CN117247459A - 靶向cd69的工程化免疫细胞及其用途 - Google Patents
靶向cd69的工程化免疫细胞及其用途 Download PDFInfo
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Abstract
本发明提供了靶向CD69的工程化免疫细胞及其用途。具体地,本发明提供了一种靶向CD69的嵌合抗原受体及包含该嵌合抗原受体的工程化免疫细胞。本发明还提供了靶向CD69的工程化免疫细胞在制备治疗/预防/诊断癌症、感染或自身免疫性疾病药物中的用途。
Description
技术领域
本发明属于免疫治疗领域。更具体地,本发明涉及一种靶向CD69的工程化免疫细胞及其用途。
背景技术
目前,CAR T疗法已经在血液瘤领域取得巨大的成功,随着对其功能、机制等的理解不断加深,CAR T在实体瘤领域也在逐渐取得突破。通用型CAR T产品因其潜在的低成本、现货供应等优势不断受到研究者关注,但与自体CAR T相比,通用型CAR T始终面临着一些挑战。
在通用型CAR T所面临的挑战中,体内持久性较差是一个最重要的问题。目前的解决方案一般有两种,一种是敲除CAR-T细胞中引起宿主免疫排异的基因例如TCR、HLA-I类基因等,这种方案会使CAR-T细胞的持久性得到一定程度的改善;另一种方案则是针对性地清除或抑制宿主体内的NK细胞和激活型T细胞,从而降低这些免疫细胞对外源性CAR-T细胞的排斥和杀伤,提高CAR-T细胞的持久性。
CD69是C型凝集素受体家族的成员,其在静息T细胞中一般不表达。当T细胞通过TCR接受刺激信号后,细胞表面就会合成和表达一些新的糖蛋白,例如CD25、CD69、CD71等,其中最早表达的是CD69。因此,CD69通常是作为激活型T细胞早期表达的标志物。此外,与T细胞一样,CD69在静止状态的NK细胞中也不表达,而在NK细胞被刺激后迅速表达。因此,CD69同样也是NK细胞激活的标志物。
因此,本发明提供表达靶向CD69的嵌合抗原受体的工程化免疫细胞,其同时具有清除肿瘤细胞、患者自身NK细胞和激活型T细胞的能力,能显著提高对靶细胞的杀伤功能。另外,在自身免疫性疾病和器官移植伴随的移植物抗宿主病(GVHD)、宿主抗移植物病(HVGD)中,同样存在着T细胞过度激活、不正常激活等现象,靶向CD69的工程化免疫细胞同样可用于这些情形的治疗、控制。
发明内容
本发明的目的在提供一种靶向CD69的工程化免疫细胞,其可用于细胞免疫治疗中对患者自身NK细胞和激活型T细胞的杀伤,进而降低患者的免疫排斥反应,增强细胞治疗的效果。同时,其也可用于治疗和控制自身免疫性疾病和器官移植伴随的GVHD和HVGD。
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CD69的抗体、跨膜结构域和胞内信号传导结构域。
在一个实施方案中,本发明中所述抗体是完整抗体、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,所述靶向CD69的抗体包含如SEQ ID NO:1所示的CDR-H1、如SEQ ID NO:2所示的CDR-H2、如SEQ ID NO:3所示的CDR-H3、如SEQ ID NO:4所示的CDR-L1、如SEQ ID NO:5所示的CDR-L2、如SEQ ID NO:6所示的CDR-L3。优选地,所述靶向CD69的抗体包含与SEQ ID NO:7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和与SEQ ID NO:8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。更为优选地,所述靶向CD69的抗体包含与SEQ ID NO:9所示的氨基酸序列,或SEQ ID NO:10所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%序列同一性的序列。
在一个实施方案中,所述嵌合抗原受体还包含靶向第二靶点的抗体。在一个具体的实施方案中,所述第二靶点选自:TSHR、CD7、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-l lRa、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、***蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、***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-TES1、LCK、AKAP-4、SSX2、RAGE-1、人端粒酶逆转录酶、RU1、RU2、肠道羧酸酯酶、muthsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、PD1、PDL1、PDL2、TGFβ、APRIL、NKG2D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、AFP、Folate受体α、CEA、PSCA、PSMA、Her2、EGFR、IL13Ra2、GD2、NKG2D、EGFRvIII、CS1、BCMA、间皮素、Cluadin18.2、ROR1、NY-ESO-1、MAGE-A4或其任意组合。
在一个实施方案中,所述第二靶点是CD19,其包含如SEQ ID NO:11所示的CDR-H1、如SEQ ID NO:12所示的CDR-H2、如SEQ ID NO:13所示的CDR-H3、如SEQ ID NO:14所示的CDR-L1、如SEQ ID NO:15所示的CDR-L2、如SEQ ID NO:16所示的CDR-L3。优选地,所述靶向CD19的抗体包含与SEQ ID NO:17、21、23任一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和与SEQID NO:18、22、24任一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。更为优选地,所述靶向CD19的抗体包含与SEQ ID NO:19、25-28任一所示的氨基酸序列,或SEQ ID NO:20、29-32任一所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%序列同一性的序列。
在一个实施方案中,所述嵌合抗原受体中靶向CD69的抗体和靶向第二靶点的抗体是串联或并联的形式。
在一个实施方案中,所述嵌合抗原受体包含:(1)抗原结合区,包含靶向CD69的抗体和靶向第二靶点的抗体;(2)跨膜结构域;和(3)胞内信号传导结构域。在另一个实施方案中,本发明的嵌合抗原受体包含:(1)靶向CD69的第一单元结构,包含靶向CD69的抗体、跨膜结构域和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体、跨膜结构域和胞内信号传导结构域。
在一个实施方案中,所述胞内信号传导结构域包含共刺激结构域和/或初级信号传导结构域。
在一个实施方案中,所述共刺激结构域选自以下蛋白质的共刺激信号传导结构域: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或其任意组合。优选地,所述共刺激结构域选自4-1BB、CD28、CD27、OX40、CD278或其任意组合。
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。
在一个实施方案中,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。优选地,所述跨膜结构域选自CD8α、CD4、CD28或CD278的跨膜结构域。
在第二个方面,本发明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。
在第三个方面,本发明提供含上述核酸分子或载体,或表达上述嵌合抗原受体的工程化免疫细胞。
在一个实施方案中,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细胞和/或NKT细胞等。优选地,所述免疫细胞是T细胞、NK细胞或NKT细胞。更为优选地,所述T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细胞和/或αβ-T细胞。
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或其任意组合,优选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,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或其任意组合。
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或其任意组合,所述至少一种MHC相关基因是B2M、RFX5、RFXAP、RFXANK、CIITA或其任意组合。在一个实施方案中,所述工程化免疫细胞的TRAC或TRBC,和B2M的表达被抑制或沉默。在一个实施方案中,所述工程化免疫细胞的TRAC或TRBC,和CIITA的表达被抑制或沉默。在一个优选的实施方案中,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。在一个优选的实施方案中,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或其任意组合被抑制或沉默。
在一个实施方案中,所述工程化免疫细胞还表达细胞***元件。优选地,所述的细胞***元件位于嵌合抗原受体的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***元件选自下组:HSV-TK、iCasp9、ΔCD20、mTMPK、ΔCD19、RQR8、EGFRt或其任意组合。
在第四个方面,本发明提供一种药物组合物,包含上述的本发明的工程化免疫细胞和一种或多种药学上可接受的赋型剂。
在第五个方面,本发明提供上述嵌合抗原受体或工程化免疫细胞或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及在制备治疗/缓解/消除GVHD或HVGD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、***、绒毛膜癌、结肠和直肠癌、***癌症、消化***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、***癌、视网膜母细胞瘤、横纹肌肉瘤、直肠癌、呼吸***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***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抗原结合结构域(例如抗体的抗原结合部分)、跨膜结构域和胞内信号传导结构域。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。
本发明提供一种嵌合抗原受体,其包含靶向CD69的抗体、跨膜结构域和胞内信号传导结构域。在一个实施方案中,本发明中所述的抗体是完整抗体、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,所述靶向CD69的抗体包含如SEQ ID NO:1所示的CDR-H1、如SEQ ID NO:2所示的CDR-H2、如SEQ ID NO:3所示的CDR-H3、如SEQ ID NO:4所示的CDR-L1、如SEQ ID NO:5所示的CDR-L2、如SEQ ID NO:6所示的CDR-L3。优选地,所述靶向CD69的抗体包含与SEQ ID NO:7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和与SEQ ID NO:8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。更为优选地,所述靶向CD69的抗体包含与SEQ ID NO:9所示的氨基酸序列,或SEQ ID NO:10所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%序列同一性的序列。
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。本发明所述抗体可为任何种类(例如IgG、IgE、IgM、IgD、IgA等)或亚类(例如IgG1、IgG2、IgG2a、IgG3、IgG4、IgA1、IgA2等)。本发明的抗体也包含重组抗体、人抗体、人源化抗体、驼源抗体、鼠源抗体、嵌合抗体及其抗原结合部分。
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***)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Fc融合多肽中。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。
在另一个实施方案中,所述嵌合抗原受体还包含靶向第二靶点的抗体。在一个实施方案中,靶向CD69的抗体和靶向第二靶点的抗体是串联或并联的形式。在本文中,“串联”是指靶向CD69的抗体和靶向第二靶点的抗体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CD69的抗体和靶向第二靶点的抗体;(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CD69的抗体和靶向第二靶点的抗体可以通过接头以任何顺序连接。并且,当两个抗体均为scFv时,还可以以例如以下顺序连接(从N端至C端):VL1-VL2-接头-VH2-VH1、VL2-VL1-接头-VH1-VH2、VH1-VH2-接头-VL2-VL1、VH12-VH1-接头-VL1-VL2。在本文中,“并联”是指靶向CD69的抗体和靶向第二靶点的抗***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CD69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CD69的第一单元结构,包含靶向CD69的抗体、跨膜结构域和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体、跨膜结构域和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:CD2、CD3、CD4、CD7、CD8、CD14、CD15、CD19、CD20、CD21、CD22、CD23、CD24、CD25、CD30、CD33、CD37、CD38、CD40、CD40L、CD44、CD46、CD47、CD52、CD54、CD56、CD70、CD73、CD80、CD97、CD123、CD126、CD138、CD171、CD 179a、DR4、DR5、TAC、TEM1/CD248、VEGF、GUCY2C、EGP40、EGP-2、EGP-4、CD133、IFNAR1、DLL3、kappa轻链、TIM3、TSHR、CD19、BAFF-R、CLL-1、EGFRvIII、tEGFR、GD2、GD3、BCMA、Tn抗原、PSMA、ROR1、FLT3、FAP、TAG72、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、IL-llRa、IL-22Ra、IL-2、间皮素、PSCA、PRSS21、VEGFR2、LewisY、PDGFR-β、SSEA-4、AFP、Folate受体α、ErbB2(Her2/neu)、ErbB3、ErbB4、MUC1、MUC16、EGFR、CS1、NCAM、Claudin18.2、c-Met、Prostase、PAP、ELF2M、Ephrin B2、IGF-I受体、CAIX、LMP2、gpl00、bcr-abl、酪氨酸酶、EphA2、Fucosyl GMl、sLe、GM3、TGS5、HMWMAA、o-乙酰基-GD2、Folate受体β、TEM7R、CLDN6、GPRC5D、CXORF61、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、MAGE-A3、MAGE-A6、豆荚蛋白、HPV E6、E7、ETV6-AML、***蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、PSA、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、TMPRSS2 ETS融合基因、NA17、PAX3、雄激素受体、孕酮受体、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、NKG2D配体,和/或病原体特异性抗原、生物素化分子、由HIV、HCV、HBV和/或其他病原体表达的分子;和/或新表位或新抗原。优选地,所述第二靶点选自CD7、CD19、CD20、CD22、CD30、CD33、CD38、CD123、CD138、CD171、MUC1、AFP、Folate受体α、CEA、PSCA、PSMA、Her2、EGFR、IL13Ra2、GD2、NKG2D、Claudin18.2、ROR1、EGFRvIII、CS1、BCMA、GPRC5D和间皮素,更优选选自CD19、Claudin18.2和BCMA。
在一个实施方案中,第二靶点是CD19。优选地,靶向CD19的抗体包含如SEQ ID NO:11所示的CDR-H1、如SEQ ID NO:12所示的CDR-H2、如SEQ ID NO:13所示的CDR-H3、如SEQ IDNO:14所示的CDR-L1、如SEQ ID NO:15所示的CDR-L2、如SEQ ID NO:16所示的CDR-L3。优选地,所述靶向CD19的抗体包含与SEQ ID NO:17、21、23任一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和与SEQ ID NO:18、22、24任一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。更为优选地,所述靶向CD19的抗体包含与SEQ ID NO:19、25-28任一所示的氨基酸序列,或SEQ ID NO:20、29-32任一所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%序列同一性的序列。
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,所述跨膜结构域选自CD8α、CD4、CD28或CD278的跨膜结构域。更为优选地,所述跨膜结构域为CD8α跨膜结构域,与SEQ ID NO:39所示的氨基酸序列,或与SEQ ID NO:40或41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原结合区的任何寡肽或多肽。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,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链的铰链区部分,与SEQ ID NO:45所示的氨基酸序列,或与SEQ ID NO:46或47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和/或初级信号传导结构域。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包含两种不同类型的细胞质信号序列:引发抗原依赖性初级活化的那些,以及以不依赖抗原的方式起作用以提供次级或共刺激信号的那些。初级细胞质信号序列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单不限于源自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SEQID NO:36所示的氨基酸,或与SEQ ID NO:37或38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或其任意组合。优选地,所述共刺激结构域选自4-1BB、CD28、CD27、OX40、CD278或其任意组合。更为优选地,所述共刺激结构域为4-1BB,与SEQ ID NO:33所示的氨基酸序列,或与SEQ ID NO:34或35所示具有至少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。更为优选地,所述信号肽与SEQ ID NO:42所示的氨基酸序列,或与SEQ ID NO:43或44所示的核苷酸序列具有至少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体之间、抗体的VH与VL之间、抗体与铰链区之间、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例如SEQ ID NO:48或SEQ ID NO:49。
工程化免疫细胞及其制备方法
本发明提供工程化免疫细胞,其包含上述嵌合抗原受体或其编码核酸分子。
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CD69的抗体、跨膜结构域和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体、跨膜结构域和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***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,或者是衍生自干细胞,例如成体干细胞、胚胎干细胞、脐带血干细胞、祖细胞、骨髓干细胞、诱导多能干细胞、全能干细胞或造血干细胞等的免疫细胞。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、***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+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Fc融合多肽。
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CD69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(CHYSEls),最初在***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。
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分子,在免疫细胞中所述核酸分子分子可以例如复制和/或表达。
在一个实施方案中,本发明的载体包括但不限于线性核酸分子分子(例如DNA或RNA)、质粒、病毒(例如逆转录病毒、慢病毒、腺病毒、牛痘病毒、劳氏肉瘤病毒(RSV、多瘤病毒和腺相关病毒(AAV)等)、噬菌体、噬菌粒、粘粒和人工染色体(包括BAC和YAC)。载体本身通常是核苷酸序列,通常是包含***物(转基因)的DNA序列和作为载体“骨架”的较大序列。工程化载体通常还包含在免疫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)。
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。
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还包含至少一种TCR/CD3基因的表达被抑制或沉默。
在一个实施方案中,使至少一种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。
在一个实施方案中,所述工程化免疫细胞还表达细胞***元件。优选地,所述的细胞***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***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***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、***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。
用途
本发明还提供上述嵌合抗原受体或工程化免疫细胞或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。本发明还提供上述嵌合抗原受体或工程化免疫细胞或药物组合物在治疗/缓解GVHD或HVGD中的用途。
在一个实施方案中,所述疾病是与CD69或第二靶点表达有关的癌症。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、***、绒毛膜癌、结肠和直肠癌、***癌症、消化***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、***癌、视网膜母细胞瘤、横纹肌肉瘤、直肠癌、呼吸***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***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。
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示出了Jurkat、Nalm6、K562肿瘤细胞系中的CD69和CD19的表达情况,其中,unstrain为空白对照,isotype为同型对照。
图2示出了不同CAR T细胞中的单链抗体的总体表达水平。
图3示出了不同CAR T细胞对Jurkat(A)、Nalm6(B)、K562(C)肿瘤细胞的体外杀伤情况。
图4示出了不同CAR T细胞与靶细胞共培养后的细胞因子IL2(A)和IFNγ(B)的释放水平。
具体实施方式
实施例1.肿瘤细胞系验证
使用抗体PE anti-human CD69 antibody(Biolegend,货号310906),通过流式细胞术分别检测Jurkat、Nalm6、K562细胞系中的CD69的表达情况。使用抗体APC anti-humanCD19 antibody(Biolegend,货号302212),通过流式细胞术分别检测Jurkat、Nalm6、K562细胞系中的CD19的表达情况。结果如图1所示。可以看出,Jurkat表达CD69但不表达CD19,因此用作CD69阳性靶细胞;Nalm6不表达CD69但表达CD19,因此用作CD19阳性靶细胞;K562几乎不表达CD69且不表达CD19,因此用作非靶细胞。
实施例2.制备靶向CD69的CAR T细胞并验证其功能
2.1制备CAR T细胞
分别合成编码下述蛋白的基因:CD8α信号肽(SEQ ID NO:42)、CD69 scFv(SEQ IDNO:9)、CD19 scFv(SEQ ID NO:19)、CD8α铰链(SEQ ID NO:45)、CD8α跨膜区(SEQ ID NO:42)、4-1BB共刺激结构域(SEQ ID NO:33)、CD3ζ信号传导结构域(SEQ ID NO:36)、接头(SEQID NO:49)、T2A(SEQ ID NO:50),按照表1中给出的CAR结构,合成相关CAR基因。
将其分别克隆至pLVX载体(Public Protein/Plasmid Library(PPL),货号:PPL00157-4a),分别构建CD69 CAR、Dual CAR、Bi CAR和CD19 CAR质粒。通过测序确认目标序列的正确***。
表1不同CAR质粒中的结构
将上述质粒包装入慢病毒,并进一步转染激活的T细胞,获得相应的CAR T细胞。
在37℃和5%CO2下培养10天之后,使用FITC-Rabbit anti-mouse IgG,F(ab')specific(jackson immunoresearch,货号315-095-006),通过流式细胞仪检测CAR T细胞中单链抗体的表达水平,结果如图2所示。可以看出,本发明制备的CAR T细胞中的单链抗体能够正常表达。
2.2检测CAR T细胞对靶细胞的杀伤效果
以1×104个细胞/孔的浓度将靶细胞Jurkat、Nalm6或非靶细胞K562铺入96孔板中,然后以16:1、8:1、4:1、2:1的效靶比将NT细胞和各CAR T细胞铺入到96孔板进行共培养,8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3所示。
可以看出,在各种效靶比下,本发明的CD69 CAR T、Dual CAR T、Bi CAR T细胞对Jurkat细胞存在强烈杀伤作用,且其作用显著强于CD19 CAR T和NT。值得注意的是,当效靶比为2:1时,Dual CAR T细胞和Bi CAR T细胞对Jurkat的杀伤效果显著高于CD69 CAR-T细胞。同样地,Dual CAR T、Bi CAR T、CD19 CAR T细胞对Nalm6细胞也存在强烈杀伤作用,且其作用显著强于CD69 CAR T和NT。另外,各CAR T细胞对非靶细胞K562细胞的杀伤作用很弱,表明各CAR T细胞仅对表达CD69或CD19的细胞呈现特异性杀伤。
2.3检测CAR T细胞的细胞因子释放水平
以1×105个细胞/孔的浓度将靶细胞Jurkat、Nalm6和非靶细胞K562细胞铺于96孔板中,按1:1的比例分别加入Dual CAR T、Bi CAR T细胞、CD19 CAR T细胞、CD69 CAR T细胞、和NT细胞(阴性对照),共培养18-24小时后收集细胞共培养上清液。
分别使用Human IL-2DuoSet ELISA Kit(R&D systems,货号DY202)、Human IFN-gamma DuoSet ELISA Kit(R&D systems,货号DY285)检测共培养上清液中IL2和IFNγ的含量,结果如图4所示。
可以看出,本发明的CAR T细胞与靶细胞共培养后,细胞因子IL2和IFNγ的释放水平均显著升高。
以上结果表明,本发明的靶向CD69的CAR T细胞能够在体外有效地对靶细胞产生特异性杀伤。此外,同时靶向CD19和CD69的Dual CAR T细胞和Bi CAR T细胞对Jurkat的杀伤活性显著高于CD69 CAR T细胞,表明这种双靶设计相对于单靶而言能够提高对靶细胞的杀伤。
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。
序列表
<110> 南京北恒生物科技有限公司
<120> 靶向CD69的工程化免疫细胞及其用途
<130> BHCN55
<160> 51
<170> SIPOSequenceListing 1.0
<210> 1
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Ser Tyr Asp Met His
1 5
<210> 2
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Trp Ile Asn Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 3
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Met Tyr Tyr Asp Lys Asp Tyr Leu Ser Trp Gly Thr Asp Ser
1 5 10
<210> 4
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Ser Gly Asp Ser Leu Gly Ser Lys Tyr Val Tyr
1 5 10
<210> 5
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Gly Asp Ser Lys Arg Pro Ser
1 5
<210> 6
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gly Ser Tyr Thr Thr Gly Ala Lys Ser His Val
1 5 10
<210> 7
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Met Tyr Tyr Asp Lys Asp Tyr Leu Ser Trp Gly Thr Asp Ser
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 8
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Asp Ile Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln
1 5 10 15
Thr Ala Arg Ile Ser Cys Ser Gly Asp Ser Leu Gly Ser Lys Tyr Val
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Val Val Ile Tyr
35 40 45
Gly Asp Ser Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Tyr Thr Thr Gly Ala Lys Ser
85 90 95
His Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105
<210> 9
<211> 247
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Met Tyr Tyr Asp Lys Asp Tyr Leu Ser Trp Gly Thr Asp Ser
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Glu Leu Thr Gln
130 135 140
Pro Pro Ser Val Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Ser Cys
145 150 155 160
Ser Gly Asp Ser Leu Gly Ser Lys Tyr Val Tyr Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Ala Pro Val Val Val Ile Tyr Gly Asp Ser Lys Arg Pro
180 185 190
Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala
195 200 205
Thr Leu Thr Ile Ser Gly Thr Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
210 215 220
Cys Gly Ser Tyr Thr Thr Gly Ala Lys Ser His Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Gly
245
<210> 10
<211> 741
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
caggtgcagc tggtgcagag cggcgccgag gtgaagaagc ctggcgccag cgtgaaggtg 60
agctgcaagg cctccggcta cacctttacc tcctacgaca tgcactgggt gaggcaggcc 120
cctggccagg gactggagtg gatgggctgg atcaacccct actccggcaa cacaaattac 180
gcccagaagt ttcagggcag ggtgacaatg accagagaca caagcatctc cacagcctac 240
atggagctga gcagcctgag gagcgaggac acagccgtgt actactgcgc cagaatgtac 300
tacgacaagg attacctgag ctggggcacc gacagctggg gccagggaac cctggtgaca 360
gtgagttccg gcggcggcgg aagcggagga ggaggatctg gcggcggcgg tagcgacatc 420
gagctgaccc agccccctag cgtgtccgtg gccccaggac agacagccag gatcagctgt 480
tccggcgaca gcctgggcag caagtacgtg tactggtacc agcagaagcc tggccaggcc 540
cctgtggtgg tcatctatgg cgatagcaag aggcccagcg gcatccctga gagattcagc 600
ggctccaata gcggcaacac cgccacactg accatctccg gcacacaggc cgaggatgag 660
gccgactact actgcggcag ctacacaacc ggcgccaaga gccacgtgtt tggcggcggc 720
acaaagctga cagtgctggg c 741
<210> 11
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Gly Val Ser Leu Pro Asp Tyr
1 5
<210> 12
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Trp Gly Ser Glu Thr
1 5
<210> 13
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr
1 5 10
<210> 14
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn
1 5 10
<210> 15
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
His Thr Ser Arg Leu His Ser
1 5
<210> 16
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Gln Gln Gly Asn Thr Leu Pro Tyr Thr
1 5
<210> 17
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 18
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
100 105
<210> 19
<211> 242
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu
115 120 125
Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys
130 135 140
Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg
145 150 155 160
Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser
165 170 175
Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile
180 185 190
Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln
195 200 205
Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly
210 215 220
Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
225 230 235 240
Ser Ser
<210> 20
<211> 725
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 20
gacatccaga tgacacagac caccagcagc ctgtccgcca gcctgggcga cagggtgacc 60
atctcctgta gagccagcca ggacatcagc aagtacctga actggtacca gcaaaagccc 120
gatggcaccg tgaagctgct gatctaccac acatccaggc tgcactccgg cgtgcccagc 180
aggttctccg gcagcggaag cggcaccgat tactccctga ccatcagcaa tctggagcag 240
gaggacatcg ccacatactt ctgccagcag ggcaatacac tgccctacac atttggcggc 300
ggaacaaagc tggagatcac cggcggcggc ggcagcggag gaggcggaag cggcggagga 360
ggaagcgagg tgaagctgca ggagtccggc cctggcctgg tggctccttc ccagagcctg 420
tccgtgacat gcacagtgtc cggcgtgagc ctgcccgact acggcgtgag ctggatcaga 480
cagcctccta gaaagggcct ggagtggctg ggcgtgatct ggggctccga gaccacctac 540
tacaacagcg ccctgaagag caggctgaca atcatcaagg ataactccaa gagccaggtg 600
tttctgaaga tgaacagcct gcagaccgat gatacagcca tctactactg tgccaagcac 660
tactactacg gcggctccta cgccatggac tactggggcc agggcacctc cgtgaccgtg 720
tccag 725
<210> 21
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
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> 22
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
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 Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Gln
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105
<210> 23
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
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
Lys 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> 24
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val 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 Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile
100 105
<210> 25
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
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 Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Leu Tyr His Thr Ser Arg Leu His Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Gln Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu
225 230 235 240
Ile
<210> 26
<211> 240
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
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> 27
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
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
Lys 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 Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Arg Leu Glu
225 230 235 240
Ile
<210> 28
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val 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 Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser
115 120 125
Gly Pro Val Leu Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr
130 135 140
Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln
145 150 155 160
Pro Pro Gly Lys Ala Leu Glu Trp Leu Ala Val Ile Trp Gly Ser Glu
165 170 175
Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys
180 185 190
Asp Thr Ser Lys Ser Gln Val Val Leu Thr Met Thr Asn Met Asp Pro
195 200 205
Val Asp Thr Ala Thr Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly
210 215 220
Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Met Val Thr Val Ser
225 230 235 240
Ser
<210> 29
<211> 723
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 29
caggtaacct tgaaagaatc aggcccagtc ctggtaaagc cgacggagac attgacgctg 60
acctgcacag tcagtggagt gtcattgccc gattatggtg tctcttggat tcgccagcct 120
cctggcaagg ctcttgaatg gttggctgtc atctggggca gtgagactac ttattataac 180
agtgcgttga aatcccggct gactattagt aaagatactt ccaaaagcca agtagtcctc 240
actatgacaa acatggatcc tgtagacacg gctacttatt attgtgcacg gcattactac 300
tacggcggct cttatgctat ggattactgg ggtcaaggaa caatggttac tgtttcatct 360
ggcggcgggg ggtcaggtgg gggtggttcc gggggtggtg gtagtgacat ccaaatgaca 420
caatctccga gtagtctctc cgcaagtgtg ggcgatcgag ttacaattac ttgtcgagcc 480
tcacaggaca tatctaagta cttgaattgg taccaacaga agccggggaa ggcaccaaag 540
ttgctgctgt atcacactag tagattgcat agtggggtgc cctcaagatt cagtggaagt 600
ggatcaggca ctgattacac tttgactatt agtagtctgc aacaggaaga cttcgcaacg 660
tactattgtc agcaaggtaa caccttgccg tacacattcg gtcaaggtac caaagtggaa 720
att 723
<210> 30
<211> 723
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 30
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> 31
<211> 723
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 31
caggtgacat tgaaagagtc cggacctgtt ctcgtcaaac cgacggagac gctcaccctt 60
acatgcacgg tcagtggcgt ctcactgcca gattatgggg tttcttggat aagacagccc 120
cctggcaagg cccttgaatg gcttgcggtc atctggggtt ctgaaacaac atattataac 180
agtgcactca aatcacgcct tacgatttca aaggatacaa gtaaatctca agttgttctg 240
accatgacga atatggatcc agtggacacc gcgacgtact attgcgcgaa acattactac 300
tacggcggaa gctacgctat ggactattgg ggacaaggaa cgatggtcac tgtctctagc 360
ggcgggggtg gaagtggagg agggggatca gggggaggag gaagtgacat tcaaatgacg 420
cagtctccta gttcagtctc tgcatctgtg ggcgacagag tcacgattac ctgtagggca 480
agccaggata tctctaagta ccttaattgg tatcaacaaa aaccagggaa ggccccgaag 540
cttcttatct accatacaag ccgactccat agtggggttc cctcacgatt tagcgggtct 600
ggctctggta cagacttcac tctcactatt agtagcctgc aaccagagga cttcgcaacc 660
tactactgcc agcagggaaa cactcttcca tatacattcg gacagggaac ccggctcgag 720
att 723
<210> 32
<211> 723
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 32
gatatacaaa tgacgcagtc tccatcatcc gtatccgcca gcgtaggaga tagagtcacc 60
atcacatgtc gcgcgagtca ggacatcagc aaatacctca attggtacca gcaaaagccc 120
ggcaaggctc caaaattgct gatataccat acgagtaggt tgcacagtgg agtacccagt 180
agattttctg ggtcagggag tggcacagat ttcacgctga caataagtag tcttcaacct 240
gaagatttcg caacctatta ctgtcaacaa ggtaatacgc tgccgtacac gtttggtcag 300
ggtacgaggc tcgaaatcgg tggcggggga agtggaggtg gtggatctgg gggtgggggc 360
tctcaagtta ctttgaaaga gagtggacca gtgctcgtaa agcctacgga gacgcttacc 420
cttacgtgca cagtatctgg ggtgagtctc ccagattacg gtgtaagttg gatacgccag 480
ccgccgggga aagccttgga atggctcgca gtgatttggg gatccgaaac tacctattac 540
aatagcgccc ttaaatccag gctgactatt tccaaagaca cgagcaaatc ccaggtcgtc 600
cttaccatga caaacatgga cccagttgac accgctacct actactgtgc gaaacattat 660
tactacggtg ggagctatgc tatggactac tggggccaag gcacaatggt cactgttagt 720
agc 723
<210> 33
<211> 40
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
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> 34
<211> 126
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 34
aagagaggca ggaagaagct gctgtacatc ttcaagcagc ctttcatgag acctgtgcag 60
accacccagg aggaggacgg ctgtagctgc agattccccg aggaggagga gggcggctgt 120
gagctc 126
<210> 35
<211> 126
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 35
aaaaggggca gaaagaagct gctctacatc ttcaaacagc cttttatgag gcccgtgcag 60
accacacagg aggaggatgg ctgctcctgt agattccccg aagaggagga gggaggctgt 120
gagctg 126
<210> 36
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
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> 37
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 37
agagtgaagt tctccagaag cgccgatgcc cctgcctaca agcagggcca gaatcagctg 60
tacaatgagc tgaatctggg caggagagag gagtacgatg tgctggataa gaggagaggc 120
agggaccctg agatgggcgg caagcccagg agaaagaacc ctcaggaggg cctgtacaat 180
gaactgcaga aggacaagat ggccgaggcc tactccgaga tcggcatgaa gggcgagagg 240
aggaggggca agggccacga tggcctgtac cagggcctgt ccacagccac caaggacacc 300
tacgatgccc tgcacatgca ggccctgcct cccagg 336
<210> 38
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 38
agagtgaagt ttagcaggtc cgccgacgcc cctgcctata agcagggcca aaatcagctg 60
tataatgagc tgaacctggg caggcgggag gagtacgacg tgctggataa aaggagaggc 120
cgggaccctg agatgggagg caagcctaga agaaagaatc cccaggaggg cctctacaat 180
gaactccaga aggacaaaat ggccgaggct tacagcgaga tcggcatgaa aggcgagaga 240
aggaggggca aaggccacga tggactgtac cagggactgt ccacagctac aaaggatacc 300
tacgacgccc tgcacatgca agccctgccc cccaga 336
<210> 39
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
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> 40
<211> 72
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 40
atctacatct gggcccctct ggccggcaca tgtggcgtgc tgctgctgag cctggtcatt 60
acactgtact gt 72
<210> 41
<211> 72
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 41
atctacattt gggcccccct ggccggcacc tgcggagtgc tgctgctctc cctggtcatt 60
accctgtact gt 72
<210> 42
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
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> 43
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 43
atggccctgc ctgtgaccgc cctgctgctg cctctggccc tgctgctcca cgccgctagg 60
cct 63
<210> 44
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 44
atggccctgc ccgtgacagc cctgctgctg ccactggccc tgctcctgca cgccgctaga 60
ccc 63
<210> 45
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
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> 46
<211> 135
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 46
accacaacac ctgcccccag gccccctaca cctgccccta caatcgcctc ccagcctctg 60
tccctgagac ccgaggcctg cagacctgcc gccggaggag ctgtgcacac aagaggcctg 120
gatttcgcct gcgat 135
<210> 47
<211> 135
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 47
accaccacac ctgccccaag acctcctacc cctgccccca ccatcgcctc ccaacctctg 60
tccctcaggc ctgaggcctg taggcccgcc gctggaggag ctgtccacac cagaggcctg 120
gactttgcct gtgac 135
<210> 48
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
1 5 10 15
Lys Gly
<210> 49
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 50
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 50
Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro
1 5 10 15
Gly Pro
<210> 51
<211> 54
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 51
gagggcagag gaagtcttct aacatgcggt gacgtggagg agaatcccgg ccct 54
Claims (22)
1.一种嵌合抗原受体,其包含靶向CD69的抗体、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,其中所述靶向CD69的抗体包含如SEQ ID NO:1所示的CDR-H1、如SEQ ID NO:2所示的CDR-H2、如SEQ ID NO:3所示的CDR-H3、如SEQ ID NO:4所示的CDR-L1、如SEQ ID NO:5所示的CDR-L2、如SEQ ID NO:6所示的CDR-L3。
3.根据权利要求2所述的嵌合抗原受体,其中所述靶向CD69的抗体包含与SEQ ID NO:7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和与SEQ ID NO:8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。
4.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体;其中所述第二靶点选自:TSHR、CD7、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-l lRa、PSCA、PRSS21、VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、CD20、Folate受体α、ERBB2、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、***蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、***特异性蛋白、存活蛋白和端粒酶、PCTA-l/Galectin8、MelanA/MARTl、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、ERG、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或其任意组合。
5.根据权利要求4所述的嵌合抗原受体,其中所述嵌合抗原受体还包含靶向CD19的抗体,其包含如SEQ ID NO:11所示的CDR-H1、如SEQ ID NO:12所示的CDR-H2、如SEQ ID NO:13所示的CDR-H3、如SEQ ID NO:14所示的CDR-L1、如SEQ ID NO:15所示的CDR-L2、如SEQ IDNO:16所示的CDR-L3。
6.根据权利要求5所述的嵌合抗原受体,其中所述靶向CD19的抗体包含与SEQ ID NO:17、21、23任一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和与SEQ ID NO:18、22、24任一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。
7.根据权利要求4所述的嵌合抗原受体,其中所述嵌合抗原受体中靶向CD69的抗体和靶向第二靶点的抗体是串联的形式,所述嵌合抗原受体包含:(1)抗原结合区,包含靶向CD69的抗体和靶向第二靶点的抗体;(2)跨膜结构域;和(3)胞内信号传导结构域。
8.根据权利要求4所述的嵌合抗原受体,其中所述嵌合抗原受体中靶向CD69的抗体和靶向第二靶点的抗体是并联的形式,所述嵌合抗原受体包含:(1)靶向CD69的第一单元结构,包含靶向CD69的抗体、跨膜结构域和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体、跨膜结构域和胞内信号传导结构域。
9.根据权利要求1-8任一项所述的嵌合抗原受体,其中所述抗体为完整抗体、Fab、Fab’、F(ab’)2、Fv片段、scFv抗体片段、线性抗体、sdAb或纳米抗体。
10.根据权利要求1或4所述的嵌合抗原受体,所述胞内信号传导结构域包含共刺激结构域和/或初级信号传导结构域。
11.根据权利要求10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共刺激信号传导结构域: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或其任意组合。
12.根据权利要求10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信号传导结构域:FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b、CD66d或其任意组合。
13.根据权利要求1或4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。
14.编码权利要求1-13任一项所述嵌合抗原受体的核酸分子。
15.包含权利要求14所述核酸分子的载体。
16.包含权利要求14所述核酸分子或权利要求15所述载体,或表达权利要求1-13任一项所述嵌合抗原受体的工程化免疫细胞。
17.根据权利要求16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细胞和/或NKT细胞。
18.根据权利要求17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细胞和/或αβ-T细胞。
19.根据权利要求16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。
20.根据权利要求19所述的工程化免疫细胞,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;所述TCR/CD3基因选自TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ或其任意组合。
21.一种药物组合物,其中包含权利要求15-20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和/或赋型剂。
22.权利要求1-13任一项所述嵌合抗原受体或权利要求15-20任一项所述工程化免疫细胞或权利要求21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,或治疗/缓解/消除GVHD或HVGD药物中的用途。
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