CN110343710B - 嵌合抗原受体和其治疗肝癌的方法 - Google Patents
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Abstract
本发明提供了新的嵌合抗原受体。本发明提供了表达所述嵌合抗原受体的表达载体和宿主细胞。本发明还提供了嵌合抗原受体在治疗癌症或制备治疗癌症的药物中的用途。本发明提供的嵌合抗原受体和药物能够有效地治疗肝癌等癌症。
Description
本申请要求2018年4月4日提交的、申请号为201810299324.8、发明名称为“NKG2D嵌合抗原受体和其治疗癌症的方法”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。
技术领域
本发明涉及免疫学和医药领域。具体的,本发明提供了新的嵌合抗原受体。本发明还提供了所述新的嵌合抗原受体在治疗癌症或制备治疗癌症的药物中的用途。
背景技术
原发性肝癌是世界上最常见的癌症形式之一。肝细胞癌(也被称作恶性肝细胞瘤)是原发性肝癌的最常见形式,并且在肝细胞内形成。肝细胞癌主要发生在男性和遭受肝硬化的患者中。许多具有肝细胞癌的患者保持无症状直到该疾病处于它的晚期,从而产生无效的治疗和预后不良;大部分不可切除的肝细胞癌患者在一年内死亡。
NKG2D(natural-killer group 2member D,或NKG2D受体),即杀伤细胞凝集素样受体亚家族K成员1,是在所有自然杀伤细胞,自然杀伤T细胞和γδ+T细胞表达的II型跨膜蛋白。在人体中,NKG2D受体主要与两种配体结合,这两种配体分别是UL16-结合蛋白(UL16-binding protein,ULBP)和MHC I型链相关蛋白A/B(MHC class I-chain-relatedprotein,MICA/B)。人类NKG2D配体的表达很少在健康组织中检测到,但在肿瘤细胞中以及在细胞应激和病毒感染期间上调。NKG2D及其配体的结合作为针对肿瘤和病毒感染的免疫应答中的激活信号。
近年在使用利用基因工程化产生的嵌合抗原受体(CAR)T细胞进行自体治疗的B细胞淋巴瘤和白血病中获得了空前的效果,所以已经开始将该方法应用至实体肿瘤。经CAR修饰的T细胞将单克隆抗体的独立于HLA的靶向特异性与被激活的T细胞的溶细胞活性、增殖和归巢性质相结合,但是不响应于检查点抑制。但是,由于其直接杀死表达靶标的抗原的能力,CAR T细胞对于任何抗原阳性的细胞或组织是高度毒性的,这使得有需要通过高度肿瘤特异性的结构构建CAR。
2005年,NKG2D受体-NKG2D配体系统首次用于嵌合抗原受体(CAR)治疗(T.Zhang等,Blood,vol.106,no.5,pp.1544–1551,Sep.2005)。在自然杀伤细胞和T细胞中,DNAX活化蛋白10(DAP10)是NKG2D受体的细胞表面衔接子。
肝癌的治疗选择受到限制,特别是在晚期或复发性肝癌的情况下。外科手术和辐射疗法是早期肝癌的选择,但是对于晚期或复发性肝癌不是非常有效的。全身化学疗法尚未成为特别有效的,并且存在非常有限数目的可用药物。已经证实目前批准的激酶抑制剂索拉非尼在治疗肝癌中是有效的。但是,与没有治疗相比,它可以减慢或阻止晚期肝癌进展仅几个月。
因此,本领域需要更有效以及更安全的用于治疗肝癌的方法。
发明内容
本发明提供了一种新的嵌合抗原受体,其包含:(a)抗原结合结构域,其包括NKG2D或其活性片段;(b)跨膜结构域和(c)胞内信号传导结构域。本发明还提供了新的嵌合抗原受体和其辅助蛋白DAP10或其活性片段的联合。本发明还提供了编码所述嵌合抗原受体和/或DAP10的核酸和表达载体,以及表达所述嵌合抗原受体和/或DAP10的细胞。本发明还提供了采用所述嵌合抗原受体和/或DAP10的、其表达载体和细胞在治疗癌症的方法和制备治疗癌症的药物中的用途。
本发明提供了一种嵌合抗原受体(CAR),其包含:(a)抗原结合结构域,其包括NKG2D或其活性片段;(b)跨膜结构域和(c)胞内信号传导结构域。
本发明还提供了一种前面所述的嵌合抗原受体(CAR)和一种辅助蛋白的组合,其中所述CAR包含:(a)抗原结合结构域,其包括NKG2D或其活性片段;(b)跨膜结构域和(c)胞内信号传导结构域,以及其中所述辅助蛋白为DAP10或其活性片段。在本发明的其中一个方面,所述DAP10具有SEQ ID NO:4的氨基酸序列。
“NKG2D”或“NKG2D受体”,亦称“NKG2-D”、“CD314”、“KLRK1”、“杀伤细胞凝集素样受体亚家族K成员1”,是指哺乳动物特别是人的杀伤细胞激活性受体基因(其mRNA如NCBIRefSeq NM_007360)或其基因产物(如NCBI RefSeq NP_031386)或其天然存在的变体。在人类NK细胞和T细胞中,配体结合形式的NKG2D受体是同二聚体(Li等,Nat Immunol 2001;2:443-451)。NKG2D活性,包括细胞活化、抗体识别等,还包括与两种配体结合,这两种配体分别是UL16-结合蛋白(UL16-binding protein,ULBP)和MHC I型链相关蛋白A/B(MHC classI-chain-related protein MICA/B)。
DAP10(membrane protein 10)是指哺乳动物特别是人的表面蛋白基因或其基因产物(如GenBank:AAG29425.1所示)。DAP10的活性包括与NKG2D形成复合体(Wu,J.等,Science 285(5428),730-732,1999)。
在本发明的其中一个方面,所述嵌合抗原受体(CAR)的抗原结合结构域包含NKG2D的活性片段。所述活性片段例如为NKG2D的a.a.82-216片段,即具有SEQ ID NO:2的氨基酸序列的第82-216个氨基酸:LFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV。
在本发明的其中一个方面,所述抗原结合结构域可包含前导序列(leadingpeptide)。前导序列可协助蛋白在细胞膜上的表达或进出膜。本领域已知的前导序列可用于本发明的CAR。在本发明中,前导序列可以位于所述NKG2D或其活性片段的上游。在本发明的其中一种实施方案中,在所述前导序列为CD33的前导序列,其具有SEQ ID NO:18的氨基酸序列。前导序列可以促进CAR在细胞表面上的表达,但是在表达的CAR中存在前导序列不是CAR发挥功能所必需的。在本发明的实施方案中,CAR在细胞表面上表达后,前导序列可以从CAR上切除。因此,在本发明的实施方案中,CAR可以没有前导序列。
在本发明的其中一个方面,所述CAR包括跨膜结构域。本领域已知的跨膜结构域可用于本发明。跨膜结构域包括T细胞受体的α、β、或ζ、CD28,CD3ε,CD45,CD4,CD5,CD8,CD9,CD16,CD22,CD33,CD37,CD64,CD80,CD86,CD134,CD137,CD154,KIRDS2,OX40,CD2,CD27,LFA-1(CD11a,CD18),ICOS(CD278),4-1BB(CD137),GITR,CD40,BAFFR,HVEM(LIGHTR),SLAMF7,NKp80(KLRF1),CD160,CD19,IL2Rβ,IL2Rγ,IL7Rα,ITGA1,VLA1,CD49a,ITGA4,IA4,CD49D,ITGA6,VLA-6,CD49f,ITGAD,CD11d,ITGAE,CD103,ITGAL,CD11a,LFA-1,ITGAM,CD11b,ITGAX,CD11c,ITGB1,CD29,ITGB2,CD18,LFA-1,ITGB7,TNFR2,DNAM1(CD226),SLAMF4(CD244,2B4),CD84,CD96(Tactile),CEACAM1,CRTAM,Ly9(CD229),CD160(BY55),PSGL1,CD100(SEMA4D),SLAMF6(NTB-A,Ly108),SLAM(SLAMF1,CD150,IPO-3),BLAME(SLAMF8),SELPLG(CD162),LTBR,PAG/Cbp,NKp44,NKp30,NKp46等的跨膜结构域。
在本发明的其中一个方面,本发明的CAR的跨膜结构域包含i)CD8和/或ii)CD28的跨膜结构域。在本发明的其中又一个方面,本发明的CAR的跨膜结构域为CD28的跨膜结构域,例如,其可具有SEQ ID NO:8的氨基酸序列。
在本发明的其中一个方面,所述CAR包括胞内信号传导结构域。包含可用于本发明的胞内信号传导结构域的实例包括来自CD2、CD4、CD5、CD8α、CD8β、CD28、CD134、CD137、ICOS和CD154的胞内信号传导结构域。其具体实例包括具有以下序列的肽:CD2(NCBI RefSeq:NP_001758.2)的氨基酸编号236-351、CD4(NCBI RefSeq:NP_000607.1)的氨基酸编号421-458、CD5(NCBI RefSeq:NP_055022.2)的氨基酸编号402-495、CD8α(NCBI RefSeq:NP_001759.3)的氨基酸编号207-235、CD8β(GenBank:AAA35664.1)的氨基酸编号196-210、CD28(NCBI RefSeq:NP_006130.1)的氨基酸编号181-220(SEQ ID NO::25)、CD137(4-1BB,NCBIRefSeq:NP_001552.2)的氨基酸编号214-255、CD134(OX40,NCBI RefSeq:NP_003318.1)的氨基酸编号241-277和ICOS(NCBI RefSeq:NP_036224.1)的氨基酸编号166-199等,及其与这些肽具有相同功能的变体。
优选的,本发明CAR的细胞内T细胞信号传导结构域包含以下任何一种或多种的:i)CD28,ii)4-1BB,和/或iii)CD3ζ的胞内信号传导结构域。在优选的实施方案中,本发明CAR的细胞内T细胞信号传导结构域为CD28、4-1BB和CD3ζ的胞内信号传导结构域。更优选的,本发明CAR的细胞内T细胞信号传导结构域从氨基端到羧基端按顺序为CD28、4-1BB和CD3ζ。其中,CD28为T细胞共刺激中重要的T细胞标志物,其胞内信号传导结构域的序列例如可以包含SEQ ID NO:10所示的氨基酸序列。4-1BB,也被称为CD137,向T细胞传送有效的共刺激信号,从而促进T淋巴细胞的分化并增强其长期存活。CD3ζ与TCR联合以产生信号并含有基于免疫受体酪氨酸的激活基序(ITAM)。在本发明的其中一个方面,所述CAR的细胞内T细胞信号传导结构域包含的CD28、4-1BB和CD3ζ的胞内信号传导结构域分别具有SEQ IDNO:10、SEQ ID NO:12、SEQ ID NO:14的氨基酸序列。在本发明的其中又一个方面,所述CAR的细胞内T细胞信号传导结构域包含的CD28的胞内信号传导结构域具有例如SEQ ID NO:10的氨基酸序列。在本发明的其中又一个方面,所述CAR的细胞内T细胞信号传导结构域包含的4-1BB的胞内信号传导结构域具有例如SEQ ID NO:12的氨基酸序列。在本发明的其中又一个方面,所述CAR的细胞内T细胞信号传导结构域包含的CD3ζ的胞内信号传导结构域具有例如SEQ ID NO:14的氨基酸序列。
在包含多个胞内信号传导结构域的CAR中,可在胞内结构域之间插入寡肽接头或多肽接头以连接各结构域。优选地,可使用长度为2-10个氨基酸的接头。尤其是,可使用具有甘氨酸-丝氨酸连续序列的接头。
在本发明的其中一种实施方案中,所述CAR包含(a)抗原结合结构域,其为NKG2D的a.a.82-216片段;(b)CD28的跨膜结构域和(c)从氨基端按顺序为CD28、4-1BB和CD3ζ的胞内信号传导结构域。
在本发明的其中一个方面,其中所述CAR中,(a)抗原结构域和(b)跨膜结构域之间还具有铰链区。本领域已知的铰链区可用于本发明,包括IgG1H,IgG2H,IgG3H,IgG4H。在本发明的其中又一个方面,(a)抗原结构域和(b)跨膜结构域之间的铰链区包含IgG1H或其片段或变体,其氨基酸序列例如为SEQ ID NO:6。
包括在本发明范围内的是本文描述的本发明的蛋白质的功能变体,如CAR或其中各功能片段(包括抗原结合结构域,跨膜结构域,胞内信号传导结构域,铰链区,前导序列等)的功能变体。本文使用的术语“功能变体”是指具有与亲本蛋白质,如CAR大量的或显著的序列同一性或相似性的CAR、多肽或蛋白质,所述功能变体保留了CAR变体的生物活性。功能变体涵盖,例如,本文描述的CAR(亲本CAR)的那些变体,其保留了能够以与亲本CAR类似的程度、以与亲本CAR相同的程度或以比亲本CAR更高的程度识别靶细胞。关于亲本CAR,功能变体的氨基酸序列与亲本CAR的氨基酸序列可,例如,具有至少约30%、约50%、约75%、约80%、约90%、约98%、约99%或更高的同一性。
功能变体可,例如,包含具有至少一个保守性氨基酸置换的亲本CAR的氨基酸序列。替代地或另外地,功能变体可包含具有至少一个非保守性氨基酸置换的亲本CAR的氨基酸序列。在这种情况下,优选的是不会干扰或抑制功能变体的生物活性的非保守性氨基酸置换。非保守性氨基酸置换可以增强功能变体的生物活性,使得功能变体的生物活性与亲本CAR相比有所增加。
本发明的实施方案还提供包含编码本文描述的任何CAR的核苷酸序列的分离的核酸。本发明的核酸可包含编码本文描述的任何前导序列、抗原结合结构域、跨膜结构域和/或细胞内T细胞信号传导结构域的核苷酸序列。
在本发明的其中一个方面,提供了分离的核酸,其包括编码前面所述的嵌合抗原受体(CAR)的核苷酸序列,所述CAR包含:(a)抗原结合结构域,其包括NKG2D或其活性片段;(b)跨膜结构域和(c)胞内信号传导结构域,
在本发明的其中又一个方面,其中编码所述CAR的抗原结合结构域的核苷酸序列包含编码NKG2D的活性片段,优选为编码NKG2D的a.a.82-216片段的核苷酸序列,例如其具有SEQ ID NO:1所示的核苷酸序列。
在本发明的其中又一个方面,其中编码所述跨膜结构域的核苷酸序列包括编码CD8和/或CD28的跨膜结构域,优选为CD28的跨膜结构域的核苷酸序列,例如为SEQ ID NO:7的核苷酸序列。
在本发明的其中又一个方面,其中编码所述胞内信号传导结构域的核苷酸序列包括编码CD28,4-1BB和CD3ζ的胞内信号传导结构域中的一个或多个的核苷酸序列,优选包括编码CD28,4-1BB和CD3ζ的胞内信号传导结构域的核苷酸序列,更优选包括编码从氨基端到羧基端按顺序为CD28、4-1BB和CD3ζ的蛋白质的核酸序列;
本发明的其中又一个方面,所述编码CD28的胞内信号传导结构域的核酸具有例如SEQ ID NO:9的核苷酸序列;
本发明的其中又一个方面,所述编码4-1BB的胞内信号传导结构域具有例如SEQID NO:11的核苷酸序列;
本发明的其中又一个方面,所述编码CD3ζ的胞内信号传导结构域具有例如SEQ IDNO:13的核苷酸序列;
本发明的其中又一个方面,其中编码所述CAR的胞内信号传导结构域的核苷酸序列具有如SEQ ID NO:20的核苷酸序列,其包括编码CD28,4-1BB和CD3ζ的胞内信号传导结构域的核苷酸序列。
本发明的其中又一个方面,本发明提供的核酸中还包括编码(a)抗原结构域和(b)跨膜结构域之间还具有的铰链区的核苷酸序列,优选为编码IgGH1的核苷酸序列,其具有例如SEQ ID NO:5的核苷酸序列。
本发明的其中又一个方面,本发明提供的核酸中还包括编码位于所述NKG2D或其活性片段的上游的前导序列的核苷酸序列,优选为编码CD33的前导序列的核苷酸序列,例如为SEQ ID NO:17所示的核苷酸序列。
如前所述,本发明还提供了前面定义的嵌合抗原受体(CAR)和一种辅助蛋白的组合,所述辅助蛋白为DAP10或其活性片段。
本发明的其中又一个方面,本发明提供的核酸中还包括编码该嵌合抗原受体(CAR)和所述辅助蛋白的核苷酸序列,所述CAR包含:(a)抗原结合结构域,其包括NKG2D或其活性片段;(b)跨膜结构域和(c)胞内信号传导结构域,以及所述辅助蛋白为DAP10或其活性片段。其中,编码所述CAR的抗原结合结构域的核苷酸序列包含编码NKG2D的活性片段,例如为NKG2D的a.a.82-216片段的核苷酸序列,例如为SEQ ID NO:1所示的核苷酸序列。以及,其中编码所述DAP10的核酸具有序列为SEQ ID NO:3的核苷酸序列。
本文使用的“核酸”包括“多核苷酸”、“寡核苷酸”和“核酸分子”,并且通常意指DNA或RNA的聚合物,其可为单链或双链的,由天然来源合成或获得(如分离和/或纯化)的,可含有天然的、非天然的或改变的核苷酸,以及可含有天然的、非天然的或改变的核苷酸间连接,如氨基磷酸酯键或硫代磷酸酯键替代未修饰的寡核苷酸的核苷酸之间存在的磷酸二酯。在一些实施方案中,核酸不包含任何插入、缺失、倒置和/或置换。然而,在一些情况下,如本文所讨论的,包含一个或多个插入、缺失、倒置和/或置换的核酸可能为合适的。在一些实施方案中,核酸可以编码不会影响CAR的功能并且在宿主细胞表达核酸之后可以被翻译或不被翻译的另外的氨基酸序列。
本发明的实施方案还提供分离或纯化的核酸,所述核酸包含与本文描述的任何核酸的核苷酸序列互补的核苷酸序列或在严格条件下与本文描述的任何核酸的核苷酸序列杂交的核苷酸序列。
在严格条件下杂交的核苷酸序列可以在高严格条件下杂交。“高严格条件”意指核苷酸序列以强于非特异性杂交可检测的量与靶序列(本文描述的任何核酸的核苷酸序列)特异性杂交。高严格条件包括区分多核苷酸与精确的互补序列,或仅含有来自随机序列的一些分散的错配的互补序列的条件,所述随机序列碰巧具有匹配核苷酸序列的一些小区域(如3-10个碱基)。此类互补性的小区域比14-17个或更多个碱基的全长互补更容易熔融,并且高严格杂交使得它们易于被区分。相对地高严格条件将包括,例如,低盐和/或高温条件,如在约50-70℃的温度下通过约0.02-0.1M NaCl或等价物提供。此类高严格条件容许如果有的话,核苷酸序列与模板或靶链之间很少的错配,并且特别适于检测任何本发明CAR的表达。通常应理解可通过加入增加量的甲酰胺使条件更严格。
本发明还提供包含与本文描述的任何核酸具有至少约70%或更高,如约80%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%的同一性的核苷酸序列的核酸。
在实施方案中,本发明的核酸可掺入至重组表达载体中。在这方面,本发明的实施方案提供包含本发明的任何核酸的重组表达载体。为了本文的目的,术语“重组表达载体”意指基因修饰的寡核苷酸或多核苷酸构建体,当构建体包含编码mRNA、蛋白质、多肽或肽的核苷酸序列,并且在足以在细胞内表达mRNA、蛋白质、多肽或肽的条件下载体与细胞接触时,所述基因修饰的寡核苷酸或多核苷酸构建体允许宿主细胞表达mRNA、蛋白质、多肽或肽。本发明的载体并非是整个天然存在的。然而,载体的一部分可为天然存在的。本发明的重组表达载体可包含任何类型的核苷酸,包括但不限于DNA和RNA,所述DNA和RNA可为单链或双链,部分由天然来源合成或获得,并且可含有天然的、非天然的或改变的核苷酸。重组表达载体可包含天然存在的或非天然存在的核苷酸间连键或者这两种类型的连键。优选地,非天然存在的或改变的核苷酸或核苷酸间连键不会阻碍载体的转录或复制。
在实施方案中,本发明的重组表达载体可为任何合适的重组表达载体,并且可用于转化或转染任何合适的宿主细胞。本发明的合适的载体包括设计用于繁殖和扩增或用于表达或这两者的那些载体,如质粒和病毒。载体可选自pUC系列(FermentasLife Sciences,Glen Burnie,MD)、pBluescript系列(Stratagene,LaJolla,CA)、pET系列(Novagen,Madison,WI)、pGEX系列(Pharmacia Biotech,Uppsala,Sweden)和pEX系列(Clontech,PaloAlto,CA)。也可使用噬菌体载体,如λGT10、λGTl1、λZapII(Stratagene)、λEMBL4和λΝΜ1149。植物表达载体的实例包括pBI0l、pBI101.2、pBI101.3、pBI121和pBIN19(Clontech)。动物表达载体的实例包括pEUK-Cl、pMAM和pMAMneo(Clontech)。重组表达载体可以为病毒载体,如逆转录病毒载体或慢病毒载体。
重组表达载体可包含天然或非天然的启动子,其可操作地连接至编码CAR(包括其功能部分和功能变体)的核苷酸序列或至与编码CAR的核苷酸序列互补或杂交的核苷酸序列。启动子的选择,如强、弱、可诱导的、组织特异的和发育特异的,在本领域技术人员的能力内。类似地,核苷酸序列与启动子的组合也在本领域技术人员的普通技术内。启动子可为非病毒启动子或病毒启动子,如EF1α启动子,巨细胞病毒(CMV)启动子、SV40启动子、RSV启动子。EF1α启动子来源于EF1a启动子来自人类靶向延长因子1α(EF1A)基因。在本发明的其中又一个方面,本发明的重组表达载体中采用EF1α启动子,其具有例如为SEQ ID NO:15的核苷酸序列。
在本发明的一个方面,提供了前述本发明的嵌合抗原受体(CAR)表达载体,包含编码所述CAR的核酸,所述CAR包含:(a)抗原结合结构域,其包括NKG2D或其活性片段;(b)跨膜结构域和(c)胞内信号传导结构域。
在本发明的一个方面,还提供了前述本发明的嵌合抗原受体(CAR)和辅助蛋白的表达载体,其包含编码所述CAR的核酸和编码辅助蛋白的核酸,所述CAR包含:(a)抗原结合结构域,其包括NKG2D或其活性片段;(b)跨膜结构域和(c)胞内信号传导结构域,以及所述辅助蛋白为DAP10或其活性片段。在本发明的其中又一个方面,本发明的嵌合抗原受体(CAR)和辅助蛋白的表达载体可以在不同载体上具有编码所述嵌合抗原受体(CAR)或所述辅助蛋白的核酸。优选的,本发明的嵌合抗原受体(CAR)和辅助蛋白的表达载体在同一个载体上具有编码所述嵌合抗原受体(CAR)和所述辅助蛋白的核酸。
在本发明的一个方面,本发明的表达载体中编码所述CAR的抗原结合结构域的核苷酸序列包含编码NKG2D的活性片段,例如为NKG2D的
a.a.82-216片段的核苷酸序列,例如为SEQ ID NO:1所示的核苷酸序列。
在本发明的一个方面,本发明的表达载体中中编码所述跨膜结构域的核苷酸序列包括编码CD8和/或CD28的跨膜结构域,优选为CD28的跨膜结构域的核苷酸序列,例如为SEQID NO:7的核苷酸序列。
在本发明的一个方面,本发明的表达载体中中编码所述胞内信号传导结构域的核苷酸序列包括编码CD28,4-1BB和CD3ζ的胞内信号传导结构域中的一个或多个的核苷酸序列,优选包括编码CD28,4-1BB和CD3ζ的胞内信号传导结构域的核苷酸序列,更优选包括编码从氨基端到羧基端按顺序为CD28、4-1BB和CD3ζ的蛋白质的核酸序列。
其中,编码CD28的胞内信号传导结构域的核酸可具有例如SEQ ID NO:9的核苷酸序列。
其中,编码4-1BB的胞内信号传导结构域可具有例如SEQ ID NO:11的核苷酸序列;
其中,编码CD3ζ的胞内信号传导结构域可具有例如SEQ ID NO:13的核苷酸序列;
在本发明的又一个方面,其中编码所述CAR的胞内信号传导结构域的核苷酸序列具有如SEQ ID NO:20的核苷酸序列。
在本发明的一个方面,本发明的表达载体中还包括编码(a)抗原结构域和(b)跨膜结构域之间的铰链区的核苷酸序列,优选为编码IgGH1的核苷酸序列,其具有例如SEQ IDNO:5的核苷酸序列。
在本发明的一个方面,本发明的表达载体中还包括编码位于所述NKG2D或其活性片段的上游的前导序列的核苷酸序列,优选为编码CD33的前导序列的的核苷酸序列,例如为SEQ ID NO:17所示的核苷酸序列。
在本发明的一个方面,本发明的表达载体中还包括编码所述抗原结构域的引导肽的序列的上游的转录子,优选为Kozak片段的核苷酸序列,例如为SEQ ID NO:16的核苷酸序列。
在本发明的一个方面,本发明的表达载体中编码所述抗原结构域的引导肽的序列的上游具有启动子,优选为EF1α启动子,例如其序列为SEQ ID NO:15的核苷酸序列。
在本发明的一个方面,本发明的表达载体中编码所述DAP10的核酸具有序列为SEQID NO:3的核苷酸序列。
在本发明的一个方面,本发明的表达载体中,编码CAR和DAP10的片段之间还具有IRES的核苷酸序列,例如为SEQ ID NO:19的核苷酸序列。
在本发明的其中一个方面,还提供了表达前面描述的嵌合抗原受体(CAR)的宿主细胞。在本发明的其中一个方面,还提供了表达前面描述的嵌合抗原受体(CAR)和辅助蛋白的组合的宿主细胞。在本发明的其中一个方面,还提供包含前面描述的任何重组表达载体的宿主细胞。
如本文所用,术语“宿主细胞”是指可含有本发明重组表达载体的任何类型的细胞。宿主细胞可为真核细胞,如植物、动物、真菌或藻类,或者可为原核细胞,如细菌或原生动物。宿主细胞可为培养的细胞或原代细胞,即直接分离自生物体,如人。宿主细胞可为粘附细胞或悬浮细胞,即在悬浮液中生长的细胞。合适的宿主细胞为本领域中已知的并且包括,例如DH5α大肠杆菌细胞、中国仓鼠卵巢细胞、猴VERO细胞、COS细胞、HEK293细胞等。为了扩增或复制重组表达载体的目的,宿主细胞可以为原核细胞,如DH5α细胞。为了产生重组CAR的目的,宿主细胞可以为哺乳动物细胞。宿主细胞可以为人细胞。宿主细胞可为任何细胞类型,可来源于任何类型的组织并且可为任何发育阶段。例如,宿主细胞可以为外周血淋巴细胞(PBL)或外周血单核细胞(PBMC)。
在本发明的其中一个方面,宿主细胞为T细胞。为了本文的目的,T细胞可为任何T细胞,如培养的T细胞,例如原代T细胞或来自培养的T细胞系的T细胞,如Jurkat、SupTl等,或从哺乳动物获得的T细胞。如果从哺乳动物获得,则T细胞可从许多来源获得,包括但不限于血液、骨髓、淋巴结、胸腺或其它组织或液体。T细胞也可被富集或纯化。T细胞可以为人T细胞。T细胞可以为分离自人的T细胞。T细胞可为任何类型的T细胞并且可为任何发育阶段,包括但不限于CD4+/CD8+双阳性T细胞、CD4+辅助T细胞如Th 1和Th 2细胞、CD8+T细胞(如细胞毒性T细胞)、肿瘤浸润细胞、记忆T细胞、初始T细胞等。T细胞可以为CD8+T细胞或CD4+T细胞。
在本发明的其中一个方面,宿主细胞是自然杀伤(NK)细胞。术语“NK细胞”(也被称为自然杀伤细胞)是指起源于骨髓并且在先天免疫系统中起重要作用的一类淋巴细胞。NK细胞提供针对病毒感染的细胞、肿瘤细胞或其他应激细胞的快速免疫反应,即使是细胞表面上不存在抗体和主要组织相容性复合体。NK细胞可以是被分离的,也可以从商业上可获得的来源得到。
术语“分离的细胞”通常是指细胞基本上和组织的其他细胞分离。“免疫细胞”包括例如衍生自在骨髓中产生的造血干细胞(HSC)的白血细胞(白细胞)、淋巴细胞(T细胞、B细胞、自然杀伤(NK)细胞)和骨髓来源的细胞(嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、单核细胞、巨噬细胞、树突状细胞)。“T细胞”包括表达CD3的所有类型的免疫细胞,包括T辅助细胞(CD4+细胞)、细胞毒性T细胞(CD8+细胞)、自然杀伤T细胞、T调节细胞(Treg)和γδT细胞。“细胞毒性细胞”包括CD8+T细胞、自然杀伤(NK)细胞和嗜中性粒细胞,这些细胞能够介导细胞毒性反应。
本发明的CAR物质可以配制成药物组合物。在这方面,本发明的实施方案提供包含任何CAR、功能部分、功能变体、核酸、表达载体、宿主细胞(包括其群体)和抗体(包括其抗原结合部分)以及药学上可接受的载体的药物组合物。含有任何本发明的CAR物质的本发明药物组合物可包含多于一种的本发明CAR物质,如CAR和核酸,或两种或更多种不同的CAR。可选地,药物组合物可包含与其它药物活性剂或药物如化学治疗剂,如天冬酰胺酶、白消安、卡铂、顺铂、柔红霉素、阿霉素、氟尿嘧啶、吉西他滨(gemcitabine)、羟基脲、甲氨蝶呤、紫杉醇、利妥昔单抗(rituximab)、长春碱、长春新碱等组合的本发明的CAR物质。在优选的实施方案中,药物组合物包含本发明的宿主细胞或其群体。
关于药物组合物,药学上可接受的载体可为任何常规使用的那些载体并且仅受限于化学-物理考虑因素,如溶解性和与活性剂缺乏反应性以及给予途径。本文描述的药学上可接受的载体,例如媒介物、佐剂、赋形剂和稀释剂,为本领域技术人员熟知的并且公众容易获得。优选的是对活性剂为化学惰性的药学上可接受的载体和在使用条件下无有害的副作用或毒性的药学上可接受的载体。
用于制备可给予的(如可胃肠外给予的)组合物的方法为已知的或对本领域技术人员为显而易见的,且更详细地描述于,例如Remington:The Science and Practice ofPharmacy,Lippincott Williams&Wilkins;第21版(2005年5月1日)。
用于口服、气雾、胃肠外(如皮下、静脉内、动脉内、肌内、皮内、腹膜内和硬膜内)和外用给予的以下制剂仅为示例性的而非限制。可使用多于一种途径来给予本发明的CAR物质,并且在某些情况下,特定的途径可提供比另一途径更直接且更有效的应答。
为了本发明方法的目的,其中给予宿主细胞或细胞群体时,所述细胞可为与哺乳动物同种异体或哺乳动物自体的细胞。优选地,所述细胞为哺乳动物自体的。
本文提及的哺乳动物可为任何哺乳动物。如本文所用,术语“哺乳动物”是指任何哺乳动物,包括但不限于啮齿目的哺乳动物,如小鼠和仓鼠,以及兔形目的哺乳动物,如兔子。哺乳动物可以来自食肉目,包括猫科动物(猫)和犬科动物(犬)。哺乳动物可以来自偶蹄目,包括牛科动物(牛)和猪科动物(猪)或奇蹄目,包括马科动物(马)。哺乳动物可以为灵长目、猿目或猴目(猴)或猿猴亚目(人和猿)。优选地,哺乳动物为人。
本发明的药物组合物可用于治疗或预防癌症。
本发明还提供了采用前面所述的本发明的嵌合抗原受体(CAR)、或所述嵌合抗原受体(CAR)和辅助蛋白的组合,或所述核酸或是所述表达载体,或所述宿主细胞治疗或预防癌症的方法。本发明还提供了前面所述的本发明的嵌合抗原受体(CAR)、或所述嵌合抗原受体(CAR)和辅助蛋白的组合,或所述核酸或是所述表达载体,或所述宿主细胞在制备用于治疗或预防癌症的药物中的用途。所述癌症可为任何癌症,包括白血病、淋巴瘤、多发性骨髓瘤或实体瘤,在本发明的其中一个方面,所述癌症为NKG2D相关癌症。在所述癌症中,NKG2D受体-NKG2D配体系统在癌症细胞中表达和发挥生理生化作用。在这些癌症的细胞上,通常表达NKG2D配体,包括UL16-结合蛋白(UL16-binding protein,ULBP)或MHC I型链相关蛋白A/B(MHC class I-chain-related protein,MICA/B)。
在本发明的其中一个方面,所述癌症为肝癌。
附图说明
图1在Raji细胞株上检测NKG2D配体的表达的流式细胞仪分析结果图。
图2表达载体构建图。A:pCCL-DRCAR-IRES-DAP10表达载体;B:pHAGE-DRCAR表达载体。
图3表达载体pCCL-DRCAR-IRES-DAP10插入片段核苷酸序列和说明示意图。
图4表达载体pHAGE-DRCAR插入片段核苷酸序列和说明示意图。
图5质粒共转染293T细胞表达DRCAR的流式细胞仪分析结果图。最左边为对照(仅加入慢病毒包装质粒,不包括重组质粒)。中间为加入pHAGE-DRCAR重组质粒后包装慢病毒感染。右边为加入pCCL-DRCAR-IRES-DAP10重组质粒后包装慢病毒感染。
图6表达DRCAR的慢病毒的滴定。(A)为用不同量表达DRCAR的慢病毒的比例的流式细胞仪分析结果。(B)为对应柱状图。(C)根据流式细胞仪分析数据计算慢病毒滴度公式和结果。
图7.DRCAR-T细胞杀灭癌细胞效果图。图7(a)-图7(c)显示对3种表达NKG2D配体的肝癌细胞株的效果。图7(d)显示对不表达NKG2D配体的Raji细胞的效果。用流式细胞仪分析癌细胞的死亡率。
图8.DRCAR T细胞在人肝癌移植动物模型体内抑制肿瘤。图8(a)是实验设计图。图8(b)是注射4×106个的DRCAR T细胞的实验组的肝癌移植小鼠的存活结果图。图8(c)是注射5×106个的DRCAR T细胞的实验组的肝癌移植小鼠的存活结果图。
具体实施方式
实施例1实验和方法
细胞
白细胞层(buffy coat)从香港红十字会输血服务组织(Hong Kong Red CrossBlood Transfusion Service)获得。通过使用Ficoll-Paque PLUS(GE Healthcare)从白细胞层中分离外周血单核细胞(PBMC)。通过使用CD3/CD28Dynabeads(Thermo)从PBMC分离T细胞。将分离自PBMC的T细胞在由补充有5%人血清(Sigma),2mM L-谷氨酰胺(Thermo)和50U/ml IL-2(Peprotech)的AIM-V培养基(Thermo)组成的起始培养基或由补充有5%人血清,2mM L-谷氨酰胺和300U/ml IL-2的AIM-V培养基组成的扩增培养基(expansion medium)。
所有以下细胞系来自ATCC、ECACC或中国科学院细胞库。
在补充有10%FBS(Thermo),100U/ml青霉素和100U/ml链霉素(Thermo)的DMEM培养基(Thermo)中培养人胚胎肾上皮细胞系-293T(ATCC#CRL-3216)。
在补充有10%FBS,100U/ml青霉素和100U/ml链霉素的IMDM培养基中培养慢性骨髓性白血病细胞系-K562(ATCC#CCL-243)。
在补充有10%FBS,100U/ml青霉素和100U/ml链霉素的RPMI1640培养基(Thermo)中培养肝癌细胞系-QGY7703、SMMC7721和BEL7402。逆转录病毒质粒构建
慢病毒包装,浓缩和纯化
通过磷酸钙转染法将第三代慢病毒质粒pMDLg/pRRE,pMD2.G,pRSV-Rev和构建的表达载体以2:1:1:4的比例将质粒共转染293T细胞产生慢病毒。将新收集或解冻的含有慢病毒的上清液以300g离心3分钟以排除上清液中的细胞碎片。将上清液通过连接至30-ml注射器(TERUMO)的0.45-μm微型注射器过滤器过滤。将上清液在20000g,4℃下离心90分钟。超速离心后,除去上清液。将1/10起始慢病毒体积的AIM-V培养基加入离心管中重新悬浮沉淀。通过移液将慢病毒悬浮液混合。将浓缩的慢病毒分装并储存在-80℃冰箱中。
慢病毒滴度测定
在补充有10%FBS,100U/ml青霉素和100U/ml链霉素的1ml RPMI1640培养基中,将1×105个Jurkat细胞接种到12孔板的每个孔中。过夜培养后,将不同量的(5μl至100μl)浓缩的慢病毒分别加入孔中。样品重复三次以提高准确性。加入聚凝胺(Sigma)至每个孔中6ug/ul的终浓度。24小时后,通过离心收集细胞并重悬于1ml补充有10%FBS,100U/ml青霉素和100U/ml链霉素的新鲜RPMI1640培养基中。另外48小时后,收集细胞并通过流式细胞术测定表达CAR的Jurkat细胞的百分比。慢病毒滴度按下式计算。
T细胞分离,转导和培养
通过使用包被有CD3和CD28抗体的Dynabeads,以3:1的磁珠与细胞比率用于分离1×107个PBMC的CD3+细胞。将细胞和磁珠混合物在摇床上在室温下孵育1小时。用磁铁进行CD3+细胞富集,并以1x106个细胞/ml重新悬浮在起始培养基中。24小时后,通过离心(300xg,3分钟)收集细胞。丢弃上清液。将500μl AIM-V培养基中5×10 8TU慢病毒加入细胞并以2000×g离心2小时。将细胞重悬于慢病毒培养物中并加入1.5ml起始培养基。将细胞放回6孔板并置于培养箱(37度,5%CO2)中。24小时后,再次进行转导。另外24小时后,通过离心(300xg,3分钟)收集细胞并重悬于2ml扩增培养基中。将细胞放回6孔板并置于培养箱(37度,5%CO2)中。72小时后,将细胞转移至100-cm培养皿并以4×105个细胞/ml的浓度重新悬浮于扩增培养基中。转导率可以通过使用流式细胞仪来确定,并且当T细胞足够时可以进行细胞毒性测定。
蛋白表达和流式细胞术分析
为了检测细胞表面上的CAR表达(T细胞和Jurkat细胞),将1×106个细胞重悬于1ml PBS缓冲液中并用生物素山羊抗人IgG(H+L)(Jackson Lab)染色,随后用链霉亲和素-Apc(eBioscience)。
细胞毒性分析
通过离心收集靶细胞并以1×106个细胞/ml的浓度重悬于PBS中。将5ml细胞用2.5ul Oregon Green 488(Thermo)在37度下染色20分钟。加入20ml培养基以吸收过量的染料。将靶细胞以4×105个细胞/ml的浓度重新悬浮于培养基中。
通过离心收集T细胞并用靶细胞所需的培养基重新悬浮,浓度为1.6×107个细胞/ml。
将T细胞和靶细胞以5,10,20和40的比率混合。
[注:E:T比例即效应细胞(T细胞)与靶细胞的比例。]
将细胞在培养箱中相应地孵育5~8小时。通过离心收集细胞并重悬于500μl 7-AAD溶液(1μg/ml)中。细胞在冰上孵育30分钟。用流式细胞仪分析死亡率(7-AAD:激发波长561nm,发射波长670nm)。
实施例2 NKG2D配体在各种癌症细胞株上的表达
在不同癌症细胞株上检测NKG2D配体(人MICA/B和人ULBP1-ULBP6)的表达,以判断以NKG2D作为抗原结构域的CAR是否可用于杀伤这些细胞株。
为了检测人MICA/B,将1×106个待测细胞重悬于0.5ml PBS缓冲液中,并用单克隆小鼠抗人MICA/B(R&D Cat#MAB13001),然后用生物素山羊抗小鼠IgG(H+L)和链霉亲和素-APC染色。
为了检测人ULBP2/5/6,将1×106个待测细胞重悬于0.5ml PBS缓冲液中,并用单克隆小鼠抗人ULBP2/5/6(R&D Cat#MAB1298),然后用生物素山羊抗小鼠IgG(H+L)和链霉亲和素-APC染色。
为了检测人ULBP1,将1×106个待测细胞重悬于0.5ml PBS缓冲液中,并用单克隆小鼠抗人ULBP1(R&D Cat#MAB1380),然后用生物素山羊抗小鼠IgG(H+L)和链霉亲和素-APC染色。
为了检测人ULBP3,将1×106个待测细胞重悬于0.5ml PBS缓冲液中,并用单克隆小鼠抗人ULBP3(R&D Cat#MAB1517),然后用生物素山羊抗小鼠IgG(H+L)和链霉亲和素-APC染色。
为了检测人ULBP4,将1×106个待测细胞重悬于0.5ml PBS缓冲液中,并用单克隆小鼠抗人ULBP4(R&D Cat#AF6285),然后用生物素牛抗山羊IgG(H+L)和链霉亲和素-APC染色。
对以下肝癌细胞株进行检测NKG2D配体(人MICA/B和人ULBP1-ULBP6)的表达的检测:
肝癌细胞系-QGY7703、SMMC7721和BEL7402
实验结果证明,在上述3种癌症细胞株中,表达了NKG2D配体。将上述3种癌症细胞株在下面的CAR T细胞杀伤实验作为靶细胞进行测试。
另外,如图1所示,Raji细胞不表达NKG2D配体(人MICA/B和人ULBP1-ULBP6)。Raji细胞在CAR T细胞杀伤实验中作为阴性对照。
实施例3表达DRCAR的慢病毒载体的构建
1.构建pCCL-DRCAR-IRES-DAP10
pCCL-DRCAR-IRES-DAP10具有如图2A所示的结构。pCCL-DRCAR-IRES-DAP10的构建通过以下方法。
合成核苷酸序列如图3所示的编码DRCAR和DAP10的核酸插入片段。该插入片段从5’端到3’端包括:1.HpaI酶切位点;2.EF1α启动子;3.Kozak;4.CD33前导序列;5.NKG2D的a.a.82-216片段;6.作为铰链区的IgG1H;7.CD28跨膜结构域;8.CD28的胞内信号传导结构域;9.4-1BB胞内信号传导结构域;10.CD3ζ的胞内信号传导结构域;11.连接片段;12.IRES;13.连接片段;14.DAP10;15.Sal I酶切位点。
将上述插入片段与质粒Pax5(Addgene,plasmid#35003)用限制性内切酶HpaI和Sal I进行双酶切,酶切产物切胶回收后,用T4连接酶16℃过夜连接。连接后转化大肠杆菌感受态,涂布平板,次日挑取单克隆进行双酶切及测序鉴定,得到pCCL-DRCAR-IRES-DAP10。
2.构建pHAGE-DRCAR
pHAGE-DRCAR具有如图2B所示的结构。pHAGE-DRCAR的构建通过以下方法。
合成核苷酸序列如图4所示的编码DRCAR的核酸插入片段。该插入片段从5’端到3’端包括:1.HpaI酶切位点;2.EF1α启动子;3.Kozak;4.CD33前导序列;5.NKG2D的a.a.82-216片段;6.作为铰链区的IgG1H;7.CD28跨膜结构域;8.CD28的胞内信号传导结构域;9.4-1BB胞内信号传导结构域;10.CD3ζ的胞内信号传导结构域;11.Sal I酶切位点。
将上述插入片段与质粒Pax5用限制性内切酶HpaI和Sal I进行双酶切,酶切产物切胶回收后,用T4连接酶16℃过夜连接。连接后转化大肠杆菌感受态,涂布平板,次日挑取单克隆进行双酶切及测序鉴定,得到pHAGE-DRCAR。
3.产生慢病毒载体
分别以pHAGE-DRCAR和pCCL-DRCAR-IRES-DAP10作为表达质粒,与第三代慢病毒质粒pMDLg/pRRE,pMD2.G,pRSV-Rev,共转染293T细胞制备得到对应的慢病毒载体。
根据实施例1记载方法计算慢病毒表达DRCAR的能力。图5是质粒共转染293T细胞表达DRCAR的流式细胞仪分析结果图。结果显示,与pHAGE-DRCAR相比,含有pCCL-DRCAR-IRES-DAP10的慢病毒的DRCAR表达水平明显较高。
根据实施例1记载方法计算含pCCL-DRCAR-IRES-DAP10的慢病毒的滴度。图6显示pCCL-DRCAR-IRES-DAP10包装慢病毒的滴度为约2×107TU/ml。与pHAGE-DRCAR相比,含有pCCL-DRCAR-IRES-DAP10的慢病毒,慢病毒效价较高。
实施例4 DRCAR-T细胞体外杀伤癌细胞
根据实施例1记载的方法,从人的PBMC中提取和获得T细胞。然后用实施例3制备得到的含有pCCL-DRCAR-IRES-DAP10的慢病毒转染T细胞。
根据实施例1记载的方法进行细胞毒性测定,检查表达DRCAR的T细胞对各种肿瘤细胞的特异性细胞毒性作用。其中,分别以含有pCCL-DRCAR-IRES-DAP10的T细胞和未用慢病毒转染的T细胞作为效应细胞,以21种癌细胞作为靶细胞。
使用不表达NKG2D配体的Raji细胞株作为阴性对照。
结果如图7(a)-图7(c)所示,在相同实验条件下,与不含有DRCAR的正常T细胞相比,表达DRCAR的T细胞能够诱导显著更多的靶肿瘤细胞死亡。所述肿瘤细胞包括:肝癌细胞系-QGY7703、SMMC7721和BEL7402。
如图7(d)所示,在不表达NKG2D配体的Raji细胞株的阴性对照中,DRCAR-T细胞没有表现出比对照的天然T细胞有所区别。
实施例5 DRCAR T细胞在人肝癌移植动物模型体内抑制肿瘤
图8(a)是实验设计图。
实验小鼠(NSG小鼠,6-8周龄,香港科技大学动物房提供)共20只,分为DRCAR T细胞治疗组(随机选择12只)和对照组(8只)。所有小鼠在实验第0天注射肝癌细胞SMMC7721(1×106个),各组在实验第2周、第5周和第7周分三次注射同样个数的DRCAR T细胞(治疗组)或T细胞(对照组)。每天观察小鼠肿瘤生长情况和生存情况,并记录数据。实验终点的小鼠特征为死亡,或体重减轻20%或以上,眼睛凹陷或眼睑闭合,反应迟钝或离群。
实验一:
在实验第2周、第5周和第7周分三次注射4×106个的DRCAR T细胞(治疗组)或T细胞(空白组)
实验结果如图8(b)所示。
实验二:
在实验第2周、第5周和第7周分三次注射5×106个的DRCAR T细胞(治疗组)或T细胞(空白组)
实验结果如图8(c)所示。
从实验结果得出,和对照组比较,本发明的DRCAR T细胞能够比不含有DRCAR的天然T细胞更有效地保护患癌动物的存活。
以上各实验结果表明,本发明提供的具有NKG2D抗原受体结构的DRCAR和DRCAR-T细胞,能够有效地识别具有NKG2D配体的癌症细胞,并激活肿瘤细胞特异性的抗肿瘤细胞免疫应答和杀伤相关肿瘤细胞。实验还证明,本发明提供的DRCAR和DRCAR-T细胞能够广谱地杀伤各种肝癌细胞,并在动物体内证明了其抑制肝癌的效果。
上面是对本发明进行的说明,不能将其看成是对本发明进行的限制。除非另外指出,本发明的实践将使用有机化学、聚合物化学、生物技术等的常规技术,显然除在上述说明和实施例中所特别描述之外,还可以别的方式实现本发明。其它在本发明范围内的方面与改进将对本发明所属领域的技术人员显而易见。根据本发明的教导,许多改变和变化是可行的,因此其在本发明的范围之内。以下
如无特别表示,本文中出现的温度的单位“度”是指摄氏度,即℃。
以下文献以全文引入方式在本申请进行参考。
序列表
<110> 达仁生物科技有限公司
<120> 嵌合抗原受体和其治疗肝癌的方法
<150> 201810299324.8
<151> 2018-04-04
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Claims (4)
1.宿主细胞在用于制备治疗或预防肝癌的药物中的用途,所述宿主细胞为由分离自受试者的T细胞衍生的T细胞,其包含核酸或是包含所述核酸的表达载体,
其中所述核酸包括编码嵌合抗原受体(CAR)的核酸和编码DAP10的核酸,所述CAR包含:(a)抗原结合结构域,其包括NKG2D的a.a.82-216片段,其为氨基酸序列如SEQ ID NO:2所示的第82-216个氨基酸的多肽;(b)跨膜结构域,其氨基酸序列如SEQ ID NO:8所示;和(c)从氨基端到羧基端按顺序为CD28、4-1BB和CD3ζ的胞内信号传导结构域,其中CD28胞内结构域的氨基酸序列如SEQ ID NO:10所示,4-1BB胞内结构域的氨基酸序列如SEQ ID NO:12所示,CD3ζ胞内结构域的氨基酸序列如SEQ ID NO:14所示;所述DAP10氨基酸序列如SEQ ID NO:4所示;以及,编码所述CAR的核酸片段和编码所述DAP10的核酸片段之间具有IRES的片段;
其中所述核酸还包括编码(a)抗原结构域和(b)跨膜结构域之间的铰链区的核酸,所述铰链区为IgG1H,其氨基酸序列如SEQ ID NO:6所示,
其中所述核酸还包括编码位于所述NKG2D片段的上游的前导片段的核酸,所述前导片段为CD33的前导片段,其氨基酸序列如SEQ ID NO:18所示。
2.根据权利要求1所述的用途,其中编码所述CAR的(a)抗原结合结构域的核苷酸序列如SEQ ID NO:1所示;编码所述CAR的(b)跨膜结构域的核苷酸序列如SEQ ID NO:7所示;编码所述CAR的(c)从氨基端到羧基端按顺序为CD28、4-1BB和CD3ζ的胞内信号传导结构域的核苷酸序列分别如SEQ ID NO:9、SEQ ID NO:11和SEQ ID NO:13所示;编码所述DAP10的核苷酸序列如SEQ ID NO:3所示;以及,编码所述CAR的核酸片段和编码所述DAP10的核酸片段之间的IRES的核苷酸序列如SEQ ID NO:19所示;
其中编码(a)抗原结构域和(b)跨膜结构域之间的铰链区的核苷酸序列如SEQ ID NO:5所示,以及其中编码CD33的前导序列的核苷酸序列如SEQ ID NO:17所示。
3.根据权利要求2所述的用途,其中编码所述CAR的(c)从氨基端到羧基端按顺序为CD28、4-1BB和CD3ζ的胞内信号传导结构域的核苷酸序列如SEQ ID NO:20所示。
4.根据权利要求1所述的用途,其中所述表达载体为慢病毒载体。
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CN111632135A (zh) * | 2020-05-09 | 2020-09-08 | 深圳宾德生物技术有限公司 | 靶向nkg2d的嵌合抗原受体t细胞在治疗前列腺癌中的应用、治疗前列腺癌的药物 |
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US11661459B2 (en) | 2020-12-03 | 2023-05-30 | Century Therapeutics, Inc. | Artificial cell death polypeptide for chimeric antigen receptor and uses thereof |
EP4263600A1 (en) | 2020-12-18 | 2023-10-25 | Century Therapeutics, Inc. | Chimeric antigen receptor systems with adaptable receptor specificity |
WO2024012585A1 (zh) * | 2022-07-14 | 2024-01-18 | 达仁生物科技有限公司 | Nkg2d嵌合抗原受体和pd1抑制剂联合治疗癌症的方法和药物 |
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