CHO细胞(野生型和Lgr5过表达)的染色。简言之,用PBS洗涤2×105CHO细胞,并将BNC101抗体以总体积为50μl PBS中400μg/μl的最终浓度添加到每根管中。CHO细胞在BNC101抗体存在下于4℃孵育30分钟,然后用PBS洗涤、重悬并用流式细胞仪分析。
如图7所示,相对于野生型CHO细胞,过表达Lgr5的CHO细胞清楚地显示出Lgr5表达的升高,表明它们适合作为CNA-CAR构建体的靶细胞。
将上述CHO靶细胞以1×104个细胞的浓度接种在圆底96孔板中的每孔50μl培养基中。每项试验一式三份,并对结果进行平均。使用未转导的T细胞作为对照。
用六种CAR结构中的五种(CNA3002、CNA3004、CNA30102、CNA3103和CNA3104)转导的T细胞以及未转导的(UT)T细胞与目标癌细胞系以10:1、3:1和1:1的T细胞与靶细胞比在37℃和5%CO2下共培养18小时。
根据制造商的说明书,使用基于Bright-GloTM荧光素酶的测定系统来测定共培养物中靶细胞的裂解。
如图8A所示,所有五种测试的抗Lgr5 CAR构建体都显示出过表达Lgr5的CHO靶细胞的显著裂解(大于70%),而未转染的T细胞的裂解率低于20%。相比之下,野生型CHO细胞没有被任何表达CAR的T细胞显著裂解(图8B)。
实施例5-抗Lgr5CART细胞对肿瘤细胞系的活性。
确定了表达CAR的T细胞对模型靶细胞的疗效后,对来自澳大利亚CellBank的以下癌细胞系进行了体外测试:LoVo(转移性结肠上皮细胞癌症)、LIM1215(结肠上皮细胞癌)、Raji(伯基特淋巴瘤)、Namalwa(伯基特淋巴瘤)、OVCAR-3(卵巢癌)、SHY-5Y-SY(神经母细胞瘤)和BE(2)-M17(神经母细胞瘤)。
将各种细胞系(稳定表达荧光素酶报告基因)以1×104个细胞在96孔圆形底板的每孔50μl中铺板。对每个比例进行三次测定,并测试T细胞处理。使用未转化的T细胞作为对照细胞。
将6个CAR-T细胞群和未转导的T细胞分别与靶向癌细胞系以10:1、3:1和1:1的E:T比率共同培养18小时。如上所述,使用基于BrightGlo荧光素酶的分析系统测定CD3 CAR-T细胞对五种不同癌细胞系的细胞溶解潜力。
图9A至9G显示了表达抗Lgr5 CAR的T细胞对上述七种癌细胞系的疗效。
可见,CNA3004(VL-VH长铰链)以及CNA3102(VH-VL短铰链)、CNA3103(VH-VL-中等铰链)和CNA3104(VH-VL-长铰链)均显示出对LoVo、LIM1215细胞、Namalwa、SHY-5Y-SY和Be(2)-M17细胞的有效裂解。此外,CNA3102、CNA3103和CNA3104显示出Raji细胞的有效裂解,特别是在效应细胞与靶细胞(E:T)之比为10比1时,其中CNA103和CNA104最有效。此外,抗Lgr5 CAR T细胞有效地裂解OVCAR3细胞,其中CNA3102、CNA3103和CNA3104在靶向OVCAR3方面最有效。
已经证明抗Lgr5 CAR T细胞在效应细胞与靶细胞的比例为10:1、3:1和1:1时有效裂解LoVo和LIM1215,测试了效应细胞与靶细胞的更小比例(1:3、1:10和1:30)(图10)。
如图10A和10B所示,即使在效应物与靶细胞的比例为1:10时,抗Lgr5 CAR T细胞也能够有效地溶解癌细胞。
实施例6–抗Lgr5CART细胞对抗原发性肿瘤细胞的活性。
确定了抗Lgr5 CAR T细胞可以溶解过度表达Lgr5的CHO细胞和癌细胞系,评估了抗Lgr5 CAR T细胞对原代卵巢癌细胞的疗效。
来自腹水的原发性卵巢癌细胞(n=8)收集自晚期浆液性卵巢癌症患者,获得患者知情同意和RoyalAdelaide医院人类伦理委员会批准。此前已对培养方法进行了描述(Carmon,K.S.等人,PNAS.,2011,108,11452-7和Ricciardelli,C.等人,CancerLett.,2018,421,51-58)。简言之,将腹水中的肿瘤细胞在补充有2mM GlutaMAX(LifeTechnologies)、10%FBS和PSF抗生素的高级RPMI-1640培养基(Life Technologies,Thermo Fisher Scientific,Waltham,MA,美国)中培养。原代卵巢癌细胞系在使用前保存在液氮中。这些细胞被修饰以表达FF萤光素酶。
将分离的原发性卵巢癌细胞1×104接种在50μl培养基中的96孔周形底板孔中,并与不同比例的抗Lgr5 CAR T细胞共同孵育。如上所述进行BrightGlo萤光素酶细胞裂解测定以评估靶细胞的裂解。
如图11所示,抗Lgr5 CAR T细胞以1:1的比率(效应物与靶细胞的比率)有效地溶解原发性卵巢癌细胞。
实施例7–Lrg5阻断抗体抑制CART细胞裂解
为了证实CNA CAR-T细胞以抗原特异性方式裂解靶细胞,使用抗体BNC101阻断Lgr5上的靶表位(见上文)。
如图9和图10所示,LoVo结直肠癌癌细胞可被CNA家族CAR T细胞裂解。因此,为了评估抗原特异性裂解,将LoVo细胞与BNC101抗体孵育4小时,然后用PBS洗涤,随后悬浮在完整的XVIVO培养基中,并以1×104个细胞/孔的速度在96孔板中铺板。
对于阴性对照,同样数量的靶细胞也在PBS或完整的XVIVO培养基中孵育4小时,然后用PBS洗涤并如上所述在完整的XVIVO培养基中铺板。
将四种抗Lgr5 CAR-T细胞(CNA3004、CNA3102、CNA3103和CNA3104)与接种的LoVo细胞共同孵育,以产生10:1、3:1、1:1、1:3、1:10和1:30的效应细胞与靶细胞比率。在添加CART细胞之后,将额外的BNC101抗体(2mg/ml)添加到处理组(抗体预处理组)。然后将平板在37℃和5%CO2下孵育16小时。在16小时孵育完成时,进行BrightGlo萤光素酶细胞裂解测定(如上所述)以评估靶细胞的裂解。
如图12A和12B所示,未与抗体孵育的细胞(即仅与XVIVO培养基或PBS孵育)被CNA家族CAR T细胞(即CNA3004、CNA3102、CNA3103和CNA3104)有效且大范围地杀死,即使效应物与靶标的比例低至1:10和1:30。
相比之下,图12C表明,当靶LoVo细胞与抗Lgr5抗体BNC101预孵育和共孵育时,与对照XVIVO和PBS孵育的靶细胞相比,受试CNA家族CAR T细胞对靶细胞的裂解显著减少。
实施例8–CNA CAR T细胞有效减少体内肿瘤生长
为了评估CNA家族CAR T细胞是否能够有效预防或减少体内癌细胞的生长,我们使用了如下所述的小鼠异种移植癌症模型。
动物
从动物资源中心(Perth,WA)购买5至6周大的雄性免疫功能低下的NOD.Cg-Prkdscid Il2rgtm1Wjl/SzJ(NSG)小鼠。小鼠被安置在无病原体的条件下,12小时的光/暗循环,并被允许适应至少一周。所有实验都是在伦理批准的情况下进行的。
组织培养
在补充有10%热灭活胎牛血清(FCS;Corning)和100U/ml青霉素/链霉素(LifeTechnologies)的RPMI(Gibco)中生长和维持人结直肠癌LoVo细胞系,并在37℃、5%CO2中培养。细胞每2-3天传代一次,方法是用无菌PBS冲洗烧瓶,并在37℃下用PBS(Gibco)中的胰蛋白酶/EDTA解离细胞约4分钟。
CAR-T制造
CD3+Lgr5靶向CAR-T细胞如上所述产生。具体地,在该模型中测试了CNA3004(带长接头的轻链-重链取向)、CNA3102(带短接头的重链-轻链取向),CNA3103(带中等接头的重链-轻链取向)和CNA3104(带长接头的重链-轻链取向)。
异种移植小鼠模型
用重悬于无菌PBS中的2×106个LoVo人结直肠癌细胞将6至7周大的NSG小鼠皮下注射到小腹中。每组由5至7只小鼠组成。
在注射癌细胞三天后,将无菌Dulbecco PBS中总共2×107个活的抗Lgr5 CAR T细胞(特别是CNA3004、CNA3102、CNA3103和CNA3104)静脉注射到小鼠体内。将未转化的T细胞(2×107)作为阴性对照给予小鼠,第二对照组由单独给予PBS的小鼠组成。
从第7天开始,使用数字卡尺每2天测定一次肿瘤大小,将最长距离测定为长度,将垂直距离测定为宽度。肿瘤面积计算为长度×宽度。包括注射、肿瘤测定和监测在内的体内程序以盲测实验进行。
每天监测小鼠的健康状况,当肿瘤溃烂、肿瘤长度等于或大于15mm、肿瘤面积等于或大于100mm2时,或当小鼠表现出包括以下任何一种疾病症状的组合时,用CO2对小鼠实施安乐死:皮毛褶皱、驼背姿态、不愿移动、呼吸困难、体重减轻为初始体重的10%或更多、和/或行为或步态的变化。此外,在长达100天的小鼠中监测存活率和无肿瘤天数。
统计分析
所有统计分析均使用GraphPad Prism进行。使用双因素ANOVA检验和Bonferroni事后检验进行统计。***=p≤0.0001。或图中所示具有显著性值的对数秩分析(Mantel-Cox)。
如图13A所示,所有四种CNA CAR T细胞在第21天统计学上显著减小了肿瘤大小,在施用CNA CART细胞的小鼠中,第21天没有或几乎没有可检测到的肿瘤。因此,CNA CAR T细胞在体内发挥作用,以防止或减少小鼠癌症模型中癌症的形成,表明其在体内具有功能性。
如图14A和14B所示,尽管所有四种CNA CAR T细胞在第21天都显著缩小了肿瘤大小,但在施用CNA-CAR T细胞的小鼠中,第21天没有或几乎没有可检测到的肿瘤,CNA3102和CNA3103在小鼠存活至第100天(图14A)和无肿瘤天数(图14B)方面均优于CNA3104和CNA3004。
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115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 20
<211> 326
<212> PRT
<213> 智人(Homo sapiens)
<400> 20
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ser Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly Lys
325
<210> 21
<211> 377
<212> PRT
<213> 智人(Homo sapiens)
<400> 21
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro
100 105 110
Arg Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg
115 120 125
Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys
130 135 140
Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro
145 150 155 160
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
165 170 175
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
180 185 190
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr
195 200 205
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
210 215 220
Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His
225 230 235 240
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
245 250 255
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
260 265 270
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
275 280 285
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
290 295 300
Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn
305 310 315 320
Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
325 330 335
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile
340 345 350
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln
355 360 365
Lys Ser Leu Ser Leu Ser Pro Gly Lys
370 375
<210> 22
<211> 327
<212> PRT
<213> 智人(Homo sapiens)
<400> 22
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 23
<211> 110
<212> PRT
<213> 智人(Homo sapiens)
<400> 23
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105 110
<210> 24
<211> 107
<212> PRT
<213> 智人(Homo sapiens)
<400> 24
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
1 5 10 15
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 25
<211> 110
<212> PRT
<213> 智人(Homo sapiens)
<400> 25
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105 110
<210> 26
<211> 107
<212> PRT
<213> 智人(Homo sapiens)
<400> 26
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
1 5 10 15
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 27
<211> 110
<212> PRT
<213> 智人(Homo sapiens)
<400> 27
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
100 105 110
<210> 28
<211> 106
<212> PRT
<213> 智人(Homo sapiens)
<400> 28
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
1 5 10 15
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Ile Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
100 105
<210> 29
<211> 110
<212> PRT
<213> 智人(Homo sapiens)
<400> 29
Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105 110
<210> 30
<211> 107
<212> PRT
<213> 智人(Homo sapiens)
<400> 30
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
1 5 10 15
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
100 105
<210> 31
<211> 164
<212> PRT
<213> 智人(Homo sapiens)
<400> 31
Met Lys Trp Lys Ala Leu Phe Thr Ala Ala Ile Leu Gln Ala Gln Leu
1 5 10 15
Pro Ile Thr Glu Ala Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys
20 25 30
Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala
35 40 45
Leu Phe Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
50 55 60
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
65 70 75 80
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
85 90 95
Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
100 105 110
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
115 120 125
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
130 135 140
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
145 150 155 160
Leu Pro Pro Arg
<210> 32
<211> 207
<212> PRT
<213> 智人(Homo sapiens)
<400> 32
Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser
1 5 10 15
Val Gly Val Trp Gly Gln Asp Gly Asn Glu Glu Met Gly Gly Ile Thr
20 25 30
Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr
35 40 45
Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln His Asn Asp Lys
50 55 60
Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp
65 70 75 80
His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr
85 90 95
Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu
100 105 110
Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met Glu Met Asp Val Met
115 120 125
Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile Thr Gly Gly Leu
130 135 140
Leu Leu Leu Val Tyr Tyr Trp Ser Lys Asn Arg Lys Ala Lys Ala Lys
145 150 155 160
Pro Val Thr Arg Gly Ala Gly Ala Gly Gly Arg Gln Arg Gly Gln Asn
165 170 175
Lys Glu Arg Pro Pro Pro Val Pro Asn Pro Asp Tyr Glu Pro Ile Arg
180 185 190
Lys Gly Gln Arg Asp Leu Tyr Ser Gly Leu Asn Gln Arg Arg Ile
195 200 205
<210> 33
<211> 180
<212> PRT
<213> 智人(Homo sapiens)
<400> 33
Met Glu Gln Gly Lys Gly Leu Ala Val Leu Ile Leu Ala Ile Ile Leu
1 5 10 15
Leu Gln Gly Thr Leu Ala Gln Ser Ile Lys Gly Asn His Leu Val Lys
20 25 30
Val Tyr Asp Tyr Gln Glu Asp Gly Ser Val Leu Leu Thr Cys Asp Ala
35 40 45
Glu Ala Lys Asn Ile Thr Trp Phe Lys Asp Gly Lys Met Ile Gly Phe
50 55 60
Leu Thr Glu Asp Lys Lys Lys Trp Asn Leu Gly Ser Asn Ala Lys Asp
65 70 75 80
Pro Arg Gly Met Tyr Gln Cys Lys Gly Ser Gln Asn Lys Ser Lys Pro
85 90 95
Leu Gln Val Tyr Tyr Arg Met Cys Gln Asn Cys Ile Glu Leu Asn Ala
100 105 110
Ala Thr Ile Ser Gly Phe Leu Phe Ala Glu Ile Val Ser Ile Phe Val
115 120 125
Leu Ala Val Gly Val Tyr Phe Ile Ala Gly Gln Asp Gly Val Arg Gln
130 135 140
Ser Arg Ala Ser Asp Lys Gln Thr Leu Leu Pro Asn Asp Gln Leu Tyr
145 150 155 160
Gln Pro Leu Lys Asp Arg Glu Asp Asp Gln Tyr Ser His Leu Gln Gly
165 170 175
Asn Gln Leu Arg
180
<210> 34
<211> 171
<212> PRT
<213> 智人(Homo sapiens)
<400> 34
Met Glu His Ser Thr Phe Leu Ser Gly Leu Val Leu Ala Thr Leu Leu
1 5 10 15
Ser Gln Val Ser Pro Phe Lys Ile Pro Ile Glu Glu Leu Glu Asp Arg
20 25 30
Val Phe Val Asn Cys Asn Thr Ser Ile Thr Trp Val Glu Gly Thr Val
35 40 45
Gly Thr Leu Leu Ser Asp Ile Thr Arg Leu Asp Leu Gly Lys Arg Ile
50 55 60
Leu Asp Pro Arg Gly Ile Tyr Arg Cys Asn Gly Thr Asp Ile Tyr Lys
65 70 75 80
Asp Lys Glu Ser Thr Val Gln Val His Tyr Arg Met Cys Gln Ser Cys
85 90 95
Val Glu Leu Asp Pro Ala Thr Val Ala Gly Ile Ile Val Thr Asp Val
100 105 110
Ile Ala Thr Leu Leu Leu Ala Leu Gly Val Phe Cys Phe Ala Gly His
115 120 125
Glu Thr Gly Arg Leu Ser Gly Ala Ala Asp Thr Gln Ala Leu Leu Arg
130 135 140
Asn Asp Gln Val Tyr Gln Pro Leu Arg Asp Arg Asp Asp Ala Gln Tyr
145 150 155 160
Ser His Leu Gly Gly Asn Trp Ala Arg Asn Lys
165 170
<210> 35
<211> 244
<212> PRT
<213> 智人(Homo sapiens)
<400> 35
Met Asp Thr Glu Ser Asn Arg Arg Ala Asn Leu Ala Leu Pro Gln Glu
1 5 10 15
Pro Ser Ser Val Pro Ala Phe Glu Val Leu Glu Ile Ser Pro Gln Glu
20 25 30
Val Ser Ser Gly Arg Leu Leu Lys Ser Ala Ser Ser Pro Pro Leu His
35 40 45
Thr Trp Leu Thr Val Leu Lys Lys Glu Gln Glu Phe Leu Gly Val Thr
50 55 60
Gln Ile Leu Thr Ala Met Ile Cys Leu Cys Phe Gly Thr Val Val Cys
65 70 75 80
Ser Val Leu Asp Ile Ser His Ile Glu Gly Asp Ile Phe Ser Ser Phe
85 90 95
Lys Ala Gly Tyr Pro Phe Trp Gly Ala Ile Phe Phe Ser Ile Ser Gly
100 105 110
Met Leu Ser Ile Ile Ser Glu Arg Arg Asn Ala Thr Tyr Leu Val Arg
115 120 125
Gly Ser Leu Gly Ala Asn Thr Ala Ser Ser Ile Ala Gly Gly Thr Gly
130 135 140
Ile Thr Ile Leu Ile Ile Asn Leu Lys Lys Ser Leu Ala Tyr Ile His
145 150 155 160
Ile His Ser Cys Gln Lys Phe Phe Glu Thr Lys Cys Phe Met Ala Ser
165 170 175
Phe Ser Thr Glu Ile Val Val Met Met Leu Phe Leu Thr Ile Leu Gly
180 185 190
Leu Gly Ser Ala Val Ser Leu Thr Ile Cys Gly Ala Gly Glu Glu Leu
195 200 205
Lys Gly Asn Lys Val Pro Glu Asp Arg Val Tyr Glu Glu Leu Asn Ile
210 215 220
Tyr Ser Ala Thr Tyr Ser Glu Leu Glu Asp Pro Gly Glu Met Ser Pro
225 230 235 240
Pro Ile Asp Leu
<210> 36
<211> 374
<212> PRT
<213> 智人(Homo sapiens)
<400> 36
Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln
1 5 10 15
Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser
20 25 30
Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu
35 40 45
Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln
50 55 60
Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser
65 70 75 80
Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile
85 90 95
Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser Arg
100 105 110
Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys
115 120 125
Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe
130 135 140
Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile
145 150 155 160
Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg Tyr
165 170 175
Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu Leu Phe Pro Ala Pro
180 185 190
Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu Glu Gly Asn Leu Val
195 200 205
Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln Arg Pro Gly Leu Gln
210 215 220
Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr Leu Arg Gly Arg Asn
225 230 235 240
Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg Arg Glu Asp Ser Gly
245 250 255
Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Gly Asn Val Leu Lys Arg
260 265 270
Ser Pro Glu Leu Glu Leu Gln Val Leu Gly Leu Gln Leu Pro Thr Pro
275 280 285
Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met Phe Leu
290 295 300
Val Asn Thr Val Leu Trp Val Thr Ile Arg Lys Glu Leu Lys Arg Lys
305 310 315 320
Lys Lys Trp Asp Leu Glu Ile Ser Leu Asp Ser Gly His Glu Lys Lys
325 330 335
Val Ile Ser Ser Leu Gln Glu Asp Arg His Leu Glu Glu Glu Leu Lys
340 345 350
Cys Gln Glu Gln Lys Glu Glu Gln Leu Gln Glu Gly Val His Arg Lys
355 360 365
Glu Pro Gln Gly Ala Thr
370
<210> 37
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CAR VH CDR1
<400> 37
Gly Tyr Ser Phe Thr Ala Tyr Trp
1 5
<210> 38
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CAR VH CDR2
<400> 38
Ile Leu Pro Gly Ser Asp Ser Thr
1 5
<210> 39
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CAR VH CDR3
<400> 39
Ala Arg Ser Gly Leu Tyr Gly Ser Ser Gln Tyr
1 5 10
<210> 40
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CAR VL CDR1
<400> 40
Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe
1 5 10
<210> 41
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> CAR VL CDR2
<400> 41
Leu Thr Ser
1
<210> 42
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CAR VL CDR3
<400> 42
Gln Gln Asn Ala Glu Asp Pro Arg Thr
1 5
<210> 43
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> CAR VH CDR1编码DNA
<400> 43
ggctattcat tcactgctta ctgg 24
<210> 44
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> CAR VH CDR2编码DNA
<400> 44
atacttccgg gatccgactc cact 24
<210> 45
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> CAR VH CDR3编码DNA
<400> 45
gcccgcagcg ggctgtacgg gtcaagtcaa tat 33
<210> 46
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> CAR VL CDR1编码DNA
<400> 46
gagtctgtag actcctacgg gaatagtttt 30
<210> 47
<211> 9
<212> DNA
<213> 人工序列
<220>
<223> CAR VL CDR2编码DNA
<400> 47
cttacttcc 9
<210> 48
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> CAR VL CDR3编码DNA
<400> 48
caacagaatg ctgaggaccc acgaact 27
<210> 49
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体可变轻链
<400> 49
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Thr Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Ala
85 90 95
Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 50
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体可变轻链
<400> 50
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ala Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Leu Tyr Gly Ser Ser Gln Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 51
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> CAR DNA构建体可变轻链30xx
<400> 51
gacatagttc tcacccaatc tccggcgtct ctggccgtgt cacccggcca aagagctacc 60
attacgtgta gggcgtcaga gtctgtagac tcctacggga atagttttat gcactggtac 120
cagcagaaac cgggtcagcc gcccaaactt ctgatctatc ttacttccaa tctcgagtct 180
ggcgtgcccg ataggttttc aggatcagga tctggtaccg actttacact gaccattaat 240
ccagtcgaag cgaacgacgc cgcaacatac tattgccaac agaatgctga ggacccacga 300
acttttggag gagggacaaa attggagatc aag 333
<210> 52
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> CAR DNA构建体可变重链30xx
<400> 52
gaggtgcaac tcgttcaaag cggtgccgag gtaaagaagc caggcgagag tctcagaatt 60
agctgtaaag gctcaggcta ttcattcact gcttactgga tcgaatgggt tcgccaggcg 120
ccaggtaagg gcctcgaatg gattggtgag atacttccgg gatccgactc cactaattat 180
aacgaaaaat tcaaagggca cgtgacgatc tccgccgata agagtatctc aactgcgtac 240
ttgcagtggt catcattgaa ggcgagcgac acggccgtgt attattgcgc ccgcagcggg 300
ctgtacgggt caagtcaata ttggggacag gggactcttg tcacggtttc aagc 354
<210> 53
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体结合域CNA30xx-可变轻链-可变重链
<400> 53
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Thr Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Ala
85 90 95
Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly
100 105 110
Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys
115 120 125
Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly
130 135 140
Glu Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ala
145 150 155 160
Tyr Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Ile Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn Tyr Asn Glu Lys
180 185 190
Phe Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala
195 200 205
Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Ser Gly Leu Tyr Gly Ser Ser Gln Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser
245
<210> 54
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体结合域CNA31xx-可变重链-可变轻链
<400> 54
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ala Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Leu Tyr Gly Ser Ser Gln Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly
115 120 125
Ser Gly Glu Gly Ser Thr Lys Gly Asp Ile Val Leu Thr Gln Ser Pro
130 135 140
Ala Ser Leu Ala Val Ser Pro Gly Gln Arg Ala Thr Ile Thr Cys Arg
145 150 155 160
Ala Ser Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe Met His Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Thr Ser
180 185 190
Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asn Asp Ala Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Asn Ala Glu Asp Pro Arg Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Leu Glu Ile Lys
245
<210> 55
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体IgG4突变铰链接头
<400> 55
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 56
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体铰链-CH3接头
<400> 56
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Gly Gln Pro Arg
1 5 10 15
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
20 25 30
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
35 40 45
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
50 55 60
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
65 70 75 80
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
85 90 95
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
100 105 110
Leu Ser Leu Ser Leu Gly Lys
115
<210> 57
<211> 229
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体铰链-CH2-CH3接头
<400> 57
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Asp Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Lys
225
<210> 58
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体CD3ζ信号结构域
<400> 58
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
<210> 59
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体4-1BB信号结构域
<400> 59
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 60
<211> 460
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体CNA3002
<400> 60
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
20 25 30
Val Ser Pro Gly Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Ser Tyr Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Thr Ser Asn Leu Glu Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Thr Ile Asn Pro Val Glu Ala Asn Asp Ala Ala Thr Tyr Tyr Cys
100 105 110
Gln Gln Asn Ala Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
130 135 140
Gly Ser Thr Lys Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val
145 150 155 160
Lys Lys Pro Gly Glu Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr
165 170 175
Ser Phe Thr Ala Tyr Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys
180 185 190
Gly Leu Glu Trp Ile Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn
195 200 205
Tyr Asn Glu Lys Phe Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser
210 215 220
Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr
225 230 235 240
Ala Val Tyr Tyr Cys Ala Arg Ser Gly Leu Tyr Gly Ser Ser Gln Tyr
245 250 255
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Ser Lys Tyr Gly
260 265 270
Pro Pro Cys Pro Pro Cys Pro Met Phe Trp Val Leu Val Val Val Gly
275 280 285
Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile
290 295 300
Phe Trp Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln
305 310 315 320
Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser
325 330 335
Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys
340 345 350
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
355 360 365
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
370 375 380
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
385 390 395 400
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
405 410 415
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
420 425 430
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
435 440 445
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
450 455 460
<210> 61
<211> 567
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体CNA3003
<400> 61
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
20 25 30
Val Ser Pro Gly Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Ser Tyr Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Thr Ser Asn Leu Glu Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Thr Ile Asn Pro Val Glu Ala Asn Asp Ala Ala Thr Tyr Tyr Cys
100 105 110
Gln Gln Asn Ala Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
130 135 140
Gly Ser Thr Lys Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val
145 150 155 160
Lys Lys Pro Gly Glu Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr
165 170 175
Ser Phe Thr Ala Tyr Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys
180 185 190
Gly Leu Glu Trp Ile Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn
195 200 205
Tyr Asn Glu Lys Phe Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser
210 215 220
Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr
225 230 235 240
Ala Val Tyr Tyr Cys Ala Arg Ser Gly Leu Tyr Gly Ser Ser Gln Tyr
245 250 255
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Ser Lys Tyr Gly
260 265 270
Pro Pro Cys Pro Pro Cys Pro Gly Gln Pro Arg Glu Pro Gln Val Tyr
275 280 285
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
290 295 300
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
305 310 315 320
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
325 330 335
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
340 345 350
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
355 360 365
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
370 375 380
Gly Lys Met Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys
385 390 395 400
Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Lys Arg
405 410 415
Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro
420 425 430
Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu
435 440 445
Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala
450 455 460
Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
465 470 475 480
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
485 490 495
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
500 505 510
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
515 520 525
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
530 535 540
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
545 550 555 560
His Met Gln Ala Leu Pro Pro
565
<210> 62
<211> 677
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体CNA3004
<400> 62
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
20 25 30
Val Ser Pro Gly Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Ser Tyr Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Thr Ser Asn Leu Glu Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Thr Ile Asn Pro Val Glu Ala Asn Asp Ala Ala Thr Tyr Tyr Cys
100 105 110
Gln Gln Asn Ala Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
130 135 140
Gly Ser Thr Lys Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val
145 150 155 160
Lys Lys Pro Gly Glu Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr
165 170 175
Ser Phe Thr Ala Tyr Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys
180 185 190
Gly Leu Glu Trp Ile Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn
195 200 205
Tyr Asn Glu Lys Phe Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser
210 215 220
Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr
225 230 235 240
Ala Val Tyr Tyr Cys Ala Arg Ser Gly Leu Tyr Gly Ser Ser Gln Tyr
245 250 255
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Ser Lys Tyr Gly
260 265 270
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Asp Gly Gly Pro Ser
275 280 285
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
290 295 300
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
305 310 315 320
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
325 330 335
Lys Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val
340 345 350
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
355 360 365
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
370 375 380
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
385 390 395 400
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
405 410 415
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
420 425 430
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
435 440 445
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
450 455 460
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
465 470 475 480
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
485 490 495
Met Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser
500 505 510
Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Lys Arg Gly Arg
515 520 525
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
530 535 540
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
545 550 555 560
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
565 570 575
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
580 585 590
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
595 600 605
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
610 615 620
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
625 630 635 640
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
645 650 655
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
660 665 670
Gln Ala Leu Pro Pro
675
<210> 63
<211> 459
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体CNA3102
<400> 63
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe
35 40 45
Thr Ala Tyr Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser
85 90 95
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Gly Leu Tyr Gly Ser Ser Gln Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Ser Gly
130 135 140
Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Asp Ile Val Leu Thr
145 150 155 160
Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly Gln Arg Ala Thr Ile
165 170 175
Thr Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe Met
180 185 190
His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr
195 200 205
Leu Thr Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
210 215 220
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asn
225 230 235 240
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Ala Glu Asp Pro Arg Thr
245 250 255
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Glu Ser Lys Tyr Gly Pro
260 265 270
Pro Cys Pro Pro Cys Pro Met Phe Trp Val Leu Val Val Val Gly Gly
275 280 285
Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe
290 295 300
Trp Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro
305 310 315 320
Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys
325 330 335
Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe
340 345 350
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
355 360 365
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
370 375 380
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys
385 390 395 400
Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala
405 410 415
Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys
420 425 430
Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr
435 440 445
Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
450 455
<210> 64
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体CNA3103
<400> 64
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe
35 40 45
Thr Ala Tyr Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser
85 90 95
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Gly Leu Tyr Gly Ser Ser Gln Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Ser Gly
130 135 140
Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Asp Ile Val Leu Thr
145 150 155 160
Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly Gln Arg Ala Thr Ile
165 170 175
Thr Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe Met
180 185 190
His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr
195 200 205
Leu Thr Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
210 215 220
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asn
225 230 235 240
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Ala Glu Asp Pro Arg Thr
245 250 255
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Glu Ser Lys Tyr Gly Pro
260 265 270
Pro Cys Pro Pro Cys Pro Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
275 280 285
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
290 295 300
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
305 310 315 320
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
325 330 335
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
340 345 350
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
355 360 365
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
370 375 380
Lys Met Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr
385 390 395 400
Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Lys Arg Gly
405 410 415
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
420 425 430
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
435 440 445
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
450 455 460
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
465 470 475 480
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
485 490 495
Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly
500 505 510
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
515 520 525
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
530 535 540
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
545 550 555 560
Met Gln Ala Leu Pro Pro
565
<210> 65
<211> 676
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体CNA3104
<400> 65
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe
35 40 45
Thr Ala Tyr Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser
85 90 95
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Gly Leu Tyr Gly Ser Ser Gln Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Thr Ser Gly Ser Gly
130 135 140
Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Asp Ile Val Leu Thr
145 150 155 160
Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly Gln Arg Ala Thr Ile
165 170 175
Thr Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe Met
180 185 190
His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr
195 200 205
Leu Thr Ser Asn Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
210 215 220
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asn
225 230 235 240
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Ala Glu Asp Pro Arg Thr
245 250 255
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Glu Ser Lys Tyr Gly Pro
260 265 270
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Asp Gly Gly Pro Ser Val
275 280 285
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
290 295 300
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
305 310 315 320
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
325 330 335
Thr Lys Pro Arg Glu Glu Gln Phe Gln Ser Thr Tyr Arg Val Val Ser
340 345 350
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
355 360 365
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
370 375 380
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
385 390 395 400
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
405 410 415
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
420 425 430
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
435 440 445
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
450 455 460
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
465 470 475 480
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Met
485 490 495
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
500 505 510
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Lys Arg Gly Arg Lys
515 520 525
Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr
530 535 540
Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
545 550 555 560
Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro
565 570 575
Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly
580 585 590
Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro
595 600 605
Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr
610 615 620
Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly
625 630 635 640
Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln
645 650 655
Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln
660 665 670
Ala Leu Pro Pro
675
<210> 66
<211> 1380
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体编码DNA CNA3002
<400> 66
atgtccgttc ccactcaagt ccttggactt ttgctgcttt ggctgaccga cgctcgatgc 60
gacatagttc tcacccaatc tccggcgtct ctggccgtgt cacccggcca aagagctacc 120
attacgtgta gggcgtcaga gtctgtagac tcctacggga atagttttat gcactggtac 180
cagcagaaac cgggtcagcc gcccaaactt ctgatctatc ttacttccaa tctcgagtct 240
ggcgtgcccg ataggttttc aggatcagga tctggtaccg actttacact gaccattaat 300
ccagtcgaag cgaacgacgc cgcaacatac tattgccaac agaatgctga ggacccacga 360
acttttggag gagggacaaa attggagatc aagggtagca cgagtggttc tggaaagccg 420
ggtagtggtg aggggagcac gaaaggagag gtgcaactcg ttcaaagcgg tgccgaggta 480
aagaagccag gcgagagtct cagaattagc tgtaaaggct caggctattc attcactgct 540
tactggatcg aatgggttcg ccaggcgcca ggtaagggcc tcgaatggat tggtgagata 600
cttccgggat ccgactccac taattataac gaaaaattca aagggcacgt gacgatctcc 660
gccgataaga gtatctcaac tgcgtacttg cagtggtcat cattgaaggc gagcgacacg 720
gccgtgtatt attgcgcccg cagcgggctg tacgggtcaa gtcaatattg gggacagggg 780
actcttgtca cggtttcaag cgaatccaag tacggaccgc cctgcccccc ttgccctatg 840
ttctgggtgc tggtggtggt cggaggcgtg ctggcctgct acagcctgct ggtcaccgtg 900
gccttcatca tcttttgggt gaaacggggc agaaagaaac tcctgtatat attcaaacaa 960
ccatttatga gaccagtaca aactactcaa gaggaagatg gctgtagctg ccgatttcca 1020
gaagaagaag aaggaggatg tgaactgcgg gtgaagttca gcagaagcgc cgacgcccct 1080
gcctaccagc agggccagaa tcagctgtac aacgagctga acctgggcag aagggaagag 1140
tacgacgtcc tggataagcg gagaggccgg gaccctgaga tgggcggcaa gcctcggcgg 1200
aagaaccccc aggaaggcct gtataacgaa ctgcagaaag acaagatggc cgaggcctac 1260
agcgagatcg gcatgaaggg cgagcggagg cggggcaagg gccacgacgg cctgtatcag 1320
ggcctgtcca ccgccaccaa ggatacctac gacgccctgc acatgcaggc cctgccccca 1380
<210> 67
<211> 1701
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体编码DNA CNA3003
<400> 67
atgtccgttc ccactcaagt ccttggactt ttgctgcttt ggctgaccga cgctcgatgc 60
gacatagttc tcacccaatc tccggcgtct ctggccgtgt cacccggcca aagagctacc 120
attacgtgta gggcgtcaga gtctgtagac tcctacggga atagttttat gcactggtac 180
cagcagaaac cgggtcagcc gcccaaactt ctgatctatc ttacttccaa tctcgagtct 240
ggcgtgcccg ataggttttc aggatcagga tctggtaccg actttacact gaccattaat 300
ccagtcgaag cgaacgacgc cgcaacatac tattgccaac agaatgctga ggacccacga 360
acttttggag gagggacaaa attggagatc aagggtagca cgagtggttc tggaaagccg 420
ggtagtggtg aggggagcac gaaaggagag gtgcaactcg ttcaaagcgg tgccgaggta 480
aagaagccag gcgagagtct cagaattagc tgtaaaggct caggctattc attcactgct 540
tactggatcg aatgggttcg ccaggcgcca ggtaagggcc tcgaatggat tggtgagata 600
cttccgggat ccgactccac taattataac gaaaaattca aagggcacgt gacgatctcc 660
gccgataaga gtatctcaac tgcgtacttg cagtggtcat cattgaaggc gagcgacacg 720
gccgtgtatt attgcgcccg cagcgggctg tacgggtcaa gtcaatattg gggacagggg 780
actcttgtca cggtttcaag cgaatccaag tacggaccgc cctgcccccc ttgccctggc 840
cagcctagag aaccccaggt gtacaccctg cctcccagcc aggaagagat gaccaagaac 900
caggtgtccc tgacctgcct ggtcaaaggc ttctacccca gcgatatcgc cgtggaatgg 960
gagagcaacg gccagcccga gaacaactac aagaccaccc cccctgtgct ggacagcgac 1020
ggcagcttct tcctgtactc ccggctgacc gtggacaaga gccggtggca ggaaggcaac 1080
gtcttcagct gcagcgtgat gcacgaggcc ctgcacaacc actacaccca gaagtccctg 1140
agcctgagcc tgggcaagat gttctgggtg ctggtggtgg tcggaggcgt gctggcctgc 1200
tacagcctgc tggtcaccgt ggccttcatc atcttttggg tgaaacgggg cagaaagaaa 1260
ctcctgtata tattcaaaca accatttatg agaccagtac aaactactca agaggaagat 1320
ggctgtagct gccgatttcc agaagaagaa gaaggaggat gtgaactgcg ggtgaagttc 1380
agcagaagcg ccgacgcccc tgcctaccag cagggccaga atcagctgta caacgagctg 1440
aacctgggca gaagggaaga gtacgacgtc ctggataagc ggagaggccg ggaccctgag 1500
atgggcggca agcctcggcg gaagaacccc caggaaggcc tgtataacga actgcagaaa 1560
gacaagatgg ccgaggccta cagcgagatc ggcatgaagg gcgagcggag gcggggcaag 1620
ggccacgacg gcctgtatca gggcctgtcc accgccacca aggataccta cgacgccctg 1680
cacatgcagg ccctgccccc a 1701
<210> 68
<211> 2031
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体编码DNA CNA3004
<400> 68
atgtccgttc ccactcaagt ccttggactt ttgctgcttt ggctgaccga cgctcgatgc 60
gacatagttc tcacccaatc tccggcgtct ctggccgtgt cacccggcca aagagctacc 120
attacgtgta gggcgtcaga gtctgtagac tcctacggga atagttttat gcactggtac 180
cagcagaaac cgggtcagcc gcccaaactt ctgatctatc ttacttccaa tctcgagtct 240
ggcgtgcccg ataggttttc aggatcagga tctggtaccg actttacact gaccattaat 300
ccagtcgaag cgaacgacgc cgcaacatac tattgccaac agaatgctga ggacccacga 360
acttttggag gagggacaaa attggagatc aagggtagca cgagtggttc tggaaagccg 420
ggtagtggtg aggggagcac gaaaggagag gtgcaactcg ttcaaagcgg tgccgaggta 480
aagaagccag gcgagagtct cagaattagc tgtaaaggct caggctattc attcactgct 540
tactggatcg aatgggttcg ccaggcgcca ggtaagggcc tcgaatggat tggtgagata 600
cttccgggat ccgactccac taattataac gaaaaattca aagggcacgt gacgatctcc 660
gccgataaga gtatctcaac tgcgtacttg cagtggtcat cattgaaggc gagcgacacg 720
gccgtgtatt attgcgcccg cagcgggctg tacgggtcaa gtcaatattg gggacagggg 780
actcttgtca cggtttcaag cgaatccaag tacggaccgc cctgcccccc ttgccctgcc 840
cccgagttcg acggcggacc cagcgtgttc ctgttccccc ccaagcccaa ggacaccctg 900
atgatcagcc ggacccccga ggtgacctgc gtggtggtgg acgtgagcca ggaagatccc 960
gaggtccagt tcaattggta cgtggacggc gtggaagtgc acaacgccaa gaccaagccc 1020
agagaggaac agttccagag cacctaccgg gtggtgtctg tgctgaccgt gctgcaccag 1080
gactggctga acggcaaaga atacaagtgc aaggtgtcca acaagggcct gcccagcagc 1140
atcgaaaaga ccatcagcaa ggccaagggc cagcctcgcg agccccaggt gtacaccctg 1200
cctccctccc aggaagagat gaccaagaac caggtgtccc tgacctgcct ggtgaagggc 1260
ttctacccca gcgacatcgc cgtggagtgg gagagcaacg gccagcctga gaacaactac 1320
aagaccaccc ctcccgtgct ggacagcgac ggcagcttct tcctgtacag ccggctgacc 1380
gtggacaaga gccggtggca ggaaggcaac gtctttagct gcagcgtgat gcacgaggcc 1440
ctgcacaacc actacaccca gaagagcctg agcctgtccc tgggcaagat gttctgggtg 1500
ctggtggtgg tgggcggggt gctggcctgc tacagcctgc tggtgacagt ggccttcatc 1560
atcttttggg tgaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 1620
agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1680
gaaggaggat gtgaactgcg ggtgaagttc agcagaagcg ccgacgcccc tgcctaccag 1740
cagggccaga atcagctgta caacgagctg aacctgggca gaagggaaga gtacgacgtc 1800
ctggataagc ggagaggccg ggaccctgag atgggcggca agcctcggcg gaagaacccc 1860
caggaaggcc tgtataacga actgcagaaa gacaagatgg ccgaggccta cagcgagatc 1920
ggcatgaagg gcgagcggag gcggggcaag ggccacgacg gcctgtatca gggcctgtcc 1980
accgccacca aggataccta cgacgccctg cacatgcagg ccctgccccc a 2031
<210> 69
<211> 1377
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体编码DNA CNA3102
<400> 69
atggaatgga gctgggtttt cctctttttt ctttctgtca ccaccggggt gcattctgaa 60
gtgcagttgg ttcagtccgg tgcggaggta aaaaagccgg gagaatcact tcggattagt 120
tgcaaaggat cagggtatag tttcaccgcg tactggattg agtgggtgag acaggcgcca 180
gggaagggcc ttgaatggat tggtgagatc cttccgggct cagattccac gaactataac 240
gagaaattta agggtcatgt tactatctca gcagataaaa gcatcagtac ggcatatctt 300
cagtggtcca gtctgaaggc cagtgacacg gctgtgtact attgcgcccg ctctggtctc 360
tacggtagtt ctcaatactg gggccagggt acactcgtca ccgtatcttc cgggtccact 420
tcagggtccg gcaagcctgg gagtggtgag ggatccacta agggggatat cgtactgacc 480
caaagtccag catctctggc agtgtcacca gggcaaagag ctactattac ttgtagagct 540
tccgagtccg tggacagcta tggcaactcc ttcatgcatt ggtatcaaca aaaaccagga 600
caaccaccta agttgctcat ctacttgacc agcaacttgg aatcaggggt tccagaccgg 660
ttctctgggt ccggctccgg aacggatttt actcttacca taaacccggt ggaggcaaac 720
gatgctgcaa catactactg tcaacaaaac gccgaggatc cccgaacatt cggcggtgga 780
acgaagttgg aaattaagga gtcaaagtac ggaccgccct gccccccttg ccctatgttc 840
tgggtgctgg tggtggtcgg aggcgtgctg gcctgctaca gcctgctggt caccgtggcc 900
ttcatcatct tttgggtgaa acggggcaga aagaaactcc tgtatatatt caaacaacca 960
tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1020
gaagaagaag gaggatgtga actgcgggtg aagttcagca gaagcgccga cgcccctgcc 1080
taccagcagg gccagaatca gctgtacaac gagctgaacc tgggcagaag ggaagagtac 1140
gacgtcctgg ataagcggag aggccgggac cctgagatgg gcggcaagcc tcggcggaag 1200
aacccccagg aaggcctgta taacgaactg cagaaagaca agatggccga ggcctacagc 1260
gagatcggca tgaagggcga gcggaggcgg ggcaagggcc acgacggcct gtatcagggc 1320
ctgtccaccg ccaccaagga tacctacgac gccctgcaca tgcaggccct gccccca 1377
<210> 70
<211> 1698
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体编码DNA CNA3103
<400> 70
atggaatgga gctgggtttt cctctttttt ctttctgtca ccaccggggt gcattctgaa 60
gtgcagttgg ttcagtccgg tgcggaggta aaaaagccgg gagaatcact tcggattagt 120
tgcaaaggat cagggtatag tttcaccgcg tactggattg agtgggtgag acaggcgcca 180
gggaagggcc ttgaatggat tggtgagatc cttccgggct cagattccac gaactataac 240
gagaaattta agggtcatgt tactatctca gcagataaaa gcatcagtac ggcatatctt 300
cagtggtcca gtctgaaggc cagtgacacg gctgtgtact attgcgcccg ctctggtctc 360
tacggtagtt ctcaatactg gggccagggt acactcgtca ccgtatcttc cgggtccact 420
tcagggtccg gcaagcctgg gagtggtgag ggatccacta agggggatat cgtactgacc 480
caaagtccag catctctggc agtgtcacca gggcaaagag ctactattac ttgtagagct 540
tccgagtccg tggacagcta tggcaactcc ttcatgcatt ggtatcaaca aaaaccagga 600
caaccaccta agttgctcat ctacttgacc agcaacttgg aatcaggggt tccagaccgg 660
ttctctgggt ccggctccgg aacggatttt actcttacca taaacccggt ggaggcaaac 720
gatgctgcaa catactactg tcaacaaaac gccgaggatc cccgaacatt cggcggtgga 780
acgaagttgg aaattaagga gtcaaagtac ggaccgccct gccccccttg ccctggccag 840
cctagagaac cccaggtgta caccctgcct cccagccagg aagagatgac caagaaccag 900
gtgtccctga cctgcctggt caaaggcttc taccccagcg atatcgccgt ggaatgggag 960
agcaacggcc agcccgagaa caactacaag accacccccc ctgtgctgga cagcgacggc 1020
agcttcttcc tgtactcccg gctgaccgtg gacaagagcc ggtggcagga aggcaacgtc 1080
ttcagctgca gcgtgatgca cgaggccctg cacaaccact acacccagaa gtccctgagc 1140
ctgagcctgg gcaagatgtt ctgggtgctg gtggtggtcg gaggcgtgct ggcctgctac 1200
agcctgctgg tcaccgtggc cttcatcatc ttttgggtga aacggggcag aaagaaactc 1260
ctgtatatat tcaaacaacc atttatgaga ccagtacaaa ctactcaaga ggaagatggc 1320
tgtagctgcc gatttccaga agaagaagaa ggaggatgtg aactgcgggt gaagttcagc 1380
agaagcgccg acgcccctgc ctaccagcag ggccagaatc agctgtacaa cgagctgaac 1440
ctgggcagaa gggaagagta cgacgtcctg gataagcgga gaggccggga ccctgagatg 1500
ggcggcaagc ctcggcggaa gaacccccag gaaggcctgt ataacgaact gcagaaagac 1560
aagatggccg aggcctacag cgagatcggc atgaagggcg agcggaggcg gggcaagggc 1620
cacgacggcc tgtatcaggg cctgtccacc gccaccaagg atacctacga cgccctgcac 1680
atgcaggccc tgccccca 1698
<210> 71
<211> 2028
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体编码DNA CNA3104
<400> 71
atggaatgga gctgggtttt cctctttttt ctttctgtca ccaccggggt gcattctgaa 60
gtgcagttgg ttcagtccgg tgcggaggta aaaaagccgg gagaatcact tcggattagt 120
tgcaaaggat cagggtatag tttcaccgcg tactggattg agtgggtgag acaggcgcca 180
gggaagggcc ttgaatggat tggtgagatc cttccgggct cagattccac gaactataac 240
gagaaattta agggtcatgt tactatctca gcagataaaa gcatcagtac ggcatatctt 300
cagtggtcca gtctgaaggc cagtgacacg gctgtgtact attgcgcccg ctctggtctc 360
tacggtagtt ctcaatactg gggccagggt acactcgtca ccgtatcttc cgggtccact 420
tcagggtccg gcaagcctgg gagtggtgag ggatccacta agggggatat cgtactgacc 480
caaagtccag catctctggc agtgtcacca gggcaaagag ctactattac ttgtagagct 540
tccgagtccg tggacagcta tggcaactcc ttcatgcatt ggtatcaaca aaaaccagga 600
caaccaccta agttgctcat ctacttgacc agcaacttgg aatcaggggt tccagaccgg 660
ttctctgggt ccggctccgg aacggatttt actcttacca taaacccggt ggaggcaaac 720
gatgctgcaa catactactg tcaacaaaac gccgaggatc cccgaacatt cggcggtgga 780
acgaagttgg aaattaagga gtcaaagtac ggaccgccct gccccccttg ccctgccccc 840
gagttcgacg gcggacccag cgtgttcctg ttccccccca agcccaagga caccctgatg 900
atcagccgga cccccgaggt gacctgcgtg gtggtggacg tgagccagga agatcccgag 960
gtccagttca attggtacgt ggacggcgtg gaagtgcaca acgccaagac caagcccaga 1020
gaggaacagt tccagagcac ctaccgggtg gtgtctgtgc tgaccgtgct gcaccaggac 1080
tggctgaacg gcaaagaata caagtgcaag gtgtccaaca agggcctgcc cagcagcatc 1140
gaaaagacca tcagcaaggc caagggccag cctcgcgagc cccaggtgta caccctgcct 1200
ccctcccagg aagagatgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1260
taccccagcg acatcgccgt ggagtgggag agcaacggcc agcctgagaa caactacaag 1320
accacccctc ccgtgctgga cagcgacggc agcttcttcc tgtacagccg gctgaccgtg 1380
gacaagagcc ggtggcagga aggcaacgtc tttagctgca gcgtgatgca cgaggccctg 1440
cacaaccact acacccagaa gagcctgagc ctgtccctgg gcaagatgtt ctgggtgctg 1500
gtggtggtgg gcggggtgct ggcctgctac agcctgctgg tgacagtggc cttcatcatc 1560
ttttgggtga aacggggcag aaagaaactc ctgtatatat tcaaacaacc atttatgaga 1620
ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga agaagaagaa 1680
ggaggatgtg aactgcgggt gaagttcagc agaagcgccg acgcccctgc ctaccagcag 1740
ggccagaatc agctgtacaa cgagctgaac ctgggcagaa gggaagagta cgacgtcctg 1800
gataagcgga gaggccggga ccctgagatg ggcggcaagc ctcggcggaa gaacccccag 1860
gaaggcctgt ataacgaact gcagaaagac aagatggccg aggcctacag cgagatcggc 1920
atgaagggcg agcggaggcg gggcaagggc cacgacggcc tgtatcaggg cctgtccacc 1980
gccaccaagg atacctacga cgccctgcac atgcaggccc tgccccca 2028
<210> 72
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体CD28跨膜结构域
<400> 72
Met Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser
1 5 10 15
Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 73
<211> 741
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体ScFv CNA30xx -可变轻链-可变重链DNA
<400> 73
gacatagttc tcacccaatc tccggcgtct ctggccgtgt cacccggcca aagagctacc 60
attacgtgta gggcgtcaga gtctgtagac tcctacggga atagttttat gcactggtac 120
cagcagaaac cgggtcagcc gcccaaactt ctgatctatc ttacttccaa tctcgagtct 180
ggcgtgcccg ataggttttc aggatcagga tctggtaccg actttacact gaccattaat 240
ccagtcgaag cgaacgacgc cgcaacatac tattgccaac agaatgctga ggacccacga 300
acttttggag gagggacaaa attggagatc aagggtagca cgagtggttc tggaaagccg 360
ggtagtggtg aggggagcac gaaaggagag gtgcaactcg ttcaaagcgg tgccgaggta 420
aagaagccag gcgagagtct cagaattagc tgtaaaggct caggctattc attcactgct 480
tactggatcg aatgggttcg ccaggcgcca ggtaagggcc tcgaatggat tggtgagata 540
cttccgggat ccgactccac taattataac gaaaaattca aagggcacgt gacgatctcc 600
gccgataaga gtatctcaac tgcgtacttg cagtggtcat cattgaaggc gagcgacacg 660
gccgtgtatt attgcgcccg cagcgggctg tacgggtcaa gtcaatattg gggacagggg 720
actcttgtca cggtttcaag c 741
<210> 74
<211> 741
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体ScFv CNA31xx - 可变重链-可变轻链DNA
<400> 74
gaagtgcagt tggttcagtc cggtgcggag gtaaaaaagc cgggagaatc acttcggatt 60
agttgcaaag gatcagggta tagtttcacc gcgtactgga ttgagtgggt gagacaggcg 120
ccagggaagg gccttgaatg gattggtgag atccttccgg gctcagattc cacgaactat 180
aacgagaaat ttaagggtca tgttactatc tcagcagata aaagcatcag tacggcatat 240
cttcagtggt ccagtctgaa ggccagtgac acggctgtgt actattgcgc ccgctctggt 300
ctctacggta gttctcaata ctggggccag ggtacactcg tcaccgtatc ttccgggtcc 360
acttcagggt ccggcaagcc tgggagtggt gagggatcca ctaaggggga tatcgtactg 420
acccaaagtc cagcatctct ggcagtgtca ccagggcaaa gagctactat tacttgtaga 480
gcttccgagt ccgtggacag ctatggcaac tccttcatgc attggtatca acaaaaacca 540
ggacaaccac ctaagttgct catctacttg accagcaact tggaatcagg ggttccagac 600
cggttctctg ggtccggctc cggaacggat tttactctta ccataaaccc ggtggaggca 660
aacgatgctg caacatacta ctgtcaacaa aacgccgagg atccccgaac attcggcggt 720
ggaacgaagt tggaaattaa g 741
<210> 75
<211> 36
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体CNA30xx -IgG4突变铰链接头DNA
<400> 75
gaatccaagt acggaccgcc ctgcccccct tgccct 36
<210> 76
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体CNA30xx -铰链-CH3接头DNA
<400> 76
gaatccaagt acggaccgcc ctgcccccct tgccctggcc agcctagaga accccaggtg 60
tacaccctgc ctcccagcca ggaagagatg accaagaacc aggtgtccct gacctgcctg 120
gtcaaaggct tctaccccag cgatatcgcc gtggaatggg agagcaacgg ccagcccgag 180
aacaactaca agaccacccc ccctgtgctg gacagcgacg gcagcttctt cctgtactcc 240
cggctgaccg tggacaagag ccggtggcag gaaggcaacg tcttcagctg cagcgtgatg 300
cacgaggccc tgcacaacca ctacacccag aagtccctga gcctgagcct gggcaag 357
<210> 77
<211> 687
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体CNA30xx -铰链-CH2-CH3接头DNA
<400> 77
gaatccaagt acggaccgcc ctgcccccct tgccctgccc ccgagttcga cggcggaccc 60
agcgtgttcc tgttcccccc caagcccaag gacaccctga tgatcagccg gacccccgag 120
gtgacctgcg tggtggtgga cgtgagccag gaagatcccg aggtccagtt caattggtac 180
gtggacggcg tggaagtgca caacgccaag accaagccca gagaggaaca gttccagagc 240
acctaccggg tggtgtctgt gctgaccgtg ctgcaccagg actggctgaa cggcaaagaa 300
tacaagtgca aggtgtccaa caagggcctg cccagcagca tcgaaaagac catcagcaag 360
gccaagggcc agcctcgcga gccccaggtg tacaccctgc ctccctccca ggaagagatg 420
accaagaacc aggtgtccct gacctgcctg gtgaagggct tctaccccag cgacatcgcc 480
gtggagtggg agagcaacgg ccagcctgag aacaactaca agaccacccc tcccgtgctg 540
gacagcgacg gcagcttctt cctgtacagc cggctgaccg tggacaagag ccggtggcag 600
gaaggcaacg tctttagctg cagcgtgatg cacgaggccc tgcacaacca ctacacccag 660
aagagcctga gcctgtccct gggcaag 687
<210> 78
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体CD3ζ信号结构域DNA
<400> 78
cgggtgaagt tcagcagaag cgccgacgcc cctgcctacc agcagggcca gaatcagctg 60
tacaacgagc tgaacctggg cagaagggaa gagtacgacg tcctggataa gcggagaggc 120
cgggaccctg agatgggcgg caagcctcgg cggaagaacc cccaggaagg cctgtataac 180
gaactgcaga aagacaagat ggccgaggcc tacagcgaga tcggcatgaa gggcgagcgg 240
aggcggggca agggccacga cggcctgtat cagggcctgt ccaccgccac caaggatacc 300
tacgacgccc tgcacatgca ggccctgccc cca 333
<210> 79
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体T2A自切割位点
<400> 79
Arg Leu Glu Gly Gly Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly
1 5 10 15
Asp Val Glu Glu Asn Pro Gly Pro Arg
20 25
<210> 80
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体T2A自切割位点DNA
<400> 80
cgggtgaagt tcagcagaag cgccgacgcc cctgcctacc agcagggcca gaatcagctg 60
tacaacgagc tgaacctggg cagaagggaa gagtacgacg tcctggataa gcggagaggc 120
cgggaccctg agatgggcgg caagcctcgg cggaagaacc cccaggaagg cctgtataac 180
gaactgcaga aagacaagat ggccgaggcc tacagcgaga tcggcatgaa gggcgagcgg 240
aggcggggca agggccacga cggcctgtat cagggcctgt ccaccgccac caaggatacc 300
tacgacgccc tgcacatgca ggccctgccc cca 333
<210> 81
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体EGFRt
<400> 81
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Arg Lys Val Cys Asn Gly Ile Gly Ile Gly
20 25 30
Glu Phe Lys Asp Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe
35 40 45
Lys Asn Cys Thr Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala
50 55 60
Phe Arg Gly Asp Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu
65 70 75 80
Leu Asp Ile Leu Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile
85 90 95
Gln Ala Trp Pro Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu
100 105 110
Glu Ile Ile Arg Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala
115 120 125
Val Val Ser Leu Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu
130 135 140
Ile Ser Asp Gly Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr
145 150 155 160
Ala Asn Thr Ile Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys
165 170 175
Thr Lys Ile Ile Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly
180 185 190
Gln Val Cys His Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu
195 200 205
Pro Arg Asp Cys Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys
210 215 220
Val Asp Lys Cys Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu
225 230 235 240
Asn Ser Glu Cys Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met
245 250 255
Asn Ile Thr Cys Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala
260 265 270
His Tyr Ile Asp Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val
275 280 285
Met Gly Glu Asn Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His
290 295 300
Val Cys His Leu Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro
305 310 315 320
Gly Leu Glu Gly Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala
325 330 335
Thr Gly Met Val Gly Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly
340 345 350
Ile Gly Leu Phe Met
355
<210> 82
<211> 1074
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体EGFRt DNA
<400> 82
atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccagc attcctcctg 60
atcccacgca aagtgtgtaa cggaataggt attggtgaat ttaaagactc actctccata 120
aatgctacga atattaaaca cttcaaaaac tgcacctcca tcagtggcga tctccacatc 180
ctgccggtgg catttagggg tgactccttc acacatactc ctcctctgga tccacaggaa 240
ctggatattc tgaaaaccgt aaaggaaatc acagggtttt tgctgattca ggcttggcct 300
gaaaacagga cggacctcca tgcctttgag aacctagaaa tcatacgcgg caggaccaag 360
caacatggtc agttttctct tgcagtcgtc agcctgaaca taacatcctt gggattacgc 420
tccctcaagg agataagtga tggagatgtg ataatttcag gaaacaaaaa tttgtgctat 480
gcaaatacaa taaactggaa aaaactgttt gggacctccg gtcagaaaac caaaattata 540
agcaacagag gtgaaaacag ctgcaaggcc acaggccagg tctgccatgc cttgtgctcc 600
cccgagggct gctggggccc ggagcccagg gactgcgtct cttgccggaa tgtcagccga 660
ggcagggaat gcgtggacaa gtgcaacctt ctggagggtg agccaaggga gtttgtggag 720
aactctgagt gcatacagtg ccacccagag tgcctgcctc aggccatgaa catcacctgc 780
acaggacggg gaccagacaa ctgtatccag tgtgcccact acattgacgg cccccactgc 840
gtcaagacct gcccggcagg agtcatggga gaaaacaaca ccctggtctg gaagtacgca 900
gacgccggcc atgtgtgcca cctgtgccat ccaaactgca cctacggatg cactgggcca 960
ggtcttgaag gctgtccaac gaatgggcct aagatcccgt ccatcgccac tgggatggtg 1020
ggggccctcc tcttgctgct ggtggtggcc ctggggatcg gcctcttcat gtga 1074
<210> 83
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体IgG4 CH3区
<400> 83
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
1 5 10 15
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
100 105
<210> 84
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体IgG4 CH2区
<400> 84
Ala Pro Glu Phe Asp Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Phe Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105 110
<210> 85
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> CAR构建体轻链前导序列
<400> 85
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys
20
<210> 86
<211> 60
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体轻链前导序列DNA
<400> 86
atgtccgttc ccactcaagt ccttggactt ttgctgcttt ggctgaccga cgctcgatgc 60
<210> 87
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> CAR Construct heavy chain leader sequence
<400> 87
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser
<210> 88
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体重链前导序列DNA
<400> 88
atggaatgga gctgggtttt cctctttttt ctttctgtca ccaccggggt gcattct 57
<210> 89
<211> 36
<212> DNA
<213> 人工序列
<220>
<223> CNA31xx -IgG4突变铰链接头DNA
<400> 89
gagtcaaagt acggaccgcc ctgcccccct tgccct 36
<210> 90
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体CNA31xx -铰链-CH3接头DNA
<400> 90
gagtcaaagt acggaccgcc ctgcccccct tgccctggcc agcctagaga accccaggtg 60
tacaccctgc ctcccagcca ggaagagatg accaagaacc aggtgtccct gacctgcctg 120
gtcaaaggct tctaccccag cgatatcgcc gtggaatggg agagcaacgg ccagcccgag 180
aacaactaca agaccacccc ccctgtgctg gacagcgacg gcagcttctt cctgtactcc 240
cggctgaccg tggacaagag ccggtggcag gaaggcaacg tcttcagctg cagcgtgatg 300
cacgaggccc tgcacaacca ctacacccag aagtccctga gcctgagcct gggcaag 357
<210> 91
<211> 687
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体CNA31xx -铰链-CH2-CH3接头DNA
<400> 91
gagtcaaagt acggaccgcc ctgcccccct tgccctgccc ccgagttcga cggcggaccc 60
agcgtgttcc tgttcccccc caagcccaag gacaccctga tgatcagccg gacccccgag 120
gtgacctgcg tggtggtgga cgtgagccag gaagatcccg aggtccagtt caattggtac 180
gtggacggcg tggaagtgca caacgccaag accaagccca gagaggaaca gttccagagc 240
acctaccggg tggtgtctgt gctgaccgtg ctgcaccagg actggctgaa cggcaaagaa 300
tacaagtgca aggtgtccaa caagggcctg cccagcagca tcgaaaagac catcagcaag 360
gccaagggcc agcctcgcga gccccaggtg tacaccctgc ctccctccca ggaagagatg 420
accaagaacc aggtgtccct gacctgcctg gtgaagggct tctaccccag cgacatcgcc 480
gtggagtggg agagcaacgg ccagcctgag aacaactaca agaccacccc tcccgtgctg 540
gacagcgacg gcagcttctt cctgtacagc cggctgaccg tggacaagag ccggtggcag 600
gaaggcaacg tctttagctg cagcgtgatg cacgaggccc tgcacaacca ctacacccag 660
aagagcctga gcctgtccct gggcaag 687
<210> 92
<211> 84
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体xx02/03 - CD28跨膜结构域DNA
<400> 92
atgttctggg tgctggtggt ggtcggaggc gtgctggcct gctacagcct gctggtcacc 60
gtggccttca tcatcttttg ggtg 84
<210> 93
<211> 84
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体xx04 - CD28跨膜结构域DNA
<400> 93
atgttctggg tgctggtggt ggtgggcggg gtgctggcct gctacagcct gctggtgaca 60
gtggccttca tcatcttttg ggtg 84
<210> 94
<211> 126
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体4-1BB信号结构域DNA
<400> 94
aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 60
actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120
gaactg 126
<210> 95
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 抗体18G7.1重链CDR1
<400> 95
Gly Tyr Thr Phe Ser Gly Tyr Trp
1 5
<210> 96
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗体18G7H6A1重链CDR3
<400> 96
Ala Arg Ser Gly Tyr Tyr Gly Ser Ser Gln Tyr
1 5 10
<210> 97
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗体18G7.1轻链CDR3
<400> 97
Gln Gln Asn Asn Glu Asp Pro Arg Thr
1 5
<210> 98
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> Scfv融合结构域
<400> 98
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
1 5 10 15
Lys Gly
<210> 99
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段Ab 18G7.1重链
<400> 99
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Thr Gly Tyr Thr Phe Ser Gly Tyr
20 25 30
Trp Ile Glu Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Phe Thr Ala Asp Thr Ser Ser Asn Thr Val Tyr
65 70 75 80
Met Gln Phe Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Tyr Tyr Gly Ser Ser Gln Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 100
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段Ab 18G7.1轻链
<400> 100
Asn Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Thr Ser Asn Leu Glu Ser 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 Ala Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 101
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段18G7H6A1重链
<400> 101
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ala Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Tyr Tyr Gly Ser Ser Gln Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120
<210> 102
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段18G7H6A1轻链
<400> 102
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Thr Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Ala
85 90 95
Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 103
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体可变重链31xx DNA
<400> 103
gatatcgtac tgacccaaag tccagcatct ctggcagtgt caccagggca aagagctact 60
attacttgta gagcttccga gtccgtggac agctatggca actccttcat gcattggtat 120
caacaaaaac caggacaacc acctaagttg ctcatctact tgaccagcaa cttggaatca 180
ggggttccag accggttctc tgggtccggc tccggaacgg attttactct taccataaac 240
ccggtggagg caaacgatgc tgcaacatac tactgtcaac aaaacgccga ggatccccga 300
acattcggcg gtggaacgaa gttggaaatt aag 333
<210> 104
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> CAR构建体可变重链31xx DNA
<400> 104
gaagtgcagt tggttcagtc cggtgcggag gtaaaaaagc cgggagaatc acttcggatt 60
agttgcaaag gatcagggta tagtttcacc gcgtactgga ttgagtgggt gagacaggcg 120
ccagggaagg gccttgaatg gattggtgag atccttccgg gctcagattc cacgaactat 180
aacgagaaat ttaagggtca tgttactatc tcagcagata aaagcatcag tacggcatat 240
cttcagtggt ccagtctgaa ggccagtgac acggctgtgt actattgcgc ccgctctggt 300
ctctacggta gttctcaata ctggggccag ggtacactcg tcaccgtatc ttcc 354
Claims (70)
1.一种嵌合抗原受体,包含:
胞外结构域,其包括识别Lgr5的结合域;
跨膜结构域;和
激活细胞功能的胞内信号结构域。
2.根据权利要求1所述的嵌合抗原受体,其中所述结合域识别Lgr5凸表面上的表位。
3.根据权利要求1或权利要求2所述的嵌合体抗原受体,其中所述结合区识别Lgr5的富含亮氨酸重复序列6至9位内的表位。
4.根据权利要求1至3中任一项所述的嵌合抗原受体,其中所述结合域包括结合Lgr5的抗体的可变重链或可变重链的功能变体。
5.根据权利要求1至4中任一项所述的嵌合抗原受体,其中所述结合域包括结合Lgr5的抗体的可变轻链或所述可变轻链的功能变体。
6.根据权利要求1至5中任一项所述的嵌合抗原受体,其中所述结合域包括抗体18G7.1、18G7H6A1或18G7H6A3的结合部分或其功能变体。
7.根据权利要求1至6中任一项所述的嵌合抗原受体,其中所述结合域包含:
重链CDR1,其具有SEQ ID No.37中所示氨基酸序列或具有SEQ IDNo.37中所示的具有至多2个氨基酸修饰的氨基酸序列,
重链CDR2,其具有SEQ ID No.38中所示氨基酸序列或带有SEQ IDNo.38中所示的具有至多2个氨基酸修饰的氨基酸序列,和
重链CDR3,其具有SEQ ID No.39中所示氨基酸序列,或具有SEQ IDNo.39中所示的具有至多2个氨基酸修饰的氨基酸序列。
8.根据权利要求1至7中任一项所述的嵌合抗原受体,其中所述结合域包括:
轻链CDR1,其具有SEQ ID No.40所示氨基酸序列或具有SEQ IDNo.40所示的具有至多2个氨基酸修饰的氨基酸序列,
轻链CDR1,其具有SEQ ID No.41所示氨基酸序列或具有SEQ IDNo.41所示的具有至多2个氨基酸修饰的氨基酸序列,和
轻链CDR3,其具有SEQ ID No.42中所示氨基酸序列或具有SEQ IDNo.42中所示的具有至多2个氨基酸修饰的氨基酸序列。
9.根据权利要求1至8中任一项所述的嵌合抗原受体,其中所述结合域包含与单结构域抗体(sdAb)相同的序列,所述sdAb包含与结合Lgr5的抗体的VH或VL链相同的序列,或包含与衍生自结合Lgr5的抗体的抗原结合片段(Fab)相同的序列,或包含与单链可变片段(scFv)相同的序列,所述scFv包含结合Lgr5的抗体的VH和VL区。
10.根据权利要求1至6中任一项所述的嵌合抗原受体,其中所述结合域包括与可变轻(VL)链的N端连接的可变重(VH)链的C端,
其中所述VH链包括:具有SEQ ID No.37序列的CDR1、具有SEQ IDNo.38序列的CDR2和具有SEQ ID No.39序列的CDR3,
VL链包括:具有SEQ ID No.40序列的CDR1、具有SEQ ID No.41序列的CDR2和具有SEQID No.42序列的CDR3,并且
其中每个CDR可以具有至多2个氨基酸修饰。
11.根据权利要求1至6中任一项所述的嵌合抗原受体,其中所述单链可变片段包括连接到所述可变轻(VH)链的N端的所述可变重(VL)链C端,
其中所述VL链包括:具有SEQ ID No.40序列的CDR1、具有SEQ IDNo.41序列的CDR2和具有SEQ ID No.42序列的CDR3,
VH链包括:具有SEQ ID No.37序列的CDR1、具有SEQ ID No.38序列的CDR2和具有SEQID No.39序列的CDR3,并且
其中每个CDR可以具有至多2个氨基酸修饰。
12.根据权利要求1至3中任一项所述的嵌合抗原受体,其中所述结合域包含SEQ IDNo.49和/或SEQ ID No.50,或其与SEQ ID No.49或50具有至少90%序列同一性的变体。
13.根据权利要求1至3中任一项所述的嵌合抗原受体,其中所述结合域包含SEQ IDNo.53或SEQ ID No.54,或其与SEQ ID No.53或54具有至少90%的序列同一性的变体。
14.根据权利要求1至13中任一项所述的嵌合抗原受体,其中所述胞外结构域包含连接所述结合域和所述跨膜结构域的接头结构域。
15.根据权利要求14所述的嵌合抗原受体,其中所述接头结构域的长度为至少12个氨基酸,或长度为至少约12个氨基酸。
16.根据权利要求14所述的嵌合抗原受体,其中所述接头结构域的长度为至少119个氨基酸,或长度为至少约119个氨基酸。
17.根据权利要求14所述的嵌合抗原受体,其中所述接头结构域的长度为至少229个氨基酸,或长度为至少约229个氨基酸。
18.根据权利要求15所述的嵌合抗原受体,其中所述接头结构域的长度为至多119个氨基酸,或至多约119个氨基酸。
19.根据权利要求16所述的嵌合抗原受体,其中所述接头结构域的长度为至多229个氨基酸,或至多约229个氨基酸。
20.根据权利要求14至19所述的嵌合抗原受体,其中所述接头结构域包含与IgG4铰链的序列相同的氨基酸序列,或包含与IgG4铰链具有至多2个氨基酸修饰的修饰版本相同的序列。
21.根据权利要求14所述的嵌合抗原受体,其中所述接头结构域包含选自SEQ IDNo.55、SEQ ID No.56或SEQ ID No.57的序列或其功能变体,或由它们组成。
22.根据权利要求11所述的嵌合抗原受体,其中所述胞外结构域包含长度大于12个氨基酸、长度至少119个氨基酸、长度大于119个氨基酸或长度至少229个氨基酸的接头,并且所述接头将所述结合域连接至所述跨膜结构域,并且其中所述接头结构域连接至VH结构域的C端。
23.根据权利要求1至22中任一项所述的嵌合抗原受体,其中所述胞内信号结构域包含与具有与活化受体的信号传导部分或其功能变体相同的氨基酸序列的部分。
24.根据权利要求23所述的嵌合抗原受体,其中所述活化受体是所述CD3共受体复合物的成员。
25.根据权利要求23所述的嵌合抗原受体,其中所述活化受体是CD3-ζ(CD3 zeta)。
26.根据权利要求1-25中任一项所述的嵌合抗原受体,其中所述信号结构域包含与具有与共刺激受体的信号传导部分相同的氨基酸序列的部分。
27.根据权利要求26所述的嵌合抗原受体,其中所述共刺激受体选自CD27、CD28、CD30、CD40、DAP10、OX40、4-1BB(CD137)和ICOS。
28.根据权利要求26所述的嵌合抗原受体,其中所述共刺激受体是4-1BB(CD137)。
29.根据权利要求1至28中任一项所述的嵌合抗原受体,其中所述胞内结构域包含与CD3-ζ(CD3zeta)的至少一个信号传导部分相同的氨基酸序列和与4-1BB的信号传导部分相同的氨基酸序列。
30.根据权利要求1至22中任一项所述的嵌合抗原受体,其中所述胞内结构域包含SEQID No.58和/或SEQ ID No.59。
31.一种嵌合抗原受体,所述嵌合抗原受体包含选自SEQ ID No.60、61、62、63、64和65的氨基酸序列或其功能变体,或由它们组成。
32.嵌合抗原受体,所述嵌合抗原受体包含选自SEQ ID No.62、63、64和65的氨基酸序列或其功能变体,或由它们组成。
33.一种核酸分子,包括编码权利要求1-32中任一项所述的嵌合抗原受体的核苷酸序列。
34.一种核酸构建体,包含权利要求33所述的核酸分子和启动子。
35.根据权利要求34所述的核酸构建体,其中所述启动子选自:猿猴病毒40(SV40)、巨细胞病毒(CMV)、P-肌动蛋白、泛素C(UBC)、延伸因子-1α(EF1A)、磷酸甘油酸激酶(PGK)和CMV早期增强子/鸡β肌动蛋白(CAGG)。
36.根据权利要求34所述的核酸构建体,其中所述启动子是CMV启动子。
37.根据权利要求34至权利要求36中任一项所述的核酸构建体,其中所述核酸构建体是载体。
38.根据权利要求33的核酸分子或权利要求34至37中任一项的核酸构建体,其用于制备遗传修饰的细胞。
39.权利要求33所述的核酸分子或权利要求34至37中任一项所述的核酸构建体在制备遗传修饰细胞中的用途。
40.一种病毒载体,包括权利要求33所述的核酸分子或权利要求34至37中任一项所述的核酸构建体。
41.根据权利要求40的病毒载体,其中所述病毒载体是慢病毒。
42.根据权利要求40或权利要求41所述的病毒载体,其用于遗传修饰细胞的制备方法。
43.权利要求40或权利要求41所述的病毒载体在遗传修饰细胞的制备方法中的用途。
44.根据权利要求40或41所述的病毒载体,其用于制备用于治疗与Lgr5表达相关的癌症或用于杀死表达或异常表达Lgr5的细胞的药物。
45.根据权利要求40或41所述的病毒载体在制备用于治疗与Lgr5表达相关的癌症或用于杀死表达或异常表达Lgr5的细胞的药物中的用途。
46.一种细胞,包含权利要求1-32中任一项所述的嵌合抗原受体。
47.一种遗传修饰的细胞,所述细胞包含权利要求33所述的核酸分子、或权利要求34至37中任一项所述的核酸构建体、或所述核酸分子或构建体的基因组整合形式。
48.根据权利要求46所述的细胞或权利要求47所述的遗传修饰的细胞,其中所述细胞是白细胞、外周血单核细胞(PBMC)、淋巴细胞、T细胞、自然杀伤细胞或自然杀伤T细胞。
49.根据权利要求48所述的细胞或遗传修饰的细胞,其中所述T细胞是CD4+T细胞。
50.根据权利要求48所述的细胞或遗传修饰的细胞,其中所述T细胞是CD8+T细胞。
51.一种杀死表达或异常表达Lgr5的靶细胞的方法,所述方法包括将所述靶细胞暴露于表达嵌合抗原受体的细胞或遗传修饰的细胞,其中所述嵌合抗原受体靶向Lgr5。
52.根据权利要求51所述的方法,其中所述细胞或遗传修饰的细胞包含根据权利要求1-32中任一项所述的嵌合抗原受体。
53.根据权利要求51所述的方法,其中所述细胞或所述遗传修饰的细胞是权利要求46至50中任一项所述的细胞或遗传修饰的细胞。
54.根据权利要求51至53中任一项所述的方法,其中所述细胞或遗传修饰的细胞是所述靶细胞的自体。
55.根据权利要求51至53中任一项所述的方法,其中所述细胞或遗传修饰的细胞是所述靶细胞的同种异体。
56.根据权利要求51至55中任一项所述的方法,其中所述靶细胞在受试者体内。
57.根据权利要求51至56中任一项所述的方法,其中所述靶细胞为癌细胞。
58.根据权利要求57所述的方法,其中所述癌细胞选自以下一种或多种:乳腺癌细胞、胰腺癌细胞、前列腺癌细胞、结肠癌细胞、结直肠癌细胞、胃肠道癌细胞、肺癌细胞(NSCLC)、淋巴瘤癌细胞、卵巢癌细胞或B细胞淋巴瘤癌细胞。
59.根据权利要求57所述的方法,其中所述癌细胞选自:结肠癌细胞、结肠癌细胞或胃肠道癌细胞。
60.根据权利要求51至59中任一项所述的方法,其进一步包括在将所述靶细胞暴露于表达嵌合抗原受体的细胞或遗传修饰的细胞之前分析所述靶细胞上Lgr5的表面表达。
61.根据权利要求60所述的方法,其中靶细胞是癌细胞,将靶细胞上Lgr5的表面表达与可比较的非癌细胞进行比较,以确定异常表达。
62.一种预防或治疗患有与Lgr5表达相关的癌症的患者的方法,所述方法包括将患者暴露于表达嵌合抗原受体的细胞,其中嵌合抗原受体以Lgr5为靶点。
63.根据权利要求62所述的方法,其中给所述患者施用根据权利要求1-32中任一项所述的嵌合抗原受体。
64.根据权利要求63所述的方法,其中给所述患者施用权利要求46至50中任一项的细胞或遗传修饰的细胞。
65.根据权利要求64所述的方法,其中所述细胞或遗传修饰的细胞是患者自体的。
66.根据权利要求64所述的方法,其中所述细胞或遗传修饰的细胞是所述患者同种异体的。
67.根据权利要求62至66中任一权利要求所述的方法还包括在将患者暴露于表达嵌合抗原受体的细胞之前识别患者中是否存在癌干细胞。
68.根据权利要求62至67中任一项所述的方法,其中所述癌症为转移性或复发性癌症。
69.一种药物组合物,包括根据权利要求33所述的核酸分子、根据权利要求34至37中任一项所述的核酸构建体、根据权利权利要求40至42中任一项所述的病毒载体或根据权利要求46至50中任一项所述的细胞或遗传修饰的细胞,并且还包括药学上可接受的载体、赋形剂或稀释剂。
70.根据权利要求69所述的药物组合物,其进一步包含细胞因子。
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