CN117187185A - 一种工程化免疫细胞及其用途 - Google Patents
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Abstract
本发明提供一种工程化免疫细胞,其表达嵌合多肽和嵌合共刺激分子;所述嵌合多肽包含第一抗原结合区;所述嵌合共刺激分子包含第二抗原结合区、第二跨膜结构域和第二共刺激结构域,其中所述第一抗原结合区和第二抗原结合区包含特异性结合NK抑制性受体的配体、抗体或抗原结合片段;所述嵌合共刺激分子不包含初级信号传导结构域。本发明还提供了包含本发明的工程化免疫细胞的组合物,以及工程化免疫细胞/组合物在预防/治疗/诊断癌症、感染或自身免疫性疾病中的用途。
Description
技术领域
本发明属于免疫治疗领域。更具体地,本发明涉及一种工程化免疫细胞、包含工程化免疫细胞的组合物及其用途,尤其是在预防/治疗/诊断癌症方面的用途。
背景技术
近几年,癌症免疫治疗技术发展迅速,尤其是嵌合抗原受体T细胞(CAR-T)相关的免疫疗法在血液瘤的治疗上获得了优异的临床效果。CAR-T细胞免疫疗法是将T细胞在体外进行基因改造,使其能够识别肿瘤抗原,在扩增到一定数量后回输至病人体内,进行肿瘤细胞杀伤,从而达到治疗肿瘤的目的。
目前,随着技术的发展,已经出现了四代不同的CAR结构。第一代CAR的初级信号传导结构域仅包含初级信号传导结构域,例如CD3ζ,因此携带CAR的细胞(例如CAR-T细胞)活性差,体内存活时间短。第二代CAR引入了共刺激结构域,例如CD28或4-1BB,使得细胞能够持续增殖,增强抗肿瘤活性。第三代CAR则包含两个共刺激结构域(例如CD28+4-1BB),第四代CAR则加入了细胞因子或共刺激配体以进一步增强T细胞应答,或加入自杀基因以在需要时使CAR-T细胞自我毁灭。现在临床研究中大多使用的仍然是第二代CAR结构。
然而,CAR-T细胞疗法在临床应用中仍然存在一些问题,例如在血液瘤治疗中存在大量肿瘤复发现象,CAR-T细胞在患者体内持续性不够久等,这些可能是由肿瘤抗原丢失、CAR-T细胞耗竭、宿主免疫细胞排斥等因素造成。
因此,仍然需要对现有的CAR-T细胞疗法进行改进,以促进CAR-T细胞在体内的增殖,降低宿主细胞对CAR-T细胞的排斥反应,进而提高CAR-T细胞疗法对肿瘤的整体治疗效果。
发明内容
在第一个方面,本发明提供一种工程化免疫细胞,其表达嵌合多肽和嵌合共刺激分子;所述嵌合多肽包含第一抗原结合区、第一跨膜结构域和初级信号传导结构域;所述嵌合共刺激分子包含第二抗原结合区、第二跨膜结构域和第二共刺激结构域,其中所述第一抗原结合区和第二抗原结合区包含特异性结合NK抑制性受体的配体、抗体或抗原结合片段,所述NK抑制性受体选自PD1、NKG2A、CEACAM1、LAIR1、LIR1、KIR、SIGLEC7、SIGLEC9和KLRG1;所述嵌合共刺激分子不包含初级信号传导结构域。
在一个实施方案中,所述嵌合多肽选自CAR、TCR、TRuC、TAC、ImmTAC或它们的任意组合。在一个具体的实施方案中,所述嵌合多肽选自CAR和/或TCR。优选地,所述嵌合多肽选自CAR,包含第一抗原结合区、第一跨膜结构域、第一共刺激结构域和初级信号传导结构域。
在一个实施方案中,所述第一抗原结合区包含结合NKG2A的配体、抗体或抗原结合片段,且/或所述第二抗原结合区包含结合KIR的配体、抗体或抗原结合片段。
在一个实施方案中,所述第一抗原结合区包含特异性结合肿瘤抗原的配体、抗体或其抗原结合片段,第二抗原结合区不包含特异性结合肿瘤抗原的配体、抗体或其抗原结合片段,或者第一抗原结合区不包含特异性结合肿瘤抗原的配体、抗体或其抗原结合片段,第二抗原结合区包含特异性结合肿瘤抗原的配体、抗体或其抗原结合片段。
在另一个实施方案中,所述第一抗原结合区和第二抗原结合区均包含特异性结合肿瘤抗原的配体、抗体或其抗原结合片段,所述肿瘤抗原相同或者虽然不同但在同一靶细胞上表达。
在一个实施方案中,所述第一抗原结合区和/或第二抗原结合区还包含特异性结合肿瘤抗原的配体、抗体或其抗原结合片段,所述肿瘤抗原选自:CD7、TSHR、CD19、CD123、CD22、BAFF-R、CD30、CD171、CS-1、CLL-1、CD33、EGFRvIII、GD2、GD3、BCMA、GPRC5D、Tn Ag、PSMA、ROR1、FLT3、FAP、TAG72、CD38、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、间皮素、IL-llRa、PSCA、PRSS21、VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、CD20、Folate受体α、ERBB2(Her2/neu)、MUC1、EGFR、NCAM、Claudin18.2、Prostase、PAP、ELF2M、Ephrin B2、IGF-I受体、CAIX、LMP2、gploo、bcr-abl、酪氨酸酶、EphA2、Fucosyl GMl、sLe、GM3、TGS5、HMWMAA、o-乙酰基-GD2、Folate受体β、TEM1/CD248、TEM7R、CLDN6、GPRC5D、CXORF61、CD97、CD179a、ALK、多聚唾液酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-la、MAGE-A1、豆荚蛋白、HPV E6、E7、MAGE Al、ETV6-AML、精子蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、前列腺特异性蛋白、存活蛋白和端粒酶、PCTA-l/Galectin 8、MelanA/MARTl、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、ERG(TMPRSS2 ETS融合基因)、NA17、PAX3、雄激素受体、Cyclin Bl、MYCN、RhoC、TRP-2、CYP1B 1、BORIS、SART3、PAX5、OY-TES 1、LCK、AKAP-4、SSX2、RAGE-1、人端粒酶逆转录酶、RU1、RU2、肠道羧酸酯酶、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、PD1、PDL1、PDL2、TGFβ、APRIL、NKG2D和它们的任意组合;优选地,所述肿瘤抗原选自:CD7、CD19、CD20、CD22、CD30、CD33、CD38、CD123、CD138、CD171、MUC1、AFP、Folate受体α、CEA、PSCA、PSMA、Her2、EGFR、IL13Ra2、GD2、NKG2D、EGFRvIII、CS1、BCMA、间皮素、Claudin18.2、ROR1、NY-ESO-1、MAGE-A4和它们的任意组合。
在一个实施方案中,所述抗体或抗原结合片段是完整抗体、Fab、Fab’、F(ab’)2、Fv片段、scFv抗体片段、线性抗体、sdAb或纳米抗体。
在一个实施方案中,所述第一抗原结合区结合CD19和NKG2A,所述第二抗原结合区结合KIR。更优选地,所述第一抗原结合区结合CD19和NKG2A,所述第二抗原结合区结合KIR和CD22。
在一个实施方案中,所述第一抗原结合区包含结合NKG2A的配体、抗体或抗原结合片段,优选抗体或其抗原结合片段,其包含与SEQ ID NO:1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%序列同一性的轻链可变区序列和与SEQ ID NO:2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%序列同一性的重链可变区序列。
在一个实施方案中,所述第一抗原结合区还包含结合CD19的抗体或抗原结合片段,其包含与SEQ ID NO:5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%序列同一性的轻链可变区序列和与SEQ ID NO:6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%序列同一性的重链可变区序列。
在一个实施方案中,所述第二抗原结合区包含结合KIR的配体、抗体或抗原结合片段,优选抗体或其抗原结合片段,其包含与SEQ ID NO:9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%序列同一性的轻链可变区序列和与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%序列同一性的重链可变区序列。
在一个实施方案中,所述第二抗原结合区还包含结合CD22的抗体或抗原结合片段,其包含与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%序列同一性的重链可变区序列。
在一个实施方案中,所述CD19和NKG2A、CD22和KIR之间使用GS连接肽连接,所述GS连接肽为(GSSSS)n,n为1-6之间的自然数。
在一个实施方案中,所述第一跨膜结构域或第二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或它们的任意组合。优选地,所述第一跨膜结构域或第二跨膜结构域选自CD8α、CD4、CD28或CD278的跨膜结构域。
在一个实施方案中,所述第一跨膜结构域为CD8α跨膜结构域,与SEQ ID NO: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。
在一个实施方案中,所述第二跨膜结构域为CD28跨膜结构域,与SEQ ID NO:17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,所述第一共刺激结构域或第二共刺激结构域选自以下蛋白质的共刺激结构域:LTB、CD94、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、CD7、CD8、CD18、CD27、CD28、CD30、CD40、CD54、CD83、CD134(OX40)、CD137(4-1BB)、CD270(HVEM)、CD272(BTLA)、CD276(B7-H3)、CD278(ICOS)、CD357(GITR)、DAP10、DAP12、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM、ZAP70或它们的任意组合。优选地,所述第一共刺激结构域或第二共刺激结构域选自4-1BB、CD28、CD27、OX40、CD278或它们的任意组合。更优选地,所述第一共刺激结构域为CD28共刺激结构域,第二共刺激结构域为4-1BB共刺激结构域,或所述第一共刺激结构域为CD28共刺激结构域,第二共刺激结构域为4-1BB共刺激结构域。其中,CD28能够增强工程化免疫细胞刺激作用,4-1BB能够延长工程化免疫细胞持续时间。
在一个实施方案中,所述第一共刺激结构域为4-1BB共刺激结构域,与SEQ ID NO: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。
在一个实施方案中,所述第二共刺激结构域为CD28共刺激结构域,与SEQ ID NO: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。
在一个实施方案中,所述初级信号传导结构域选自以下蛋白的信号传导结构域:FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b、CD66d或它们的任意组合。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。
在一个实施方案中,所述初级信号传导结构域与SEQ ID NO:23或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。
在一个实施方案中,所述嵌合抗原受体与嵌合共刺激分子之间用连接肽连接。优选地,所述连接肽是一种自切割肽。更优选地,所述自切割肽选自P2A、T2A、E2A和F2A。
在一个实施方案中,所述工程化免疫细胞中,至少一种MHC相关基因的表达被抑制或沉默。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或它们的任意组合,优选HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA或它们的任意组合。
在一个实施方案中,所述工程化免疫细胞中,至少一种TCR/CD3相关基因的表达被抑制或沉默。所述TCR/CD3基因选自TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ或它们的任意组合。
在一个优选的实施方案中,所述工程化免疫细胞的至少一种TCR/CD3基因和至少一种MHC相关基因的表达被抑制或沉默,其中所述至少一种TCR/CD3基因选自TRAC、TRBC或它们的任意组合,所述至少一种MHC相关基因是B2M、RFX5、RFXAP、RFXANK、CIITA或它们的任意组合。在一个具体的实施方案中,所述工程化免疫细胞的TCR/CD3、B2M和CIITA的表达被抑制或沉默。
在一个实施方案中,所述工程化免疫细胞中还有以下的一个或多个基因的表达被抑制或沉默: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、TGFBRII、TGFRBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、EIF2AK4、CSK、PAG1、SIT、FOXP3、PRDM1、BATF、GUCY1A2、GUCY1A3、GUCY1B2和GUCY1B3。优选地,所述工程化免疫细胞的CD52、dCK、PD1、LAG3、TIM3、CTLA4、TIGIT或它们的任意组合被抑制或沉默。
在一个实施方案中,本发明的免疫细胞选自T细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞或NKT细胞。优选地,所述T细胞是CD4+/CD8+双阳性T细胞、CD4+T细胞、CD8+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细胞或αβ-T细胞。
在第二个方面,本发明提供一种药物组合物,包含上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。
在第三个方面,本发明提供上述工程化免疫细胞,或上述的药物组合物在制备用于预防/治疗/诊断癌症、感染或自身免疫性疾病的药物中的用途。
在一个实施方案中,所述癌症选自: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、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、淋巴瘤、黑色素瘤、骨髓瘤、神经母细胞瘤、口腔癌、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、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)。
发明详述
除非另有说明,否则本文中所使用的所有科学技术术语的含义与本发明所属领域的普通技术人员通常所了解的相同。
嵌合多肽和嵌合共刺激分子
如本文所用,术语“嵌合多肽”包含第一抗原结合区、第一跨膜结构域和初级信号传导结构域,可以选自CAR、TCR、TRuC、TAC、ImmTAC或它们的任意组合。
如本文所用,“T细胞受体”或“TCR”是T细胞表面的特异性受体,负责识别由主要组织相容性复合体(MHC)所呈递的抗原。T细胞受体是异源二聚体,由两个不同的亚基所构成。95%的T细胞的受体由α亚基和β亚基构成,另外5%的受体由γ亚基和δ亚基构成。这个比例会因个体发育或是疾病而变化。T细胞受体与MHC所呈递的多肽的特异性结合会引发一系列生化反应,并通过众多的辅助受体、酶和转录因子激活T细胞,促进其分裂与分化。
如本文中所用,“T细胞受体融合结构”或“TRuC”是指一种与T细胞受体亚单位融合的抗体结合域,设计用于有效识别肿瘤表面抗原。TRuC由靶向肿瘤相关抗原的特异性抗体融合到5个TCR亚基(TCRα、TCRβ、CD3、CD3γ和CD3δ)的胞外N-末端组成,为工程化T细胞提供了新的靶向特异性和HLA非依赖性靶细胞清除能力,可被相应的靶细胞激活。
如本文中所用,“T细胞抗原偶联剂”或“TAC”是一种工程化TCR细胞,以非MHC依赖性方式诱导更有效的抗肿瘤反应并降低毒性。TAC嵌合蛋白通过与CD3结构域的结合,从而形成TCR/CD3复合物并获得更多的T细胞应答。与第二代CAR相比,TAC基因工程化的T细胞不仅有利于过继后在实体瘤的更大浸润,而且减少了T细胞在表达抗原的健康组织中的扩增和肿瘤外毒性。
如本文中所用,“免疫动员单克隆T细胞受体”或“ImmTAC”是使用工程化、可溶性和亲和增强的单克隆TCR(mTCR)设计的。ImmTAC通过特异性靶向肿瘤细胞表面的HLA-肽复合物,并通过scFv抗体片段与CD3的相互作用促进T细胞介导的效应器功能。ImmTAC还以剂量依赖性方式激活CD8+T细胞,并能有效地重定向和激活效应和记忆CD8+和CD4+细胞。ImmTAC通过分泌多种细胞因子表现出多功能反应,如TNF-α、IFN-γ、IL-6、MIP1α-β和IFN-γ诱导蛋白10等。
如本文所用,“嵌合抗原受体”或“CAR”是指人工构建的杂合多肽,该杂合多肽的基础结构包括抗原结合区(例如抗体的抗原结合部分)、跨膜结构域和初级信号传导结构域。CAR能够利用抗原结合区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CAR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。此外,当在T细胞内表达时,CAR有利地不与内源性T细胞受体(TCR)的α链和β链二聚化。本发明的嵌合抗原受体包含第一抗原结合区、第一跨膜结构域、第一共刺激结构域和初级信号传导结构域。
如本文中所用,术语“嵌合共刺激分子”是指另一种人工构建的杂合多肽,其基础结构包括:第二抗原结合区、第二跨膜结构域和第二共刺激结构域,且不包含初级信号传导结构域。当免疫细胞同时表达嵌合多肽和嵌合共刺激分子时,嵌合多肽与嵌合共刺激分子共享初级信号传导结构域。此外,嵌合共刺激分子与其靶向抗原的结合也可以通过额外的对接效应来消除由第一抗原结合区靶向的抗原造成的空间位阻,进而增强工程化免疫细胞的功效。
在一个实施方案中,所述第一抗原结合区和第二抗原结合区均包含特异性结合NK抑制性受体的配体、抗体或抗原结合片段以抑制NK细胞对表达所述工程化免疫细胞的杀伤,所述NK抑制性受体选自PD1、NKG2A、CEACAM1、LAIR1、LIR1、KIR、SIGLEC7、SIGLEC9和KLRG1。嵌合多肽和嵌合共刺激分子通过结合NK抑制性受体,能够抑制宿主NK细胞对表达其的工程化免疫细胞的杀伤,进而促进本发明工程化免疫细胞的增殖,提高其持久性,最终增强治疗效果。
如本文所用,“抗体”或“抗原结合片段”是指可以与抗原或受体结合的任何结构或其功能性变体。抗原结合片段可以是抗体结构,包括但不限于单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体、嵌合抗体及其功能性片段。例如,抗原结合片段包括但不限于单链抗体(scFv)、单结构域抗体(sdAb)、纳米抗体(Nb)、重组纤连蛋白结构域、anticalin和DARPIN等,优选为scFv、sdAb或纳米抗体。在本发明中,抗体或抗原结合片段可以是单价或二价,且可以是单特异性、双特异性或多特异性的。
术语“功能性变体”或“功能性片段”是指基本上包含亲本的氨基酸序列但与该亲本氨基酸序列相比含有至少一个氨基酸修饰(即取代、缺失或插入)的变体,条件是所述变体保留亲本氨基酸序列的生物活性。在一个实施方案中,所述氨基酸修饰优选是保守型修饰。
如本文所用,术语“保守性修饰”是指不会明显影响或改变含有该氨基酸序列的抗体或抗体片段的结合特征的氨基酸修饰。这些保守修饰包括氨基酸取代、添加及缺失。修饰可以通过本领域中已知的标准技术,如定点诱变和PCR介导的诱变而引入本发明的嵌合抗原受体或嵌合共刺激分子中。保守氨基酸取代是氨基酸残基被具有类似侧链的氨基酸残基置换的取代。具有类似侧链的氨基酸残基家族已在本领域中有定义,包括碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸)、β-分支侧链(例如苏氨酸、缬氨酸、异亮氨酸)及芳香族侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。保守性修饰可以例如基于极性、电荷、溶解度、疏水性、亲水性和/或所涉及残基的两亲性质的相似性来进行选择。
因此,“功能性变体”或“功能性片段”与亲本氨基酸序列具有至少75%,优选至少76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列同一性,并且保留亲本氨基酸的生物活性,例如结合活性。
如本文所用,术语“序列同一性”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。
在一个实施方案中,本发明的第一抗原结合区和/或第二抗原结合区还包括与肿瘤抗原特异性结合的配体、抗体或其抗原结合片段,所述肿瘤抗原选自:CD7、TSHR、CD19、CD123、CD22、CD30、CD171、CS-1、CLL-1、CD33、EGFRvIII、GD2、GD3、BCMA、Tn Ag、PSMA、ROR1、FLT3、FAP、TAG72、CD38、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、间皮素、IL-l lRa、PSCA、PRSS21、VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、CD20、Folate受体α、ERBB2(Her2/neu)、MUC1、EGFR、NCAM、Prostase、PAP、ELF2M、Ephrin B2、IGF-I受体、CAIX、LMP2、gplOO、bcr-abl、酪氨酸酶、EphA2、Fucosyl GMl、sLe、GM3、TGS5、HMWMAA、o-乙酰基-GD2、Folate受体β、TEM1/CD248、TEM7R、CLDN6、GPRC5D、CXORF61、CD97、CD179a、ALK、多聚唾液酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-la、MAGE-A1、豆荚蛋白、HPV E6、E7、MAGE Al、ETV6-AML、精子蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、前列腺特异性蛋白、存活蛋白和端粒酶、PCTA-l/Galectin 8、MelanA/MARTl、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、ERG(TMPRSS2ETS融合基因)、NA17、PAX3、雄激素受体、Cyclin Bl、MYCN、RhoC、TRP-2、CYP1B 1、BORIS、SART3、PAX5、OY-TES 1、LCK、AKAP-4、SSX2、RAGE-1、人端粒酶逆转录酶、RU1、RU2、肠道羧酸酯酶、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、PD1、PDL1、PDL2、TGFβ、APRIL、NKG2D或它们的任意组合。优选地,所述肿瘤抗原选自:CD7、CD19、CD20、CD22、CD30、CD33、CD38、CD123、CD138、CD171、MUC1、AFP、Folate受体α、CEA、PSCA、PSMA、Her2、EGFR、IL13Ra2、GD2、NKG2D、EGFRvIII、CS1、BCMA、间皮素、Claudin18.2、ROR1、NY-ESO-1、MAGE-A4和它们的任意组合。在一个实施方案中,第一抗原结合区包含特异性结合肿瘤抗原的抗体,第二抗原结合区不包含特异性结合肿瘤抗原的抗体,或者第一抗原结合区不包含特异性结合肿瘤抗原的抗体,第二抗原结合区包含特异性结合肿瘤抗原的抗体。在另一个实施方案中,所述第一抗原结合区和第二抗原结合区均包含特异性结合肿瘤抗原的抗体或其抗原结合片段;在该实施方案中,第一抗原结合区和第二抗原结合区靶向的肿瘤抗原相同或者虽然不同但是在同一靶细胞上表达,以避免肿瘤抗原丢失或逃逸造成的活性下降,从而增强对靶细胞的杀伤活性。
在一个实施方案中,所述第一抗原结合区包含结合NKG2A的配体、抗体或抗原结合片段,优选抗体或其抗原结合片段,其包含与SEQ ID NO:1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%序列同一性的轻链可变区序列和与SEQ ID NO:2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%序列同一性的重链可变区序列;优选地,所述第一抗原结合区还包含结合CD19的抗体或抗原结合片段,其包含与SEQ ID NO:5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%序列同一性的轻链可变区序列和与SEQ ID NO:6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%序列同一性的重链可变区序列。
在一个实施方案中,所述第二抗原结合区包含结合KIR的配体、抗体或抗原结合片段,优选抗体或其抗原结合片段,其包含与SEQ ID NO:9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%序列同一性的轻链可变区序列和与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%序列同一性的重链可变区序列;优选地,所述第二抗原结合区还包含结合CD22的抗体或抗原结合片段,其包含与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%序列同一性的重链可变区序列。在一个实施方案中,所述第一抗原结合区结合CD19和NKG2A,所述第二抗原结合区结合KIR。更为优选地,所述第一抗原结合区结合CD19和NKG2A,所述第二抗原结合区结合CD22和KIR。
如本文所用,术语“跨膜结构域”是指能够使嵌合抗原受体在免疫细胞(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或它们的任意组合。或者,跨膜结构域可以是合成的并且可以主要地包含疏水性残基如亮氨酸和缬氨酸。优选地,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,所述第一跨膜结构域为CD8α跨膜结构域,与SEQ ID NO: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;所述第二跨膜结构域为CD28跨膜结构域,与SEQ ID NO:17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和嵌合共刺激分子还可以包含位于抗原结合区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原结合区的任何寡肽或多肽。具体地,铰链区用来为抗原结合区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,如源自全部或部分的CD8、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链、FcγRIIIα受体、IgG4或IgG1的铰链区部分。在一个实施方案中,第一抗原结合区和第一跨膜结构域之间的第一铰链区为CD8α链铰链区,与SEQ ID NO:27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;第二抗原结合区和第二跨膜结构域之间的第二铰链区为IgG4链铰链区,与SEQ ID NO:29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“初级信号传导结构域”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。初级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初级活化。换言之,初级信号传导结构域负责活化其中表达CAR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初级活化信号传导,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许多免疫受体酪氨酸激活基序(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或它们的任意组合。优选地,本发明CAR的信号传导结构域可以包含CD3ζ信号传导结构域,与SEQID NO:23或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。
在一个实施方案中,本发明的嵌合受体和嵌合共刺激分子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包括但不限于源自以下蛋白质的共刺激信号传导结构域:TLR9、TLR10、CARD11、CD2、CD7、CD8、CD18、CD27、CD28、CD30、CD40、CD54、CD83、CD134(OX40)、CD137(4-1BB)、CD270(HVEM)、CD272(BTLA)、CD276(B7-H3)、CD278(ICOS)、CD357(GITR)、DAP10、DAP12、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM、ZAP70或它们的任意组合。优选地,所述第一共刺激结构域或第二共刺激结构域选自4-1BB、CD28、CD27、OX40、CD278或它们的任意组合。更优选地,所述第一共刺激结构域为CD28共刺激结构域,第二共刺激结构域为4-1BB共刺激结构域,或所述第一共刺激结构域为CD28共刺激结构域,第二共刺激结构域为4-1BB共刺激结构域。在一个具体的实施方案中,所述4-1BB共刺激结构域与SEQ ID NO: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;所述CD28共刺激结构域与SEQ ID NO: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。
本发明的嵌合抗原受体和嵌合共刺激分子还可以包含信号肽,使得当其在细胞例如T细胞中表达时,新生蛋白质被引导至内质网并随后引导至细胞表面。信号肽的核心可以含有长的疏水性氨基酸区段,其具有形成单个α-螺旋的倾向。在信号肽的末端,通常有被信号肽酶识别和切割的氨基酸区段。信号肽酶可以在移位期间或完成后切割,以产生游离信号肽和成熟蛋白。然后,游离信号肽被特定蛋白酶消化。可用于本发明的信号肽是本领域技术人员熟知的,例如衍生自CD8α、IgG1、GM-CSFRα、B2M等的信号肽。在一个实施方案中,所述嵌合抗原受体的信号肽为CD8α信号肽,与SEQ ID NO:31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%、99%或100%的序列同一性;所述嵌合共刺激分子的信号肽为B2M信号肽,与SEQ ID NO:33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%、99%或100%的序列同一性。
工程化免疫细胞
本发明提供工程化免疫细胞,其包含嵌合多肽或其编码核酸,和嵌合共刺激分子或其编码核酸。
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T细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞和/或NKT细胞。优选地,免疫细胞是T细胞。T细胞可以是任何T细胞,如体外培养的T细胞,例如原代T细胞,或者来自体外培养的T细胞系例如Jurkat、SupT1等的T细胞,或获得自受试者的T细胞。受试者的实例包括人、狗、猫、小鼠、大鼠及其转基因物种。T细胞可以从多种来源获得,包括外周血单核细胞、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。T细胞也可以被浓缩或纯化。T细胞可以是任何类型的T细胞并且可以处于任何发育阶段,包括但不限于,CD4+/CD8+双阳性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。在本发明中,免疫细胞被工程化以表达嵌合抗原受体和嵌合共刺激分子。
在一个实施方案中,编码嵌合多肽的第一核酸序列和编码嵌合共刺激分子的第二核酸序列位于同一载体。例如,可以通过在两个核酸序列之间插入编码2A肽的核酸,使得本发明的嵌合多肽和嵌合共刺激分子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。在另一个实施方案中,编码嵌合多肽的第一核酸序列和编码共刺激分子的第二核酸序列位于不同载体。
如本文所用,术语“载体”是用作将(外源)遗传材料转移到免疫细胞中的媒介核酸分子,在免疫细胞中所述核酸分子可以例如复制和/或表达。
在一个实施方案中,本发明的工程化免疫细胞还包含至少一种MHC相关基因表达被抑制或沉默,例如使至少一种MHC基因的表达被抑制或沉默,或使与至少一种MHC基因相互作用或调控其表达的基因的表达被抑制或沉默。优选地,在一个实施方案中,MHC相关基因表达被抑制或沉默是指使选自以下的一个或多个基因的表达被抑制或沉默:HLA-A、HLA-B、HLA-C、B2M、HLA-DPA、HLA-DQ、HLA-DRA、TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK、CIITA或它们的任意组合,优选选自HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA或它们的任意组合。
在一个实施方案中,本发明的工程化免疫细胞还包含至少一种TCR/CD3基因的表达被抑制或沉默。优选地,TCR/CD3基因表达被抑制或沉默是指使选自以下的一个或多个基因的表达被抑制或沉默:TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ。
在一个优选的实施方案中,所述工程化免疫细胞包括至少一种TCR/CD3基因和至少一种MHC相关基因的表达被抑制或沉默,其中所述至少一种TCR/CD3基因选自TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ或它们的任意组合;所述至少一种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或它们的任意组合,优选选自HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA或它们的任意组合。
在一个优选的实施方案中,所述至少一种TCR/CD3基因选自TRAC、TRBC或它们的任意组合,所述至少一种MHC相关基因选自B2M、RFX5、RFXAP、RFXANK、CIITA或它们的任意组合。在一个具体的实施方案中,所述工程化免疫细胞的TCR/CD3、B2M和CIITA的表达被抑制或沉默。
在一个实施方案中,除了MHC相关基因和TCR/CD3基因,本发明的工程化免疫细胞还可以包含至少一种选自以下的基因的表达被抑制或沉默: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、TGFBRII、TGFRBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、EIF2AK4、CSK、PAG1、SIT、FOXP3、PRDM1、BATF、GUCY1A2、GUCY1A3、GUCY1B2和GUCY1B3。
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酶、锌指核酸酶、TALE核酸酶或CRISPR系统中的Cas酶介导DNA断裂、或通过反义寡核苷酸、RNAi、shRNA等技术使基因失活。
药物组合物
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载体或赋型剂。因此,本发明还涵盖所述工程化免疫细胞在制备药物组合物或药物中的用途。
如本文所用,术语“药学上可接受的载体或赋型剂”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。包含所述工程化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预防/治疗/诊断相关疾病的其它药剂组合施用。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(sorfimersodiumphotofrin II)、替莫唑胺、拓扑替康、葡萄糖醛酸曲美沙特(trimetreateglucuronate)、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。
制药用途
本发明还提供一种上述工程化免疫细胞或药物组合物在制备用于预防/治疗/诊断癌症、感染或自身免疫性疾病的药物中的用途。
在一个实施方案中,所述疾病是与抗原结合区结合的靶标表达有关的癌症。例如,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预防/治疗/诊断的疾病选自:白血病、淋巴瘤、多发性骨髓瘤、脑神经胶质瘤、胰腺癌、胃癌等。
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示出了不同CAR-T细胞上的CD19 scFv的表达水平。
图2示出了不同CAR-T细胞中的KIR scFv的表达水平。
图3示出了不同CAR-T细胞中的增殖情况。
图4示出了不同CAR-T细胞对Raji靶细胞的特异性裂解率。
图5示出了不同CAR-T细胞对NK细胞的抑制效果。
图6示出了不同CAR-T细胞对体内肿瘤的抑制效果。
具体实施方式
实施例1.制备靶向CD19和NKG2A的UCAR-T细胞
1.1质粒构建和CAR T细胞制备
合成编码以下蛋白的序列,并将其依次克隆至MSCV载体(通用生物合成):CD8α信号肽(SEQ ID NO:27)、抗CD19 scFv(SEQ ID NO:7)、GS连接肽(SEQ ID NO:35)、NKG2A scFv(SEQ ID NO:3)、CD8α铰链区(SEQ ID NO:27)、CD8α跨膜区(SEQ ID NO:15)、4-1BB胞内区(SEQ ID NO:19)、CD3ζ初级信号传导结构域(SEQ ID NO:23),通过测序确认目标序列的正确插入,并将质粒命名为cCAR。
在cCAR质粒中进一步包括嵌合共刺激分子(两者通过F2A肽连接),所述嵌合共刺激分子包含B2M信号肽(SEQ ID NO:33)、KIR scFv(SEQ ID NO:11)、IgG4铰链区(SEQ IDNO:29)、CD28跨膜区(SEQ ID NO:15)、CD28共刺激结构域(SEQ ID NO:21),所得质粒命名为2A19-K。
在cCAR质粒中进一步包括嵌合共刺激分子(两者通过F2A肽连接),所述嵌合共刺激分子包含B2M信号肽(SEQ ID NO:33)、CD22 VHH(SEQ ID NO:13)、GS连接肽(SEQ ID NO:35)、KIR scFv(SEQ ID NO:11)、IgG4铰链区(SEQ ID NO:29)、CD28跨膜区(SEQ ID NO:15)、CD28共刺激结构域(SEQ ID NO:21),所得质粒命名为2A19-22K。
在无菌管中加入3ml Opti-MEM(Gibco,货号31985-070)稀释上述质粒后,再根据质粒:辅助载体=1:1的比例加入包装载体RD114(Addgene,货号17576),总量为60μg。然后,加入120μl X-treme GENE HP DNA转染试剂(Roche,货号06366236001),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293GP细胞的培养瓶中。在72小时和96小时收集病毒,将其合并后,保存于-80℃备用。
用DynaBeads CD3/CD28 CTSTM(Gibco,货号40203D)激活T细胞,并在37℃和5%CO2下继续培养2天后,采用CRISPR/Cas9系统敲除野生型T细胞中的TCR/CD3组分(具体为TRAC基因)、B2M和CIITA基因,获得TCR/B2M/CIITA三敲除的tKO-T细胞。
采用RetroNectin(TAKARA,货号:T100B)包被12孔板,4℃过夜包被PBS清洗后,将tKO-T细胞(D3)和病毒同时加入孔板中进行2000g离心2h后放置于37℃培养,第二天离心换液后继续培养,获得cCAR T、2A19-K CAR T、2A19-22K CAR T细胞。敲除但不转导病毒的T细胞用作阴性对照(NT-KO)。
使用Biotin-SP(long spacer)AffiniPure Goat Anti-human IgG,F(ab')2Fragment Specific(min X Hu,Bov,Hrs Sr Prot)(jackson immunoresearch,货号109-065-097)作为一抗,APC Streptavidin(BD Pharmingen,货号554067)或PE Streptavidin(BD Pharmingen,货号554061)作为二抗,检测CAR T细胞上的CD19 scFv的表达水平,结果如图1所示。
使用recombinant human KIR2DL2 protein(Sino Biological,货号12828-H02H)作为一抗,PE anti-human IgG Fc(biolegend,货号409304)作为二抗检测细胞中KIR scFv的表达,结果如图2所示。可以看出,本发明制备的CAR T细胞中的CD19 scFv和KIR scFv均可以有效表达。
CAR T扩增过程中通过计数仪检测细胞的增殖情况,如图3所示。可以看出,与cCART相比,2A19-K CAR T和2A19-22K CAR T组细胞有明显的增殖优势,且2A19-22K CAR T组细胞比2A19-K CAR T组展现了更好的细胞增殖能力。
实施例2.CART细胞对靶细胞的杀伤效果
1.对靶细胞的杀伤效果
为了检测CAR T细胞对靶细胞的杀伤能力,首先以1×104/孔将携带荧光素基因的Raji靶细胞铺入96孔板中,然后以不同的效靶比(即效应T细胞与靶细胞之比)将NT-KO、cCAR T、2A19-K CAR T、2A19-22K CAR T这四组细胞铺入到96孔板进行共培养,16-18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4所示。
可以看出,2A19-K CAR T和2A19-22K CAR T组细胞杀伤能力均明显优于cCAR T组,且2A19-22K CAR T组细胞比2A19-K CAR T组展现了更强的杀伤能力。
实施例3.共表达NK抑制分子的CAR-T细胞对NK细胞的抑制效果
用Far-Red(invitrogen,货号C34564)标记NT-KO、cCAR T、2A19-K CAR T、2A19-22K CAR T这四组细胞。然后按照1×104个细胞/孔的浓度将标记好的细胞铺入96孔板,并以2:1的效靶比加入NK92细胞进行共培养。16-18小时后,用流式细胞仪检测培养物中T细胞的比例,结果如图5所示。
可以看出,与cCAR T组相比,2A19-K CAR T组和2A19-22K CAR T组细胞均可有效抑制NK细胞的杀伤,且2A19-22K CAR T组细胞比2A19-K CAR T组抑制NK细胞杀伤的作用更显著。
实施例4.共表达NK抑制分子的CAR-T细胞的体内抑瘤效果
将20只8周龄的健康雌性NCG小鼠分成四组:NT组、cCAR组、2A19-K CAR T组和2A19-22K CAR组。在第0天(D0),向每只小鼠尾静脉注射0.5×106个Raji细胞。3天后(D3),根据分组情况向每只小鼠尾静脉注射2×106个NT-KO细胞、cCAR T细胞、2A19-K CAR T细胞或2A19-22K CAR T细胞。每周评估小鼠的存活率变化,结果如图6所示。
可以看出,相对于cCAR T组,2A19-K CAR T组能略微延长荷瘤小鼠的存活时间,而2A19-22K CAR T组则可明显提高小鼠的存活率。
以上结果表明,本发明的嵌合共刺激分子能够显著提高CAR T细胞的增殖水平和体外杀伤活性,同时也能够更好地抑制NK细胞对CAR T细胞的杀伤。此外,当本发明的嵌合共刺激分子还包含针对与CAR靶向的肿瘤抗原在同一靶细胞上表达的肿瘤抗原的抗体时(CD19和CD22均在B细胞上表达),能进一步增强CAR T细胞的增殖水平和体外杀伤活性,并可显著提高CAR T细胞在体内的肿瘤抑制效果。
序列表
<110> 南京北恒生物科技有限公司
<120> 一种工程化免疫细胞及其用途
<130> BHCN54
<160> 35
<170> SIPOSequenceListing 1.0
<210> 1
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Ser Tyr
20 25 30
Ile Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Leu Thr Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 2
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg His Gly Asp Tyr Pro Arg Phe Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 3
<211> 244
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Ser Tyr
20 25 30
Ile Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Leu Thr Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Ser Thr Ser Gly
100 105 110
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser
145 150 155 160
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Glu Ile
165 170 175
Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Thr Arg His
210 215 220
Gly Asp Tyr Pro Arg Phe Phe Asp Val Trp Gly Gln Gly Thr Leu Val
225 230 235 240
Thr Val Ser Ser
<210> 4
<211> 732
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
gaaatagtct tgacccagtc tcccgctacc ctcagtcttt cacccggtga acgcgctacg 60
atgacgtgtt cagcatccag ctctgtgtct tcctacattt attggtacca gcagaaacca 120
ggccaagcgc cgcgcctcct catttacctt acttcaaacc ttgcatccgg tattcccgcg 180
agattcagcg gtagtggttc tggaacggat tttacactta cgattagttc acttgaaccc 240
gaagatttcg ccacgtatta ctgtcagcaa tggtcaggaa atccttacac tttcggccaa 300
ggtaccaaag tcgagatcaa agggtccact tctggttcag gtaagccagg tagtggcgag 360
gggagtacaa agggggaagt gcagctcgtc gagtcaggtg gcggacttgt aaaaccgggg 420
gggtcactcc ggctgtcctg cgcagcgagt ggatttacct ttagcagtta tgcaatgtcc 480
tgggtaagac aagctccggg caagggactg gaatgggtgg ctgaaatctc tagtggtgga 540
agttatacct actaccctga tagcgtgaag ggtagattta ctattagtcg ggacaacgct 600
aagaatagct tgtaccttca aatgaacagt ttgcgagcag aggacactgc agtttattat 660
tgcacccggc acggagatta tcctcgcttt tttgacgtat ggggacaggg aactctcgtg 720
actgttagta gc 732
<210> 5
<211> 105
<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 Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Leu
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Gln Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105
<210> 6
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Ala Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Ser Gln Val Val Leu
65 70 75 80
Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 7
<211> 240
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
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 Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Leu
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Gln Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Gly Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser Gly
115 120 125
Pro Val Leu Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val
130 135 140
Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro
145 150 155 160
Pro Gly Lys Ala Leu Glu Trp Leu Ala Val Ile Trp Gly Ser Glu Thr
165 170 175
Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp
180 185 190
Thr Ser Lys Ser Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val
195 200 205
Asp Thr Ala Thr Tyr Tyr Cys Ala Arg His Tyr Tyr Tyr Gly Gly Ser
210 215 220
Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
225 230 235 240
<210> 8
<211> 723
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
gatattcaga tgacccaaag tccgtctagc ttgtcagcct ccgtagggga cagagttacg 60
ataacttgta gagcttcaca ggatatatca aagtacctta attggtatca acaaaagcct 120
ggtaaagccc cgaagcttct cctttaccat acgtctcgac tccactccgg tgtcccttct 180
cgcttcagtg gttctgggag tgggaccgac tatacattga ccatctcttc tttgcaacaa 240
gaggacttcg ctacgtatta ctgtcagcaa ggtaatactc ttccgtatac tttcggacaa 300
ggcacgaaag tagaaattgg tggtggcggt tcaggcgggg gtggaagcgg ggggggtggg 360
tctcaggtca ccttgaagga atctggacct gttctggtga agcctacaga aactttgaca 420
ctgacatgca ccgtctctgg tgtatcattg ccggactacg gtgtgtcatg gattaggcaa 480
ccgcctggaa aagccttgga atggctcgcc gtcatctggg ggtctgagac gacctattac 540
aactcagcgt tgaagtcacg cctcacgatt tcaaaggaca cgtctaaatc acaagtggtt 600
ttgacaatga ctaacatgga cccggtcgat acggctactt actactgcgc tcgccactat 660
tattatgggg ggtcctatgc gatggactat tggggacagg gcacaatggt gacagtctca 720
agc 723
<210> 9
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Glu Ile Val Leu Thr Gln Ser Pro Val Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Met Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr
100 105
<210> 10
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
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 Phe Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Ile Pro Ile Phe Gly Ala Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Pro Ser Gly Ser Tyr Tyr Tyr Asp Tyr Asp Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 11
<211> 247
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Glu Ile Val Leu Thr Gln Ser Pro Val Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Met Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu
115 120 125
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
130 135 140
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Phe Tyr Ala Ile Ser Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Gly Phe Ile
165 170 175
Pro Ile Phe Gly Ala Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val
180 185 190
Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
195 200 205
Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ile Pro
210 215 220
Ser Gly Ser Tyr Tyr Tyr Asp Tyr Asp Met Asp Val Trp Gly Gln Gly
225 230 235 240
Thr Thr Val Thr Val Ser Ser
245
<210> 12
<211> 1068
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
gaaattgtgt tgacacagtc tccagtcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120
ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg cagtttatta ttgtcagcag cgtagcaact ggatgtacac ttttggccag 300
gggaccaagc tggagatcaa acgaactgaa attgtgttga cacagtctcc agtcaccctg 360
tctttgtctc caggggaaag agccaccctc tcctgcaggg ccagtcagag tgttagcagc 420
tacttagcct ggtaccaaca gaaacctggc caggctccca ggctcctcat ctatgatgca 480
tccaacaggg ccactggcat cccagccagg ttcagtggca gtgggtctgg gacagacttc 540
actctcacca tcagcagcct agagcctgaa gattttgcag tttattattg tcagcagcgt 600
agcaactgga tgtacacttt tggccagggg accaagctgg agatcaaacg aactggagga 660
ggaggttcag gtgggggtgg tagtggcggg ggaggatcac aggtccagct ggtgcagtct 720
ggggctgagg tgaagaagcc tgggtcctcg gtgaaggtct cctgcaaggc ttctggaggc 780
accttcagtt tctatgctat cagctgggtg cgacaggccc ctggacaagg gcttgagtgg 840
atgggagggt tcatccctat ctttggtgca gcaaactacg cacagaagtt ccagggcaga 900
gtcacgatta ccgcggacga atccacgagc acagcctaca tggaactgag cagcctgaga 960
tctgacgaca cggccgtgta ttactgtgcg agaatcccta gtgggagcta ctactacgac 1020
tacgatatgg acgtctgggg ccaagggacc acggtcaccg tctcctca 1068
<210> 13
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Asn Thr Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Pro Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Arg Ile Ser Ala Ser Gly Ala Ser Thr Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Arg Tyr Gly Leu Arg Tyr Ser Pro Val Asp Val Tyr Pro
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 14
<211> 312
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
agctgcgcag cctctgggct gacttttaat acctattata tgggttggtt taggcagcca 60
cccggtaaag agagagagtt cgtggccaga attagcgctt ccggtgctag cacagattac 120
gcagattctg tcaaagggcg ctttactatt tcccgcgaca acgcaaagaa caccatgtac 180
ctccaaatga gcagtctgaa acctgaggat acagccgtgt attattgcga agccgaccgc 240
tacggcctgc ggtactcacc cgtggacgtt tacccatact ggggccaagg cactcaggtc 300
acagtttcct cc 312
<210> 15
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
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 Lys
20 25
<210> 16
<211> 75
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 60
accctttact gcaaa 75
<210> 17
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 18
<211> 81
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 18
ttttgggtcc tcgtcgtagt tggaggggta cttgcctgtt atagcctcct ggttaccgta 60
gcatttatta tattctgggt g 81
<210> 19
<211> 40
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
1 5 10 15
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
20 25 30
Glu Glu Glu Glu Gly Gly Cys Glu
35 40
<210> 20
<211> 120
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 20
cggggcagaa agaaactcct gtatatattc aaacaaccat ttatgagacc agtacaaact 60
actcaagagg aagatggctg tagctgccga tttccagaag aagaagaagg aggatgtgaa 120
<210> 21
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 22
<211> 123
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 22
aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 60
gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 120
tcc 123
<210> 23
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
1 5 10 15
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
20 25 30
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
35 40 45
Lys Pro 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
<210> 24
<211> 339
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 24
ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 60
ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga caagagacgt 120
ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga aggcctgtac 180
aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 240
cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 300
acctacgacg cccttcacat gcaggccctg ccccctcgc 339
<210> 25
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
1 5 10 15
Gly Gln Asn Gln Leu Phe Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
20 25 30
Phe Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
35 40 45
Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
50 55 60
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
65 70 75 80
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Phe Gln Gly Leu Ser
85 90 95
Thr Ala Thr Lys Asp Thr Phe Asp Ala Leu His Met Gln Ala Leu Pro
100 105 110
Pro Arg
<210> 26
<211> 342
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Cys Thr Gly Ala Gly Ala Gly Thr Gly Ala Ala Gly Thr Thr Cys Ala
1 5 10 15
Gly Cys Ala Gly Gly Ala Gly Cys Gly Cys Ala Gly Ala Cys Gly Cys
20 25 30
Cys Cys Cys Cys Gly Cys Gly Thr Ala Cys Cys Ala Gly Cys Ala Gly
35 40 45
Gly Gly Cys Cys Ala Gly Ala Ala Cys Cys Ala Gly Cys Thr Cys Thr
50 55 60
Thr Thr Ala Ala Cys Gly Ala Gly Cys Thr Cys Ala Ala Thr Cys Thr
65 70 75 80
Ala Gly Gly Ala Cys Gly Ala Ala Gly Ala Gly Ala Gly Gly Ala Gly
85 90 95
Thr Thr Cys Gly Ala Thr Gly Thr Thr Thr Thr Gly Gly Ala Cys Ala
100 105 110
Ala Gly Ala Gly Ala Cys Gly Thr Gly Gly Cys Cys Gly Gly Gly Ala
115 120 125
Cys Cys Cys Thr Gly Ala Gly Ala Thr Gly Gly Gly Gly Gly Gly Ala
130 135 140
Ala Ala Gly Cys Cys Gly Cys Ala Gly Ala Gly Ala Ala Gly Gly Ala
145 150 155 160
Ala Gly Ala Ala Cys Cys Cys Thr Cys Ala Gly Gly Ala Ala Gly Gly
165 170 175
Cys Cys Thr Gly Thr Ala Cys Ala Ala Thr Gly Ala Ala Cys Thr Gly
180 185 190
Cys Ala Gly Ala Ala Ala Gly Ala Thr Ala Ala Gly Ala Thr Gly Gly
195 200 205
Cys Gly Gly Ala Gly Gly Cys Cys Thr Ala Cys Ala Gly Thr Gly Ala
210 215 220
Gly Ala Thr Thr Gly Gly Gly Ala Thr Gly Ala Ala Ala Gly Gly Cys
225 230 235 240
Gly Ala Gly Cys Gly Cys Cys Gly Gly Ala Gly Gly Gly Gly Cys Ala
245 250 255
Ala Gly Gly Gly Gly Cys Ala Cys Gly Ala Thr Gly Gly Cys Cys Thr
260 265 270
Thr Thr Thr Cys Cys Ala Gly Gly Gly Thr Cys Thr Cys Ala Gly Thr
275 280 285
Ala Cys Ala Gly Cys Cys Ala Cys Cys Ala Ala Gly Gly Ala Cys Ala
290 295 300
Cys Cys Thr Thr Thr Gly Ala Cys Gly Cys Cys Cys Thr Thr Cys Ala
305 310 315 320
Cys Ala Thr Gly Cys Ala Gly Gly Cys Cys Cys Thr Gly Cys Cys Cys
325 330 335
Cys Cys Thr Cys Gly Cys
340
<210> 27
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 28
<211> 135
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 28
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gacttcgcct gtgat 135
<210> 29
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 30
<211> 36
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 30
gaaagcaaat acgggccgcc gtgtccaccc tgtccg 36
<210> 31
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
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> 32
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 32
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccg 63
<210> 33
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser
1 5 10 15
Gly Leu Glu Ala
20
<210> 34
<211> 60
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 34
atgtcccgct ctgttgcttt ggctgtgctg gcccttttgt cccttagcgg actggaggcc 60
<210> 35
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Claims (23)
1.一种工程化免疫细胞,其表达嵌合多肽和嵌合共刺激分子;所述嵌合多肽包含第一抗原结合区、第一跨膜结构域和初级信号传导结构域;所述嵌合共刺激分子包含第二抗原结合区、第二跨膜结构域和第二共刺激结构域,其中所述第一抗原结合区和第二抗原结合区包含特异性结合NK抑制性受体的配体、抗体或抗原结合片段,所述NK抑制性受体选自PD1、NKG2A、CEACAM1、LAIR1、LIR1、KIR、SIGLEC7、SIGLEC9和KLRG1;所述嵌合共刺激分子不包含初级信号传导结构域。
2.根据权利要求1所述的工程化免疫细胞,其中所述嵌合多肽选自CAR、TCR、TRuC、TAC、ImmTAC或它们的任意组合。
3.根据权利要求1或2所述的工程化免疫细胞,其中所述嵌合多肽是CAR,包含第一抗原结合区、第一跨膜结构域、第一共刺激结构域和初级信号传导结构域。
4.根据权利要求1所述的工程化免疫细胞,其中所述第一抗原结合区包含结合NKG2A的配体、抗体或抗原结合片段。
5.根据权利要求1所述的工程化免疫细胞,其中所述第二抗原结合区包含结合KIR的配体、抗体或抗原结合片段。
6.根据权利要求1-5任一项所述的工程化免疫细胞,其中所述第一抗原结合区包含特异性结合肿瘤抗原的配体、抗体或其抗原结合片段,第二抗原结合区不包含特异性结合肿瘤抗原的配体、抗体或其抗原结合片段,或者第一抗原结合区不包含特异性结合肿瘤抗原的配体、抗体或其抗原结合片段,第二抗原结合区包含特异性结合肿瘤抗原的配体、抗体或其抗原结合片段。
7.根据权利要求1-5任一项所述的工程化免疫细胞,其中所述第一抗原结合区和第二抗原结合区均包含特异性结合肿瘤抗原的配体、抗体或其抗原结合片段,所述肿瘤抗原相同或者虽然不同但在同一靶细胞上表达。
8.根据权利要求6或7所述的工程化免疫细胞,其中所述肿瘤抗原选自:CD7、CD19、CD20、CD22、CD30、CD33、CD38、CD123、CD138、CD171、MUC1、AFP、Folate受体α、CEA、PSCA、PSMA、Her2、EGFR、IL13Ra2、GD2、NKG2D、EGFRvIII、CS1、BCMA、间皮素、Claudin18.2、ROR1、NY-ESO-1、MAGE-A4或它们的任意组合。
9.根据权利要求8所述的工程化免疫细胞,其中所述第一抗原结合区还包含结合CD19的抗体或抗原结合片段。
10.根据权利要求8所述的工程化免疫细胞,其中所述第二抗原结合区还包含结合CD22的抗体或抗原结合片段。
11.根据权利要求1所述的工程化免疫细胞,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或它们的任意组合。
12.根据权利要求1所述的工程化免疫细胞,其中所述共刺激结构域选自以下蛋白质的共刺激结构域: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或它们的任意组合。
13.根据权利要求12所述的工程化免疫细胞,其中所述第一共刺激结构域为CD28共刺激结构域,第二共刺激结构域为4-1BB共刺激结构域,或所述第一共刺激结构域为CD28共刺激结构域,第二共刺激结构域为4-1BB共刺激结构域。
14.根据权利要求1所述的工程化免疫细胞,其中所述初级信号传导结构域选自以下蛋白的信号传导结构域:FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b、CD66d或它们的任意组合。
15.根据权利要求1所述的工程化免疫细胞,其中至少一种MHC相关基因的表达被抑制或沉默。
16.根据权利要求15所述的工程化免疫细胞,其中所述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或它们的任意组合。
17.根据权利要求1所述的工程化免疫细胞,其中至少一种TCR/CD3相关基因的表达被抑制或沉默。
18.根据权利要求17所述的工程化免疫细胞,其中所述TCR/CD3基因选自TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ或它们的任意组合。
19.根据权利要求15-18任一项所述的工程化免疫细胞,其中所述工程化免疫细胞的TCR/CD3、B2M和CIITA的表达被抑制或沉默。
20.根据权利要求1所述的工程化免疫细胞,其中所述免疫细胞选自T细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞或NKT细胞。
21.根据权利要求20所述的工程化免疫细胞,其中所述工程化免疫细胞是CD4+/CD8+T细胞、CD4+T细胞、CD8+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细胞或αβ-T细胞。
22.一种药物组合物,包含权利要求1-21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载体或赋型剂。
23.根据权利要求1-21任一项所述的工程化免疫细胞,或根据权利要求22所述的药物组合物在制备用于预防/治疗/诊断癌症、感染或自身免疫性疾病的药物中的用途。
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