CN110372796B - 靶向bcma的嵌合抗原受体及其制法和应用 - Google Patents
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Abstract
本发明提供了一种靶向BCMA的嵌合抗原受体及其制法和应用。具体地,本发明提供了一种靶向BCMA的嵌合抗原受体,其包括靶向BCMA的scFv,铰链区,跨膜区,和胞内信号结构域。本发明提供编码该嵌合抗原受体的核酸分子和相应的表达载体、CAR‑T细胞及其应用。本发明的嵌合抗原受体靶向BCMA阳性细胞,可以用于治疗BCMA阳性B细胞淋巴瘤,多发性骨髓瘤和浆细胞白血病等疾病。
Description
技术领域
本发明涉及生物医药领域,更具体地涉及一种靶向BCMA的嵌合抗原受体及其制法和应用。
背景技术
BCMA是B细胞成熟抗原,又名CD269或TNFRSF17,是肿瘤坏死因子受体超家族的成员,它的配体是B细胞激活因子(BAFF)和增殖诱导配体(APRIL)。
BCMA与BAFF和APRIL的结合引发NF-kB激活,诱导抗凋亡Bcl-2成员例如Bcl-xL或者Bcl-2和Mcl-1的上调。BCMA和其配体的相互作用从不同方面调控体液免疫,B细胞的生长分化从而维护人体内环境稳定平衡。
BCMA的表达局限于B细胞系,在浆母细胞,浆细胞和一部分成熟B细胞上表达,在末端B细胞分化时增加,而在大部分B细胞,例如幼稚B细胞,记忆B细胞和B细胞生发中心以及其它器官都不表达。据报道,BCMA的表达对于骨髓中长寿的,固着的浆细胞很重要。所以,BCMA缺陷小鼠在骨髓中的浆细胞减少然而在脾脏中的浆细胞水平不受影响。成熟B细胞在BCMA敲除的小鼠中能正常分化成浆细胞。BCMA敲除小鼠看上去一切正常,似乎很健康,而且B细胞数量正常,但浆细胞却不能长期存活。
BCMA也在恶性浆细胞中高表达,例如多发性骨髓瘤和浆细胞白血病,霍奇金淋巴瘤患者的HRS细胞中也被检测出BCMA。在美国,血液***的恶性肿瘤占所有恶性肿瘤约10%,骨髓瘤占全部恶性血液肿瘤的15%。据文献报道,BCMA的表达和多发性骨髓瘤疾病进展有关。BCMA基因在骨髓瘤样本中高表达,但在慢性淋巴细胞白血病,急性淋巴细胞白血病,急性T细胞型淋巴细胞白血病中表达很低。过表达BCMA配体BAFF和APRIL的老鼠模型中B细胞淋巴瘤明显增长。与BCMA结合的配体被证明能调控表达BCMA的多发性骨髓瘤细胞的生长和生存。BCMA与BAFF和APRIL的结合能让恶性浆细胞存活,因此,使表达BCMA的肿瘤细胞损耗,破坏BCMA配体与受体之间的相互作用能改善对多发性骨髓瘤或其他BCMA阳性B系恶性淋巴瘤的治疗结果。
多发性骨髓瘤,也被称作浆细胞瘤或者卡勒氏病,是一种难治愈的B细胞系的恶性肿瘤,特征是浆细胞异常增生,浆细胞是一种白细胞的类型,负责抗体的产生。美国国立癌症研究所2017年发布的数据显示骨髓瘤占所有肿瘤案例的1.8%,致死率为2.1%。2010年-2014年的统计结果显示发病率约为十万分之6.6每年,死亡率约为50%。多发性骨髓瘤属于中老年疾病,在欧美国家中位发病年龄为68岁,男性多于女性,我国统计的发病年龄高峰为55-65岁,男女之比为2.35:1,我国尚无多发性骨髓瘤的确切流行病学调查资料,一般估计发病率与周边东南亚和日本发病率相近,约为十万分之一。多发性骨髓瘤的传统治疗方式包括化疗和造血干细胞移植,但是这些方法复发率高。硼替佐米(PS-341)是第一个蛋白酶体抑制剂,于2003年获FDA批准用于治疗复发难治多发性骨髓瘤,以单独或者联合现有药物治疗的形式,结果喜人。该药也于2005年在中国上市,现已成为与沙利度胺,***等常用治疗多发性骨髓瘤的方案选择之一。多发性骨髓瘤治疗方法通常是联合的,但如果多种药物同时使用也存在费用昂贵,副作用累积的不良后果。临床上仍然迫切需要开发治疗多发性骨髓瘤的新方法。
近期,免疫疗法,特别是过继性T细胞疗法,在治疗针对血液***的恶性肿瘤临床试验中显示了强大的疗效和光明前景。T细胞可以被基因修饰来表达嵌合抗原受体(CAR),它包括抗原识别部分和T细胞激活区。CAR利用单克隆抗体的抗原结合性质能重定向T细胞的特异性和反应性并且以一种非MHC限制的方式靶向靶标。这种非MHC限制抗原识别使表达CAR的T细胞不需要抗原加工就能识别抗原,因此避免了肿瘤逃逸的一种主要机制。除此之外,CAR也不会和内源性TCR的α链,β链产生二聚体。
目前,国外已有两个靶向CD19的嵌合抗原受体T细胞疗法(CAR-T)产品获批上市,用于治疗儿童和年轻成年患者急性淋巴细胞白血病和成人二线或多线***治疗的复发性或难治性大B细胞淋巴瘤。然而,CD19很少在多发性骨髓瘤的恶性浆细胞中表达。本领域迫切需要开发靶向BCMA的CAR-T产品治疗多发性骨髓瘤。
发明内容
本发明的目的在于提供一种靶向BCMA的嵌合抗原受体及其制法和应用。
具体地,本发明的目的在于提供一种靶向BCMA抗原嵌合抗原受体的序列,及其修饰T细胞(CART-BCMA)的制备方法和活性鉴定。本发明提供了一种用于治疗BCMA阳性B细胞淋巴瘤的嵌合性抗原受体结构。
在本发明的第一方面,提供了一种嵌合抗原受体(CAR)(序列),所述嵌合抗原受体的抗原结合结构域为靶向BCMA的细胞外区域的抗体单链可变区序列。
在另一优选例中,所述的抗原结合结构域为靶向BCMA序列的第24至41位氨基酸残基的抗体单链可变区序列。
在另一优选例中,所述的BCMA序列的NCBI登录号为AY684975.1。
在另一优选例中,所述的抗原结合结构域的结构如下式I所示:
VL-VH (I)
其中,VH为抗体重链可变区;VL为抗体轻链可变区;“-”为连接肽或肽键;
并且,VL的氨基酸序列如SEQ ID NO.:1所示,VH的氨基酸序列如SEQ ID NO.:2所示;
或者,VL的氨基酸序列如SEQ ID NO.:3所示,VH的氨基酸序列如SEQ ID NO.:4所示;
或者,VL的氨基酸序列如SEQ ID NO.:5所示,VH的氨基酸序列如SEQ ID NO.:6所示。
在另一优选例中,所述的连接肽的氨基酸序列如SEQ ID NO.:10或SEQ ID NO.:11所示。
在另一优选例中,所述的抗体单链可变区包括人源的、鼠源的、人鼠嵌合的抗体单链可变区。
在另一优选例中,所述嵌合抗原受体的结构如下式II所示:
S-VL-VH-H-TM-C-CD3ζ (II)
其中,
S为任选的信号肽(即signal peptide);
H为绞链区;
TM为跨膜结构域;
C为共刺激信号分子;
CD3ζ为源于CD3ζ的胞浆信号传导序列;
VH和VL分别如上所述。
在另一优选例中,所述的S为选自下组的蛋白的信号肽:CD8、CD28、GM-CSF、CD4、CD137、或其组合。
在另一优选例中,所述的S为CD8来源的信号肽。
在另一优选例中,S的氨基酸序列如SEQ ID NO.9所示。
在另一优选例中,所述的H为选自下组的蛋白的铰链区:CD8、CD28、CD137、或其组合。
在另一优选例中,所述的H为CD8来源的铰链区。
在另一优选例中,H的氨基酸序列如SEQ ID NO.12所示。
在另一优选例中,所述的TM为选自下组的蛋白的跨膜区:CD28、CD3epsilon、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、或其组合。
在另一优选例中,所述的TM为CD8来源的跨膜区。
在另一优选例中,TM的序列如SEQ ID NO.13所示。
在另一优选例中,所述的C为选自下组的蛋白的共刺激信号分子:OX40、CD2、CD7、CD27、CD28、CD30、CD40、CD70、CD134、4-1BB(CD137)、PD1、Dap10、CDS、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、NKG2D、GITR、TLR2、或其组合。
在另一优选例中,所述的C为4-1BB来源的共刺激信号分子。
在另一优选例中,C的氨基酸序列如SEQ ID NO.14所示。
在另一优选例中,CD3ζ的氨基酸序列如SEQ ID NO.15所示。
在本发明的第二方面,提供了一种核酸分子,所述核酸分子编码本发明第一方面所述的嵌合抗原受体(CAR)。
在另一优选例中,所述核酸分子为分离的。
在本发明的第三方面,提供了一种载体,所述的载体含有本发明第二方面所述的核酸分子。
在另一优选例中,所述的载体选自下组:DNA、RNA、质粒、慢病毒载体、腺病毒载体、逆转录病毒载体、转座子、或其组合。
在另一优选例中,所述载体为慢病毒载体。
在本发明的第四方面,提供了一种宿主细胞,所述的宿主细胞中含有本发明第三方面所述的载体或染色体中整合有外源的本发明第二方面所述的核酸分子或表达本发明第一方面所述的CAR。
在另一优选例中,所述细胞为分离的细胞,和/或所述细胞为基因工程化的细胞。
在另一优选例中,所述细胞为哺乳动物细胞。
在另一优选例中,所述细胞为T细胞。
在本发明的第五方面,提供了一种制备CAR-T细胞的方法,所述的CAR-T细胞表达本发明第一方面所述的CAR,包括以下步骤:
将本发明第二方面所述的核酸分子或本发明第三方面所述的载体转导入T细胞内,从而获得所述CAR-T细胞。
在本发明的第六方面,提供了一种制剂,所述制剂含有本发明第一方面所述的嵌合抗原受体、本发明第二方面所述的核酸分子、本发明第三方面所述的载体、或本发明第四方面所述的细胞,以及药学上可接受的载体、稀释剂或赋形剂。
在另一优选例中,所述制剂为液态制剂。
在另一优选例中,所述制剂的剂型为注射剂。
在另一优选例中,所述制剂中所述CAR-T细胞的浓度为1×103-1×108个细胞/ml,较佳地1×104-1×107个细胞/ml。
在本发明的第七方面,提供了一种本发明第一方面所述的嵌合抗原受体、本发明第二方面所述的核酸分子、本发明第三方面所述的载体、或本发明第四方面所述的细胞的用途,用于制备预防和/或治疗癌症或肿瘤的药物或制剂。
在另一优选例中,所述肿瘤选自下组:血液肿瘤、实体瘤、或其组合。
在另一优选例中,所述血液肿瘤选自下组:急性髓细胞白血病(AML)、多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、急性淋巴白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、或其组合。
在另一优选例中,所述实体瘤选自下组:胃癌、胃癌腹膜转移、肝癌、白血病、肾脏肿瘤、肺癌、小肠癌、骨癌、***癌、结直肠癌、乳腺癌、大肠癌、***、卵巢癌、淋巴癌、鼻咽癌、肾上腺肿瘤、***、非小细胞肺癌(NSCLC)、脑胶质瘤、子宫内膜癌、或其组合。
在另一优选例中,所述的肿瘤为BCMA阳性肿瘤,较佳地为BCMA阳性B细胞淋巴瘤、多发性骨髓瘤、或浆细胞白血病。
在本发明的第八方面,提供了一种用于制备本发明第四方面所述细胞的试剂盒,所述试剂盒含有容器,以及位于容器内的本发明第二方面所述的核酸分子、或本发明第三方面所述的载体。
在本发明的第九方面,提供了一种本发明第四方面所述细胞、或本发明第六方面所述的制剂的用途,用于预防和/或治疗癌症或肿瘤。
在本发明的第十方面,提供了一种治疗疾病的方法,包括给需要治疗的对象施用适量的本发明第四方面所述的细胞、或本发明第六方面所述的制剂。
在另一优选例中,所述疾病为癌症或肿瘤。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了CART-BCMAs对比例筛选结果图。图1A显示了靶向BCMA嵌合型抗原受体工程化T细胞转染效率的检测。重组人BCMA蛋白Fc段染色方法鉴定培养到第6天的CART-BCMAs细胞中CAR基因编码蛋白在T细胞膜表面的表达水平。依次取1*105培养到第10天的CART-BCMAs细胞,分别与BCMA阳性的K562-BCMA-B9肿瘤细胞系,天然表达BCMA的肿瘤细胞系MM.1S和RPMI8226,以及BCMA阴性的K562肿瘤细胞系或不添加肿瘤细胞,在200μl GT-551培养基中按照1:1比例培养18h后分别检测T细胞膜表面CD137的表达水平(图1B)和培养上清中IFNγ的分泌水平(图1C)。
图2显示了靶向BCMA嵌合型抗原受体结构示意图。CAR的结构包括前导序列、抗原识别序列、连接区、跨膜区、共刺激因子信号区和CD3zeta信号传导区。
图3显示了靶向BCMA嵌合型抗原受体工程化T细胞转染效率的检测。重组人BCMA蛋白Fc段染色方法鉴定培养到第7天(图3A),第21天(图3B)和第29天(图3C)的CART-BCMAs细胞中CAR基因编码蛋白在T细胞膜表面的表达水平。
图4显示了T细胞膜表面CD137的表达水平(图4A)和培养上清中IFNγ的分泌水平(图4B)。具体地,依次取1×105个培养到第7天的CART-BCMAs细胞,分别与BCMA阳性的K562-BCMA-E7肿瘤细胞系,以及BCMA阴性的K562肿瘤细胞系或不添加肿瘤细胞,在200μl GT-551培养基中按照1:1比例培养18h后分别检测T细胞膜表面CD137的表达水平和培养上清中IFNγ的分泌水平。
图5显示了CART-BCMAs诱导肿瘤细胞晚期凋亡水平的检测。具体地,分别取1×104个经过CFSE标记的BCMA阴性(NH929)或BCMA阳性的(NH929-BCMA)肿瘤细胞系,在100μl GT-551培养基中按照图示比例与相应的T细胞分别共培养4h后,用100μl 25%PI染料染色15min后,在流式细胞仪上分析CFSE阳性细胞中PI阳性细胞的比例。此图显示了PI阳性细胞在相应共培养样品中的统计分析结果。
图6显示了CART-BCMAs诱导肿瘤细胞晚期凋亡水平的检测。图6A显示所分析样品CART阳性细胞比率,其中NT和BCMA-MO6按60%计算;分别取1×104个经过CFSE标记的BCMA阴性(NH929)或BCMA阳性的(NH929-BCMA,MM.1S)肿瘤细胞系,在100μl GT-551培养基中按照图示比例与相应的T细胞分别共培养4h后,用100μl25%PI染料染色15min后,在流式细胞仪上分析CFSE阳性细胞中PI阳性细胞的比例。图6B显示了PI阳性细胞在相应共培养样品中的统计分析结果。
具体实施方式
本发明人经过广泛而深入地研究,进行了大量的筛选,首次获得了一种靶向BCMA抗原嵌合抗原受体。具体地,本发明获得了以BCMA-1,BCMA-20,BCMA-CA8,BCMA-MO6四种单抗序列为基础构建的靶向BCMA的嵌合型抗原受体结构,并完成了这些嵌合型抗原受体在原代T细胞中的表达水平、体外活化能力及肿瘤细胞杀伤效能等层面的分析与鉴定。研究表明,本发明的嵌合抗原受体靶向BCMA阳性细胞,可以用于治疗BCMA阳性B细胞淋巴瘤、多发性骨髓瘤、浆细胞白血病或其他疾病。
具体地,本发明鉴定了不同CAR结构在病毒感染后细胞膜表面表达时间和表达强度的相关性,进而鉴定出不同CAR结构蛋白表达难易程度的差异,这一发现提示不同CAR结构在相同感染条件下CAR蛋白在膜表面的表达水平和CART体内活性持久性存在差异。经过大量的筛选,获得了本发明结构的CAR,结果表明,本发明中的CAR结构编码蛋白都可以充分表达和膜定位。
本发明中,我们对靶向BCMA抗原CAR结构修饰T细胞的制备工艺作了改进,主要是选用补加1%人血白蛋白的GT-551无血清培养基在体外培养淋巴细胞。
术语
为了可以更容易地理解本公开,首先定义某些术语。如本申请中所使用的,除非本文另有明确规定,否则以下术语中的每一个应具有下面给出的含义。在整个申请中阐述了其它定义。
术语“约”可以是指在本领域普通技术人员确定的特定值或组成的可接受误差范围内的值或组成,其将部分地取决于如何测量或测定值或组成。
术语“给予”是指使用本领域技术人员已知的各种方法和递送***中的任一种将本发明的产品物理引入受试者,包括静脉内,肌内,皮下,腹膜内,脊髓或其它肠胃外给药途径,例如通过注射或输注。
术语“抗体”(Ab)应包括但不限于免疫球蛋白,其特异性结合抗原并包含通过二硫键互连的至少两条重(H)链和两条轻(L)链,或其抗原结合部分。每条H链包含重链可变区(本文缩写为VH)和重链恒定区。重链恒定区包含三个恒定结构域CH1、CH2和CH3。每条轻链包含轻链可变区(本文缩写为VL)和轻链恒定区。轻链恒定区包含一个恒定结构域CL。VH和VL区可以进一步细分为称为互补决定区(CDR)的高变区,其散布有更保守的称为框架区(FR)的区域。每个VH和VL包含三个CDR和四个FR,从氨基末端到羧基末端按照以下顺序排列:FR1,CDR1,FR2,CDR2,FR3,CDR3,FR4。重链和轻链的可变区含有与抗原相互作用的结合结构域。
嵌合抗原受体(CAR)
本发明的嵌合抗原受体(CAR)包括细胞外结构域、跨膜结构域、和细胞内结构域。胞外结构域包括靶-特异性结合元件(也称为抗原结合结构域)。细胞内结构域包括共刺激信号传导区和ζ链部分。共刺激信号传导区指包括共刺激分子的细胞内结构域的一部分。共刺激分子为淋巴细胞对抗原的有效应答所需要的细胞表面分子,而不是抗原受体或它们的配体。
在CAR的胞外结构域和跨膜结构域之间,或在CAR的胞浆结构域和跨膜结构域之间,可并入接头。如本文所用的,术语“接头”通常指起到将跨膜结构域连接至多肽链的胞外结构域或胞浆结构域作用的任何寡肽或多肽。接头可包括0-300个氨基酸,优选地2至100个氨基酸和最优选地3至50个氨基酸。
在本发明的一个较佳的实施方式中,本发明提供的CAR的胞外结构域包括靶向BCMA的抗原结合结构域。本发明的CAR当在T细胞中表达时,能够基于抗原结合特异性进行抗原识别。当其结合其关联抗原时,影响肿瘤细胞,导致肿瘤细胞不生长、被促使死亡或以其他方式被影响,并导致患者的肿瘤负荷缩小或消除。抗原结合结构域优选与来自共刺激分子和ζ链中的一个或多个的细胞内结构域融合。优选地,抗原结合结构域与4-1BB信号传导结构域、和CD3ζ信号结构域组合的细胞内结构域融合。
如本文所用,“抗原结合结构域”“单链抗体片段”均指具有抗原结合活性的Fab片段,Fab’片段,F(ab’)2片段,或单一Fv片段。Fv抗体含有抗体重链可变区、轻链可变区,但没有恒定区,并具有全部抗原结合位点的最小抗体片段。一般的,Fv抗体还包含VH和VL结构域之间的多肽接头,且能够形成抗原结合所需的结构。抗原结合结构域通常是scFv(single-chain variable fragment)。scFv的大小一般是一个完整抗体的1/6。单链抗体优选是由一条核苷酸链编码的一条氨基酸链序列。作为本发明的优选方式,所述scFv包含特异性识别BCMA细胞外区域的抗体,尤其是特异性识别BCMA序列的第24至41位氨基酸残基的抗体,较佳地为单链抗体。
对于绞链区和跨膜区(跨膜结构域),CAR可被设计以包括融合至CAR的胞外结构域的跨膜结构域。在一个实施方式中,使用天然与CAR中的结构域之一相关联的跨膜结构域。在一些例子中,可选择跨膜结构域,或通过氨基酸置换进行修饰,以避免将这样的结构域结合至相同或不同的表面膜蛋白的跨膜结构域,从而最小化与受体复合物的其他成员的相互作用。
本发明的CAR中的胞内结构域包括4-1BB的信号传导结构域和CD3ζ的信号传导结构域。
优选的,本发明的CAR的结构包括信号肽、抗原识别序列(抗原结合结构域)、连接区、跨膜区、共刺激因子信号区和CD3zeta信号传导区(ζ链部分),连接顺序如下:
[CD8 S]-[VL-Linker-VH]-[hinge-CD8TM]-[4-1BB]-[CD3zeta]
具体地,在本发明中选用序列如下:
(1)信号肽为CD8来源的信号肽序列:
MALPVTALLLPLALLLHAARP(SEQ ID NO.:9)
(2)BCMA-1抗体来源的单链可变区轻链(VL)序列:
DIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIHWYQQKPGQPPTLLIQLASNVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLEIK(SEQ ID NO.:7)
(3)BCMA-1抗体来源的单链可变区重链(VH)序列:
QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWINTETREPAYAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDYWGQGTSVTVSS(SEQ ID NO.:8)
其中,BCMA-1为已发表的Car-T序列中包含的抗体序列,在本申请中用作对照。
(4)BCMA-20抗体来源的单链可变区轻链(VL)序列:
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLNWYQQKPGKAPKPLIYYTSNLQSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCMGQTISSYTFGQGTKLEIK(SEQ ID NO.:1)
(5)BCMA-20抗体来源的单链可变区重链(VH)序列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFDMAWVRQAPGKGLVWVSSITTGADHAIYADSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCVRHGYYDGYHLFDYWGQGTLVTVSS
(SEQ ID NO.:2)
(6)BCMA-CA8抗体来源的单链可变区轻链(VL)序列:
DIQLTQTTSSLSASLGDRVTISCSASTTTSNYLNWYQQKPDGTVELVIYYTSNLHGGGPSRFSGSGSGTDYSLTIGYLEPEDVATYYCQQYRKLPWTFGGGSKLEIKR(SEQ ID NO.:3)
(7)BCMA-CA8抗体来源的单链可变区重链(VH)序列:
EVQLQQSGAVLARPGASVKMSCKGSGYTFTNYWMHWVKQRPGQGLEWIGATYRGHSDTYYNQKFKGKAKLTAVTSTSTAYMELSSLTNEDSAVYYCTRGAIYNGYDVLDNWGQGTLVTVSS
(SEQ ID NO.:4)
(8)BCMA-MO6抗体来源的单链可变区轻链(VL)序列:
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKR(SEQ ID NO.:5)
(9)BCMA-MO6抗体来源的单链可变区重链(VH)序列:
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSS
(SEQ ID NO.:6)
(10)BCMA-1单链可变区重链与轻链之间的连接序列为:
GSTSGSGKPGSGEGSTKG(SEQ ID NO.:10)
(11)BCMA-20,BCMA-CA8,BCMA-MO6单链可变区重链与轻链之间的连接序列为:
GGGGSGGGGSGGGGS(SEQ ID NO.:11)
(12)铰链区和连接区的序列:
FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD(SEQ ID NO.:12)
(13)跨膜区为CD8(CD8TM)抗原的跨膜区序列:
IYIWAPLAGTCGVLLLSLVITLYC(SEQ ID NO.:13)
(14)共刺激因子信号区来自4-1BB的胞内信号传导基序的序列:
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(SEQ ID NO.:14)
(15)CD3zeta的信号传导区来自TCR复合体中CD3zeta的以酪氨酸为中心的免疫受体激活基序(immunorecceptor tyrosine-based activation motif,ITAM)的序列:
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO.:15)
嵌合抗原受体T细胞(CAR-T细胞)
如本文所用,术语“CAR-T细胞”、“CAR-T”、“CART”、“本发明CAR-T细胞”均指本发明第二方面所述的CAR-T细胞。
本发明涉及靶向BCMA嵌合抗原受体结构的构建、靶向BCMA嵌合抗原受体工程化T细胞的制备方法及其活性鉴定。
载体
编码期望分子的核酸序列可利用在本领域中已知的重组方法获得,诸如例如通过从表达基因的细胞中筛选文库,通过从已知包括该基因的载体中得到该基因,或通过利用标准的技术,从包含该基因的细胞和组织中直接分离。可选地,感兴趣的基因可被合成生产。
本发明也提供了其中***本发明的表达盒的载体。源于逆转录病毒诸如慢病毒的载体是实现长期基因转移的合适工具,因为它们允许转基因长期、稳定的整合并且其在子细胞中增殖。慢病毒载体具有超过源自致癌逆转录病毒诸如鼠科白血病病毒的载体的优点,因为它们可转导非增殖的细胞,诸如肝细胞。它们也具有低免疫原性的优点。
简单概括,通常可操作地连接本发明的表达盒或核酸序列至启动子,并将其并入表达载体。该载体适合于复制和整合真核细胞。典型的克隆载体包含可用于调节期望核酸序列表达的转录和翻译终止子、初始序列和启动子。
本发明的表达构建体也可利用标准的基因传递方案,用于核酸免疫和基因疗法。基因传递的方法在本领域中是已知的。见例如美国专利号5,399,346、5,580,859、5,589,466,在此通过引用全文并入。在另一个实施方式中,本发明提供了基因疗法载体。
该核酸可被克隆入许多类型的载体。例如,该核酸可被克隆入如此载体,其包括但不限于质粒、噬菌粒、噬菌体衍生物、动物病毒和粘粒。特定的感兴趣载体包括表达载体、复制载体、探针产生载体和测序载体。
进一步地,表达载体可以以病毒载体形式提供给细胞。病毒载体技术在本领域中是公知的并在例如Sambrook等(2001,Molecular Cloning:A Laboratory Manual,ColdSpring Harbor Laboratory,New York)和其他病毒学和分子生物学手册中进行了描述。可用作载体的病毒包括但不限于逆转录病毒、腺病毒、腺伴随病毒、疱疹病毒和慢病毒。通常,合适的载体包含在至少一种有机体中起作用的复制起点、启动子序列、方便的限制酶位点和一个或多个可选择的标记(例如,WO01/96584;WO01/29058;和美国专利号6,326,193)。
已经开发许多基于病毒的***,用于将基因转移入哺乳动物细胞。例如,逆转录病毒提供了用于基因传递***的方便的平台。可利用在本领域中已知的技术将选择的基因***载体并包装入逆转录病毒颗粒。该重组病毒可随后被分离和传递至体内或离体的对象细胞。许多逆转录病毒***在本领域中是已知的。在一些实施方式中,使用腺病毒载体。许多腺病毒载体在本领域中是已知的。在一个实施方式中,使用慢病毒载体。
额外的启动子元件,例如增强子,可以调节转录开始的频率。通常地,这些位于起始位点上游的30-110bp区域中,尽管最近已经显示许多启动子也包含起始位点下游的功能元件。启动子元件之间的间隔经常是柔性的,以便当元件相对于另一个被倒置或移动时,保持启动子功能。在胸苷激酶(tk)启动子中,启动子元件之间的间隔可被增加隔开50bp,活性才开始下降。取决于启动子,表现出单个元件可合作或独立地起作用,以起动转录。
合适的启动子的一个例子为即时早期巨细胞病毒(CMV)启动子序列。该启动子序列为能够驱动可操作地连接至其上的任何多核苷酸序列高水平表达的强组成型启动子序列。合适的启动子的另一个例子为延伸生长因子-1α(EF-1α)。然而,也可使用其他组成型启动子序列,包括但不限于类人猿病毒40(SV40)早期启动子、小鼠乳癌病毒(MMTV)、人免疫缺陷病毒(HIV)长末端重复(LTR)启动子、MoMuLV启动子、鸟类白血病病毒启动子、艾伯斯坦-巴尔(Epstein-Barr)病毒即时早期启动子、鲁斯氏肉瘤病毒启动子、以及人基因启动子,诸如但不限于肌动蛋白启动子、肌球蛋白启动子、血红素启动子和肌酸激酶启动子。进一步地,本发明不应被限于组成型启动子的应用。诱导型启动子也被考虑为本发明的一部分。诱导型启动子的使用提供了分子开关,其能够当这样的表达是期望的时,打开可操作地连接诱导型启动子的多核苷酸序列的表达,或当表达是不期望的时关闭表达。诱导型启动子的例子包括但不限于金属硫蛋白启动子、糖皮质激素启动子、孕酮启动子和四环素启动子。
为了评估CAR多肽或其部分的表达,被引入细胞的表达载体也可包含可选择的标记基因或报道基因中的任一个或两者,以便于从通过病毒载体寻求被转染或感染的细胞群中鉴定和选择表达细胞。在其他方面,可选择的标记可被携带在单独一段DNA上并用于共转染程序。可选择的标记和报道基因两者的侧翼都可具有适当的调节序列,以便能够在宿主细胞中表达。有用的可选择标记包括例如抗生素抗性基因,诸如neo等等。
报道基因用于鉴定潜在转染的细胞并用于评价调节序列的功能性。通常地,报道基因为以下基因:其不存在于受体有机体或组织或由受体有机体或组织进行表达,并且其编码多肽,该多肽的表达由一些可容易检测的性质例如酶活性清楚表示。在DNA已经被引入受体细胞后,报道基因的表达在合适的时间下进行测定。合适的报道基因可包括编码荧光素酶、β-半乳糖苷酶、氯霉素乙酰转移酶、分泌型碱性磷酸酶或绿色萤光蛋白的基因(例如,Ui-Tei等,2000FEBS Letters479:79-82)。合适的表达***是公知的并可利用已知技术制备或从商业上获得。通常,显示最高水平的报道基因表达的具有最少5个侧翼区的构建体被鉴定为启动子。这样的启动子区可被连接至报道基因并用于评价试剂调节启动子-驱动转录的能力。
将基因引入细胞和将基因表达入细胞的方法在本领域中是已知的。在表达载体的内容中,载体可通过在本领域中的任何方法容易地引入宿主细胞,例如,哺乳动物、细菌、酵母或昆虫细胞。例如,表达载体可通过物理、化学或生物学手段转移入宿主细胞。
将多核苷酸引入宿主细胞的物理方法包括磷酸钙沉淀、脂质转染法、粒子轰击、微注射、电穿孔等等。生产包括载体和/或外源核酸的细胞的方法在本领域中是公知的。见例如Sambrook等(2001,Molecular Cloning:A Laboratory Manual,Cold Spring HarborLaboratory,New York)。将多核苷酸引入宿主细胞的优选方法为磷酸钙转染。
将感兴趣的多核苷酸引入宿主细胞的生物学方法包括使用DNA和RNA载体。病毒载体,特别是逆转录病毒载体,已经成为最广泛使用的将基因***哺乳动物例如人细胞的方法。其他病毒载体可源自慢病毒、痘病毒、单纯疱疹病毒I、腺病毒和腺伴随病毒等等。见例如美国专利号5,350,674和5,585,362。
将多核苷酸引入宿主细胞的化学手段包括胶体分散***,诸如大分子复合物、纳米胶囊、微球、珠;和基于脂质的***,包括水包油乳剂、胶束、混合胶束和脂质体。用作体外和体内传递工具(delivery vehicle)的示例性胶体***为脂质体(例如,人造膜囊)。
在使用非病毒传递***的情况下,示例性传递工具为脂质体。考虑使用脂质制剂,以将核酸引入宿主细胞(体外、离体(ex vivo)或体内)。在另一方面,该核酸可与脂质相关联。与脂质相关联的核酸可被封装入脂质体的水性内部中,散布在脂质体的脂双层内,经与脂质体和寡核苷酸两者都相关联的连接分子附接至脂质体,陷入脂质体,与脂质体复合,分散在包含脂质的溶液中,与脂质混合,与脂质联合,作为悬浮液包含在脂质中,包含在胶束中或与胶束复合,或以其他方式与脂质相关联。与组合物相关联的脂质、脂质/DNA或脂质/表达载体不限于溶液中的任何具体结构。例如,它们可存在于双分子层结构中,作为胶束或具有“坍缩的(collapsed)”结构。它们也可简单地被散布在溶液中,可能形成大小或形状不均一的聚集体。脂质为脂肪物质,其可为天然发生或合成的脂质。例如,脂质包括脂肪小滴,其天然发生在细胞质以及包含长链脂肪族烃和它们的衍生物诸如脂肪酸、醇类、胺类、氨基醇类和醛类的该类化合物中。
在本发明的一个优选地实施方式中,所述载体为慢病毒载体。
制剂
本发明提供了一种含有本发明第一方面所述的CAR-T细胞,以及药学上可接受的载体、稀释剂或赋形剂。在一个实施方式中,所述制剂为液态制剂。优选地,所述制剂为注射剂。优选地,所述制剂中所述CAR-T细胞的浓度为1×103-1×108个细胞/ml,更优地1×104-1×107个细胞/ml。
在一个实施方式中,所述制剂可包括缓冲液诸如中性缓冲盐水、硫酸盐缓冲盐水等等;碳水化合物诸如葡萄糖、甘露糖、蔗糖或葡聚糖、甘露醇;蛋白质;多肽或氨基酸诸如甘氨酸;抗氧化剂;螯合剂诸如EDTA或谷胱甘肽;佐剂(例如,氢氧化铝);和防腐剂。本发明的制剂优选配制用于静脉内施用。
治疗性应用
本发明包括用编码本发明表达盒的慢病毒载体(LV)转导的细胞(例如,T细胞)进行的治疗性应用。转导的T细胞可靶向肿瘤细胞的标志物BCMA,协同激活T细胞,引起T细胞免疫应答,从而显著提高其对肿瘤细胞的杀伤效率。
因此,本发明也提供了刺激对哺乳动物的靶细胞群或组织的T细胞-介导的免疫应答的方法,其包括以下步骤:给哺乳动物施用本发明的CAR-T细胞。
在一个实施方式中,本发明包括一类细胞疗法,分离病人自体T细胞(或者异源供体),激活并进行基因改造产生CAR-T细胞,随后注入同一病人体内。这种方式患移植物抗宿主病概率极低,抗原被T细胞以无MHC限制方式识别。此外,一种CAR-T就可以治疗表达该抗原的所有癌症。不像抗体疗法,CAR-T细胞能够体内复制,产生可导致持续肿瘤控制的长期持久性。
在一个实施方式中,本发明的CAR-T细胞可经历稳固的体内T细胞扩展并可持续延长的时间量。另外,CAR介导的免疫应答可为过继免疫疗法步骤的一部分,其中CAR-修饰T细胞诱导对CAR中的抗原结合结构域特异性的免疫应答。例如,抗BCMA的CAR-T细胞引起抗表达BCMA的细胞的特异性免疫应答。
尽管本文公开的数据具体公开了包括抗BCMA scFv、铰链和跨膜区、和4-1BB和CD3ζ信号传导结构域的慢病毒载体,但本发明应被解释为包括对构建体组成部分中的每一个的任何数量的变化。
可治疗的癌症包括没有被血管化或基本上还没有被血管化的肿瘤,以及血管化的肿瘤。癌症可包括非实体瘤(诸如血液学肿瘤,例如白血病和淋巴瘤)或可包括实体瘤。用本发明的CAR治疗的癌症类型包括但不限于癌、胚细胞瘤和肉瘤,和某些白血病或淋巴恶性肿瘤、良性和恶性肿瘤、和恶性瘤,例如肉瘤、癌和黑素瘤。也包括成人肿瘤/癌症和儿童肿瘤/癌症。
血液学癌症为血液或骨髓的癌症。血液学(或血原性)癌症的例子包括白血病,包括急性白血病(诸如急性淋巴细胞白血病、急性髓细胞白血病、急性骨髓性白血病和成髓细胞性、前髓细胞性、粒-单核细胞型、单核细胞性和红白血病)、慢性白血病(诸如慢性髓细胞(粒细胞性)白血病、慢性骨髓性白血病和慢性淋巴细胞白血病)、真性红细胞增多症、淋巴瘤、霍奇金氏疾病、非霍奇金氏淋巴瘤(无痛和高等级形式)、多发性骨髓瘤、瓦尔登斯特伦氏巨球蛋白血症、重链疾病、骨髓增生异常综合征、多毛细胞白血病和脊髓发育不良。
实体瘤为通常不包含囊肿或液体区的组织的异常肿块。实体瘤可为良性或恶性的。不同类型的实体瘤以形成它们的细胞类型命名(诸如肉瘤、癌和淋巴瘤)。实体瘤诸如肉瘤和癌的例子包括纤维肉瘤、粘液肉瘤、脂肪肉瘤间皮瘤、淋巴恶性肿瘤、胰腺癌卵巢癌、。
本发明的CAR-修饰T细胞也可用作对哺乳动物离体免疫和/或体内疗法的疫苗类型。优选地,哺乳动物为人。
对于离体免疫,以下中的至少一项在将细胞施用进入哺乳动物前在体外发生:i)扩增细胞,ii)将编码CAR的核酸引入细胞,和/或iii)冷冻保存细胞。
离体程序在本领域中是公知的,并在以下更完全地进行讨论。简单地说,细胞从哺乳动物(优选人)中分离并用表达本文公开的CAR的载体进行基因修饰(即,体外转导或转染)。CAR-修饰的细胞可被施用给哺乳动物接受者,以提供治疗益处。哺乳动物接受者可为人,和CAR-修饰的细胞可相对于接受者为自体的。可选地,细胞可相对于接受者为同种异基因的、同基因的(syngeneic)或异种的。
除了就离体免疫而言使用基于细胞的疫苗之外,本发明也提供了体内免疫以引起针对患者中抗原的免疫应答的组合物和方法。
本发明提供了***的方法,其包括施用给需要其的对象治疗有效量的本发明的CAR-修饰的T细胞。
本发明的CAR-修饰的T细胞可被单独施用或作为药物组合物与稀释剂和/或与其他组分诸如IL-2、IL-17或其他细胞因子或细胞群结合施用。简单地说,本发明的药物组合物可包括如本文所述的靶细胞群,与一种或多种药学或生理学上可接受载体、稀释剂或赋形剂结合。这样的组合物可包括缓冲液诸如中性缓冲盐水、硫酸盐缓冲盐水等等;碳水化合物诸如葡萄糖、甘露糖、蔗糖或葡聚糖、甘露醇;蛋白质;多肽或氨基酸诸如甘氨酸;抗氧化剂;螯合剂诸如EDTA或谷胱甘肽;佐剂(例如,氢氧化铝);和防腐剂。本发明的组合物优选配制用于静脉内施用。
本发明的药物组合物可以以适于待治疗(或预防)的疾病的方式施用。施用的数量和频率将由这样的因素确定,如患者的病症、和患者疾病的类型和严重度——尽管适当的剂量可由临床试验确定。
当指出“免疫学上有效量”、“抗肿瘤有效量”、“肿瘤-抑制有效量”或“治疗量”时,待施用的本发明组合物的精确量可由医师确定,其考虑患者(对象)的年龄、重量、肿瘤大小、感染或转移程度和病症的个体差异。可通常指出:包括本文描述的T细胞的药物组合物可以以104至109个细胞/kg体重的剂量,优选105至106个细胞/kg体重的剂量(包括那些范围内的所有整数值)施用。T细胞组合物也可以以这些剂量多次施用。细胞可通过使用免疫疗法中公知的注入技术(见例如Rosenberg等,NewEng.J.of Med.319:1676,1988)施用。对于具体患者的最佳剂量和治疗方案可通过监测患者的疾病迹象并因此调节治疗由医学领域技术人员容易地确定。
对象组合物的施用可以以任何方便的方式进行,包括通过喷雾法、注射、吞咽、输液、植入或移植。本文描述的组合物可被皮下、皮内、瘤内、结内、脊髓内、肌肉内、通过静脉内(i.v.)注射或腹膜内施用给患者。在一个实施方式中,本发明的T细胞组合物通过皮内或皮下注射被施用给患者。在另一个实施方式中,本发明的T细胞组合物优选通过i.v.注射施用。T细胞的组合物可被直接注入肿瘤,***或感染位置。
在本发明的某些实施方式中,利用本文描述的方法或本领域已知的其他将T细胞扩展至治疗性水平的方法活化和扩展的细胞,与任何数量的有关治疗形式结合(例如,之前、同时或之后)施用给患者,所述治疗形式包括但不限于用以下试剂进行治疗:所述试剂诸如抗病毒疗法、西多福韦和白细胞介素-2、阿糖胞苷(也已知为ARA-C)或对MS患者的那他珠单抗治疗或对牛皮癣患者的厄法珠单抗治疗或对PML患者的其他治疗。在进一步的实施方式中,本发明的T细胞可与以下结合使用:化疗、辐射、免疫抑制剂,诸如,环孢菌素、硫唑嘌呤、甲氨喋呤、麦考酚酯和FK506,抗体或其他免疫治疗剂。在进一步的实施方式中,本发明的细胞组合物与骨髓移植、利用化疗剂诸如氟达拉滨、外部光束放射疗法(XRT)、环磷酰胺结合(例如,之前、同时或之后)而施用给患者。例如,在一个实施方式中,对象可经历高剂量化疗的标准治疗,之后进行外周血干细胞移植。在一些实施方式中,在移植后,对象接受本发明的扩展的免疫细胞的注入。在一个额外的实施方式中,扩展的细胞在外科手术前或外科手术后施用。
施用给患者的以上治疗的剂量将随着治疗病症的精确属性和治疗的接受者而变化。病人施用的剂量比例可根据本领域接受的实践实施。通常,每次治疗或每个疗程,可将1×106个至1×1010个本发明经修饰的T细胞(如,CAR-T-BCMA细胞),通过例如静脉回输的方式,施用于患者。
本发明的主要优点包括:
(a)本发明的嵌合抗原受体,其细胞外抗原结合结构域为特定的抗BCMA scFv,该特定的抗BCMA scFv结合特定的绞链区和胞内结构域形成的CAR显示出了极大的对肿瘤细胞的杀伤能力,而且细胞毒性较小,副作用低。
(b)本发明提供的嵌合抗原受体可在携带CAR基因的慢病毒感染T细胞后实现CAR蛋白的稳定表达和膜定位。
(c)本发明的CAR修饰的T细胞在体内存活时间较长,且抗肿瘤效力较强;本发明所用的scFv为人源化或来自于人的抗体,较小可能产生种特异的免疫排斥反应。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring HarborLaboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1
慢病毒表达载体的构建
委托上海博益生物科技有限公司进行全长DNA合成和克隆,实现编码质粒的构建。选择pWPT慢病毒载体作为克隆载体,克隆位点为BamH I和Sal I位点。具体序列如前所述。
实施例2
CAR-T细胞的制备
(1)取健康人静脉血,通过密度梯度离心方法,分离获得单个核细胞(PBMCs)。
(2)在第0天,将PBMCs接种于预先经过终浓度为5μg/mL CD3单克隆抗体(OKT3)及终浓度为10μg/mL的Retronectin(购自TAKARA公司)包被的细胞培养瓶中,培养基为含1%人血白蛋白的GT-551细胞培养基,培养基里添加终浓度为1000U/mL的重组人白介素2(IL-2),在37℃,饱和湿度为5%CO2培养箱中培养。
(3)在第1天,缓慢吸取并弃去培养PBMCs的上清液,并加入新的含1%人血白蛋白的GT-551细胞培养基,培养基里添加终浓度为1000U/mL的重组人白介素2(IL-2),在37℃,饱和湿度为5%CO2培养箱继续培养。
(4)在第3天,加入新鲜培养液,浓缩纯化的CAR-BCMAs慢病毒液,protaminesulfate(12μg/ml),以及终浓度为1000U/mL IL-2。置于37℃,5%CO2培养箱中感染12小时后,弃培养液,加入新鲜的培养基,于37℃,5%CO2培养箱继续进行培养。
(5)从第6天开始,可取CART-BCMAs细胞进行相应的活性检测试验。
实施例3
CAR基因在T细胞基因组整合率及其编码蛋白在膜表面表达水平的检测
分别取0.5×106个实施例2中培养到第7天(图3A),第21天(图3B)和第29天(图3C)的CART-BCMAs细胞样品,在重组人BCMA蛋白Fc段染色后,在流式细胞仪上分析CAR-BCMA蛋白在T细胞膜表面的表达水平。
结果如图3所示,本发明中所设计的4种CAR结构均可在其相应修饰的T细胞中表达并完成细胞膜表面定位。
实施例4
CART-BCMAs体外激活能力的检测
采用实施例2中培养到第7天的CART-BCMAs细胞进行细胞激活水平指标蛋白CD137和IFNγ的检测。依次取1×105个培养到第7天的CART-BCMA细胞,分别与BCMA阳性的K562-BCMA+E7肿瘤细胞系,以及BCMA阴性的K562肿瘤细胞系或不添加肿瘤细胞,在200μl GT-551培养基中按照1:1比例培养18h后流式方法检测T细胞膜表面CD137的表达水平,ELISA方法检测培养上清中IFNγ的分泌水平。
结果如图4A所示,4种CART细胞的表面均可以检测到CD137的表达,并且均可以在培养上清中检测到IFNγ的表达。其中,CAR-BCMA-20有最好的CD137活化水平和IFNγ释放水平;以人源化MO6抗体序列为基础构建的CART-BCMA-MO6比以鼠源抗体序列为基础构建的CART-BCMA-CA8有弱的CD137活化水平但是更高的IFNγ释放水平。
实施例5
CART-BCMAs细胞诱导肿瘤细胞晚期凋亡活性的检测
(1)按1:1、2.5:1、5:1、10:1、20:1的比例(如图5所示的比例),分别将实施例2中培养到第17天的CART-BCMAs细胞与1×104个经过CFSE标记的BCMA阴性细胞(NH929)或BCMA阳性的自构细胞NH929-BCMA过表达肿瘤细胞株混合,在100μl GT-551培养基中共培养4h后,用100μl 25%PI染料染色15min,在流式细胞仪上分析CFSE阳性细胞中PI阳性细胞的比例。
(2)按1:1、5:1、10:1、20:1、40:1的比例(如图6B所示的比例),分别将实施例2中培养到第22天的CART-BCMAs细胞与1×104个经过CFSE标记的BCMA阴性细胞(NH929)、BCMA阳性的自构细胞NH929-BCMA过表达肿瘤细胞株、或者天然表达BCMA的MM.1S细胞系混合,在100μl GT-551培养基中共培养4h后,用100μl 25%PI染料染色15min,在流式细胞仪上分析CFSE阳性细胞中PI阳性细胞的比例。
结果如图5和图6所示,4种CART细胞均可以较好的诱导BCMA阳性肿瘤细胞凋亡。其中,CART-BCMA-20比CART-BCMA-1可以更好地诱导BCMA阳性肿瘤细胞的晚期凋亡;CART-BCMA-MO6和CART-BCMA-CA8诱导BCMA阳性肿瘤细胞的晚期凋亡能力类似。
对比例
在本申请的嵌合抗原受体的筛选过程中,发明人测试了大量的候选序列,下面举例进行说明。
待筛选抗体包括:BCMA-1、BCMA-2、BCMA-69、BCMA-72、BCMA-2A1、BCMA-1E1、BCMA-J22.9、BCMA-20、BCMA-CA8、BCMA-MO6。以上述抗体为基础构建的靶向BCMA的嵌合型抗原受体结构。其中BCMA-1和BCMA-2是已发表的Car-T序列,作为筛选的阳性对照,CAR-T细胞的制备方法与实施例2相同,检测方法与实施例3,4相同。
结果如图1所示,分别为两批CAR-T细胞的实验结果。用BCMA-Fc融合蛋白检测Car-T的表达,可见在原代T细胞有较高表达,如图1A所见。在图1B中,可见BCMA-1,BCMA-20,BCMA-1E1,BCMA-CA8,BCMA-MO6,和BCMA-J22.9能被BCMA抗原所激活。图1C显示激活的BCMA-1,BCMA-20,BCMA-1E1,BCMA-CA8,BCMA-MO6,和BCMA-J22.9Car-T能产生较高的IFN-γ。综合这些结果,显示BCMA-1、BCMA-20、CA8和MO6所得到的CAR-T功能相近,故将BCMA-20、CA8和MO6CAR-T进行了进一步分析,研究。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 上海赛比曼生物科技有限公司
无锡赛比曼生物科技有限公司
<120> 靶向BCMA的嵌合抗原受体及其制法和应用
<130> P2018-0540
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<170> PatentIn version 3.5
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Thr Phe Gly Gly Gly Ser Lys Leu Glu Ile Lys Arg
100 105
<210> 4
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Glu Val Gln Leu Gln Gln Ser Gly Ala Val Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Gly Ala Ile Tyr Asn Gly Tyr Asp Val Leu Asp Asn Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 5
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Asn Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Lys Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 6
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asn Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Tyr Asp Gly Tyr Asp Val Leu Asp Asn Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 7
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly
1 5 10 15
Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu
20 25 30
Gly Ser His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg
85 90 95
Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
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<210> 8
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Ile Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp Phe
50 55 60
Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 9
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro
20
<210> 10
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
1 5 10 15
Lys Gly
<210> 11
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 12
<211> 55
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
1 5 10 15
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
20 25 30
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
35 40 45
Gly Leu Asp Phe Ala Cys Asp
50 55
<210> 13
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys
20
<210> 14
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
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> 15
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
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 Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
Claims (13)
1.一种嵌合抗原受体(CAR),其包含抗BCMA抗原结合区,所述抗BCMA抗原结合区包含:(i)氨基酸序列如SEQ ID NO:1所示的轻链可变区(VL),和(ii)氨基酸序列如SEQ ID NO:2所示的重链可变区(VH);
其中VL位于VH的N端,
其中所述抗BCMA抗原结合区是特异性结合BCMA的单链可变片段(scFv),
其中所述CAR还包含:
(a)氨基酸序列如SEQ ID NO:9所示的信号肽,
(b)氨基酸序列如SEQ ID NO:12所示的铰链区,
(c)氨基酸序列如SEQ ID NO:13所示的跨膜结构域,
(d)氨基酸序列如SEQ ID NO:14所示的共刺激区,和
(e)氨基酸序列如SEQ ID NO:15所示的胞浆信号传导结构域;
且其中所述CAR从N端到C端为:信号肽、VL、氨基酸序列如SEQ ID NO:11所示的连接序列、VH、铰链区、跨膜结构域、共刺激区和胞浆信号传导结构域。
2.T细胞,其包含权利要求1所述的CAR。
3.药物组合物,其包含权利要求2所述的T细胞。
4.一种核酸,其编码权利要求1所述的CAR。
5.一种载体,其包含权利要求4所述的核酸。
6.药物组合物,其包含权利要求5所述的载体。
7.权利要求2所述的T细胞的用途,用于制备治疗血液癌症的药物,以施用至有需要的受试者,所述血液癌症是BCMA阳性恶性肿瘤。
8.如权利要求7所述的用途,其中所述T细胞通过输注、注射、转输、植入或移植来施用。
9.如权利要求7所述的用途,其中所述T细胞通过静脉内、皮下、皮内、结内、瘤内、髓内、肌内或腹膜内施用。
10.如权利要求7所述的用途,其特征在于,所述T细胞通过静脉内输注施用。
11.如权利要求7所述的用途,其中所述T细胞是同种异体的或自体的。
12.如权利要求7所述的用途,其中所述受试者是人。
13.如权利要求7所述的用途,其中所述血液癌症是多发性骨髓瘤(MM)。
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KR1020207032269A KR20200142036A (ko) | 2018-04-12 | 2019-04-02 | Bcma-표적화된 키메라 항원 수용체, 그의 제조 방법 및 그의 적용 |
AU2019251016A AU2019251016B2 (en) | 2018-04-12 | 2019-04-02 | BCMA-targeted chimeric antigen receptor as well as preparation method therefor and application thereof |
EP19784803.9A EP3778651A4 (en) | 2018-04-12 | 2019-04-02 | CHEMERICAL ANTIGENIC RECEPTOR TARGETING BCMA, ITS PREPARATION PROCESS AND ITS USE |
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CA3095827A CA3095827A1 (en) | 2018-04-12 | 2019-04-02 | Bcma-targeted chimeric antigen receptor as well as preparation method therefor and application thereof |
JP2020531444A JP7148611B2 (ja) | 2018-04-12 | 2019-04-02 | Bcmaを標的とするキメラ抗原受容体およびその製造方法と使用 |
US16/881,668 US11142581B2 (en) | 2018-04-12 | 2020-05-22 | BCMA-targeted chimeric antigen receptor as well as preparation method therefor and application thereof |
US17/476,661 US11498973B2 (en) | 2018-04-12 | 2021-09-16 | BCMA-targeted chimeric antigen receptor as well as preparation method therefor and application thereof |
JP2021190474A JP7299294B2 (ja) | 2018-04-12 | 2021-11-24 | Bcmaを標的とするキメラ抗原受容体およびその製造方法と使用 |
US17/951,774 US20230053305A1 (en) | 2018-04-12 | 2022-09-23 | BCMA-Targeted Chimeric Antigen Receptor as well as Preparation Method Therefor and Application Thereof |
JP2023098770A JP2023116716A (ja) | 2018-04-12 | 2023-06-15 | Bcmaを標的とするキメラ抗原受容体およびその製造方法と使用 |
AU2023204159A AU2023204159A1 (en) | 2018-04-12 | 2023-06-29 | Bcma-targeted chimeric antigen receptor as well as preparation method therefor and application thereof |
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CN110372796B (zh) * | 2018-04-12 | 2023-05-02 | 上海赛比曼生物科技有限公司 | 靶向bcma的嵌合抗原受体及其制法和应用 |
CN111333732B (zh) * | 2019-12-17 | 2023-02-28 | 中国药科大学 | 一种靶向人bcma且激活nk细胞的双特异性抗体的制备及其应用 |
KR102371151B1 (ko) * | 2020-03-13 | 2022-03-07 | 주식회사 큐로셀 | 항-bcma 결합 영역, 이를 포함하는 융합단백질, 및 이를 포함하는 조성물 |
CN112851815B (zh) * | 2020-03-17 | 2023-08-08 | 西安宇繁生物科技有限责任公司 | 抗bcma抗体或其抗原结合片段及其制备方法和应用 |
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WO2019196713A1 (zh) | 2019-10-17 |
JP2023116716A (ja) | 2023-08-22 |
KR20200142036A (ko) | 2020-12-21 |
US11498973B2 (en) | 2022-11-15 |
CA3095827A1 (en) | 2019-10-17 |
US20230053305A1 (en) | 2023-02-16 |
JP2022031784A (ja) | 2022-02-22 |
CN116836297A (zh) | 2023-10-03 |
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