CN118126191A - 靶向TGF-β的嵌合抗原受体及其用途 - Google Patents
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Abstract
本发明提供靶向TGF‑β的嵌合抗原受体,其包含靶向TGF‑β的单域抗体、跨膜结构域和胞内信号传导结构域。本发明还涉及包含本发明的嵌合抗原受体的工程化免疫细胞及其药物组合物,以及所述嵌合抗原受体、工程化免疫细胞和药物组合物在制备治疗/预防/诊断癌症、感染或自身免疫性疾病的药物中的用途。
Description
技术领域
本发明属于肿瘤免疫治疗技术领域。更具体地,本发明涉及一种靶向TGF-β的嵌合抗原受体及其用途。
背景技术
自从两款CAR-T产品Kymriah和Yescarta于2017年被美国FDA批准上市,这种新型肿瘤疗法已经进入快速发展期,并已经成功用于多种血液肿瘤的治疗,展现出非常优异的疗效。与血液肿瘤相比,CART疗法在实体瘤治疗中的进展则相对较为缓慢。具体而言,缺乏特异性靶点、肿瘤微环境的抑制作用、CART细胞归巢困难、肿瘤高度异质性等,均是实体瘤治疗面临的巨大障碍。如何解决这些问题则成为开发CART疗法的焦点和难点。
TGF-β是一种细胞因子,在肿瘤微环境中发挥抑制作用。例如,TGF-β能够促进Treg细胞的扩增,抑制效应T细胞和树突状细胞的产生和功能、诱导肿瘤细胞免疫逃逸等。TGF-β在肿瘤微环境中的存在大大降低了CART的治疗效果。因此,需要开发一种新的CART疗法,来解决上述问题。
发明内容
本发明的目的在于提供一种用靶向TGF-β的单域抗体构建的嵌合抗原受体,其能够激活T细胞,降低肿瘤微环境中TGF-β的免疫抑制作用,进而提高表达该嵌合抗原受体的免疫细胞的杀伤活性和肿瘤抑制效果。
因此,在第一个方面,本发明提供一种嵌合抗原受体,其包含靶向TGF-β的单域抗体、跨膜结构域和胞内信号传导结构域。
嵌合抗原受体
如本文所用,术语“嵌合抗原受体”是指人工构建的杂合多肽,该杂合多肽的基础结构包括胞外区(例如抗体的抗原结合部分或抗原配体的胞外区)、跨膜结构域和胞内区(包含共刺激结构域和/或初级信号传导结构域)。嵌合抗原受体能够利用抗原结合结构域的抗原结合特性以非MHC限制性的方式将T细胞和其它免疫细胞的特异性和反应性重定向至所选择的靶标。非MHC限制性的抗原识别给予表达嵌合抗原受体的T细胞与抗原处理无关的识别抗原的能力,因此绕过了肿瘤逃逸的主要机制。本发明提供靶向TGF-β的嵌合抗原受体,也称为TGF-βCAR。
在一个实施方案中,本发明的嵌合抗原受体的胞外区包含靶向TGF-β的抗体,所述抗体是单域抗体。
如本文所用,术语“抗体”具有本领域技术人员所理解的最广泛的含义,并且包括单克隆抗体(包含完整抗体)、多克隆抗体、多价抗体、和能够表现期望的生物活性的携带一个或多个CDR序列的抗体片段或合成多肽。常规抗体(例如IgG抗体)包含两条相同的重链和两条相同的轻链,每条轻链通过二硫键被连至各自的重链,呈“Y”形结构。每条重链包含重链可变区(VH)和重链恒定区,其中重链可变区包含三个互补决定区(CDR):CDR1-H、CDR2-H和CDR3-H,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(VL)和轻链恒定区,其中轻链可变区包含三个CDR:CDR1-L、CDR2-L和CDR3-L,轻链恒定区包含一个恒定结构域CL。在重链/轻链可变区中,CDR被更保守的框架区(FR)隔开。重链/轻链的可变区负责与抗原的识别和结合,因此,常规抗体中,一个抗原-抗体结合位点的形成需要6个CDR的参与。恒定区则可以介导抗体与宿主组织或因子的结合,包括免疫系统的各种细胞(例如效应细胞)和经典补体系统的第一组分。本发明的“抗体”涵盖能够特异性结合抗原的抗体片段或抗原结合片段,例如包括但不限于:Fab、Fab'、F(ab')2、Fd片段、Fd′、Fv片段、单链抗体(scFv)、二硫键-连接的Fv(sdFv)、抗体的重链可变区(VH)或轻链可变区(VL)、线性抗体、具有两个抗原结合位点的“双体”、单域抗体、纳米抗体、所述抗原的天然配体或其功能性片段等。在一个实施方案中,本发明的抗体是鼠源抗体、驼源抗体、嵌合抗体、人源化抗体或人抗体。
如本文所用,术语“单域抗体”或“sdAb”是指仅含有3个CDR的抗原结合多肽,其不需要与其他含有CDR的多肽配对即可单独结合抗原。单域抗体可以仅包含重链(VH)或轻链(VL)。目前已经在骆驼科动物(如骆驼、美洲驼或羊驼)和软骨鱼类(如鲨鱼、鳐鱼)中发现了天然缺失轻链的抗体。这种天然缺失轻链的抗体也称为重链抗体(HCAb),其一般包含重链可变区和重链恒定区。重链抗体包含的重链可变结构域称为VHH,也称为纳米抗体。在一个实施方案中,本文所用的TGF-β结合抗体可以是驼源抗体、嵌合抗体、人抗体或人源化抗体。
本领域已知的TGF-β单域抗体均可用于本发明。在一个实施方案中,所述靶向TGF-β的单域抗体包含的CDR1、CDR2、CDR3与SEQ ID NO:4包含的CDR1、CDR2、CDR3相同。在一个实施方案中,所述靶向TGF-β的单域抗体包含(a)与SEQ ID NO:1所示的氨基酸序列具有至少约85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的CDR1,(b)与SEQ ID NO:2所示的氨基酸序列具有至少约85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的CDR2,和(c)与SEQ ID NO:3所示的氨基酸序列具有至少约85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性CDR3。在一些实施方案中,具有至少约85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的CDR相对于参考序列含有取代(例如,保守取代)、插入或缺失,但包含该序列的抗TGF-β抗体保留了结合至TGF-β的能力。在一个实施方案中,所述特异性结合TGF-β的单域抗体包含(a)与SEQ IDNO:1所示的氨基酸序列相比,具有约1个、2个、3个或4个氨基酸取代(例如,保守取代)、插入或缺失的CDR1,(b)与SEQ ID NO:2所示的氨基酸序列相比,具有约1个、2个、3个或4个氨基酸取代(例如,保守取代)、插入或缺失的CDR2,和(c)与SEQ ID NO:3所示的氨基酸序列相比,具有约1个、2个、3个或4个氨基酸取代(例如,保守取代)、插入或缺失的CDR3。
在一个实施方案中,所述靶向TGF-β的单域抗体与SEQ ID NO:4具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%序列同一性。
如本文所用,术语“同一性”表示两个(核苷酸或氨基酸)序列在比对中在相同位置处具有相同残基的程度,并且通常表示为百分数。优选地,同一性在被比较的序列的整体长度上确定。因此,具有完全相同序列的两个拷贝具有100%同一性。
如本文所用,术语“跨膜结构域”是指能够使嵌合抗原受体在细胞(例如淋巴细胞、NK细胞或NKT细胞)表面上表达,并且引导免疫细胞针对靶细胞的细胞应答的多肽结构。跨膜结构域可以是天然或合成的,也可以源自任何膜结合蛋白或跨膜蛋白。当嵌合受体多肽与靶抗原结合时,跨膜结构域能够进行信号传导。特别适用于本发明中的跨膜结构域可以源自例如例如T细胞受体的α、β或ζ链、CD28、CD3ε、CD45、CD4、CD5、CD8a、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD94、CD134、CD137、CD154、KIRDS2、OX40、CD2、CD27、CD18、ICOS、4-1BB、GITR、CD40、BAFFR、HVEM、SLAMF7、NKp80、CD160、BCMA、IL-2Rβ、IL-2Rγ、IL-7Ra、ITGA1、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDl ld、ITGAE、CD103、ITGAL、CDl la、LFA-1、ITGAM、CDl lb、ITGAX、CDl lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、TNFR2、DNAM1、SLAMF4、CD84、CD96、CEACAM1、CRT AM、Ly9、CD160、PSGL1、CDIOO、SLAMF6、SLAMF1、SLAMF8、CD162、LTBR、PAG/Cbp、NKp44、NKp30、NKp46、NKG2D和/或NKG2C。优选地,所述跨膜结构域选自CD8α、CD4、CD28或CD278的跨膜结构域。在一个实施方案中,所述跨膜结构域为CD8α跨膜结构域,与SEQ ID NO:11或12所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性;或为CD28跨膜结构域,与SEQ ID NO:10所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明的嵌合抗原受体还可以包含位于抗体和跨膜结构域之间的铰链区。如本文所用,术语“铰链区”一般是指作用为连接跨膜结构域至抗体的任何寡肽或多肽。具体地,铰链区用来为抗体提供更大的灵活性和可及性。铰链区可以包含最多达300个氨基酸,优选10至100个氨基酸并且最优选25至50个氨基酸。铰链区可以源自全部或部分的天然分子的胞外区,如源自CD8α、CD28、FcγRIIIα受体、IgG4、IgG1、CD4或CD28的胞外区,或源自全部或部分的抗体恒定区。或者,铰链区可以是对应于天然存在的铰链序列的合成序列,或可以是完全合成的铰链序列。优选地,所述铰链区包含CD8α的铰链区部分,与SEQ ID NO:23或24所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。优选地,所述铰链区包含CD28的铰链区部分,与SEQ ID NO:22所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。优选地,所述铰链区包含IgG4的铰链区部分,与SEQ IDNO:25所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
如本文所用,术语“胞内信号传导结构域”是指转导效应子功能信号并指导细胞进行指定功能的蛋白质部分,其包含共刺激结构域、初级信号传导结构域或两者。胞内信号传导结构域负责在抗原结合区结合抗原以后的细胞内信号传递,从而导致免疫细胞和免疫反应的活化。换言之,胞内信号传导结构域负责活化其中表达嵌合抗原受体的免疫细胞的正常的效应子功能的至少一种。例如,T细胞的效应子功能可以是细胞溶解活性或辅助活性,包括细胞因子的分泌。
在一个实施方案中,本发明的嵌合抗原受体包含的初级信号传导结构域可以是T细胞受体和共受体的细胞质序列,其在抗原受体结合以后一同起作用以引发信号传导,以及这些序列的任何衍生物或变体和具有相同或相似功能的任何合成序列。初级信号传导结构域可以包含一个或多个基于免疫受体酪氨酸的激活基序(ITAM)。本发明的初级信号传导结构域包括但不限于源自FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b、CD66d或其任意组合。优选地,所述初级信号传导结构域包含CD3ζ的信号传导结构域。更为优选地,所述初级信号传导结构域与SEQ ID NO:16、17或18所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明的嵌合抗原受体还包含一个或多个共刺激结构域。共刺激结构域可以是来自共刺激分子的细胞内功能性信号传导结构域,其可以包含所述共刺激分子的整个细胞内部分,或其功能片段。“共刺激分子”是指在T细胞上与共刺激配体特异性结合,由此介导T细胞的共刺激反应(例如增殖)的同源结合配偶体。共刺激分子包括但不限于1类MHC分子、BTLA和Toll配体受体。本发明的共刺激结构域的非限制性施例包括但不限于源自以下蛋白质的胞内区:TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、CD7、CD8、CD18、CD27、CD28、CD30、CD40、CD54、CD83、CD134、CD137、CD270、CD272、CD276、CD278、CD357、DAP10、DAP12、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM、ZAP70或其任意组合。优选地,所述共刺激结构域来自4-1BB、CD28、CD27、OX40、CD278或其任意组合。更为优选地,所述共刺激结构域来自4-1BB,与SEQ IDNO:14或15所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。更为优选地,所述共刺激结构域来自CD28,与SEQ ID NO:13所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明的TGF-βCAR是单价的,即,仅结合TGF-β靶点。在另一个实施方案中,本发明的TGF-βCAR是多价(例如二价、三价)的,即,其还结合除TGF-β之外的其他靶点。在该实施方案中,靶向TGF-β的单域抗体和靶向第二靶点的抗原结合结构域是串联或并联的形式。在本文中,“串联”是指靶向TGF-β的单域抗体和靶向第二靶点的抗原结合结构域通过接头连接成为嵌合抗原受体的抗原结合区,并共享同一个跨膜结构域和胞内信号传导结构域。换言之,在“串联”的情况下,本发明的嵌合抗原受体包含:(1)抗原结合区,包含靶向TGF-β的单域抗体和靶向第二靶点的抗原结合结构域;(2)跨膜结构域;和(3)胞内信号传导结构域。本领域技术人员知晓,在串联形式下,靶向TGF-β的单域抗体和靶向第二靶点的抗原结合结构域可以通过接头以任何顺序连接。在本文中,“并联”是指靶向TGF-β的单域抗体和靶向第二靶点的抗原结合结构域位于两个不同的单元结构中,各自分别连接跨膜结构域和胞内信号传导结构域,所述两个不同的单元结构可以位于同一载体(例如,通过2A肽将两个单元结构连接,使其分别表达),或位于不同载体(例如,每个载体包含一个靶向TGF-β或第二靶点的单元结构,然后将两个载体一起导入免疫细胞)。换言之,在“并联”的情况下,本发明的嵌合抗原受体包含:(1)靶向TGF-β的第一单元结构,包含靶向TGF-β的单域抗体、第一跨膜结构域和第一胞内信号传导结构域;和(2)靶向第二靶点的第二单元结构,包含靶向第二靶点的抗原结合结构域、第二跨膜结构域和第二胞内信号传导结构域。任选地,所述第一单元结构和第二单元结构位于同一载体或不同载体。
在一个实施方案中,本发明的第二靶点选自:ALK、ADRB3、AKAP-4、APRIL、ASGPR1、BCMA、B7H3、B7H4、B7H6、bcr-abl、BORIS、BST2、BAFF-R、BTLA、CD2、CD3、CD4、CD5、CD7、CD8、CD19、CD20、CD22、CD24、CD25、CD28、CD30、CD33、CD38、CD40、CD44、CD44v6、CD44v7/8、CD47、CD52、CD56、CD57、CD58、CD70、CD72、CD79a、CD79b、CD80、CD81、CD86、CD97、CD123、CD133、CD137、CD 138、CD151、CD171、CD179a、CD300LF、CLEC12A、CDH16、CSPG4、CS1、CLL-1、Claudin6、Claudin18.1、Claudin 18.2、CEA、CEACAM6、c-Met、CAIX、CXORF61、CA125、CYP1B1、CS1、ELF2M、EGFR、EPCAM、EGFRvIII、EphA2、ERG/TMPRSS2ETS融合基因、ETV6-AML、EMR2、EGP2,EGP40、FAP、FAR、FBP、FLT3、FOSL1、FCRL5、FCAR、Flt3、Flt4、Frizzled、GD2、GD3、gp100、gp130、GM3、GPC2、GPC3、GPRC5D、GPR20、GloboH、GHRHR、GHR、GITR、Her2、HER3、HER-4、HMWMAA、HAVCR1、HPV E6,E7、HVEM、HIV-1Gag、HLA-A1、HLA-A2、IL6R、IL-11Ra、IL-13Ra、IGF-I受体、LTPR、LIFRP、LRP5、IGLL1、IGF1R、KIT、Kappa Light Chain、KDR、LewisY、LMP2、LY6K、LAGE-1a、legumain、LCK、LAIR1、LILRA2、LY75、MSLN、MUC1、MUC16、MAGE-A1、MAGE3、MAD-CT-1、MelanA/MART1、ML-IAP、MYCN、mut hsp70-2、NCAM、NY-BR-1、NY-ESO-1、NA17、Notch-1-4、nAchR、NKG2D、NKG2D配体、OY-TES1、OR51E2、OX40、PRSS21、PSCA、PD1、PD-L1、PD-L2、PSMA、Prostase、PAP、PDGFR-β、PCTA-1/半乳凝集素8、p53、p53突变体、prostein、PLAC1、PANX3、PAX3、PAX5、PTCH1、RANK、RAGE-1、ROR1、Ras突变体、RhoC、RU1、RU2、Robol、SSEA-4、SSX2、SART3、Sp17、TSHR、Tn Ag、TGS5、TEM1/CD248、TEM7R、TARP、TCRα、TCRβ、TGF-ΒR1、TGF-ΒR2、TNFRSF4、TWEAK-R、TLR7、TLR9、TAG72、TROP-2、Tie 2、TRP-2、TNFR1、TNFR2、TEM1、UPK2VEGFR、WT1、XAGE1、5T4、8H9、αvβ6整合素、CA9、叶酸受体α、肝配蛋白B2、酪氨酸酶、岩藻糖基GM1、邻-乙酰-GD2、叶酸受体β、多聚唾液酸、精子蛋白17、存活蛋白和端粒酶、肉瘤易位断点、人端粒末端逆转录酶/hTERT、雄激素受体、肠羧基酯酶、细胞周期蛋白B1、纤连蛋白、腱生蛋白、肿瘤坏死区的癌胚变体或其任意组合。优选地,所述第二靶点选自CD7、CD19、CD20、CD22、CD30、CD33、CD38、CD123、CD138、CD171、MUC1、MSLN、AFP、叶酸受体α、CEA、PSCA、PSMA、Her2、EGFR、IL-13Ra、GD2、NKG2D、Claudin18.2、ROR1、EGFRvIII、CS1、BCMA和GPRC5D,更优选选自CD19、Claudin18.2、MSLN、GPRC5D、CD7和BCMA。
在一个实施方案中,第二靶点是Claudin18.2。优选地,靶向Claudin18.2的抗原结合结构域是抗Claudin18.2抗体。在一个实施方案中,所述抗Claudin18.2抗体是scFv或sdAb。优选地,所述抗Claudin18.2抗体是sdAb,其包含的CDR1、CDR2和CDR3与SEQ ID NO:9所包含的CDR1、CDR2和CDR3相同。在一个实施方案中,所述抗Claudin18.2抗体与SEQ IDNO:9具有至少至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。优选地,所述抗Claudin18.2抗体如SEQ ID NO:9所示。
在一些实施方案中,本发明的CAR还包含信号肽,所述信号肽选自以下蛋白的信号肽:CD8α、IgG1、GM-CSFRα、IgG4或其任意组合。优选地,所述信号肽包含CD8α的信号肽,其与SEQ ID NO:20或21所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。优选地,所述信号肽包含B2M信号肽,其与SEQ IDNO:19所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一些实施方案中,本发明的CAR还包含接头,其用于隔开任何本文中所述的结构域/区。例如,接头可位于信号肽与抗原结合结构域之间、抗体与抗体之间、抗体的VH与VL之间、抗原结合结构域与铰链区之间、铰链区与跨膜结构域之间、侧接共刺激结构域或在共刺激结构域的N-或C-区上、和/或在跨膜结构域与初级信号传导结构域之间。接头可以是长度为约6至约40个氨基酸、或长度为约6至约25个氨基酸的肽。本领域常用的接头序列包括(GGGGS)n,n可以是1,2,3,4,5,6等。
核酸和载体
本发明还提供编码上述嵌合抗原受体的核酸分子以及包含该核酸分子的载体。
如本文所用,术语“核酸分子”包括核糖核苷酸和脱氧核糖核苷酸的序列,如经修饰的或未经修饰的RNA或DNA,各自为单链和/或双链形式的线性或环状,或它们的混合物(包括杂合分子)。因此,根据本发明的核酸包括DNA(比如dsDNA、ssDNA、cDNA)、RNA(比如dsRNA、ssRNA、mRNA、ivtRNA),它们的组合或衍生物(比如PNA)。优选地,所述核酸是DNA或RNA,更优选DNA。
可以对本发明的核酸序列进行密码子优化以在所需的细胞(如,免疫细胞)中进行最佳表达;或者用于在细菌、酵母菌或昆虫细胞中表达。密码子优化是指将目标序列中存在的在给定物种的高度表达的基因中一般罕见的密码子替换为在这类物种的高度表达的基因中一般常见的密码子,而替换前后的密码子编码相同的氨基酸。因此,最佳密码子的选择取决于宿主基因组的密码子使用偏好。
如本文所用,术语“载体”是用作将(外源)遗传材料转移到宿主细胞中的媒介核酸分子,在该宿主细胞中所述核酸分子可以例如复制和/或表达。可用于本发明的合适载体是本领域已知的,并且许多可商购获得。在一个实施方案中,本发明的载体包括但不限于质粒、病毒(例如逆转录病毒、腺病毒、腺伴随病毒、牛痘病毒、水泡性口炎病毒、麻疹病毒、腮腺炎病毒、脊髓灰质炎病毒、正粘液病毒、小病毒、马拉巴病毒、柯萨奇病毒、疱疹病毒和慢病毒等)、噬菌体、噬菌粒、粘粒和人工染色体(包括BAC和YAC)。载体一般还包含在细胞中自主复制的起点(如果需要多核苷酸的稳定表达)、选择标记和限制酶切割位点(如多克隆位点,MCS)。载体可另外包含启动子、多聚腺苷酸尾(polyA)、3’UTR、增强子、终止子、绝缘子、操纵子、选择标记、报告基因、靶向序列和/或蛋白质纯化标签等元件。在一个具体的实施方案中,所述载体是体外转录的载体。
工程化免疫细胞
本发明还提供一种工程化免疫细胞,其表达本发明的嵌合抗原受体、编码所述嵌合抗原受体的核酸分子,或包含所述核酸分子的载体。
本发明还提供一种组合物,其包含:(1)表达第一结构单元的第一工程化免疫细胞群,所述第一结构单元包含靶向TGF-β的单域抗体、第一跨膜结构域和第一胞内信号传导结构域;和(2)表达第二单元结构的第二工程化免疫细胞群,所述第二单元结构包含靶向第二靶点的抗原结合结构域、第一跨膜结构域和第一胞内信号传导结构域。在该实施方案中,第一工程化免疫细胞群和第二工程化免疫细胞群可以同时或顺次向受试者施用。
如本文所用,术语“免疫细胞”是指免疫系统的具有一种或多种效应子功能(例如,细胞毒性细胞杀伤活性、分泌细胞因子、诱导ADCC和/或CDC)的任何细胞。例如,免疫细胞可以是B细胞、T细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞或NKT细胞。免疫细胞可以从多种来源获得,例如可以来自受试者(例如,从受试者的外周血单核细胞、骨髓、淋巴结组织、脐带血、胸腺组织、来自感染部位的组织、腹水、胸膜积液、脾组织、肿瘤等分离而获得),或来自体外培养的细胞系(例如Jurkat、SupT1、NK92等),或从干细胞分化而来(例如,源自脐带血干细胞、祖细胞、骨髓干细胞、造血干细胞、成体干细胞、胚胎干细胞、多能干细胞、iPSC等)。优选地,免疫细胞是T细胞或NK细胞,更优选T细胞。T细胞也可以被浓缩或纯化。T细胞可以处于任何发育阶段,包括但不限于,CD4+CD8+T细胞、CD4+T细胞(例如Th1和Th2细胞)、CD8+T细胞(例如,细胞毒性T细胞)、CD4-CD8-T细胞、肿瘤浸润细胞、记忆T细胞、幼稚T细胞、γδ-T细胞、αβ-T细胞等。在一个优选的实施方案中,免疫细胞是人T细胞。可以使用本领域技术人员已知的多种技术,如Ficoll分离从受试者的血液获得T细胞。
采用本领域已知的常规方法(如通过转导、转染、转化等)可以将编码嵌合抗原受体的核酸分子序列引入免疫细胞,使其表达本发明的嵌合抗原受体。
在一个实施方案中,靶向TGF-β的第一单元结构与靶向第二靶点的第二单元结构位于同一载体,例如通过2A肽连接使得两个单元结构可以独立表达而互不影响。如本文所用,术语“2A肽”是一种cis-水解酶作用元件(CHYSEl),最初在口蹄疫病毒(FMDV)中发现。2A肽的平均长度为18~22氨基酸。在蛋白翻译时,2A肽可以通过核糖体跳跃从自身最后2个氨基酸C末端断裂。具体地,甘氨酸和脯氨酸之间的肽链结合群在2A位点是受损的,能引发核糖体跳跃而从第2个密码子开始翻译,从而使1个转录单元里的2个蛋白独立表达。这种2A肽介导的剪切广泛存在于真核动物细胞中。利用2A肽较高的剪切效率及其促使上下游基因平衡表达的能力,可以改进异源多聚蛋白(如细胞表面受体、细胞因子、免疫球蛋白等)的表达效率。常见的2A肽包括但不限于P2A、T2A、E2A、F2A等。
在一个实施方案中,本发明的工程化免疫细胞的至少一种内源性MHC相关基因的表达被抑制或沉默。在一个实施方案中,所述内源性MHC相关基因选自:HLA-A、HLA-B、HLA-C、B2M、HLA-DPA、HLA-DQ、HLA-DRA、TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK、CIITA或其任意组合,优选选自HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA或其任意组合。
在一个实施方案中,本发明的工程化免疫细胞的至少一种内源性TCR/CD3基因的表达被抑制或沉默。在一个实施方案中,所述TCR/CD3基因选自:TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ。
在一个实施方案中,除了MHC相关基因和任选的TCR/CD3基因,本发明的工程化免疫细胞的至少一种选自以下的基因的表达也被抑制或沉默:CD52、GR、dCK和免疫检查点基因,如PD1、LAG3、TIM3、CTLA4、PPP2CA、PPP2CB、PTPN6、PTPN22、PDCD1、HAVCR2、BTLA、CD160、TIGIT、CD96、CRTAM、TNFRSF10B、TNFRSF10A、CASP8、CASP10、CASP3、CASP6、CASP7、FADD、FAS、TGF-ΒRII、TGF-ΒRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、EIF2AK4、CSK、PAG1、SIT、FOXP3、PRDM1、BATF、GUCY1A2、GUCY1A3、GUCY1B2和GUCY1B3。
在一个实施方案中,所述工程化免疫细胞还表达细胞自杀元件。优选地,所述的细胞自杀元件位于CAR的N端或C端,所述的自剪切元件包括2A肽或IRES肽,优选P2A和T2A。更优选地,所述的细胞自杀元件选自下组:HSV-TK、iCasp9、ΔCD20、mTMPK、ΔCD19、RQR8、EGFRt或其任意组合。
抑制基因表达或使基因沉默的方法是本领域技术人员熟知的,包括但不限于例如通过大范围核酸分子酶、锌指核酸分子酶、TALE核酸分子酶或CRISPR/Cas系统产生DNA断裂、或通过反义寡核苷酸、RNAi、shRNA等技术使基因失活。
在一个实施方案中,本发明的工程化细胞是自体细胞或同种异体细胞。如本文所用,术语“同种异体”是指任何材料来源于与引入该材料的个体相同物种的不同动物或不同患者。当在一个或多个基因座处的基因不同时,认为两个或更多个体彼此为同种异体的。在一些情况下,来自同一物种的各个体的同种异体材料在基因上的不同可能足以发生抗原相互作用。
药物组合物和试剂盒
本发明还提供一种药物组合物,其包含本发明所述的工程化免疫细胞作为活性剂,和一种或多种药学上可接受的赋型剂。因此,本发明还涵盖所述工程化免疫细胞药或物组合物在制备药物中的用途。
如本文所用,术语“药学上可接受的赋型剂”是指在药理学和/或生理学上与受试者和活性成分相容(即,能够引发所需的治疗效果而不会引起任何不希望的局部或全身作用)的载体和/或赋形剂。药学上可接受的赋型剂的实例包括但不限于填充剂、粘合剂、崩解剂、包衣剂、吸附剂、抗粘附剂、助流剂、抗氧化剂、调味剂、着色剂、甜味剂、溶剂、共溶剂、缓冲剂、螯合剂、表面活性剂、稀释剂、润湿剂、防腐剂、乳化剂、包覆剂、等渗剂、吸收延迟剂、稳定剂和张力调节剂。本领域技术人员已知选择合适的赋型剂以制备本发明期望的药物组合物。用于本发明的药物组合物中的示例性赋型剂包括盐水、缓冲盐水、葡萄糖和水。通常,合适的赋形剂的选择尤其取决于所使用的活性剂、待治疗的疾病和药物组合物的期望剂型。
根据本发明的药物组合物可适用于多种途径施用。通常,通过胃肠外完成施用。胃肠外递送方法包括局部、动脉内、肌内、皮下、髓内、鞘内、心室内、静脉内、腹膜内、子宫内、阴道内、舌下或鼻内施用。
根据本发明的药物组合物也可以制备成各种形式,如固态、液态、气态或冻干形式,特别可以是软膏、乳膏、透皮贴剂、凝胶、粉末、片剂、溶液、气雾剂、颗粒、丸剂、混悬剂、乳剂、胶囊、糖浆、酏剂、浸膏剂、酊剂或流浸膏提取物的形式,或者是特别适用于所需施用方法的形式。本发明已知的用于生产药物的过程可包括例如常规混合、溶解、制粒、制糖衣、研磨、乳化、包封、包埋或冻干过程。包含例如本文所述的免疫细胞的药物组合物通常以溶液形式提供,并且优选包含药学上可接受的缓冲剂。
根据本发明的药物组合物还可以与一种或多种适用于治疗和/或预防待治疗疾病的其它药剂(生物制剂如抗体试剂,和/或小分子)或治疗方法(例如手术、化疗或放疗)组合施用。适用于组合的药剂的优选实例包括已知的抗癌药物,比如顺铂、美登素衍生物、雷查霉素(rachelmycin)、卡里奇霉素(calicheamicin)、多西紫杉醇、依托泊苷、吉西他滨、异环磷酰胺、伊立替康、美法仑、米托蒽醌、sorfimer卟啉钠II(sorfimer sodiumphotofrinII)、替莫唑胺、拓扑替康、葡萄糖醛酸曲美沙特(trimetreate glucuronate)、奥利斯他汀E(auristatin E)、长春新碱和阿霉素;肽细胞毒素,比如蓖麻毒素、白喉毒素、假单胞菌细菌外毒素A、DNA酶和RNA酶;放射性核素,比如碘131、铼186、铟111、铱90、铋210和213、锕225和砹213;前药,比如抗体定向的酶前药;免疫刺激剂,比如IL-2,趋化因子比如IL-8、血小板因子4、黑色素瘤生长刺激蛋白等;抗体或其片段,比如抗CD3抗体或其片段,补体活化剂,异种蛋白结构域,同种蛋白结构域,病毒/细菌蛋白结构域和病毒/细菌肽。
在一个实施方案中,本发明的药物组合物用于治疗患有癌症、感染或自身免疫性疾病的受试者。
在一个实施方案中,所述癌症包括但不限于:脑神经胶质瘤、胚细胞瘤、肉瘤、白血病、基底细胞癌、胆道癌、膀胱癌、骨癌、脑和CNS癌症、乳腺癌、腹膜癌、宫颈癌、绒毛膜癌、结肠和直肠癌、结缔组织癌症、消化系统的癌症、子宫内膜癌、食管癌、眼癌、头颈癌、胃癌(包括胃肠癌)、胶质母细胞瘤(GBM)、肝癌、肝细胞瘤、上皮内肿瘤、肾癌、喉癌、肝肿瘤、肺癌(例如小细胞肺癌、非小细胞肺癌、腺状肺癌和鳞状肺癌)、淋巴瘤(包括霍奇金淋巴瘤和非霍奇金淋巴瘤)、黑色素瘤、骨髓瘤、神经母细胞瘤、口腔癌(例如唇、舌、口和咽)、卵巢癌、胰腺癌、前列腺癌、视网膜母细胞瘤、横纹肌肉瘤、直肠癌、呼吸系统的癌症、唾液腺癌、皮肤癌、鳞状细胞癌、胃癌、睾丸癌、甲状腺癌、子宫或子宫内膜癌、泌尿系统的恶性肿瘤、外阴癌以及其它癌和肉瘤、以及B细胞淋巴瘤(包括低级/滤泡性非霍奇金淋巴瘤(NHL)、小淋巴细胞性(SL)NHL、中间级/滤泡性NHL、中间级扩散性NHL、高级成免疫细胞性NHL、高级成淋巴细胞性NHL、高级小型非裂化细胞性NHL、大肿块病NHL)、套细胞淋巴瘤、AIDS相关淋巴瘤、以及Waldenstrom巨球蛋白血症、慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(ALL)、B细胞急性淋巴细胞白血病(B-ALL)、T细胞急性淋巴细胞白血病(T-ALL)、B细胞幼淋巴细胞白血病、母细胞性浆细胞样树突状细胞瘤、伯基特氏淋巴瘤、弥散性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性骨髓性白血病(CML)、恶性淋巴组织增生疾病、MALT淋巴瘤、毛细胞白血病、边缘区淋巴瘤、多发性骨髓瘤、骨髓发育不良、浆母细胞性淋巴瘤、白血病前期、浆细胞样树突状细胞瘤、以及移植后淋巴细胞增生性紊乱(PTLD);以及其他与靶标表达有关的疾病。优选地,可以用本发明的工程化免疫细胞或药物组合物治疗的疾病选自:白血病、淋巴瘤、多发性骨髓瘤、脑神经胶质瘤、胰腺癌、胃癌等。
在一个实施方案中,所述感染包括但不限于由病毒、细菌、真菌和寄生虫引起的感染。
在一个实施方案中,所述自身免疫性疾病包括但不限于I型糖尿病、腹腔疾病、格雷夫斯病、炎症性肠病、多发性硬化症、银屑病、类风湿性关节炎、艾迪生病、干燥综合征、桥本甲状腺炎、重症肌无力、血管炎、恶性贫血与系统性红斑狼疮等。
下面将参考附图并结合实施例来详细说明本发明。需要说明的是,本领域的技术人员应该理解本发明的附图及其实施例仅仅是为了举例,并不能对本发明构成任何限制。在不矛盾的情况下,本申请中的实施例及实施例中的特征可以相互组合。
附图说明
图1:通过流式细胞术测定的CAR-T细胞的CAR表达水平。
图2:CAR-T细胞与TGF-β共培养后的TGF-β中和水平。
图3:CAR-T细胞与TGF-β共培养后的IFN-γ释放水平。
图4:通过流式细胞术测定的并联双靶CAR-T细胞的CAR表达水平。
图5:并联双靶CAR-T细胞与靶细胞共孵育后的靶细胞杀伤水平。
图6:并联双靶CAR-T细胞与靶细胞共培养后的IFN-γ释放水平。
图7:并联双靶CAR-T细胞与TGF-β共培养后的IFN-γ释放水平。
图8:串联双靶CAR-T细胞与靶细胞共孵育后的靶细胞杀伤水平。
图9:串联双靶CAR-T细胞与TGF-β共培养后的IFN-γ释放水平。
具体实施方式
实施例1:构建包含靶向TGF-β的单域抗体的CAR-T细胞
构建MSCV-CARbvh质粒,其包含顺次连接的以下结构:抗TGF-β单域抗体(SEQ IDNO:4)、CD8α铰链区(SEQ ID NO:23)、CD8α跨膜区(SEQ ID NO:11)、4-1BB共刺激结构域(SEQID NO:14)、CD3ζ胞内区(SEQ ID NO:17)。
将MSCV-CARbvh质粒中的抗TGF-β单域抗体替换为靶向TGF-β的scFv(SEQ ID NO:5),获得MSCV-CARbsc质粒。
在无菌管中加入3ml Opti-MEM(Gibco)、45μg制备的逆转录病毒质粒和15μg包装载体pCL-Eco(上海禾午生物科技有限公司)。然后,加入120ul X-treme GENE HP DNA转染试剂(Roche),立即混匀,于室温下孵育15min,然后将质粒/载体/转染试剂混合物逐滴加入到293T细胞的培养瓶中,于37℃,5%CO2条件下培养。转染72小时后,收集培养物并离心,获得逆转录病毒上清液。
用DynaBeads CD3/CD28 CTSTM(Gibco)激活T细胞,并在37℃和5%CO2下培养1天。然后,分别加入的逆转录病毒上清液,持续培养3天后,获得包含TGF-βscFv的CAR-T细胞(CARbsc)和包含TGF-βsdAb的CAR-T细胞(CARbvh)。
使用流式细胞仪,用anti-Flag抗体(Biolegend)检测anti-TGFβscFv和anti-TGFβsdAb表达。可以看出,本发明制备的CAR-T细胞中的CAR均能够有效表达(图1)。
实施例2.检测CAR-T细胞对TGF-β的中和水平和IFNγ释放水平
以1×105个细胞/孔的浓度将NT细胞、CARbsc细胞和CARbvh细胞铺于96孔板中,并向各孔加入hTGF-β(Peprotech),使得各孔中TGF-β的终浓度为5ng/ml。未加任何细胞的TGF-β溶液用作对照(Ctrl)。于37℃培养18小时后收集细胞上清液。将上清液稀释5倍后,用Human TGF-βELISA Kit(R&D systems)检测TGF-β的含量,结果如图2所示。可以看出,CARbvh对TGF-β的中和水平显著高于CARbsc。
以1×105个细胞/孔的浓度将NT细胞、CARbsc细胞和CARbvh细胞铺于96孔板中,并向各孔加入hTGF-β(Peprotech),使得各孔中TGF-β的终浓度为25ng/mL。未加任何细胞的TGF-β溶液用作对照(Ctrl)。于37℃培养18小时后收集细胞上清液,并用Human IFN-gammaDuoSet ELISA Kit(R&D systems)检测IFNγ的含量,结果如图3所示。可以看出,与hTGFβ共培养后,CARbvh释放的IFNγ水平显著高于CARbsc。
以上结果表明,与包含TGF-βscFv的CAR-T细胞相比,包含TGF-βsdAb的CAR-T细胞具有显著更强的TGF-β中和能力以及IFNγ释放水平。
实施例3:构建并联双靶点CAR-T细胞并验证其功能
3.1构建并联双靶点CAR-T细胞
按照实施例1的方法制备CAR18逆转录病毒,其表达靶向Claudin18.2的CAR,结构如下:抗Claudin18.2单域抗体(SEQ ID NO:9)、CD8α铰链区(SEQ ID NO:23)、CD8α跨膜区(SEQ ID NO:11)、4-1BB共刺激结构域(SEQ ID NO:14)、CD3ζ胞内区(SEQ ID NO:17)。
分别用CAR18逆转录病毒、CAR18逆转录病毒+CARbsc逆转录病毒组合,和CAR18逆转录病毒+CARbvh逆转录病毒组合感染激活的T细胞,获得CAR18 T细胞(仅表达Claudin18.2 CAR)、CARbsc+18T细胞(表达Claudin18.2 CAR和包含TGF-βscFv的CAR)和CARbvh+18T细胞(表达Claudin18.2 CAR和包含TGF-βsdAb的CAR)。
使用流式细胞仪,用anti-VHH抗体(金斯瑞)检测CAR-T细胞中的抗Claudin18.2单域抗体表达,用anti-Flag抗体(Biolegend)检测anti-TGFβscFv和anti-TGFβsdAb表达。可以看出,本发明制备的CAR-T细胞中的CAR均能够有效表达(图4)。
3.2检测并联双靶点CAR-T细胞的杀伤活性
以1×104个细胞/孔的浓度将靶细胞Panc02-Claudin18.2-luci细胞铺入96孔板中,然后以5:1的效靶比将NT细胞、CAR18 T细胞、CARbsc+18T细胞和CARbvh+18T细胞铺入到96孔板进行共培养,18小时后利用酶标仪测定荧光值。根据计算公式:(靶细胞荧光均值-样品荧光均值)/靶细胞荧光均值×100%,计算得到杀伤效率,结果如图5所示。
可以看出,CARbsc+18T细胞和CAR18 T细胞的杀伤活性相当,而CARbvh+18T细胞的杀伤活性最高。这表明,表达TGF-βsdAb的CAR能提高CAR18 T细胞对靶细胞的杀伤活性。
3.3检测并联双靶点CAR-T细胞的IFNγ释放水平
以1×104个细胞/孔的浓度将靶细胞Panc02-Claudin18.2-luci细胞和非靶细胞Pan02-luci铺入96孔板中,然后以10:1的效靶比将NT细胞、CAR18 T细胞、CARbsc+18T细胞和CARbvh+18T细胞铺入到96孔板进行共培养。于37℃培养18小时后收集细胞上清液,并用mouse IFN-gamma DuoSet ELISA Kit(R&D systems)检测IFNγ的含量,结果如图6所示。此外,根据实施例2的方法检测并联双靶点CAR-T细胞与hTGF-β共培养后的IFNγ释放水平,结果如图7所示。
可以看出,无论与靶细胞Panc02-Claudin18.2-luci细胞共孵育还是与hTGFβ共培养,CARbvh+18T细胞的IFNγ释放水平均显著高于CARbsc+18T细胞。这表明,与表达TGF-βscFv的CAR相比,表达TGF-βsdAb的CAR能显著提高CAR18 T细胞的细胞因子释放水平。
实施例4:构建串联双靶点CAR-T细胞并验证其功能
构建MSCV-CARbvh-18质粒,其包含顺次连接的以下结构:抗TGF-β单域抗体(SEQID NO:4)、接头序列(SEQ ID NO:27)、抗Claudin18.2单域抗体(SEQ IDNO:9)、CD8α铰链区(SEQ ID NO:23)、CD8α跨膜区(SEQ ID NO:11)、4-1BB共刺激结构域(SEQ ID NO:14)、CD3ζ胞内区(SEQ ID NO:17)。将MSCV-CARbvh-18质粒中的抗TGF-β单域抗体替换为靶向TGF-β的scFv(SEQ ID NO:5),获得MSCV-CARbsc-18质粒。
根据实施例1所述的方法用上述质粒转染逆转录病毒,再感染激活的T细胞,获得两种串联双靶点CAR-T细胞:CARbsc-18 T细胞和CARbvh-18 T细胞。
根据实施例3.2所述的方法,检测CAR-T细胞对靶细胞的杀伤活性,结果如图8所示。可以看出,CARbsc-18 T细胞和CARbvh+18T细胞的杀伤活性相当,均略优于CAR18 T细胞的杀伤活性,但统计学无差异。
根据实施例2的方法检测串联双靶点CAR-T细胞与hTGFβ共培养后的IFNγ释放水平,结果如图9所示。可以看出,与hTGFβ共培养后,CARbvh-18 T细胞的IFNγ释放水平均显著高于CARbsc-18 T细胞。这表明,与表达TGF-βscFv的CAR相比,表达TGF-βsdAb的CAR能显著提高CAR18 T细胞的细胞因子释放水平。
需要说明的是,以上仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。本领域技术人员理解的是,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (29)
1.一种嵌合抗原受体,其包含靶向TGF-β的单域抗体、跨膜结构域和胞内信号传导结构域。
2.根据权利要求1所述的嵌合抗原受体,其中所述抗体包含的CDR1、CDR2和CDR3分别与SEQ ID NO:4的CDR1、CDR2和CDR3相同。
3.根据权利要求1所述的嵌合抗原受体,其中所述抗体的CDR1如SEQ ID NO:1所示,CDR2如SEQ ID NO:2所示,CDR3如SEQ ID NO:3所示。
4.根据权利要求1所述的嵌合抗原受体,其中所述抗体与SEQ ID NO:4具有至少90%同一性。
5.根据权利要求1所述的嵌合抗原受体,其中所述跨膜结构域选自以下蛋白质的跨膜结构域:TCRα链、TCRβ链、TCRγ链、TCRδ链、CD3ζ亚基、CD3ε亚基、CD3γ亚基、CD3δ亚基、CD45、CD4、CD5、CD8α、CD9、CD16、CD22、CD33、CD28、CD37、CD64、CD80、CD86、CD134、CD137、CD154或其任意组合。
6.根据权利要求1所述的嵌合抗原受体,其中所述胞内信号传导结构域包含共刺激结构域、初级信号传导结构域或两者。
7.根据权利要求6所述的嵌合抗原受体,其中所述共刺激结构域选自以下蛋白质的胞内区:LTB、CD94、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、CD7、CD8、CD18、CD27、CD28、CD30、CD40、CD54、CD83、CD134、CD137、CD270、CD272、CD276、CD278、CD357、DAP10、DAP12、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM、ZAP70或其任意组合。
8.根据权利要求6所述的嵌合抗原受体,其中所述初级信号传导结构域选自以下蛋白的胞内区:FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b、CD66d或其任意组合。
9.根据权利要求1所述的嵌合抗原受体,其中所述嵌合抗原受体还包含靶向第二靶点的抗原结合结构域,所述第二靶点与TGF-β不同。
10.根据权利要求9所述的嵌合抗原受体,其中所述嵌合抗原受体中靶向TGF-β的单域抗体和靶向第二靶点的抗原结合结构域是串联的形式,所述嵌合抗原受体包含:(1)抗原结合区,包含靶向TGF-β的单域抗体和靶向第二靶点的抗原结合结构域;(2)跨膜结构域;和(3)胞内信号传导结构域。
11.根据权利要求9所述的嵌合抗原受体,其中所述嵌合抗原受体中靶向TGF-β的单域抗体和靶向第二靶点的抗原结合结构域是并联的形式,所述嵌合抗原受体包含:(1)靶向TGF-β的第一单元结构,包含靶向TGF-β的单域抗体、第一跨膜结构域和第一胞内信号传导结构域;和(2)靶向第二靶点的第二单元结构,包含靶向第二靶点的抗原结合结构域、第二跨膜结构域和第二胞内信号传导结构域。
12.根据权利要求9-11任一项所述的嵌合抗原受体,其中所述第二靶点选自ALK、ADRB3、AKAP-4、APRIL、ASGPR1、BCMA、B7H3、B7H4、B7H6、bcr-abl、BORIS、BST2、BAFF-R、BTLA、CD2、CD3、CD4、CD5、CD7、CD8、CD19、CD20、CD22、CD24、CD25、CD28、CD30、CD33、CD38、CD40、CD44、CD44v6、CD44v7/8、CD47、CD52、CD56、CD57、CD58、CD70、CD72、CD79a、CD79b、CD80、CD81、CD86、CD97、CD123、CD133、CD137、CD 138、CD151、CD171、CD179a、CD300LF、CLEC12A、CDH16、CSPG4、CS1、CLL-1、Claudin 6、Claudin18.1、Claudin 18.2、CEA、CEACAM6、c-Met、CAIX、CXORF61、CA125、CYP1B1、CS1、ELF2M、EGFR、EPCAM、EGFRvIII、EphA2、ERG/TMPRSS2ETS融合基因、ETV6-AML、EMR2、EGP2,EGP40、FAP、FAR、FBP、FLT3、FOSL1、FCRL5、FCAR、Flt3、Flt4、Frizzled、GD2、GD3、gp100、gp130、GM3、GPC2、GPC3、GPRC5D、GPR20、GloboH、GHRHR、GHR、GITR、Her2、HER3、HER-4、HMWMAA、HAVCR1、HPV E6,E7、HVEM、HIV-1Gag、HLA-A1、HLA-A2、IL6R、IL-11Ra、IL-13Ra、IGF-I受体、LTPR、LIFRP、LRP5、IGLL1、IGF1R、KIT、Kappa LightChain、KDR、LewisY、LMP2、LY6K、LAGE-1a、legumain、LCK、LAIR1、LILRA2、LY75、MSLN、MUC1、MUC16、MAGE-A1、MAGE3、MAD-CT-1、MelanA/MART1、ML-IAP、MYCN、mut hsp70-2、NCAM、NY-BR-1、NY-ESO-1、NA17、Notch-1-4、nAchR、NKG2D、NKG2D配体、OY-TES1、OR51E2、OX40、PRSS21、PSCA、PD1、PD-L1、PD-L2、PSMA、Prostase、PAP、PDGFR-β、PCTA-1/半乳凝集素8、p53、p53突变体、prostein、PLAC1、PANX3、PAX3、PAX5、PTCH1、RANK、RAGE-1、ROR1、Ras突变体、RhoC、RU1、RU2、Robol、SSEA-4、SSX2、SART3、Sp17、TSHR、Tn Ag、TGS5、TEM1/CD248、TEM7R、TARP、TCRα、TCRβ、TGF-ΒR1、TGF-ΒR2、TNFRSF4、TWEAK-R、TLR7、TLR9、TAG72、TROP-2、Tie 2、TRP-2、TNFR1、TNFR2、TEM1、UPK2VEGFR、WT1、XAGE1、5T4、8H9、αvβ6整合素、CA9、叶酸受体α、肝配蛋白B2、酪氨酸酶、岩藻糖基GM1、邻-乙酰-GD2、叶酸受体β、多聚唾液酸、精子蛋白17、存活蛋白和端粒酶、肉瘤易位断点、人端粒末端逆转录酶/hTERT、雄激素受体、肠羧基酯酶、细胞周期蛋白B1、纤连蛋白、腱生蛋白、肿瘤坏死区的癌胚变体或其任意组合。
13.根据权利要求12所述的嵌合抗原受体,其中所述第二靶点是Claudin18.2。
14.根据权利要求13所述的嵌合抗原受体,其中所述靶向Claudin18.2的抗原结合结构域是抗Claudin18.2抗体。
15.根据权利要求14所述的嵌合抗原受体,其中所述抗Claudin18.2抗体与SEQ ID NO:9具有至少90%同一性。
16.根据权利要求1-15任一项所述嵌合抗原受体,其还包含信号肽。
17.据权利要求1-16任一项所述嵌合抗原受体,其还包含源自以下蛋白的铰链区:CD8α、CD28、FcγRIIIα受体、IgG4、IgG1、CD4或CD28。
18.编码权利要求1-17任一项所述嵌合抗原受体的核酸分子。
19.包含权利要求18所述核酸分子的载体。
20.根据权利要求19所述的载体,其中所述载体选自逆转录病毒、腺病毒、腺伴随病毒、牛痘病毒、水泡性口炎病毒、麻疹病毒、腮腺炎病毒、脊髓灰质炎病毒、正粘液病毒、小病毒、马拉巴病毒、柯萨奇病毒、疱疹病毒和慢病毒。
21.一种工程化免疫细胞,其表达权利要求1-17任一项所述的嵌合抗原受体权利要求18所述的核酸分子,或权利要求19-20任一项所述的载体。
22.根据权利要求21所述的工程化免疫细胞,其中所述免疫细胞是T细胞、B细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞或NKT细胞。
23.根据权利要求22所述的工程化免疫细胞,其中所述T细胞是CD4+CD8+T细胞、CD4+T细胞、CD8+T细胞、记忆T细胞、CD4-CD8-T细胞、肿瘤浸润细胞、幼稚T细胞、γδ-T细胞或αβ-T细胞。
24.根据权利要求22所述的工程化免疫细胞,其中所述免疫细胞来源于脐带血干细胞、祖细胞、骨髓干细胞、造血干细胞、成体干细胞、胚胎干细胞、多能干细胞或iPSC。
25.根据权利要求21-24任一项所述的工程化免疫细胞,所述工程化免疫细胞中,至少一种MHC相关基因和/或至少一种TCR/CD3相关基因的表达被抑制或沉默。
26.根据权利要求25所述的工程化免疫细胞,所述被抑制或沉默的基因选自HLA-A、HLA-B、HLA-C、B2M、HLA-DPA、HLA-DQ、HLA-DRA、TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK、CIITA、TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ或其任意组合。
27.根据权利要求21-26任一项所述的工程化免疫细胞,其中所述工程化免疫细胞是自体细胞或同种异体细胞。
28.一种药物组合物,其中包含权利要求21-27任一项所述的工程化免疫细胞和一种或多种药学上可接受的赋型剂。
29.权利要求21-27任一项所述工程化免疫细胞或权利要求28所述药物组合物在制备治疗/预防/诊断癌症、感染或自身免疫性疾病药物中的用途。
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