CN117645670A - 一种新型嵌合抗原受体及其用途 - Google Patents
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Abstract
本发明提供了一种新型嵌合抗原受体及其用途,其从N端到C端包含:抗原结合结构域、跨膜结构域、共刺激结构域和初级信号传导结构域,所述跨膜结构域包含NKp44跨膜区序列,所述共刺激结构域包含2B4胞内区序列和/或4‑1BB胞内区序列。本发明还提供了表达所述新型嵌合抗原受体的工程化免疫细胞、包含工程化免疫细胞的药物组合物及其在治疗癌症等疾病中的用途。
Description
技术领域
本发明属于免疫治疗技术领域,涉及一种新型嵌合抗原受体及其用途,具体涉及一种新型嵌合抗原受体、表达所述新型嵌合抗原受体的工程化免疫细胞、包含工程化免疫细胞的组合物及其在治疗癌症等疾病中的用途。
背景技术
过继性细胞疗法是指通过对自体免疫细胞进行体外激活和扩增,然后将其重新输回至患者体内,从而达到直接杀伤肿瘤或激发机体的免疫应答杀伤肿瘤细胞的目的。常见的过继性细胞疗法包括LAK、CIK和NK等非特异性免疫疗法以及TIL、CAR-T和TCR-T等特异性免疫疗法。其中,CAR-T细胞疗法由于在血液瘤领域的出色表现成功引起了广泛关注。鉴于CAR-T细胞疗法的飞速发展,也逐渐衍生出了CAR-NK、CAR-NKT、CAR-Treg、CAR-γδT等以CAR作为核心技术的一系列新型细胞疗法,共同引领CAR细胞疗法成为肿瘤细胞免疫治疗的一大趋势。
嵌合抗原受体(CAR)是一种细胞表面受体蛋白,它赋予了免疫细胞靶向特定抗原蛋白的能力。从结构上看,CAR至少由抗原结合结构域、跨膜结构域和胞内信号传导结构域三个功能结构域组成,胞内信号传导结构域由共刺激结构域和/或初级信号传导结构域构成。CAR结构的设计经历了以下过程:第一代CAR只有一个胞内信号组份CD3ζ或者FcγRI分子,由于胞内只有一个活化结构域,因此它只能引起短暂的免疫细胞增殖和较少的细胞因子分泌,而并不能提供长时间的免疫细胞增殖信号和持续的体内抗肿瘤效应,所以并没有取得很好的临床疗效;第二代CAR在原有结构基础上引入一个共刺激分子,如CD28、4-1BB、OX40、ICOS,与第一代CAR相比功能有很大提高,进一步加强CAR-T细胞的持续性和对肿瘤细胞的杀伤能力;第三代CAR包含2个共刺激分子,以CD28与4-1BB、CD28与OX40组合作为共刺激分子在第三代CAR中最为常见;第四代CAR主要为了克服肿瘤免疫微环境的抑制,在设计时引入了促炎症细胞因子(IL-12、IL-15、IL-18等)和共刺激配体;第五代CAR-T在第二代的基础上添加了激活其它信号通路的共刺激结构域,比如IL2-2Rβ胞内结合SAAT3/5的结构域等。目前,大多数公司的CAR产品仍以第二代CAR结构为基础,进行探索开发。
研究表明,不同的功能结构域对CAR的功能有重要的影响。例如,国际申请WO2016014789A中,在不改变抗原结合结构域和胞内传导信号结构域的前提下,仅通过改变跨膜结构域,即可大幅度改善CAR的性能,降低CAR-T对非靶细胞的非特异杀伤作用。例如,目前在CAR细胞疗法领域中普遍认为,包含CD28共刺激结构域的CAR细胞显示出更好的细胞增殖活性,包含4-1BB共刺激结构域的CAR细胞显示出更好的持续性。
目前CAR细胞疗法在临床应用中仍存在一些问题,如对实体瘤疗效不佳、异体移植时可能存在移植排斥反应、持续性差、有发生并发症(如输注时常发生的严重炎症反应)的风险等。因此,有必要开发新的CAR结构,以进一步增强表达CAR细胞疗法的治疗效果。
发明内容
为了解决上述技术问题,本发明提供一种新型嵌合抗原受体,其能够激活免疫细胞对表达靶抗原的肿瘤细胞的特异性杀伤作用。
嵌合抗原受体
本发明提供一种新型嵌合抗原受体,其从N端到C端包含:抗原结合结构域、跨膜结构域、共刺激结构域和初级信号传导结构域,所述跨膜结构域包含NKp44跨膜区序列,所述共刺激结构域包含2B4胞内区序列和/或4-1BB胞内区序列。
在一些实施方案中,所述NKp44跨膜区的氨基酸序列与SEQ ID NO:1所示的氨基酸序列具有至少80%、85%、90%、95%或99%同一性或100%同一性(例如至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%同一性或100%同一性)。在一些实施方案中,所述NKp44跨膜区由SEQ IDNO:1所示的氨基酸序列组成。
在一些实施方案中,所述2B4胞内区的氨基酸序列与SEQ ID NO:2或3所示的氨基酸序列具有至少80%、85%、90%、95%或99%同一性或100%同一性(例如至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%同一性或100%同一性)。在一些实施方案中,所述2B4胞内区由SEQ ID NO:2或3所示的氨基酸序列组成。
在一些实施方案中,所述4-1BB胞内区的氨基酸序列与SEQ ID NO:4或5所示的氨基酸序列具有至少80%、85%、90%、95%或99%同一性或100%同一性(例如至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%同一性或100%同一性)。在一些实施方案中,所述4-1BB胞内区由SEQID NO:4或5所示的氨基酸序列组成。
在一些实施方案中,所述抗原结合结构域选自Fab、Fab'、F(ab')2、Fv片段、scFv、二硫键-连接的Fvs(sdFv)、由VH和CH1结构域组成的Fd片段、线性抗体、单域抗体(如sdAb)、由抗体片段(例如包括在铰链区通过二硫键连接的两个Fab片段的二价片段)形成的双特异性抗体或多特异性抗体、抗体的分离的CDR或其它表位结合片段。在一些实施方案中,所述抗原结合结构域选自scFv和/或sdAb。在一些实施方案中,所述抗原结合结构域可以是人源化抗体、鼠源抗体、嵌合抗体、人抗体或驼源抗体。
在一些实施方案中,所述抗原结合结构域结合选自以下的抗原: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、CS-1、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、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、TGFBR1、TGFBR2、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、间皮素、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。
在一些实施方案中,作为示例,所述抗原结合结构域结合的抗原可以包含CD19。可选地,所述抗原结合结构域包含抗CD19 scFv或抗CD19 sdAb。
在一些实施方案中,所述抗原结合结构域包含:(i)重链可变区(VH),其包含SEQID NO:6所示的HCDR1氨基酸序列、SEQ ID NO:7所示的HCDR2氨基酸序列和SEQ ID NO:8所示的HCDR3氨基酸序列;以及(ii)轻链可变区(VL),其包含SEQ ID NO:9所示的LCDR1氨基酸序列、SEQ ID NO:10所示的LCDR2氨基酸序列和SEQ ID NO:11所示的LCDR3氨基酸序列。
在一些实施方案中,所述抗原结合结构域包含与SEQ ID NO:13、15或17所示的氨基酸序列具有至少80%、85%、90%、95%或99%同一性或100%同一性(例如至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%同一性或100%同一性)的重链可变区序列。在一些实施方案中,所述抗原结合结构域包含SEQ ID NO:13、15或17所示的重链可变区序列。
在一些实施方案中,所述抗原结合结构域包含与SEQ ID NO:12、14或16所示的氨基酸序列具有至少80%、85%、90%、95%或99%同一性或100%同一性(例如至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%同一性或100%同一性)的轻链可变区序列。在一些实施方案中,所述抗原结合结构域包含SEQ ID NO:12、14或16所示的轻链可变区序列。
在一些实施方案中,所述抗原结合结构域包含抗CD19 scFv,其中重链可变区和轻链可变区之间使用接头(L)连接,可选地,所述接头的氨基酸序列与SEQ ID NO:33或34所示的氨基酸序列具有至少80%、85%、90%、95%或99%同一性或100%同一性(例如至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%同一性或100%同一性)。在一些实施方案中,所述接头由SEQID NO:33或34所示的氨基酸序列组成。在一些实施方案中,所述抗原结合结构域从N端到C端包含:VH-L-VL。在另一些实施方案中,所述抗原结合结构域从N端到C端包含:VL-L-VH。
在一些实施方案中,所述抗CD19 scFv包含与SEQ ID NO:18-22任一所示的氨基酸序列具有至少80%、85%、90%、95%或99%同一性或100%同一性(例如至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%同一性或100%同一性)的氨基酸序列。在一些实施方案中,所述抗CD19scFv包含SEQ ID NO:18-22任一所示的氨基酸序列。在一些实施方案中,所述抗CD19 scFv由SEQ ID NO:18-22任一所示的氨基酸序列组成。
在一些实施方案中,所述抗原结合结构域包含抗CD19 sdAb,其可以是WO2022012683A、CN112521513A、CN109721659A中记载的抗CD19 sdAb。
在一些实施方案中,所述初级信号传导结构域选自以下信号分子的胞内区:FcγR、FcεR、FcαR、FcRn、CD3、CD3ζ、CD3γ、CD3δ、CD3ε、CD4、CD5、CD8、CD21、CD22、CD28、CD32、CD40L(CD154)、CD45、CD66d、CD79a、CD79b、CD80、CD86、CD278(ICOS)、CD247ζ、CD247η、DAP10、DAP12、FYN、LAT、Lck、MAPK、MHC复合物、NFAT、NF-κB、PLC-γ、iC3b、C3dg、C3d、ZAP70或其任意组合。在一些实施方案中,所述初级信号传导结构域选自CD3ζ胞内区,可选地,所述CD3ζ胞内区的氨基酸序列与SEQ ID NO:28-30任一所示的氨基酸序列具有至少80%、85%、90%、95%或99%同一性或100%同一性(例如至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%同一性或100%同一性)。在一些实施方案中,所述CD3ζ胞内区由SEQ ID NO:28-30任一所示的氨基酸序列组成。
在一些实施方案中,所述嵌合抗原受体从N端到C端包含:
(i)抗原结合结构域、NKp44跨膜结构域、2B4胞内区和CD3ζ胞内区;
(ii)抗原结合结构域、NKp44跨膜结构域、4-1BB胞内区和CD3ζ胞内区;
(iii)抗原结合结构域、NKp44跨膜结构域、2B4胞内区、4-1BB胞内区和CD3ζ胞内区;或
(iv)抗原结合结构域、NKp44跨膜结构域、4-1BB胞内区、2B4胞内区和CD3ζ胞内区。
在一些实施方案中,所述嵌合抗原受体从N端到C端包含:
(i)抗CD19 scFv或抗CD19 sdAb、NKp44跨膜结构域、2B4胞内区和CD3ζ胞内区;
(ii)抗CD19 scFv或抗CD19 sdAb、NKp44跨膜结构域、4-1BB胞内区和CD3ζ胞内区;
(iii)抗CD19 scFv或抗CD19 sdAb、NKp44跨膜结构域、2B4胞内区、4-1BB胞内区和CD3ζ胞内区;或
(iv)抗CD19 scFv或抗CD19 sdAb、NKp44跨膜结构域、4-1BB胞内区、2B4胞内区和CD3ζ胞内区。
在一些实施方案中,所述嵌合抗原受体还包含存在于抗原结合结构域与跨膜结构域之间的铰链区。在一些实施方案中,所述铰链区来源于CD8α、CD28或IgG4。可选地,所述铰链区的氨基酸序列与SEQ ID NO:24-27任一所示的氨基酸序列具有至少80%、85%、90%、95%或99%同一性或100%同一性(例如至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%同一性或100%同一性)。在一些实施方案中,所述铰链区由SEQ ID NO:24-27任一所示的氨基酸序列组成。
在一些实施方案中,所述嵌合抗原受体从N端到C端包含:
(i)抗CD19 scFv或抗CD19 sdAb、铰链区、NKp44跨膜结构域、2B4胞内区和CD3ζ胞内区;
(ii)抗CD19 scFv或抗CD19 sdAb、铰链区、NKp44跨膜结构域、4-1BB胞内区和CD3ζ胞内区;
(iii)抗CD19 scFv或抗CD19 sdAb、铰链区、NKp44跨膜结构域、2B4胞内区、4-1BB胞内区和CD3ζ胞内区;或
(iv)抗CD19 scFv或抗CD19 sdAb、铰链区、NKp44跨膜结构域、4-1BB胞内区、2B4胞内区和CD3ζ胞内区。
在一些实施方案中,所述嵌合抗原受体从N端到C端包含:
(i)抗CD19 scFv或抗CD19 sdAb、CD8α铰链区、NKp44跨膜结构域、2B4胞内区和CD3ζ胞内区;
(ii)抗CD19 scFv或抗CD19 sdAb、CD8α铰链区、NKp44跨膜结构域、4-1BB胞内区和CD3ζ胞内区;
(iii)抗CD19 scFv或抗CD19 sdAb、CD8α铰链区、NKp44跨膜结构域、2B4胞内区、4-1BB胞内区和CD3ζ胞内区;或
(iv)抗CD19 scFv或抗CD19 sdAb、CD8α铰链区、NKp44跨膜结构域、4-1BB胞内区、2B4胞内区和CD3ζ胞内区。
在一些实施方案中,所述嵌合抗原受体还包含自杀基因开关。可选地,所述自杀基因开关是EGFRt、HSV-TK、iCasp9、CD20、mTMPK或其任意组合。可选地,所述自杀基因开关连接在CAR的C端或N端。可选地,所述自杀基因开关通过自切割肽连接在CAR的C端或N端。可选地,所述自切割肽选自F2A、PA2、T2A、和/或E2A。
核酸、载体
本发明中编码目标分子的核酸序列可利用在本领域中已知的重组方法获得。可选地,目的基因可被合成生产。
本发明也提供了其中包含本发明的CAR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、稳定整合并且其在子细胞中增殖。慢病毒载体具有优于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,具有低免疫原性。
本发明的核酸序列通常可连接至启动子,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目的核酸序列表达的转录和翻译终止子、初始序列和启动子。本发明的核酸分子可被克隆入许多类型的载体,例如质粒、噬菌粒、噬菌体衍生物、动物病毒和粘粒。特定的目的载体包括表达载体、复制载体、探针产生载体和测序载体等。
进一步地,表达载体可以以病毒载体的形式提供给细胞。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、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。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、限制酶位点和一个或多个可选择的标记。
目前已经开发出许多基于病毒的系统,用于将基因转入哺乳动物细胞。例如,逆转录病毒提供了用于基因传递系统的方便的平台。可利用在本领域中已知的技术将选择的基因插入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。许多逆转录病毒系统在本领域中是已知的。
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。例如,使用表达载体,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。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,可参见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插入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、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、马拉巴病毒和柯萨奇病毒等,可参见美国专利US5350674A、US5585362A和US10391132A。
将多核苷酸引入宿主细胞的化学手段包括胶体分散系统,诸如大分子复合物、纳米胶囊、微球、珠和基于脂质的系统,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的示例性胶体系统为脂质体(例如人造膜囊)。
工程化免疫细胞
本发明提供含有本发明所述的嵌合抗原受体的工程化免疫细胞。
在一些实施方案中,所述免疫细胞为自体免疫细胞或同种异体免疫细胞。
在一些实施方案中,所述免疫细胞可以是T细胞、NK细胞、NKT细胞、B细胞、单核细胞、巨噬细胞、中性粒细胞、树突状细胞或其任意组合。
在一些实施方案中,所述NK细胞可以是CD56dim NK细胞和/或CD56bright NK细胞。在一些实施方案中,所述NK细胞可以来源于原代NK细胞、干细胞衍生的NK细胞、NK细胞系等。其中,所述原代NK细胞可以来源于受试者(如人、小鼠或者大鼠、猫、狗、奶牛、马、绵羊、山羊或其他牲畜等),选自外周血NK细胞、脐带血NK细胞、脾脏NK细胞等;所述干细胞衍生的NK细胞可以选自多能干细胞(IPSC)衍生的NK细胞、胚胎干细胞(ESC)衍生的NK细胞、造血干细胞(HSPC)衍生的NK细胞等;所述NK细胞系选自NK92、NK92.26.5、NK92.MI、NK92Ci、NK92Fc、NK3.3、NKL、NKG、NK-YT、NK-YTS、KHYG-1、HATAK细胞等。在一些实施方案中,所述NK细胞为NK92细胞。
在一些实施方案中,所述T细胞可以是细胞毒性T细胞、辅助性T细胞、调节性T细胞或其组合。在一些实施方案中,所述T细胞可以是αβT细胞和/或γδT细胞。在一些实施方案中,所述T细胞可以是CD4+T细胞和/或CD8+T细胞。在一些实施方案中,T细胞可以来源于原代T细胞、T细胞系等。其中,所述原代T细胞可以来源于受试者(如人、小鼠或者大鼠、猫、狗、奶牛、马、绵羊、山羊或其他牲畜等)的外周血单核细胞、骨髓、淋巴结组织、脐血、胸腺组织、来自感染部位的组织、腹水、胸膜积液、脾组织及肿瘤;所述T细胞系选自Jurkat、H9、SupT1等。
在一些实施方案中,所述工程化免疫细胞具有以下一种或多种特征:
(i)所述工程化免疫细胞包含靶向第二抗原或第二抗原表位的第二嵌合抗原受体;
(ii)所述工程化免疫细胞中TCR相关基因和/或MHC相关基因的表达是被抑制或沉默的;
(iii)所述工程化免疫细胞中以下基因被抑制或沉默:CD52、GR、dCK、免疫检查点基因或其任意组合;
(iv)所述工程化免疫细胞表达或分泌PD-1抗体、PD-L1抗体、CD47抗体、Tim3抗体、Lag3抗体、Tigit抗体、OX40抗体、ICOS抗体、IL7、CXCL19、IL21、IL15、IL2、IL18或其任意组合;和
(v)表达外源性自杀基因开关。
在一些实施方案中,所述工程化免疫细胞包含靶向第二抗原或第二抗原表位的第二抗原受体,其中所述第二抗原与如上所述的嵌合抗原受体靶向的抗原相同或不同;所述第二抗原位点为与如上所述的嵌合抗原受体靶向的抗原位点相同或不同的抗原位点。
在一些实施方案中,所述第二嵌合抗原受体与如上所述的嵌合抗原受体融合在同一条多肽链上。可选地,所述第二嵌合抗原受体与如上所述的嵌合抗原受体通过自切割肽连接。可选地,所述自切割肽选自F2A、PA2、T2A、E2A或其任意组合。在一些实施方案中,所述第二嵌合抗原受体与如上所述的嵌合抗原受体在不同的多肽链上。在一些实施方案中,所述第二嵌合抗原受体与如上所述的嵌合抗原受体在同一载体上表达。在另一些实施方案中,所述第二嵌合抗原受体与如上所述的嵌合抗原受体在不同的载体上表达。
在一些实施方案中,所述工程化免疫细胞TCR相关基因和/或MHC相关基因的表达是被抑制或沉默的。可选地,所述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HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA或其任意组合。可选地,所述TCR相关基因选自TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ或其任意组合。
在一些实施方案中,所述工程化免疫细胞的至少一种TCR相关基因和至少一种MHC相关基因的表达被抑制或沉默,其中所述TCR相关基因选自TRAC、TRBC或其任意组合,所述MHC相关基因是B2M、RFX5、RFXAP、RFXANK、CIITA或其任意组合。在一些实施方案中,所述工程化免疫细胞的TRAC或TRBC,和B2M的表达被抑制或沉默。在一些实施方案中,所述工程化免疫细胞的TRAC或TRBC,和CIITA的表达被抑制或沉默。在一些实施方案中,所述工程化免疫细胞的TRAC或TRBC、B2M,和CIITA的表达被抑制或沉默。在一些实施方案中,所述工程化免疫细胞的TRAC或TRBC、B2M,和RFX5的表达被抑制或沉默。
在一些实施方案中,所述工程化免疫细胞中包含以下基因被抑制或沉默:CD52、GR、dCK、免疫检查点基因或其任意组合,可选地,所述免疫检查点基因选自PD1、LAG3、TIM3、CTLA4、PPP2CA、PPP2CB、PTPN6、PTPN22、PDCD1、HAVCR2、BTLA、CD160、TIGIT、CD96、CRTAM、TNFRSF10B、TNFRSF10A、CASP8、CASP10、CASP3、CASP6、CASP7、FADD、FAS、TGFBRII、TGFRBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、EIF2AK4、CSK、PAG1、SIT、FOXP3、PRDM1、BATF、GUCY1A2、GUCY1A3、GUCY1B2、GUCY1B3或其任意组合。
在一些实施方案中,所述工程化免疫细胞表达或分泌PD-1抗体、PD-L1抗体、CD47抗体、Tim3抗体、Lag3抗体、Tigit抗体、OX40抗体、ICOS抗体、IL7、CXCL19、IL21、IL15、IL2、IL18或其任意组合。
在一些实施方案中,所工程化免疫细胞表达自杀基因开关。可选地,所述自杀基因开关是EGFRt、HSV-TK、iCasp9、CD20、mTMPK或其任意组合。可选地,所述自杀基因开关连接在CAR的C端或N端。可选地,所述自杀基因开关通过自切割肽连接在CAR的C端或N端。可选地,所述自切割肽选自F2A、PA2、T2A、E2A或其任意组合。
药物组合物
本发明提供一种药物组合物,含有本发明所述的嵌合抗原受体的细胞,以及药学上可接受的载体。
本文所述的表达CAR的细胞可以与以下组合用于治疗方案:手术、化疗、放疗、免疫抑制剂(如环孢菌素、硫唑嘌呤、甲氨蝶呤、霉酚酸酯、和FK506)、抗体或其他免疫吸附剂(如CAMPATH、抗CD3抗体或其他抗体疗法)、细胞毒素、氟达拉滨、环孢菌素、FK506、雷帕霉素、霉酚酸、类固醇、FR901228、细胞因子以及照射、肽疫苗。
在一些实施方案中,本文所述的表达CAR的细胞可以与下述化疗药联用:烷基化剂(例如可以是乌拉莫司汀、氮芥、环磷酰胺、异环磷酰胺、美法仑、苯丁酸氮芥、哌泊溴烷、三乙烯蜜胺、三乙烯硫代磷酰胺、替莫唑胺、噻替派、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、达卡巴嗪、奥沙利铂、、更生霉素、六甲蜜胺、顺铂等)、抗代谢物(例如可以是叶酸拮抗剂、嘧啶类似物、嘌呤类似物和腺苷脱氨酶抑制剂(例如,氟达拉滨))、抑制钙依赖性磷酸酶钙调磷酸酶或p70S6激酶FK506或抑制p70S6激酶的药物、mTOR抑制剂(例如可以是坦罗莫司、地磷莫司、依维莫司、雷帕霉素、塞马莫德、替西罗莫司、内盐、XL765)、免疫调节剂(例如可以是阿托珠单抗、聚乙二醇非格司亭、来那度胺、沙利度胺、IRX-2(包括白介素1、白介素2、和干扰素γ的人细胞因子的混合物)等)、蒽环霉素(例如可以是多柔比星、博莱霉素、柔红霉素、米托蒽醌、表柔比星、伊达比星、丝裂霉素C、格尔德霉素、除莠霉素、近灰霉素、去乙酰近灰霉素等)、长春花生物碱(例如可以是酒石酸、长春瑞滨、长春新碱、长春地辛、长春碱、长春瑞滨等)、蛋白酶体抑制剂(例如可以是硼替佐米、卡非佐米、马瑞佐米、艾沙佐米、柠檬酸盐、德兰佐米等)、GITR激动剂(例如可以是GITR融合蛋白和抗GITR抗体(例如,二价抗GITR抗体))、蛋白酪氨酸磷酸酶抑制剂(例如可以是SHP-1抑制剂、SHP-2抑制剂)、CDK4激酶抑制剂(例如可以是哌柏西利)、BTK抑制剂(例如可以是依鲁替尼)、MKN激酶抑制剂(例如可以是克唑替尼、恩沙替尼等)、DGK激酶抑制剂、溶瘤病毒(例如可以是溶瘤腺病毒、溶瘤性单纯疱疹病毒、溶瘤性逆转录病毒、溶瘤性细小病毒、溶瘤性痘苗病毒、溶瘤性辛奈病毒、溶瘤性流感病毒、溶瘤性RNA病毒(例如可以是溶瘤性呼肠孤病毒、溶瘤性新城疫病毒、溶瘤性麻疹病毒、或溶瘤性水疱性口炎病毒)等)或其任意组合。
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例如患者的病症、和患者疾病的类型和严重度、临床试验的结果等因素确定。
药物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、通过静脉内注射或腹膜内施用给患者。在一些实施方案中,含表达本发明CAR的细胞的组合物通过皮内或皮下注射被施用给患者。在另一些实施方案中,本发明的T细胞组合物优选通过注射施用。T细胞的组合物可被直接注入肿瘤、淋巴结或感染位置。
在一些实施方案中,所述药物组合物为液态制剂,可选地,所述制剂为注射剂。可选地,本发明的药物组合物用于静脉内施用。在一些实施方案中,所述液态制剂中细胞浓度为1×104-1×109个细胞/ml,可选地,所述液态制剂中细胞浓度为1×105-1×108个细胞/ml。在一些实施方案中,所述药物组合物的单次用药剂量为1×104-1×109个细胞/kg体重,可选地,所述药物组合物的单次用药剂量为1×105-1×108个细胞/kg体重。
在一些实施方案中,所述药物组合物可包括缓冲液(例如中性缓冲盐水、硫酸盐缓冲盐水等等)、碳水化合物(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(例如EDTA或谷胱甘肽)、佐剂(例如氢氧化铝)、防腐剂或其任意组合。
用途
本发明提供如上所述的嵌合抗原受体,或如上所述的工程化免疫细胞,或如上所述的药物组合物在制备抗肿瘤药物的用途。CAR转导的免疫细胞可靶向肿瘤抗原,可以用于自体和异体肿瘤治疗,可以大规模制备,质量均一稳定,随时可调用给任何患者使用。
本发明也提供了刺激对哺乳动物的靶细胞群或组织的免疫应答的方法,其包括以下步骤:给哺乳动物施用本发明的工程化免疫细胞。
本发明还包括一类细胞疗法,给需要的患者施用本发明制备的工程化免疫细胞或药物组合物。可选地,表达CAR的工程化免疫细胞上增加了自杀基因开关,必要时可随时清除工程化免疫细胞,减少免疫治疗副作用。
在一些实施方案中,所述肿瘤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。所述肿瘤可包括非实体瘤(例如血液瘤,例如白血病和淋巴瘤)、实体瘤或其任意组合。所述血液瘤为血液或骨髓的癌症。血液瘤的例子包括白血病,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、脊髓发育不良或其任意组合。所述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)。实体瘤的例子包括胃癌、胃癌腹膜转移、肝癌、白血病、肾脏肿瘤、肺癌、小肠癌、骨癌、前列腺癌、结直肠癌、乳腺癌、大肠癌、宫颈癌、卵巢癌、淋巴癌、鼻咽癌、肾上腺肿瘤、膀胱肿瘤、非小细胞肺癌、脑胶质瘤、子宫内膜癌或其任意组合。
附图说明
图1示出了本发明制备的CAR-NK92细胞对Nalm-6细胞的杀伤作用。
图2示出了Nalm-6细胞激活CAR-NK92细胞后的CD107a阳性率。
图3示出了Nalm-6激活CAR-NK92细胞后的IFN-γ释放水平。
具体实施方式
本发明人经过广泛而深入地研究,首次构建了一种新型嵌合抗原受体,包含NKp44跨膜区以及2B4胞内区和/或4-1BB胞内区。以CD19作为新型嵌合抗原受体靶向抗原的示例,实验表明,与利用不同跨膜区及不同胞内区构建的CAR结构相比,本发明设计的CAR转染免疫细胞后获得的工程化免疫细胞具有更强的肿瘤杀伤效果。
为了可以更容易地理解本申请,在此对某些术语进行定义。除非本文另有明确规定,否则以下每一个术语应具有如下所述的含义。
术语“嵌合抗原受体”或者“CAR”是一种重组多肽构建体,CAR当在免疫细胞中表达时,能够基于抗原结合特异性进行抗原识别,当其结合相应肿瘤抗原时,能够影响肿瘤细胞,导致肿瘤细胞不生长、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。CAR通常至少包含抗原结合结构域、跨膜结构域和胞内信号传导结构域,胞内信号传导结构域包含至少一种共刺激结构域和/或至少一种初级信号传导结构域。
术语“抗原结合结构域”是指可以与抗原、受体、针对受体的配体结合的任何结构或其功能性变体。例如,抗原结合结构域可以是抗体或抗体片段。术语“抗体”是指源自免疫球蛋白分子的蛋白质或多肽序列,该蛋白质或多肽序列与抗原特异性结合。抗体可以是多克隆或单克隆、多链或单链或完整免疫球蛋白,可以是人源化抗体、鼠源抗体、嵌合抗体、人抗体或驼源抗体,可以是单特异性抗体、双特异性抗体或多特异性抗体,可以源自天然来源或来自重组来源。术语“抗体片段”是指完整抗体或其变体的至少一部分,并且是指足以赋予抗体片段识别和特异性结合靶标(如抗原)的抗原结合结构域(例如完整抗体的抗原决定可变区)。抗体片段的实例包括但不限于Fab、Fab'、F(ab')2和Fv片段、scFv抗体片段、线性抗体、单结构域抗体(如sdAb(VL或VH))、骆驼科VHH结构域和由相同或不同的抗体片段形成的双特异性抗体或多特异性抗体,该二价片段包含在铰链区通过二硫键连接的两个或更多个(例如两个)Fab片段,或所连接的抗体的两个或更多个(例如两个)分离的CDR或其他表位结合片段。抗体片段也可以掺入单结构域抗体、多抗体、微抗体、纳米抗体、细胞内抗体、双抗体、三抗体、四抗体、v-NAR和双scFv中(参见Hollinger和Hudson,Nature Biotechnology[自然生物技术]23:1126-1136,2005)。还可以将抗体片段移植到基于多肽如纤连蛋白III型(Fn3)的支架中(参见美国专利US6703199,其描述了纤连蛋白多肽微型抗体)。
术语“scFv”是指包含至少一个轻链可变区和至少一个重链可变区的融合蛋白,其中所述轻链可变区和重链可变区是邻接的(例如经由接头连接),并且能够以单链多肽形式表达,且其中所述scFv保留其来源的完整抗体的特异性。除非另有说明,否则本文中的scFv可以以任何顺序(例如相对于多肽的N-末端和C末端)具有所述的VL和VH可变区,例如从N-末端到C-末端,scFv从N端到C端可以包含VL-接头-VH,也可以包含VH-接头-VL。术语“接头”是指连接两个分子或同一分子上的两个序列的分子序列。在一些实施例中,接头是肽接头。优选地,接头不会不利地影响多肽的表达、分泌或生物活性。此外,接头优选地不是抗原性的并且不引发免疫应答。在一些实施例中,接头可以是内源氨基酸序列、外源氨基酸序列(例如,富含GS的序列)或非肽化学接头。
术语“sdAb”是指由具有三个CDR的单个可变区组成的抗体,其可以单独地与不与相应的含有CDR的多肽配对的抗原结合。单域抗体包括仅来自或源自骆驼科重链抗体的VHH片段,并且可以根据需要与重链恒定区融合。
术语“人源化抗体”是指来自非人物种的抗体,其中该非人物种的蛋白质序列已被修饰以增加其与人天然产生的抗体变体的相似性。
术语“双特异性抗体”是指能够结合2个抗原或抗原表位的双特异性分子。相应地,术语“多特异性抗体”是指能够结合多个(多于2个)抗原或抗原表位的多特异性分子。术语“表位”,是指与结合部分结合的靶分子表面上的位点,如抗原表面的局部区域。靶分子可以包含蛋白质、肽、核酸、碳水化合物或脂质。具有免疫原性活性的表位是引发动物中免疫应答的靶分子的一部分。如通过本领域众所周知的任何方法(包括例如通过免疫测定法)所确定的,具有抗原活性的靶分子的表位是与抗体结合的靶分子的一部分。术语“表位”通常由分子的化学活性表面基团(如氨基酸或糖侧链)组成,并且具有特定的三维结构特征以及特定的电荷特征。表位包括线性表位和构象表位。线性表位是由某些氨基酸残基按一定顺序连续排列组成的线状序列,构象表位由分子内不连续的2~3个氨基酸残基折叠排列所形成的三维结构构成。
术语“重链”是指抗体分子中天然存在的构象中存在的两种类型多肽链中较大的一种,并且通常决定抗体所属的类别。
术语“轻链”是指抗体分子中天然存在的构象中存在的两种类型多肽链中较小的一种。Kappa(κ)和lambda(λ)轻链是指两种主要的抗体轻链同种型。
术语“互补决定区”或“CDR”是指赋予抗原特异性和结合亲和力的抗体可变区内的氨基酸序列。例如,一般来说,每个重链可变区中存在三个CDR(例如HCDR1、HCDR2、和HCDR3),并且每个轻链可变区中存在三个CDR(LCDR1、LCDR2、和LCDR3)。CDR的精确氨基酸序列边界可以使用许多熟知的方案中的任一种来确定,包括:Kabat编号方案、Chothia编号方案、IMGT编号方案、AHo编号方案。本文中提供的CDR序列使用Kabat编号方案确定。
术语“抗原”是指能够被选择性结合剂结合的分子或其片段。例如,抗原可以是可以被选择性结合剂(例如受体)结合的配体;在一些情况中,受体也可以充当抗原,配体可以充当选择性结合剂。作为另一个实例,抗原可以是可以被选择性结合剂(例如抗体)结合的分子;在一些情况中,免疫蛋白可以充当抗原,并且抗原分子可以充当选择性结合剂。抗原也可以指能够在动物中用于产生能够与该抗原结合的抗体的分子或其片段。
术语“肿瘤抗原”指的是机体在肿瘤发生、发展过程中新出现的或过度表达的抗原。本发明中所述的肿瘤抗原可以是实体瘤抗原,也可以是血液瘤抗原。在一些实施方案中,肿瘤抗原是由正常细胞和癌细胞两者表达的标志物,例如谱系标志物,例如B细胞上的CD19。在一些实施方案中,肿瘤抗原是与正常细胞相比在癌细胞中过表达的细胞表面分子,例如,与正常细胞相比,1倍过表达、2倍过表达、3倍过表达或更多。在一些实施方案中,肿瘤抗原是在癌细胞中不适当合成的细胞表面分子,例如,与正常细胞上表达的分子相比含有缺失、添加或突变的分子。在一些实施方案中,肿瘤抗原仅在癌细胞的细胞表面上完全或作为片段(例如,MHC/肽)表达,并且不在正常细胞的表面上合成或表达。
术语“CD19”是指分化簇19蛋白,它是B细胞表面的跨膜蛋白,它与B细胞活化、信号传导及生长调节密切相关。人和鼠CD19的氨基酸和核苷酸序列可以在公共数据库中找到,例如GenBank、UniProt和Swiss-Prot。例如,人CD19的氨基酸序列可以是UniProt/Swiss-Prot:P15391中示出的氨基酸序列,编码人CD19的核苷酸序列可以是Genbank:NM_001178098中示出的氨基酸序列。如本文所用,“CD19”也包括含有突变的蛋白质,例如全长野生型CD19的点突变、片段、插入、缺失和剪接变体。
术语“跨膜结构域”或“跨膜区”是指能够使嵌合抗原受体在免疫细胞(例如T细胞、NK细胞或NKT细胞)表面上表达,并且引导免疫细胞产生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。抗原结合结构域与跨膜结构域之间可以通过铰链区或接头连接。
术语“铰链区”指抗原结合结构域与跨膜结构域之间的区段。在一些实施方案中,铰链区可用于向抗原结合结构域(例如scFv)提供柔性。在一些实施方案中,例如当用于检测scFv的抗体不起作用或不可用时,可使用铰链区来检测CAR在细胞表面上的表达。在一些情况中,铰链区来源于免疫球蛋白分子,并且依据靶标上表位的位置而需要进行优化,例如IgG4分子的铰链区。在一些情况中,铰链不属于免疫球蛋白分子,而是替代地属于另一种分子,例如CD8α分子的铰链区。CD8α铰链区可含有半胱氨酸和脯氨酸残基,所述半胱氨酸和脯氨酸残基可在CD8共受体和MHC分子的相互作用中起作用。在一些实施方案中,半胱氨酸和脯氨酸残基可影响CAR的性能,因此可以经工程化以影响CAR的性能。
术语“胞内信号传导结构域”或“胞内区”是指转导免疫效应功能信号且引导细胞执行特定功能的蛋白质的部分。胞内区可以是信号胞内区的全长序列,但在许多情况下不必使用全长序列,可以用其具备转导免疫效应功能信号功能的截短部分代替全长序列。因此,胞内区可以是包括足以转导免疫效应功能信号的信号分子胞内部分的全长或截短部分。在一个方面,胞内信号传导结构域包含至少一种共刺激结构域和/或至少一种初级信号传导结构域。术语“初级信号传导结构域”可以是来自负责初次刺激或抗原依赖性刺激分子的细胞内功能性信号传导结构域,其可以包括基于免疫受体酪氨酸的活化基序(ITAM)。术语“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。术语“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。
术语“自杀基因开关”或“安全开关”均指在外源性药物的作用下,可以有效清除体内的表达CAR的免疫细胞的元件。基因开关可以包括EGFRt、HSV-TK、iCasp9、△CD19、△CD20、mTMPK等。比较而言,HSV-TK、iCasp9和△CD20对T细胞的清除能力等同,但是iCasp9和△CD20的清除较迅速,HSV-TK清楚速度较慢。在一些实施方案中,CAR中可以引入安全开关icasp9。iCasp9是一种自杀基因系统,所述自杀基因系统由inducible caspase9(iCasp9)基因和无生物活性的小分子化学诱导药物组成。其中,小分子化学诱导药物选自AP1903、AP20187,优选AP1903。
术语“核酸”、“核酸分子”或“多核苷酸”是指单链或双链形式的脱氧核糖核酸(DNA)或核糖核酸(RNA)及其聚合物。除非特别限定,否则该术语涵盖含有已知的天然核苷酸类似物的核酸,这些核酸具有与参考核酸类似的结合特性并且以与天然存在的核苷酸类似的方式进行代谢。在一些实施方案中,“核酸”或“核酸分子”包括核苷酸/核苷衍生物或类似物。除非另有说明,否则特定核酸序列还隐含地涵盖其保守修饰的变体(例如简并密码子置换,例如保守置换)、等位基因、直向同源物、SNP和互补序列以及明确指出的序列。具体而言,简并密码子置换(例如,保守置换)可以通过其中一个或多个选定(或所有)密码子的第三位置被混合碱基和/或脱氧肌苷残基置换的序列来实现(Batzer等人,Nucleic AcidRes.[核酸研究]19:5081(1991);Ohtsuka等人,J.Biol.Chem.[生物化学杂志]260:2605-2608(1985);和Rossolini等人,Mol.Cell.Probes[分子与细胞探针]8:91-98(1994))。
术语“肽”、“多肽”和“蛋白质”可互换使用,并且是指包含由肽键共价连接的氨基酸残基的化合物。蛋白质或肽必须含有至少两个氨基酸,并且对可构成蛋白质或肽序列的氨基酸的最大数量没有限制。多肽包括包含由肽键彼此相连的两个或更多个氨基酸的任何肽或蛋白质。在一些情况下,该术语可以是短链,例如其在本领域中通常也称为短肽、寡肽和寡聚体。在一些情况下,该术语也可以是长链,其在本领域中通常称为蛋白质。“多肽”包括例如生物活性片段、多肽、寡肽、同源二聚体、异源二聚体、多肽的变体、经修饰的多肽及其衍生物、类似物、融合蛋白等。多肽包括天然肽、重组肽或其任意组合。
术语“同一性”或“同源性”定义为在比对序列及必要时引入空位以实现最大序列同一性百分比后且不考虑任何保守取代作为序列同一性的一部分下,候选序列中与特定肽或多肽序列中的氨基酸残基相同的氨基酸残基的百分比。可根据所属领域技能内的多种方式,使用公众可获得的计算器软件,诸如BLAST、BLAST-2、ALIGN或MEGALIGNTM(DNASTAR)软件,实现比对,以确定氨基酸序列同一性百分比。所属领域技术人员可确定用于量测比对的适当参数,包括实现所比较的全长序列上的最大比对所需的任何算法。
术语“变体”是指具有与参考氨基酸序列基本上相同的氨基酸序列,或由基本上相同的核苷酸序列编码的多肽。在一些实施方案中,变体是功能性变体。术语“功能性变体”是指具有与参考氨基酸序列基本上相同的氨基酸序列,或由基本上相同的核苷酸序列编码,并且能够具有参考氨基酸序列的一种或多种活性的多肽。
术语“免疫细胞”或“免疫效应细胞”是指参与免疫应答(例如促进免疫效应子应答)的细胞。免疫效应细胞的实例包括T细胞,例如α/βT细胞和γ/δT细胞、B细胞、自然杀伤(NK)细胞、自然杀伤T(NKT)细胞、单核细胞、巨噬细胞、中性粒细胞、树突状细胞等。
术语“自体的”是指源自与后来将其重新引入个体中的同一个体的任何材料。
术语“异种的”是指源自不同物种的动物的移植物。术语“同种异体的”是指源自与引入材料的个体相同的物种的不同动物的任何材料。当一个或多个基因座处的基因不相同时,称两个或更多个个体彼此是同种异体的。在一些方面,来自相同物种的个体的同种异体材料可以在遗传上充分不同以抗原性地相互作用。
术语“药学上可接受的载体”是指不会干扰活性成分的生物活性的有效性并且不对所述宿主或者受试者产生毒性的载体基质或者媒介物。
术语“受试者”可以是需要治疗的哺乳动物,如人类或兽医学患者(例如,啮齿类动物如小鼠或者大鼠、猫、狗、奶牛、马、绵羊、山羊或其他牲畜)。在一些实施方式中,“受试者”可以是临床患者、临床试验志愿者、实验动物等。所述受试者可能被怀疑患有以细胞增殖为特征的疾病或者具有患上以细胞增殖为特征的疾病、被诊断为患有以细胞增殖为特征的疾病,或者是被证实不患有以细胞增殖为特征的疾病的对照受试者,用于以细胞增殖为特征的疾病的诊断方法和这种诊断的临床划分对于本领域技术人员是已知的。
术语“肿瘤”或“癌症”是指以异常细胞的快速和不受控制的生长为特征的疾病。癌细胞可以局部或通过血流和淋巴系统扩散到身体的其他部位。肿瘤包括实体瘤和血液瘤,例如弥散或循环肿瘤。肿瘤包括恶化前以及恶性癌症和肿瘤。
术语“抗肿瘤作用”是指通过某一种或多种手段表现出的生物效应,包括但不限于例如肿瘤体积减小、癌细胞数量减少,转移数量减少、预期寿命增加、癌细胞增殖减少、癌细胞存活率降低或与癌症病症有关的各种生理学症状的改善,也指通过某一种或多种手段预防癌症首次出现的能力。
术语“治疗”是指减少或改善增殖性障碍的进展、严重程度和/或持续时间,或者改善增殖性障碍的一种或多种症状(优选地,一种或多种可辨别的症状),这由施用一种或多种疗法(例如一种或多种治疗剂,如本发明的表达CAR的细胞)引起。在一些实施方案中,术语“治疗”是指改善增殖性障碍的至少一种可测量的物理参数,如肿瘤的生长,这不一定是患者可辨别的。在一些实施方案中,术语“治疗”是指通过例如稳定可辨别的症状来物理地,或通过例如稳定物理参数来生理地,或通过两者,抑制增殖性障碍的进展。在一些实施方案中,术语“治疗”是指减少或稳定肿瘤大小或癌细胞计数。
术语“预防”意指对疾病或疾病状态的预防或保护性治疗。
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,或按照制造厂商所建议的条件。
实施例1 CAR结构的设计
按照表1中所示的CAR结构进行基因合成,得到S1、S2、C1、C2 4种CAR。其中,抗CD19scFv的氨基酸序列如SEQ ID NO:20所示,CD8α铰链区的氨基酸序列如SEQ ID NO:24所示,NKp44跨膜区的氨基酸序列如SEQ ID NO:1所示,NKG2D跨膜区的氨基酸序列如SEQ ID NO:23所示,2B4胞内区的氨基酸序列如SEQ ID NO:2所示,4-1BB胞内区的氨基酸序列如SEQ IDNO:4所示,CD3ζ胞内区的氨基酸序列如SEQ ID NO:28所示,DNAM1胞内区的氨基酸序列如SEQ ID NO:31所示,DAP10胞内区的氨基酸序列如SEQ ID NO:32所示。
表1本发明实施例中涉及的示例性CAR结构(S1、S2)及对照(C1、C2)
实施例2 CAR-NK细胞的制备
2.1质粒构建
将实施例1中获得的4种CAR的编码基因构建在MSCV载体中,分别得到重组载体MSCV-S1、MSCV-S2、MSCV-C1、MSCV-C2,将其用作逆转录病毒包装的质粒。
2.2逆转录病毒包装
按1.5×106/瓶的细胞密度接种293T细胞于T75细胞培养瓶中,加入D10(即DMEM+10%FBS)培养基,于37℃培养24小时。在无菌管中加入0.75ml Opti-MEM,并按照包装载体:包膜载体:质粒=1:1.86:2.8的比例加入包装载体Gag/pol和包膜载体RD114,混匀,室温放置5分钟。加入72.75μl转染试剂PEIpro,混匀,室温放置15分钟后将其逐滴加入到293T细胞的培养瓶中。在32℃、5%CO2条件下培养8小时后,换液。转染后24小时换液(去上清),72小时后收集各逆转录病毒上清。
2.3逆转录病毒转染
向NK92细胞中加入K562细胞进行激活(E:T=1:0.5)。4天后,用前述各逆转录病毒上清液转染激活后的NK92细胞,分别制备得到CAR-NK92 S1、CAR-NK92 S2、CAR-NK92 C1、CAR-NK92 C2细胞。用MSCV空质粒(不包含CAR序列)按照2.2所述的逆转录病毒包装方法进行病毒包装后,转染NK92细胞,制备得到MOCK NK92,用作阴性对照。
实施例3检测CAR-NK92对Nalm-6细胞的杀伤活性
以1×104个细胞/孔的浓度将靶细胞Nalm-6加入96孔板中,然后以1.25:1的效靶比加入各种CAR-NK92细胞(CAR-NK92 S1、CAR-NK92 S2、CAR-NK92 C1、CAR-NK92 C2、MOCKNK92)进行共培养。4小时后使用酶标仪读取荧光值。根据计算公式:(靶细胞对照荧光均值-样品荧光值)/靶细胞对照荧光均值×100%,计算得到杀伤效率。检测结果如图1所示。
从图1中可以看出,含有本发明设计的新型CAR结构的NK细胞CAR-NK92 S1、CAR-NK92 S2均对Nalm-6细胞有杀伤作用,显著优于对照CAR-NK92 C1、CAR-NK92 C2、MOCKNK92。
实施例4检测Nalm-6细胞激活CAR-NK92后的CD107a阳性率
在96孔板中,每孔加入1×105个CAR-NK92细胞(CAR-NK92 S1、CAR-NK92 S2、CAR-NK92 C2或Mock NK92细胞)、1×105个Nalm-6细胞,以及CD107a荧光抗体,于37℃孵育1小时。每孔加入20μl Golgi Stop稀释液(Golgi Stop用X10培养液稀释,Golgi Stop:X10培养液=1:1500(v/v);X10培养液:95%v/v X-VIVO 1640+5%v/v FBS),于37℃孵育2.5小时。最后加入5μl CD56荧光抗体,于37℃孵育30分钟。用流式细胞仪对样品的CD56+细胞群进行分析,计算CD107a阳性细胞占比,结果如图2所示。
从图2中可以看出,使用Nalm-6细胞激活后,各组CAR-NK92的CD107a阳性率均有所提高,其中CAR-NK92 S1、CAR-NK92 S2组的CD107a阳性率均显著高于对照CAR-NK92 C2组、MOCK NK92组。
实施例5检测Nalm-6激活CAR-NK92后的IFN-γ释放水平
以5×105个细胞/孔的浓度将Nalm-6铺于96孔板中,按E:T=1:1的比例分别加入CAR-NK92 S1、CAR-NK92 S2、CAR-NK92 C2、Mock NK92细胞,于37℃孵育4小时。400g离心5分钟,收集上清液。使用Human IFN-gamma DuoSet ELISA Kit(R&D systems,货号DY285)分别检测上清液中IFN-γ的含量,结果如图3所示。
从图3中可以看出,加入Nalm-6细胞激活后,各组CAR-NK92的IFN-γ表达水平均有所提高,其中CAR-NK92 S1组释放的IFN-γ的含量显著高于对照CAR-NK92C2组、Mock NK92组及空白对照组,CAR-NK92 S2组释放的IFN-γ的含量略高于对照CAR-NK92 C2组。
以上结果表明,表达本发明设计的包含从N端到C端顺序连接的NKp44跨膜区、2B-4胞内区和CD3ζ胞内区的新型嵌合抗原受体的细胞(例如NK细胞)能够有效增强对靶细胞的杀伤活性,提高CD107a阳性率和IFN-γ释放水平,具有良好的抗肿瘤作用。
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 (22)
1.一种嵌合抗原受体,其从N端到C端包含:抗原结合结构域、跨膜结构域、共刺激结构域和初级信号传导结构域,所述跨膜结构域包含NKp44跨膜区序列,所述共刺激结构域包含2B4胞内区序列和/或4-1BB胞内区序列。
2.根据权利要求1所述的嵌合抗原受体,其中所述NKp44跨膜区的氨基酸序列与SEQ IDNO:1所示的氨基酸序列具有至少80%同一性。
3.根据权利要求1或2所述的嵌合抗原受体,其中所述2B4胞内区的氨基酸序列与SEQID NO:2或3所示的氨基酸序列具有至少80%同一性。
4.根据权利要求1-3任一项所述的嵌合抗原受体,其中所述4-1BB胞内区的氨基酸序列与SEQ ID NO:4或5所示的氨基酸序列具有至少80%同一性。
5.根据权利要求1所述的嵌合抗原受体,其中所述抗原结合结构域选自Fab、Fab'、F(ab')2、Fv片段、scFv、二硫键连接的Fv、由VH和CH1结构域组成的Fd片段、线性抗体、单域抗体、由抗体片段形成的双特异性抗体或多特异性抗体、抗体的分离的CDR或其它表位结合片段。
6.根据权利要求1或5所述的嵌合抗原受体,其中所述抗原结合结构域结合选自以下的抗原: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、CS-1、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 Light Chain、KDR、LewisY、LMP2、LY6K、LAGE-1a、legumain、LCK、LAIR1、LILRA2、LY75、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、TGFBR1、TGFBR2、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、间皮素、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。
7.根据权利要求6所述的嵌合抗原受体,其中所述抗原结合结构域结合的抗原包括CD19。
8.根据权利要求7所述的嵌合抗原受体,其中所述抗原结合结构域包含:(i)重链可变区,其包含SEQ ID NO:6所示的HCDR1氨基酸序列、SEQ ID NO:7所示的HCDR2氨基酸序列和SEQ ID NO:8所示的HCDR3氨基酸序列;以及(ii)轻链可变区,其包含SEQ ID NO:9所示的LCDR1氨基酸序列、SEQ ID NO:10所示的LCDR2氨基酸序列和SEQ ID NO:11所示的LCDR3氨基酸序列。
9.根据权利要求8所述的嵌合抗原受体,其中所述抗原结合结构域包含与SEQ ID NO:13、15或17所示的氨基酸序列具有至少80%同一性的轻链可变区序列,以及与SEQ ID NO:12、14或16所示的氨基酸序列具有至少80%同一性的重链可变区序列。
10.根据权利要求1所述的嵌合抗原受体,其中所述初级信号传导结构域包含选自以下信号分子的胞内区:FcγR、FcεR、FcαR、FcRn、CD3、CD3ζ、CD3γ、CD3δ、CD3ε、CD4、CD5、CD8、CD21、CD22、CD28、CD32、CD40L、CD45、CD66d、CD79a、CD79b、CD80、CD86、CD278、CD247ζ、CD247η、DAP10、DAP12、FYN、LAT、Lck、MAPK、MHC复合物、NFAT、NF-κB、PLC-γ、iC3b、C3dg、C3d、ZAP70或其任意组合。
11.根据权利要求10所述的嵌合抗原受体,其从N端到C端包含:
(i)抗原结合结构域、NKp44跨膜结构域、2B4胞内区和CD3ζ胞内区;
(ii)抗原结合结构域、NKp44跨膜结构域、4-1BB胞内区和CD3ζ胞内区;
(iii)抗原结合结构域、NKp44跨膜结构域、2B4胞内区、4-1BB胞内区和CD3ζ胞内区;或
(iv)抗原结合结构域、NKp44跨膜结构域、4-1BB胞内区、2B4胞内区和CD3ζ胞内区。
12.编码权利要求1至11中任一项所述的嵌合抗原受体的核酸。
13.包含权利要求12所述的核酸分子的载体。
14.表达权利要求1-11中任一项所述的嵌合抗原受体的工程化免疫细胞。
15.根据权利要求14所述的工程化免疫细胞,其中所述免疫细胞为自体免疫细胞或同种异体免疫细胞。
16.根据权利要求14或15所述的工程化免疫细胞,其中所述免疫细胞选自T细胞、NK细胞、NKT细胞、B细胞、单核细胞、巨噬细胞、中性粒细胞、树突状细胞或其任意组合。
17.根据权利要求14-16任一项所述的工程化免疫细胞,其具备以下一种或多种特征:
(i)所述工程化免疫细胞包含靶向第二抗原或第二抗原表位的第二嵌合抗原受体;
(ii)所述工程化免疫细胞中TCR相关基因和/或MHC相关基因的表达是被抑制或沉默的;
(iii)所述工程化免疫细胞中以下基因被抑制或沉默:CD52、GR、dCK、免疫检查点基因或其任意组合;
(iv)所述工程化免疫细胞表达或分泌PD-1抗体、PD-L1抗体、CD47抗体、Tim3抗体、Lag3抗体、Tigit抗体、OX40抗体、ICOS抗体、IL7、CXCL19、IL21、IL15、IL2、IL18或其任意组合;和
(v)表达外源性自杀基因开关。
18.根据权利要求17所述的工程化免疫细胞,其中所述TCR相关基因和/或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、TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ或其任意组合。
19.根据权利要求17所述的工程化免疫细胞,其中所述自杀基因开关选自EGFRt、HSV-TK、iCasp9、CD20、mTMPK或其任意组合。
20.一种药物组合物,其包含权利要求14-19任一项所述的工程化免疫细胞和药学上可接受的载体。
21.根据权利要求20所述的药用组合物,其进一步包括第二治疗剂,所述第二治疗剂包括:烷基化剂、抗代谢物、抑制钙依赖性磷酸酶钙调磷酸酶或p70S6激酶FK506或抑制p70S6激酶的药物、mTOR抑制剂、免疫调节剂、蒽环霉素、长春花生物碱、蛋白酶体抑制剂、GITR激动剂、蛋白酪氨酸磷酸酶抑制剂、CDK4激酶抑制剂、BTK抑制剂、MKN激酶抑制剂、DGK激酶抑制剂、溶瘤病毒或其任意组合。
22.权利要求1-11中任一项所述的嵌合抗原受体,或权利要求14-19任一项所述的工程化免疫细胞,或权利要求20-21任一项所述的药物组合物在制备抗肿瘤药物的应用。
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