CN113088495A - 工程改造的t细胞、其制备及应用 - Google Patents
工程改造的t细胞、其制备及应用 Download PDFInfo
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Abstract
本发明提供一种工程改造的T细胞,该细胞中通过引入下调细胞表面TCR/CD3复合物表达的多肽从而降低细胞表面TCR/CD3复合物的表达;该工程改造的T细胞可以用于治疗目的,如癌症的治疗。
Description
技术领域
本发明属于细胞免疫治疗领域,具体涉及工程改造的T细胞、其制备及应用。
背景技术
随着肿瘤治疗的发展,嵌合抗原受体T细胞(Chimeric antigen receptor-T,CAR-T)免疫疗法逐渐成为备受关注的治疗手段。CAR-T细胞所表达的CAR一般包含胞外抗原结合域、跨膜域和胞内信号传导域。通常CAR-T细胞是由患者自体T细胞经CAR基因转导并扩增而来,最后再回输到该患者体内。CAR-T细胞可以有效的识别肿瘤抗原,引起特异性的抗肿瘤免疫应答,而不受主要组织相容性复合体(major histocompatibility complex,MHC)的限制。目前,美国FDA已经批准了两款自体CAR-T细胞产品上市,分别是诺华的Kymriah和凯特的YesCAR-Ta,用于难治性复发性非霍奇金淋巴瘤和急性淋巴细胞白血病的治疗。相关临床试验证明,CAR-T作为完全个性化的活细胞药物极具抗肿瘤潜力(Maude S L,Laetsch T W,Buechner J,et al.Tisagenlecleucel in children and young adults with B-celllymphoblastic leukemia[J].New England Journal of Medicine,2018,378(5):439-448;Park J H,Rivière I,Gonen M,et al.Long-term follow-up of CD19 CAR therapyin acute lymphoblastic leukemia[J].New England Journal of Medicine,2018,378(5):449-459;Schuster S J,Svoboda J,Chong E A,et al.Chimeric antigen receptorT cells in refractory B-cell lymphomas[J].New England Journal of Medicine,2017,377(26):2545-2554)。
上述两款CAR-T药物的制备及回输策略均是采集患者自体的外周血,分离得到T细胞,通过病毒载体将CAR的编码基因整合到T细胞的基因组上,然后进行扩大培养,最后回输到患者体内。这种完全个体化的CAR-T细胞生产不仅生产周期长,成本高,而且也给回输治疗带来许多不确定因素。例如,分离得到的T细胞数量不足或功能失常导致的CAR-T细胞制备失败、细胞制备中患者疾病快速进展而失去治疗窗口等。因此,CAR-T领域的一个共同期待是健康供者来源的即用型(off-the-shelf)同种异体CAR-T细胞,以有效避免或解决上述生产和治疗相关问题,并极大地降低生产成本。
制备同种异体CAR-T细胞,首先需要解决一个重大安全难题,即移植物抗宿主反应(graft-versus-host disease,GVHD)。GVHD是移植物中同种异型反应性T细胞识别宿主同种异型组织抗原而诱发的针对受者正常组织和器官的免疫排斥反应,严重时会致命。GVHD是通过异体T细胞表面的TCR(T cell receptor,TCR)介导的。TCR为所有成熟T细胞表面的特征性标志。TCR以非共价键在胞内与多个CD3亚基在内质网(endoplasmic reticulum,ER)中结合并组装,最终在细胞表面以TCR-CD3抗原识别复合物的形式存在。
早在2012年,Provasi et al就报道了利用基因编辑技术来尝试解决同种异体T细胞的移植物抗宿主反应问题(Provasi E,Genovese P,Lombardo A,et al.Editing T cellspecificity towards leukemia by zinc finger nucleases and lentiviral genetransfer[J].Nature medicine,2012,18(5):807)。他们通过锌指蛋白(zinc-fingernucleases,ZFN),特异性地敲除供者T细胞的TCR基因,造成TCR/CD3复合物无法形成,T细胞无法识别宿主抗原,从而消除GVHD反应。此后,其它多种新型的基因编辑技术,如TALEN(transcription activator-like effector nucleases)和CRISPR(clustered regularlyinterspaced short palindromic repeats)也在实验室水平有过成功的报道(Berdien B,Mock U,Atanackovic D,et al.TALEN-mediated editing of endogenous T-cellreceptors facilitates efficient reprogramming of T lymphocytes by lentiviralgene transfer[J].Gene therapy,2014,21(6):539;Ren J,Zhao Y.Advancing chimericantigen receptor T cell therapy with CRISPR/Cas9[J].Protein&cell,2017,8(9):634-643)。然而至今,仍只有非常有限数目的同种异体CAR-T的临床案例报道(Qasim W,Zhan H,Samarasinghe S,et al.Molecular remission of infant B-ALL afterinfusion of universal TALEN gene-edited CAR T cells[J].Science translationalmedicine,2017,9(374):eaaj2013)。基于基因编辑的同种异体CAR-T临床研究进展缓慢的主要原因可能来源于基因编辑存在的安全隐患(例如脱靶导致错误的基因编辑),基因编辑可能降低T细胞的体内持久性降低,以及生产制备中遇到的障碍(如工艺步骤繁多,对T细胞的损伤较大等)。
基于非基因编辑的同种异体CAR-T技术同样也得到行业的密切关注。此技术来源于1995年的报道,作者发现在胞内表达携带内质网滞留信号的特异性抗体,可以将IL-2受体蛋白有效滞留在内质网内,几乎完全不出现在细胞表面,达到与基因编辑类似的功能缺失(Richardson J H,Sodroski J G,Waldmann T A,et al.Phenotypic knockout of thehigh-affinity human interleukin 2receptor by intracellular single-chainantibodies against the alpha subunit of the receptor[J].Proceedings of theNational Academy of Sciences,1995,92(8):3137-3141)。这个技术最近被借鉴,用于寻找能够有效下调表面TCR/CD3复合物的多肽以及是否存在通用的规律,例如多肽中包含的抗体识别TCR/CD3复合物中的哪个蛋白或其表位最有效。但是研究结果显示,不同靶点的抗体,同一靶点的不同抗体克隆,不同的ER滞留信号,不同的接头等因素,都会影响这些抗体序列下调表面TCR/CD3复合物的活性;有活性的抗体序列又对不同供者T细胞缺乏稳定的下调活性(Kamiya T,Wong D,Png Y T,et al.A novel method to generate T-cellreceptor–deficient chimeric antigen receptor T cells[J].Blood advances,2018,2(5):517-528;WO2019032916A1;US20180086831A1)。
表面TCR/CD3复合物下调或缺失的CAR-T细胞也可能提高目前的自体CAR-T细胞治疗的疗效。从患者自体T细胞制备出的CAR-T细胞中可能同时存在识别患者自身肿瘤的TCR/CD3复合物,而TCR/CD3复合物与CAR的同时激活已知会引发CD8+T细胞的耗竭,影响CAR-T细胞的治疗效果(Yang Y,Kohler M E,Chien C D,et al.TCR engagement negativelyaffects CD8 but not CD4 CAR T cell expansion and leukemic clearance[J].Science translational medicine,2017,9(417):eaag1209)。
本领域亟需一种针对不同供者来源的T细胞,均能高效下调其表面TCR/CD3复合物的方法和细胞。本领域亟需一种针对不同供者来源的T细胞,即能表达治疗用蛋白,同时又高效下调其表面TCR/CD3复合物的方法和细胞。
发明内容
为此,本发明提供高效下调细胞表面TCR/CD3复合物的试剂、方法和细胞。
本文第一方面提供一种工程改造的T细胞,其特征在于,所述T细胞表达下调细胞表面TCR/CD3复合物的多肽,所述下调细胞表面TCR/CD3复合物的多肽包含一个重链可变区(VH),该重链可变区的氨基酸序列为SEQ ID NO:1或与SEQ ID NO:1具有95%以上相同性的氨基酸序列,和一个轻链可变区(VL),该轻链可变区的氨基酸序列为SEQ ID NO:2或与SEQID NO:2具有95%以上相同性的氨基酸序列。
在一个或多个实施方案中,所述下调细胞表面TCR/CD3复合物的多肽的VH中包含序列如SEQ ID NO:9所示的HCDR2:INX1X2X3DVT(其中X1,X2,X3为任意氨基酸)。
在一个或多个实施方案中,所述下调细胞表面TCR/CD3复合物的多肽的VH中包含序列如SEQ ID NO:15所示的HCDR3:AX4GX5X6YDYDGFVY(其中X4,X5,X6为任意氨基酸)。
在一个或多个实施方案中,所述下调细胞表面TCR/CD3复合物的多肽的VL中包含序列如SEQ ID NO:22所示的LCDR3:QQWX7X8X9X10X11T(其中X7,X8,X9,X10,X11为任意氨基酸)。
在一个或多个实施方案中,X1为脯氨酸、苏氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甲硫氨酸或色氨酸。
在一个或多个实施方案中,X2为酪氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、半胱氨酸、苯丙氨酸、色氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸或甲硫氨酸。
在一个或多个实施方案中,X3为天冬酰胺、甘氨酸、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、赖氨酸、精氨酸或组氨酸。
在一个或多个实施方案中,X4为精氨酸、赖氨酸或组氨酸。
在一个或多个实施方案中,X5为丝氨酸、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸。
在一个或多个实施方案中,X6为酪氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、半胱氨酸、苯丙氨酸、色氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、甲硫氨酸、赖氨酸、精氨酸、天冬氨酸或谷氨酸。
在一个或多个实施方案中,X7为丝氨酸、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、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、组氨酸、赖氨酸或精氨酸。
在一个或多个实施方案中,X8为丝氨酸、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、赖氨酸、精氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸。
在一个或多个实施方案中,X9为天冬酰胺、甘氨酸、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸或丝氨酸。
在一个或多个实施方案中,X10为脯氨酸、丙氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甲硫氨酸或色氨酸。
在一个或多个实施方案中,X11为亮氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、酪氨酸、半胱氨酸、丙氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸。
在一个或多个实施方案中,LCDR3选自SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ IDNO:31、SEQ ID NO:32、SEQ ID NO:33,SEQ ID NO:34。
在一个或多个实施方案中,HCDR2选自SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14。
在一个或多个实施方案中,HCDR3选自SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21。
在一个或多个实施方案中,重链可变区的氨基酸序列选自:(1)SEQ ID NO:42,(2)含所述HCDR2和/或HCDR3的SEQ ID NO:42变体,(3)与(1)或(2)具有95%以上相同性的序列,和/或,轻链可变区的氨基酸序列选自:(1)SEQ ID NO:43,(2)含所述LCDR3的SEQ IDNO:43变体;(3)与(1)或(2)具有95%以上相同性的序列。在一个或多个实施方案中,HCDR2、HCDR3、LCDR3如本文所述。
在一个或多个实施方案中,所述多肽是单链抗体。
在一个或多个实施方案中,所述下调细胞表面TCR/CD3复合物的多肽包含定位序列和任选的信号肽。
在一个或多个实施方案中,所述定位序列选自内质网滞留序列,高尔基体滞留序列,E3泛素连接酶结合序列,蛋白酶体定位序列或溶酶体定位序列;优选地,所述内质网滞留序列包括SEQ ID NO:35-40中任一或由其组成,其中X是任意氨基酸。
在一个或多个实施方案中,所述定位序列与抗体之间包含接头,所述接头如SEQID NO:41所示。
在一个或多个实施方案中,所述信号肽如SEQ ID NO:44第516-537位所示。
在一个或多个实施方案中,所述T细胞进一步表达治疗用蛋白;优选地,治疗用蛋白是嵌合抗原受体。
在一个或多个实施方案中,所述T细胞含有所述治疗用蛋白的表达框和所述下调细胞表面TCR/CD3复合物的多肽的表达框,或所述治疗用蛋白的编码序列和所述下调细胞表面TCR/CD3复合物的多肽的编码序列处于同一表达框内。
在所述治疗用蛋白的编码序列和所述下调细胞表面TCR/CD3复合物的多肽的编码序列处于同一表达框内的实施方案中,治疗用蛋白的编码序列和下调细胞表面TCR/CD3复合物的多肽的编码序列之间包含连接序列,所述连接序列使得能够在单个载体上表达多个顺反子。
在一个或多个实施方案中,所述连接序列是2A肽的编码序列。
在一个或多个实施方案中,2A肽包括F2A、P2A或T2A肽。
在一个或多个实施方案中,所述嵌合抗原受体从N端至C端含有:抗肿瘤抗原的单链抗体、铰链区、跨膜区、胞内区。
在一个或多个实施方案中,所述嵌合抗原受体特异性结合选自以下的肿瘤抗原中的一种或多种:EGFRvIII、间皮素、GD2、Tn抗原、sTn抗原、Tn-O-糖肽、sTn-O-糖肽、PSMA、CD97、TAG72、CD44v6、CEA、EPCAM、KIT、IL-13Ra2、leguman、GD3、CD171、IL-11Ra、PSCA、MAD-CT-1、MAD-CT-2、VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、叶酸受体α、ERBB、Her2/neu、MUC1、EGFR、NCAM、肝配蛋白B2、CAIX、LMP2、sLe、HMWMAA、o-乙酰基-GD2、叶酸受体β、TEM1/CD248、TEM7R、FAP、豆荚蛋白、HPV E6或E7、ML-IAP、CLDN6、TSHR、GPRC5D、ALK、聚唾液酸、Fos-相关抗原、中性粒细胞弹性蛋白酶、TRP-2、CYP1B1、精子蛋白17、β人绒毛膜促性腺激素、AFP、甲状腺球蛋白、PLAC1、globoH、RAGE1、MN-CA IX、人端粒酶逆转录酶、肠羧基酯酶、mut hsp70-2、NA-17、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、NY-ESO-1、GPR20、Ly6k、OR51E2、TARP、GFRα4和呈递在MHC上的这些抗原中任一者的多肽片段,以及CD5、CD10、CD19、CD20、CD21、CD22、CD23、CD24、CD25、CD27、CD30、CD34、CD37、CD38、CD40、CD53、CD69、CD72、CD73、CD74、CD75、CD77、CD79a、CD79b、CD80、CD81、CD82、CD83、CD84、CD85、CD86、CD123、CD135、CD138、CD179、CD269、Flt3、ROR1、BCMA、FcRn5、FcRn2、CS-1、CXCR4、CXCR5、CXCR7、IL-7/3R、IL7/4/3R和IL4R。
在一个或多个实施方案中,所述铰链区选自CD8α铰链区、IgG1 Fc CH2CH3铰链区、IgD铰链区、CD28胞外铰链区、IgG4 Fc CH2CH3铰链区和CD4胞外铰链区。
在一个或多个实施方案中,所述跨膜区选自CD28跨膜区、CD8跨膜区、CD3ζ跨膜区、CD134跨膜区、CD137跨膜区、ICOS跨膜区和DAP10跨膜区中的一种或多种。
在一个或多个实施方案中,所述胞内区选自CD28、CD134/OX40、CD137/4-1BB、LCK、ICOS、DAP10、CD3ζ和Fc310中的一种或多种的胞内区。
在一个或多个实施方案中,所述嵌合抗原受体包含信号肽。
在一个或多个实施方案中,所述抗肿瘤抗原的单链抗体是抗CD19单链抗体。
在一个或多个实施方案中,所述铰链区是CD8α铰链区。
在一个或多个实施方案中,所述跨膜区是CD8跨膜区。
在一个或多个实施方案中,所述胞内区包含4-1BB胞内区和人CD3ζ胞内区。
在一个或多个实施方案中,所述抗CD19单链抗体的轻链可变区序列包含SEQ IDNO:44第23-129位氨基酸或由其组成。
在一个或多个实施方案中,所述抗CD19单链抗体的重链可变区序列包含SEQ IDNO:44第148-267位氨基酸或由其组成。
在一个或多个实施方案中,所述铰链区的序列包含SEQ ID NO:44第268-312位氨基酸或由其组成。
在一个或多个实施方案中,所述跨膜区的序列包含SEQ ID NO:44第313-336位氨基酸或由其组成。
在一个或多个实施方案中,所述4-1BB胞内区包含SEQ ID NO:44第337-378位氨基酸或由其组成;CD3ζ胞内区包含SEQ ID NO:44第379-490位氨基酸或由其组成。
在一个或多个实施方案中,嵌合抗原受体的信号肽包含SEQ ID NO:44第1-22位氨基酸残基或由其组成。
本发明第二方面提供一种工程改造的T细胞,其特征在于,所述T细胞表达下调细胞表面TCR/CD3复合物的多肽,所述多肽包含:抗体或其抗原结合片段,或与所述抗体或其抗原结合片段具有至少90%序列相同性并保留所述抗体或抗原结合片段的抗原结合活性的突变体;其中,所述抗体包含重链可变区和轻链可变区,
所述重链可变区具有下述HCDR:如SEQ ID NO:3所示的HCDR1:GYKFTSYV,如SEQ IDNO:9所示的HCDR2:INX1X2X3DVT,其中X1,X2,X3为任意氨基酸,如SEQ ID NO:15所示的HCDR3:AX4GX5X6YDYDGFVY,其中X4,X5,X6为任意氨基酸,
所述轻链可变区具有下述LCDR:
如SEQ ID NO:6所示的LCDR1:SSVSY,如SEQ ID NO:7所示的LCDR2:DTS,如SEQ IDNO:22所示的LCDR3:QQWX7X8X9X10X11T,其中X7,X8,X9,X10,X11为任意氨基酸。
优选地,X1-X11如本文所述。
在一个或多个实施方案中,LCDR3选自SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ IDNO:31、SEQ ID NO:32、SEQ ID NO:33,SEQ ID NO:34。在一个或多个实施方案中,HCDR2选自SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SSEQ ID NO:14。在一个或多个实施方案中,HCDR3选自SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQID NO:20、SEQ ID NO:21。
在一个或多个实施方案中,重链可变区的氨基酸序列选自:(1)SEQ ID NO:42,(2)含所述HCDR2和/或HCDR3的SEQ ID NO:42变体,(3)与(1)或(2)具有95%以上相同性的序列,和/或轻链可变区的氨基酸序列选自:(1)SEQ ID NO:43,(2)含所述LCDR3的SEQ ID NO:43变体;(3)与(1)或(2)具有95%以上相同性的序列。
在一个或多个实施方案中,所述抗体是单链抗体。
在一个或多个实施方案中,所述下调细胞表面TCR/CD3复合物的多肽包含定位序列和任选的信号肽。
在一个或多个实施方案中,所述定位序列选自内质网滞留序列,高尔基体滞留序列,E3泛素连接酶结合序列,蛋白酶体定位序列或溶酶体定位序列。优选地,所述内质网滞留序列包括SEQ ID NO:35-40中任一或由其组成,其中X是任意氨基酸。
在一个或多个实施方案中,所述定位序列与抗体之间包含接头,优选地,所述接头如SEQ ID NO:41所示。
在一个或多个实施方案中,所述信号肽如SEQ ID NO:44第516-537位所示。
在一个或多个实施方案中,所述T细胞进一步表达治疗用蛋白,优选地,所述治疗用蛋白为嵌合抗原受体。
在一个或多个实施方案中,所述T细胞含有所述治疗用蛋白的表达框和所述下调细胞表面TCR/CD3复合物的多肽的表达框,或所述治疗用蛋白的编码序列和所述下调细胞表面TCR/CD3复合物的多肽的编码序列处于同一表达框内。
本发明第三方面提供一种抗体或其抗原结合片段,其特征在于,所述抗体的HCDR1的氨基酸序列为GYKFTSYV,HCDR2的氨基酸序列为INX1X2X3DVT,HCDR3的氨基酸序列为AX4GX5X6YDYDGFVY,LCDR1的氨基酸序列为SSVSY,LCDR2的氨基酸序列为DTS,LCDR3的氨基酸序列为QQWX7X8X9X10X11T;其中,X1-X11如权利要求10所述,并且HCDR2不是INPYNDVT,HCDR3不是ARGSYYDYDGFVY,LCDR3不是QQWSSNPLT。
在一个或多个实施方案中,LCDR3选自SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ IDNO:31、SEQ ID NO:32、SEQ ID NO:33,SEQ ID NO:34。在一个或多个实施方案中,HCDR2选自SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14。在一个或多个实施方案中,HCDR3选自SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQID NO:20、SEQ ID NO:21。
在一个或多个实施方案中,所述抗体的重链可变区的氨基酸序列如SEQ ID NO:42所示,但其HCDR2和/或HCDR3的序列如本文第二方面所述;所述抗体的轻链可变区的氨基酸序列如SEQ ID NO:43所示,但其LCDR3的序列如本文第二方面所述。优选地,HCDR2如SEQ IDNO:9所示:INX1X2X3DVT,其中X1,X2,X3为任意氨基酸,HCDR3如SEQ ID NO:15所示:AX4GX5X6YDYDGFVY,其中X4,X5,X6为任意氨基酸;LCDR3如SEQ ID NO:22所示:QQWX7X8X9X10X11T,其中X7,X8,X9,X10,X11为任意氨基酸。在一个或多个实施方案中,X1-X11如本文他处所述。更优选地,LCDR3选自SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ IDNO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ IDNO:32、SEQ ID NO:33,SEQ ID NO:34。更优选地,HCDR2选自SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SSEQ ID NO:14。更优选地,HCDR3选自SEQ ID NO:16、SEQ IDNO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21。
本发明还提供一种融合蛋白,包含定位序列、本文所述的下调细胞表面TCR/CD3复合物的多肽和任选的信号肽。
在一个或多个实施方案中,所述信号肽如SEQ ID NO:44第516-537位所示。
在一个或多个实施方案中,所述定位序列与下调细胞表面TCR/CD3复合物的多肽之间包含接头。所述接头优选如SEQ ID NO:41所示。
在一个或多个实施方案中,所述融合蛋白如SEQ ID NO:44第516-804位或第538-804位所示。
本发明另一方面提供一种核酸分子,选自:(1)含治疗用蛋白的编码序列和本文所述下调细胞表面TCR/CD3复合物的多肽的编码序列的多核苷酸;(2)本文所述的融合蛋白的编码序列;(3)本文所述的抗体或其抗原结合片段的编码序列;和(4)(1)或(2)或(3)的互补序列或片段。优选地,所述治疗用蛋白为嵌合抗原受体。
在一个或多个实施方案中,治疗用蛋白的编码序列和下调细胞表面TCR/CD3复合物的多肽的编码序列之间包含连接序列,所述连接序列使得能够在单个载体上表达多个顺反子。
在一个或多个实施方案中,所述连接序列是2A肽的编码序列。
在一个或多个实施方案中,2A肽包括F2A、P2A或T2A肽。
在一个或多个实施方案中,所述治疗用蛋白和所述下调细胞表面TCR/CD3复合物的多肽的特征如本文所述。
本发明另一方面提供一种核酸构建物,所述核酸构建物包含本文所述的核酸分子。
在一个或多个实施方案中,所述核酸构建物含有所述治疗用蛋白的表达框和所述下调细胞表面TCR/CD3复合物的多肽的表达框;或所述核酸构建物为一表达框,其中所述治疗用蛋白的编码序列和所述下调细胞表面TCR/CD3复合物的多肽的编码序列处于该表达框内。
在一个或多个实施方案中,所述核酸构建物是克隆载体或表达载体。
本发明另一方面提供一种慢病毒,所述慢病毒含有本文所述的核酸分子、核酸构建物。
本发明另一方面提供一种宿主细胞,所述宿主细胞包含、表达和/或分泌本文所述的抗体或其抗原结合片段,或本文所述的融合蛋白和任选的治疗用蛋白。所述宿主细胞包含本文所述的核酸分子、核酸构建物和/或慢病毒。
本发明另一方面提供一种药物组合物,含有本文所述的抗体或其抗原结合片段、融合蛋白和任选的治疗用蛋白、核酸分子、核酸构建物、慢病毒或细胞。
本发明另一方面提供下调细胞表面TCR/CD3复合物的多肽或其编码序列、本文所述的抗体或其抗原结合片段、融合蛋白和任选的治疗用蛋白、核酸分子、核酸构建物、慢病毒在制备细胞表面TCR下调的T细胞中的应用,或在制备癌症治疗用的T细胞中的应用。优选地,所述下调细胞表面TCR/CD3复合物的多肽如本文所述。
附图说明
图1,包含不同抗体序列的多肽对CAR-T细胞表面TCR和CD3蛋白水平的影响。
图2,包含不同抗体序列的多肽对CAR-T细胞表面TCR和CD3蛋白水平的影响。
图3,包含CTAB5抗体序列的多肽对不同供者来源的CAR-T细胞表面TCR和CD3蛋白水平的影响。
图4,包含CTAB5抗体序列的多肽在独立表达时下调T细胞表面的TCR和CD3蛋白水平。
图5a-5g,下调细胞表面TCR/CD3复合物的多肽与嵌合抗原受体共表达下的T细胞亚群比例。
图6,下调细胞表面TCR/CD3复合物的多肽与嵌合抗原受体共表达下的T细胞的体外扩增。
图7,下调细胞表面TCR/CD3复合物的多肽与嵌合抗原受体共表达下的T细胞的细胞毒活性。
图8,下调细胞表面TCR/CD3复合物的多肽与嵌合抗原受体共表达下的T细胞的IFN-γ分泌能力。
图9,含点突变多肽的细胞文库的表面标志物分布及细胞分选时所用的设门。
图10,示例性点突变多肽下调CAR-T细胞表面TCR和CD3的活性。
图11,示例性点突变多肽的表达增强CAR-T细胞的体外扩增。
图12,示例性点突变多肽的表达不影响CAR-T细胞的细胞毒活性。
具体实施方式
应理解,在本发明范围中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成优选的技术方案。
本发明通过表达下调细胞表面TCR/CD3复合物的多肽,制备细胞表面TCR/CD3复合物表达下降的工程改造的T细胞。采用本发明方法制备得到的T细胞中,与未表达该多肽的对照相比,TCR/CD3复合物在细胞表面的表达水平被至少50%、优选至少90%、更优选至少99%或被完全抑制。
本文中,下调细胞表面TCR/CD3复合物的多肽包含抗体或其抗原结合片段。“抗体”指这样的多肽,其包含足以令其与靶抗原特异性结合的免疫球蛋白序列元件。如本领域所知,天然的完整抗体是四聚体,包含两条相同重链多肽和两条相同轻链多肽。各重链包含至少四个结构域:氨基末端的可变结构域VH、恒定结构域CH1、恒定结构域CH2和羧基末端的恒定结构域CH3。各轻链包含两个结构域:氨基末端的可变结构域VL和羧基末端恒定结构域CL。各可变域包含三个“互补决定区”:CDR1、CDR2和CDR3,和四个“框架”区:FR1、FR2、FR3和FR4。“抗原结合片段”表示抗体中可与靶抗原特异性结合的片段。抗体或其抗原结合片段包括Fab片段、Fab’片段、F(ab’)2片段、Fd’片段、Fd片段、Fv片段、二硫键结合的Fv片段、单链抗体(scFv)、分离的CDR或CDR组、多肽-Fc融合体、单域抗体、骆驼抗体、掩蔽抗体、小模块免疫药物、双功能抗体、纳米抗体、Humabody抗体。单链抗体是由抗体重链可变区和轻链可变区通过短肽(linker)连接而成的抗体。
在优选的实施方案中,本发明下调细胞表面TCR/CD3复合物的多肽是特异性结合TCR/CD3的抗TCR/CD3抗体,更优选是抗TCR/CD3的单链抗体(scfv)。本文的抗TCR单链抗体特异性结合TCR1和/或TCR2。优选地,本文的抗TCR单链抗体特异性结合所有已知或未知的TCR。在一个或多个实施方案中,抗TCR/CD3抗体选自UCHT1、OKT3、CTAB5、CTAB2、CTAB3或CTAB4。优选地,抗TCR/CD3单链抗体衍生自这些抗TCR/CD3抗体。示例性地,UCHT1 scfv的VL和VH序列分别包含SEQ ID NO:45和46或由其组成;OKT3 scfv的VL和VH序列分别包含SEQID NO:47和48或由其组成。在优选的实施方案中,抗TCR单链抗体衍生自CTAB5。
在优选的实施方案中,所述抗TCR抗体的重链可变区具有下述HCDR:如SEQ ID NO:3所示的HCDR1:GYKFTSYV,如SEQ ID NO:9所示的HCDR2:INX1X2X3DVT,其中X1,X2,X3为任意氨基酸,如SEQ ID NO:15所示的HCDR3:AX4GX5X6YDYDGFVY,其中X4,X5,X6为任意氨基酸;所述轻链可变区具有下述LCDR:如SEQ ID NO:6所示的LCDR1:SSVSY,如SEQ ID NO:7所示的LCDR2:DTS,如SEQ ID NO:22所示的LCDR3:QQWX7X8X9X10X11T,其中X7,X8,X9,X10,X11为任意氨基酸。
在一个或多个实施方案中,X1为脯氨酸、苏氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甲硫氨酸或色氨酸,X2为酪氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、半胱氨酸、苯丙氨酸、色氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸或甲硫氨酸,X3为天冬酰胺、甘氨酸、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、赖氨酸、精氨酸或组氨酸,X4为精氨酸、赖氨酸或组氨酸,X5为丝氨酸、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸,X6为酪氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、半胱氨酸、苯丙氨酸、色氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、甲硫氨酸、赖氨酸、精氨酸、天冬氨酸或谷氨酸,X7为丝氨酸、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、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、组氨酸、赖氨酸或精氨酸,X8为丝氨酸、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、赖氨酸、精氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸,X9为天冬酰胺、甘氨酸、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸或丝氨酸,X10为脯氨酸、丙氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甲硫氨酸或色氨酸,X11为亮氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、酪氨酸、半胱氨酸、丙氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸。
优选地,LCDR3选自SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33,SEQ ID NO:34。在一个或多个实施方案中,HCDR2选自SEQ ID NO:10、SEQID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14。在一个或多个实施方案中,HCDR3选自SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ IDNO:21。
在一些实施方案中,下调细胞表面TCR/CD3复合物的多肽的重链可变区序列包含SEQ ID NO:42所示序列,或包含如下所示的HCDR的SEQ ID NO:42的变体,或由其组成:如SEQ ID NO:3所示的HCDR1:GYKFTSYV,如SEQ ID NO:9所示的HCDR2:INX1X2X3DVT,其中X1,X2,X3为任意氨基酸,如SEQ ID NO:15所示的HCDR3:AX4GX5X6YDYDGFVY,其中X4,X5,X6为任意氨基酸。在一个或多个实施方案中,X1为脯氨酸、苏氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甲硫氨酸或色氨酸,X2为酪氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、半胱氨酸、苯丙氨酸、色氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸或甲硫氨酸,X3为天冬酰胺、甘氨酸、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、赖氨酸、精氨酸或组氨酸,X4为精氨酸、赖氨酸或组氨酸,X5为丝氨酸、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸,X6为酪氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、半胱氨酸、苯丙氨酸、色氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、甲硫氨酸、赖氨酸、精氨酸、天冬氨酸或谷氨酸。
在一个或多个实施方案中,下调细胞表面TCR/CD3复合物的多肽的轻链可变区序列包含SEQ ID NO:43所示序列或包含如下所示的LCDR的SEQ ID NO:43的变体,或由其组成:如SEQ ID NO:6所示的LCDR1:SSVSY,如SEQ ID NO:7所示的LCDR2:DTS,如SEQ ID NO:22所示的LCDR3:QQWX7X8X9X10X11T,其中X7,X8,X9,X10,X11为任意氨基酸。在一个或多个实施方案中,X7为丝氨酸、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、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、组氨酸、赖氨酸或精氨酸,X8为丝氨酸、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、赖氨酸、精氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸,X9为天冬酰胺、甘氨酸、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸或丝氨酸,X10为脯氨酸、丙氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甲硫氨酸或色氨酸,X11为亮氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、酪氨酸、半胱氨酸、丙氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸。
在一些实施方案中,下调细胞表面TCR/CD3复合物的多肽的重链可变区序列包含SEQ ID NO:42所示序列,但其中HCDR2选自SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14,和/或HCDR3选自SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21。在一个或多个实施方案中,下调细胞表面TCR/CD3复合物的多肽的轻链可变区序列包含SEQ ID NO:43所示序列,但其中LCDR3选自SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33,SEQ IDNO:34。
本文下调细胞表面TCR/CD3复合物的多肽的轻链可变区和重链可变区之间可直接连接,或者可通过本领域周知的接头序列连接,例如前文所述的含G和S的接头序列。
本发明中,下调细胞表面TCR/CD3复合物的多肽也包括与所述抗体(尤其是本文所述的抗TCR抗体)或其抗原结合片段具有至少70%序列相同性并保留所述抗体或抗原结合片段的抗原结合活性的突变体。所述突变体包括:与参照序列具有至少70%,至少80%,优选至少85%,优选至少90%,优选至少95%,优选至少97%的序列相同性并保留参照序列的生物学活性(如活化T细胞、结合TCR)的氨基酸序列。可采用例如NCBI的BLASTp计算两条比对的序列之间的序列相同性。突变体还包括在所述氨基酸序列中具有一个或数个突变(插入、缺失或取代)、同时仍保留该参照序列的生物学活性的氨基酸序列。所述数个突变通常指1-50个以内,例如1-20、1-10、1-8、1-5或1-3个。取代优选是保守性取代。对于scFv,突变可以发生在CDR区内(包括前文所述的CDR区内的突变),也可以发生在FR区内,只要突变后仍保留参照序列的生物学活性即可。例如,在本领域中,用性能相近或相似的氨基酸进行保守性取代时,通常不会改变蛋白质或多肽的功能。“性能相近或相似的氨基酸”包括例如,具有相似侧链的氨基酸残基的家族,这些家族包括具有碱性侧链的氨基酸(例如赖氨酸、精氨酸、组氨酸)、具有酸性侧链的氨基酸(例如天冬氨酸、谷氨酸)、具有不带电荷的极性侧链的氨基酸(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)、具有非极性侧链的氨基酸(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)、具有β-分支侧链的氨基酸(例如苏氨酸、缬氨酸、异亮氨酸)和具有芳香侧链的氨基酸(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此,在本发明多肽中用来自同一侧链类的另一氨基酸残基替换一个或几个位点,将不会在实质上影响其活性。在一些实施方案中,下调细胞表面TCR/CD3复合物的多肽是融合蛋白,还包含能将多肽引导至亚细胞结构的定位序列。所述定位序列可位于多肽的N端或C端。所述亚细胞结构包括但不限于高尔基体或内质网、蛋白酶体、细胞膜或溶酶体。所述定位序列包括内质网滞留序列,高尔基体滞留序列,E3泛素连接酶结合序列,蛋白酶体定位序列,或溶酶体定位序列。定位序列与其相邻多肽可直接连接,或者可通过本领域周知的接头序列连接,例如前文所述的含G和S的接头序列。在一个或多个实施方案中,定位序列与其相邻多肽(例如抗体或其抗原结合片段)之间具有序列SEQ ID NO:41。
本文所述“内质网滞留序列”或“内质网滞留信号”是一种短肽信号序列。内质网滞留序列在高尔基体的膜上有相应受体,可通过回流小泡被运回内质网。适用于本发明的内质网滞留序列可以是本领域周知的内质网滞留序列。内质网滞留序列可位于相邻多肽的C端。所述“内质网体滞留序列”或“高尔基体滞留序列”包括但不限于AEKDEL(SEQ ID NO:35)、KDEL(SEQ ID NO:36)、KKXX(SEQ ID NO:37)、KXD(SEQ ID NO:38)、KXE(SEQ ID NO:39)或YQRL(SEQ ID NO:40)或由其组成,其中X是任意氨基酸。蛋白酶体定位序列通过将抗体序列连接至含E3泛素连接酶靶向结构域序列并且使E3泛素连接酶蛋白的核酸序列共表达来实现。E3泛素连接酶蛋白以高亲和力结合抗体的Fc结构域,并且可以募集泛素-蛋白体复合物以降解与抗体结合的分子(例如,蛋白质和肽)。E3泛素连接酶蛋白靶向结构域序列编码选自人免疫球蛋白G(IgG)恒定区(Fc)基因(诸如IgG1、IgG2或IgG4)的氨基酸序列,并用于形成包含抗体和Fc结构域的融合蛋白。所述“蛋白酶体定位序列”包含但不限于PEST基序。所述“溶酶体定位序列”包含但不限于KFERQ。
下调细胞表面TCR/CD3复合物的多肽还可包括信号肽。信号肽可以是膜蛋白信号肽,如抗体重链的信号肽、抗体轻链的信号肽、CD8信号肽、CD28信号肽和CD4信号肽。示例性的信号肽氨基酸序列可包含SEQ ID NO:44第516-537位氨基酸残基或由其组成。
可在该工程改造的T细胞中进一步表达治疗用多肽。在同种异体的治疗中,这些T细胞有效避免了移植物抗宿主反应。在自体回输的治疗中,本发明方法制备得到的T细胞避免TCR/CD3复合物与CAR的同时激活造成的CD8+T细胞耗竭,从而提高治疗效果。
本文所述“治疗用蛋白”或“治疗用多肽”指在细胞(特别是T细胞)中表达后发挥相应的治疗活性的分子,可以是天然的或分离自天然环境的物质,也可以是制造的物质,包括但不限于:来源于病毒、细菌、植物、动物的蛋白或多肽、小分子活性肽、抗原或其片段(例如抗原表位、抗原决定簇)、抗体或其片段(例如重链、轻链、Fab、Fv、scFv)、抗原受体(例如嵌合抗原受体CAR)、融和蛋白或多肽等。
因此,本发明还提供一种CAR-T细胞,包含靶向感兴趣肿瘤抗原的嵌合抗原受体(CAR)和下调细胞表面TCR/CD3复合物的多肽。本发明还提供一种CAR-T细胞,包含编码靶向感兴趣肿瘤抗原的嵌合抗原受体(CAR)的多核苷酸和下调细胞表面TCR/CD3复合物的多肽的多核苷酸。
本文中,合适的T细胞可以是本领域周知的各种T细胞,尤其是细胞免疫疗法中常规使用的各种T细胞,包括但不限于外周血T淋巴细胞、细胞毒杀伤T细胞、辅助T细胞、抑制/调节性T细胞、γδT细胞、细胞因子诱导的杀伤细胞和肿瘤浸润淋巴细胞等,以及上述细胞的任意一种或多种的混合物。本文中,CAR-T细胞指至少表达嵌合抗原受体的T细胞。
本文中,嵌合抗原受体具有本领域周知的含义,它是一种人工改造受体,能够将识别肿瘤细胞表面抗原的特异性分子(如抗体)锚定在免疫细胞(如T细胞)上,使免疫细胞识别肿瘤抗原并杀死肿瘤细胞。适用于本文的嵌合抗原受体可以是本领域周知的各种CAR。通常,CAR包含结合肿瘤抗原的多肽、铰链区、跨膜区和一个或多个胞内信号区。
适用于结合肿瘤抗原的多肽可以是天然多肽或人工合成多肽;优选地,人工合成多肽为单链抗体或Fab片段。本文所述“肿瘤抗原”或“肿瘤表面抗原”包括在肿瘤细胞表面表达的肿瘤特异性抗原和肿瘤相关抗原。肿瘤特异性抗原特异性地在肿瘤细胞表面表达,在正常组织中无表达。肿瘤相关抗原在肿瘤细胞表面过度表达,在正常组织中低表达。肿瘤相关抗原包括:免疫细胞的表面抗原,例如CD19;参与生长和分化信号的抗原;参与肿瘤血管生成的抗原;和肿瘤支撑结构的肿瘤间质和细胞外基质抗原。
本文中,感兴趣的肿瘤抗原包括但不限于实体瘤抗原、髓系肿瘤抗原以及非B细胞谱系血液肿瘤的抗原。合适的实体瘤抗原包括但不限于EGFRvIII、间皮素、GD2、Tn抗原、sTn抗原、Tn-O-糖肽、sTn-O-糖肽、PSMA、CD97、TAG72、CD44v6、CEA、EPCAM、KIT、IL-13Ra2、leguman、GD3、CD171、IL-11Ra、PSCA、MAD-CT-1、MAD-CT-2、VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、叶酸受体α、ERBB(例如,ERBB2)、Her2/neu、MUC1、EGFR、NCAM、肝配蛋白B2、CAIX、LMP2、sLe、HMWMAA、o-乙酰基-GD2、叶酸受体β、TEM1/CD248、TEM7R、FAP、豆荚蛋白(Legumain)、HPV E6或E7、ML-IAP、CLDN6、TSHR、GPRC5D、ALK、聚唾液酸、Fos-相关抗原、中性粒细胞弹性蛋白酶、TRP-2、CYP1B1、精子蛋白17、β人绒毛膜促性腺激素、AFP、甲状腺球蛋白、PLAC1、globoH、RAGE1、MN-CA IX、人端粒酶逆转录酶、肠羧基酯酶、mut hsp 70-2、NA-17、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、NY-ESO-1、GPR20、Ly6k、OR51E2、TARP、GFRα4和呈递在MHC上的这些抗原中任一者的多肽片段。合适的B细胞抗原包括但不限于CD5、CD10、CD19、CD20、CD21、CD22、CD23、CD24、CD25、CD27、CD30、CD34、CD37、CD38、CD40、CD53、CD69、CD72、CD73、CD74、CD75、CD77、CD79a、CD79b、CD80、CD81、CD82、CD83、CD84、CD85、CD86、CD123、CD135、CD138、CD179、CD269、Flt3、ROR1、BCMA、FcRn5、FcRn2、CS-1、CXCR4、CXCR5、CXCR7、IL-7/3R、IL7/4/3R和IL4R。
在优选的实施方案中,本发明结合肿瘤抗原的多肽是特异性结合上述任一种肿瘤抗原的单链抗体。本文中,单链抗体(scFv)指由抗体轻链可变区(VL区)氨基酸序列和重链可变区(VH区)氨基酸序列经铰链连接而成的具有结合抗原能力的抗体片段。感兴趣的单链抗体可来自感兴趣的抗体。感兴趣的抗体可以是人抗体,包括人鼠嵌合抗体和人源化抗体。抗体可以是分泌型或膜锚定型;优选地为膜锚定型。本文中,特异性结合是指抗体或其抗原结合片段与其所针对的抗原之间的反应。在某些实施方式中,特异性结合某抗原的抗体(或对某抗原具有特异性的抗体)是指,抗体以小于大约10-5M,例如小于大约10-6M、10-7M、10-8M、10-9M或10-10M或更小的亲和力(KD)结合该抗原。
适用于本发明的抗肿瘤抗原的抗体可衍生自本领域周知的各种抗肿瘤抗原的单链抗体。单链抗体可含有感兴趣抗体的重链可变区和轻链可变区,或由重链可变区和轻链可变区以及任选的接头组成。重链可变区和轻链可变区之间可通过熟知的接头连接。本文中,接头或铰链是连接不同蛋白或多肽之间的多肽片段,其目的是使所连接的蛋白或多肽保持各自的空间构象,以维持蛋白或多肽的功能或活性。示例性的接头包括含有G和/或S的接头。通常,接头含有一个或多个前后重复的基序。例如,该基序可以是GGGS、GGGGS、SSSSG、GSGSA和GGSGG。优选地,该基序在接头序列中是相邻的,在重复之间没有插入氨基酸残基。接头序列可以包含1、2、3、4或5个重复基序组成。接头的长度可以是3-25个氨基酸残基,例如3-15、5-15、10-20个氨基酸残基。在某些实施方案中,接头序列是多甘氨酸接头序列。接头序列中甘氨酸的数量无特别限制,通常为2-20个,例如2-15、2-10、2-8个。除甘氨酸和丝氨酸来,接头中还可含有其它已知的氨基酸残基,例如丙氨酸(A)、亮氨酸(L)、苏氨酸(T)、谷氨酸(E)、苯丙氨酸(F)、精氨酸(R)、谷氨酰胺(Q)等。接头长度通常为15-20个氨基酸。在某些实施方案中,本发明不同蛋白或多肽之间由(GGGS)n连接,其中n为1~5的整数。在某些实施方案中,本发明单链抗体的轻链可变区和重链可变区之间由(GGGS)n连接,其中n为1~5的整数。在某些实施方案中,本发明单链抗体的轻链可变区和重链可变区之间由GSTSGGGSGGGSGGGGSS(SEQ ID NO:41)连接。
在肿瘤抗原的单链抗体是抗CD19单链抗体的实施方案中,感兴趣的肿瘤抗原是CD19,感兴趣的单链抗体是特异性结合CD19的单链抗体。在一个或多个实施方案中,抗CD19单链抗体衍生自FMC63。示例性地,抗CD19单链抗体的轻链可变区序列包含SEQ ID NO:44第23-129位氨基酸或由其组成;抗CD19单链抗体的重链可变区序列包含SEQ ID NO:44第148-267位氨基酸或由其组成,其中,重链可变区和轻链可变区通过含G和S的接头序列连接。
CAR中所含的其它部分,如铰链区、跨膜区和胞内信号区可以是常规用于构建各类CAR的铰链区、跨膜区和胞内信号区。
本文中,铰链区指免疫球蛋白重链CH1和CH2功能区之间的区域,该区富含脯氨酸,不形成α螺旋,易发生伸展及一定程度扭曲,有利于抗体的抗原结合部位与抗原表位间的互补性结合。适用于本发明CAR的铰链区本领域周知。适用于本文的铰链区可选自CD8α铰链区、IgG1 Fc CH2CH3铰链区、IgD铰链区、CD28胞外铰链区、IgG4 Fc CH2CH3铰链区和CD4胞外铰链区。在一个或多个实施方案中,铰链区是人CD8α铰链区。所述人CD8α铰链区可衍生自本领域周知的CD8α多肽链。示例性地,人CD8α铰链区的序列包含SEQ ID NO:44第268-312位氨基酸或由其组成。
本文中,跨膜区可选自CD28跨膜区、CD8跨膜区、CD3ζ跨膜区、CD134跨膜区、CD137跨膜区、ICOS跨膜区和DAP10跨膜区中的一种或多种。优选地,用于本文的嵌合抗原受体的跨膜区为CD8跨膜区。示例性的跨膜区的氨基酸序列包含SEQ ID NO:44第313-336位氨基酸残基或由其组成。
本文中,胞内信号区可选自CD28、CD134/OX40、CD137/4-1BB、LCK、ICOS、DAP10、CD3ζ和Fc310/中的任意一种或多种的胞内信号区,优选为4-1BB胞内信号区和CD3ζ胞内信号区。本文示例性的胞内信号区的氨基酸序列可如SEQ ID NO:44第337-490位氨基酸残基所示。在一个或多个实施方案中,所述4-1BB胞内区包含SEQ ID NO:44第337-378位氨基酸或由其组成;CD3ζ胞内区包含SEQ ID NO:44第379-490位氨基酸或由其组成。
治疗用蛋白例如嵌合抗原受体还可包括信号肽。信号肽是引导新合成的蛋白质向分泌通路转移的短肽链(长度5-30个氨基酸),常指新合成多肽链中用于指导蛋白质的跨膜转移(定位)的N-末端的氨基酸序列。信号肽可以是膜蛋白信号肽,如CD8信号肽、CD28信号肽和CD4信号肽。示例性的信号肽氨基酸序列可包含SEQ ID NO:44第1-22位氨基酸残基或由其组成。
因此,在一个或多个实施方案中,所述CAR从N端至C端含有任选的抗肿瘤抗原的单链抗体、铰链区、跨膜区、一个或多个胞内区。示例性的嵌合抗原受体的氨基酸序列包含SEQID NO:44第23-490位氨基酸残基或由其组成,或者包含SEQ ID NO:44第1-490位氨基酸残基或由其组成。
形成本文嵌合抗原受体的上述各部分,如信号肽、单链抗体的轻链可变区和重链可变区、铰链区、跨膜区和胞内信号区等,相互之间可直接连接,或者可通过本领域周知的接头序列连接,例如前文所述的含G和S的接头序列。本发明的治疗用蛋白以及下调细胞表面TCR/CD3复合物的多肽之间可直接连接,或者可通过接头序列连接,例如前文所述的含G和S的接头序列。或者,治疗用蛋白以及下调细胞表面TCR/CD3复合物的多肽之间还包含能够在单个载体上表达多个多顺反子的连接序列,例如2A肽。本领域周知,2A肽是一种能诱导核糖体滑位(ribosome skipping)的短肽,包括F2A、P2A、T2A肽等。在一个或多个实施方案中,2A肽的氨基酸序列包含SEQ ID NO:44第494-515位氨基酸或由其组成。2A肽也可通过常规的含G和S的接头与两侧的多肽相连。
本发明包括编码本发明所述下调细胞表面TCR/CD3复合物的多肽或蛋白的多核苷酸。本发明的多核苷酸可以是DNA形式或RNA形式。DNA形式包括cDNA、基因组DNA或人工合成的DNA。DNA可以是单链的或是双链的。DNA可以是编码链或非编码链。本发明也包括编码多肽或蛋白的多核苷酸的简并变异体,即编码相同的氨基酸序列但核苷酸序列有所不同的多核苷酸。
本文所述多核苷酸包括经密码子优化而发生变化的序列,只要多核苷酸所编码的氨基酸序列不变即可。经密码子优化的序列可对具体物种表现出更适合的表达性。本领域周知对多核苷酸序列进行密码子优化的方法。
本发明的多核苷酸可以是治疗用蛋白例如CAR的编码序列和下调细胞表面TCR/CD3复合物的多肽的编码序列,或者是治疗用蛋白的表达框和该蛋白或多肽的表达框。本文中,编码序列指核酸序列中直接确定其蛋白产物(例如CAR、单链抗体、铰链区、跨膜区、胞内信号区或抗下调细胞表面TCR/CD3复合物的多肽等)的氨基酸序列的部分。编码序列的边界通常是由紧邻mRNA 5’端开放读码框上游的核糖体结合位点(对于原核细胞)和紧邻mRNA3’端开放读码框下游的转录终止序列确定。编码序列可以包括,但不限于DNA、cDNA和重组核酸序列。本文中,表达框指表达感兴趣基因所需的完整元件,包括启动子、基因编码序列和PolyA加尾信号序列。本文所述的多核苷酸可以是独立的两个核酸分子,分别含治疗用蛋白的编码序列和下调细胞表面TCR/CD3复合物的多肽的编码序列,如分别是治疗用蛋白的表达框和多肽的表达框;或者,所述含治疗用蛋白的编码序列和所述下调细胞表面TCR/CD3复合物的多肽的编码序列可经由接头连接为一个核酸分子,如治疗用蛋白的编码序列和多肽的编码序列在同一表达框内,或者是两个表达框经由合适的接头连接为同一核酸分子。在某些实施方案中,本发明的多核苷酸为治疗用蛋白的编码序列和多肽的编码序列同处一个表达框的核酸分子,其含有启动子、编码所述治疗用蛋白和多肽的核酸序列以及PolyA加尾信号。在一个或多个实施方案中,所述多核苷酸还包含任选的内质网滞留序列的编码序列。
在某些实施方案中,所述编码序列或表达框整合到T细胞的基因组中。因此,在这些实施方案中,本文所述的T细胞的基因组中稳定整合了包含编码本文所述治疗用蛋白和多肽的表达框。
在一个或多个实施方案中,本发明的多核苷酸含有下述序列的编码序列:抗肿瘤抗原的单链抗体、人CD8α铰链区、人CD8跨膜区、4-1BB胞内区、人CD3ζ胞内区、F2A肽、抗体多肽、以及内质网滞留序列。在一个或多个实施方案中,多核苷酸包含以下核酸序列或由其组成:(1)含本文所述治疗用蛋白的编码序列和本文所述下调细胞表面TCR/CD3复合物的多肽的编码序列的多核苷酸;(2)本文所述融合蛋白的编码序列;和(3)(1)或(2)的互补序列或片段。在一个或多个实施方案中,多核苷酸包含SEQ ID NO:51或由其组成。
本发明也涉及核酸构建物,该核酸构建物含有本文所述的多核苷酸,以及与这些序列操作性连接的一个或多个调控序列。本发明所述的多核苷酸可以多种方式被操作以保证所述下调细胞表面TCR/CD3复合物的多肽或蛋白(治疗用蛋白和/或下调的多肽)的表达。在将核酸构建物插入载体之前可根据表达载体的不同或要求而对核酸构建物进行操作。利用重组DNA方法来改变多核苷酸序列的技术是本领域已知的。
调控序列可以是合适的启动子序列。启动子序列通常与待表达蛋白的编码序列操作性连接。启动子可以是在所选择的宿主细胞中显示转录活性的任何核苷酸序列,包括突变的、截短的和杂合启动子,并且可以从编码与该宿主细胞同源或异源的胞外或胞内多肽的基因获得。调控序列也可以是合适的转录终止子序列,由宿主细胞识别以终止转录的序列。终止子序列与编码该多肽的核苷酸序列的3’末端操作性连接。在选择的宿主细胞中有功能的任何终止子都可用于本发明。调控序列也可以是合适的前导序列,对宿主细胞翻译重要的mRNA的非翻译区。前导序列与编码该多肽的核苷酸序列的5’末端可操作连接。在选择的宿主细胞中有功能的任何终止子都可用于本发明。
在某些实施方案中,所述核酸构建物是载体。载体可以是克隆载体,也可以是表达载体,或者是同源重组载体。本发明的多核苷酸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。克隆载体可用于提供本发明治疗用蛋白与多肽的编码序列,如含治疗用蛋白的编码序列与多肽的编码序列的一个核酸分子。表达载体可以以病毒载体形式提供给细胞。通常通过可操作地连接本发明的多核苷酸至启动子,并将构建体并入表达载体,实现本发明多核苷酸的表达。该载体对于复制和整合真核细胞可为合适的。典型的克隆载体包含可用于调节期望核酸序列表达的转录和翻译终止子、起始序列和启动子。病毒载体技术在本领域中是公知的并在例如Sambrook等(2001,MolecularCloning:A Laboratory Manual,Cold Spring 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、疱疹病毒和慢病毒。同源重组载体用于将本文所述的表达框整合到宿主基因组中。
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、方便的限制酶位点和一个或多个可选择的标记。例如,在某些实施方案中,本发明使用慢病毒载体,该慢病毒载体含有复制起始位点,3’LTR,5’LTR,本文所述的多核苷酸,以及任选的可选择的标记。
合适的启动子的一个例子为即时早期巨细胞病毒(CMV)启动子序列。该启动子序列是能够驱动可操作地连接至其上的任何多核苷酸序列高水平表达的强组成型启动子序列。合适的启动子的另一个例子为延伸生长因子-1α(EF-1α)。然而,也可使用其他组成型启动子序列,包括但不限于类人猿病毒40(SV40)早期启动子、小鼠乳癌病毒(MMTV)、人免疫缺陷病毒(HIV)长末端重复(LTR)启动子、MoMuLV启动子、鸟类白血病病毒启动子、EB病毒即时早期启动子、鲁斯氏肉瘤病毒启动子、以及人基因启动子,诸如但不限于肌动蛋白启动子、肌球蛋白启动子、血红素启动子和肌酸激酶启动子。
为了评估治疗用蛋白、多肽或其部分的表达,被引入细胞的表达载体也可包含可选择的标记基因或报道基因中的任一个或两者,以便于从通过病毒载体寻求被转染或感染的细胞群中鉴定和选择表达细胞。在其他方面,可选择的标记可被携带在单独一段DNA上并用于共转染程序。可选择的标记和报道基因两者的侧翼都可具有适当的调节序列,以便能够在宿主细胞中表达。有用的可选择标记包括例如抗生素抗性基因,诸如neo等等。
报道基因用于鉴定潜在转染的细胞并用于评价调节序列的功能性。在DNA已经被引入受体细胞后,报道基因的表达在合适的时间下进行测定。合适的报道基因可包括编码荧光素酶、β-半乳糖苷酶、氯霉素乙酰转移酶、分泌型碱性磷酸酶或绿色萤光蛋白基因的基因。合适的表达系统是公知的并可利用已知技术制备或从商业上获得。
本文所述的多核苷酸通常可以用PCR扩增法获得。具体而言,可根据本文所公开的核苷酸序列,尤其是开放阅读框序列来设计引物,并用市售的cDNA库或按本领域技术人员已知的常规方法所制备的cDNA库作为模板,扩增而得有关序列。当序列较长时,常常需要进行两次或多次PCR扩增,然后再将各次扩增出的片段按正确次序拼接在一起。或者,也可直接合成本文所述的核酸分子。
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。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、电穿孔等等。将感兴趣的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。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。
将多核苷酸引入宿主细胞的生物学方法包括使用病毒载体,特别是逆转录病毒载体,这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、腺病毒和腺伴随病毒等等。已经开发了许多基于病毒的系统,用于将基因转移入哺乳动物细胞。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。许多反转录病毒系统在本领域中是已知的。慢病毒是逆转录病毒科下的属。慢病毒载体是一种较复杂的逆转录病毒载体。用于慢病毒包装的试剂为本领域所周知,如常规的慢病毒载体系统包括pRsv-REV、pMDlg-pRRE、pMD2G和目的干扰质粒。在一个实施方案中,使用慢病毒载体pWPXL。
因此,在某些实施方案中,本发明还提供用于活化T细胞的慢病毒,该病毒含有本文所述的逆转录病毒载体以及相应的包装基因,如gag、pol、vsvg和/或rev。
本文中,宿主细胞含有、表达和/或分泌本文所述的抗体和/或融合蛋白以及任选的治疗用多肽。本文中,当提及细胞含有或包含、表达、分泌某种分子如多肽时,“含有”指所述所述分子含于所述细胞内或表面上;“表达”指该细胞生产所述分子;“分泌”指该细胞将所表达的分子分泌出细胞外。宿主细胞既包括最终用于疾病治疗目的的T细胞,也包括生产CAR-T细胞过程中使用到的各种细胞,如大肠杆菌细胞,以用于如提供本发明蛋白的编码序列或提供本文所述的载体。在某些实施方案中,本文提供一种稳定表达本文所述下调细胞表面TCR/CD3复合物的多肽的CAR-T细胞。
适用于本发明的T细胞可以是各种来源的各种类型的T细胞。例如,T细胞可来源于健康个体的PBMC。在某些实施方案中,获得T细胞后,可先用适量的(例如30~80ng/ml,如50ng/ml)的CD3抗体刺激活化,然后在含有适量的(例如30~80IU/ml,如50IU/ml)的IL2培养基中进行培养备用。
因此,在某些实施方案中,本发明提供一种基因修饰的T细胞,该基因修饰的T细胞含有本文所述的多核苷酸,或含有本文所述的慢病毒载体,或感染了本文所述的慢病毒,或采用本文所述的方法制备得到,或稳定表达本文所述的治疗用蛋白和多肽。
本发明的T细胞(例如CAR-T细胞)可经历稳固的体内T细胞扩展并在血液和骨髓中以高水平持续延长的时间量,并形成特异性记忆T细胞。不希望被任何具体的理论所束缚,在遇到并随后消除表达替代抗原的靶细胞后,本发明的T细胞可体内分化成中心记忆样状态。
本文还包括一种T细胞培养物,该培养物含有本文所述的T细胞以及合适的培养基。培养基可以是本领域常规用于培养T细胞的培养基。
本文还提供一种药物组合物,该药物组合物中含有本文所述的T细胞以及药学上可接受的辅料。本文中,药学上可接受的辅料是指在药理学和/或生理学上与受试者和活性成分相容的载体、稀释剂和/或赋形剂,包括但不限于:pH调节剂,表面活性剂,碳水化合物,佐剂,抗氧化剂,螯合剂,离子强度增强剂和防腐剂。更具体而言,合适的药学上可接受的辅料可以是本领域常用于T细胞(例如CAR-T细胞)给药的辅料。
通常,药物组合物中含有治疗有效量的T细胞。治疗有效量是指可在受试者中实现治疗、预防、减轻和/或缓解疾病或病症的剂量。可根据患者年龄、性别、所患病症及其严重程度、患者的其它身体状况等因素确定治疗有效量。本文中,受试者或患者通常指哺乳动物,尤其指人。
本文还提供了一种试剂盒,所述试剂盒含有本文所述的核酸构建物。试剂盒还可含有适用于将所述核酸构建物转染入细胞中的各种试剂,以及任选的指导本领域技术人员将所述重组表达载体转染入细胞的说明书。
本发明还包括一种细胞疗法,其中T细胞被基因修饰以表达本文所述的治疗用蛋白和多肽,和给对象施用T细胞。例如,施用的CAR-T细胞能够杀死接受者的肿瘤细胞。由CAR-T细胞引起的抗肿瘤免疫应答可为主动或被动免疫应答。另外,CAR介导的免疫应答可为过继免疫疗法步骤的一部分,其中CAR-T细胞诱导对CAR中的抗原结合部分特异性的免疫应答。
因此,适合使用本发明的CAR、多肽、它们的编码序列、核酸构建物、表达载体、病毒或CAR-T细胞治疗的疾病与CAR中所含的肿瘤抗原单链抗体有关。因此,本文所述的疾病包括与前文所述的肿瘤抗原相关的各类癌症,包括实体瘤和血液肿瘤,如腺癌、肺癌、结肠癌、大肠癌、乳腺癌、卵巢癌、宫颈癌、胃癌、胆管癌、胆囊癌、食管癌、胰腺癌和前列腺癌等实体瘤,以及白血病和淋巴瘤,如B细胞淋巴瘤、套细胞淋巴瘤、急性淋巴细胞白血病、慢性淋巴细胞白血病、多毛细胞白血病和急性髓性白血病等。在肿瘤抗原是CD19的实施方案中,可采用本文所述的包含抗CD19单链抗体的CAR、多肽、它们的编码序列、核酸构建物、表达载体、病毒或CAR-T细胞治疗的疾病优选为CD19介导的疾病;例如急性/慢性B系淋巴细胞白血病、非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤和套细胞淋巴瘤等。
本发明的T细胞可被单独施用或作为药物组合物施用。本发明的细胞或药物组合物可以以适于治疗(或预防)的疾病的方式施用。施用的数量和频率将由各种因素确定,如患者的病症、和患者疾病的类型和严重度。组合物的施用可以以任何方便的方式进行,包括通过注射、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。在一个实施方案中,本发明的T细胞组合物通过皮内或皮下注射被施用给患者。在另一个实施方案中,本发明的T细胞组合物优选通过静脉注射施用。T细胞的组合物可被直接注入肿瘤、淋巴结或感染位置。
在本发明的一些实施方案中,本发明的T细胞或其组合物可与本领域已知的其它疗法结合。所述疗法包括但不限于化疗、放疗和免疫抑制剂。例如,可结合本领域周知的治疗肿瘤抗原介导的疾病的放疗或化疗制剂进行治疗。
本文中,“抗肿瘤效应”指一种生物学效应,其可由肿瘤体积的减少、肿瘤细胞数的减少、转移数的减少、预期寿命的增加或与癌相关的各种生理症状的改善表示。
本发明采用抗CD19抗体(具体是衍生自克隆号FMC63的scFV)的基因序列作为示例,并从NCBI GenBank数据库中搜索到人CD8α铰链区、人CD8跨膜区、4-1BB胞内区、人CD3ζ胞内区和抗TCR单链抗体等序列信息,全基因合成嵌合抗原受体的基因片段,插入到慢病毒载体中。重组质粒在293T细胞中包装病毒,感染T细胞,使T细胞表达该嵌合抗原受体。本发明实现嵌合抗原受体基因修饰的T淋巴细胞的转化方法是基于慢病毒转化方法。该方法具有转化效率高,外源基因能够稳定表达,且可以缩短体外培养T淋巴细胞到达临床级数量的时间等优点。在该转基因T淋巴细胞表面,转化的核酸通过转录、翻译表达在其上。本发明制备的CAR-T细胞对特异性肿瘤细胞具强烈的杀伤功能,效靶比是2.5比1的情况下,含有不同抗TCR克隆单链抗体的CAR-T细胞的杀伤效率均超过98%。
本发明通过参考以下实验实施例进一步详细地进行描述。这些实施例仅出于说明性的目的提供,并不意欲为限制性的,除非另有规定。因此,本发明决不应被解释为限于以下实施例,而是应被解释为包括由于本文提供的教导变得显而易见的任何和全部的变化。实施例中所用的方法和试剂,除非另有说明,否则为本领域常规的方法和试剂。
实施例
实施例1-载体构建
1、从NCBI网站数据库搜索到人CD8α铰链区、人CD8跨膜区、4-1BB胞内区、人CD3ζ胞内区、抗人CD19抗体(克隆FMC63)的重链和轻链可变区、对照抗人TCR/CD3抗体(克隆UCHT1和OKT3的重链和轻链可变区基因序列信息。其余的抗体序列来自专有的抗人TCR/CD3抗体克隆。所有相关的氨基酸序列在网站https://www.thermofisher.com/order/geneartgenes上进行密码子优化,保证在编码氨基酸序列不变的情况下更适合人类细胞表达。
2、采用重叠PCR将上述序列依次按抗CD19-scFv基因、人CD8铰链区基因、人CD8跨膜区基因、4-1BB胞内区基因、人CD3ζ胞内区、F2A和CD3-scFv基因、内质网滞留序列(AEKDEL)进行连接,形成完整的基因序列信息。其包含信号肽编码序列的序列如SEQ IDNO:51第1-66位残基或第1546-1611位残基所示,氨基酸序列如SEQ ID NO:44第1-22位残基和第516-537位残基所示。
3、该CAR分子的核苷酸序列经无缝克隆到慢病毒质粒pWPXL(Addgene)的BamHI/EcoRI位点,转化到感受态大肠杆菌(Stbl3)。
4、将重组质粒送苏州金唯智生物科技有限公司进行测序,将测序结果与拟合成的序列比对来验证序列是否正确。测序引物为
正义序列:TCAAGCCTCAGACAGTGGTTC(SEQ ID NO:49)
反义序列:CCAGTCAATCTTTCACAAATTTTG(SEQ ID NO:50)。
实施例2-病毒包装
经测序正确后,使用Qiagen公司的质粒纯化试剂盒提取并纯化质粒,采用磷酸钙法将纯化的质粒转染293T细胞,进行慢病毒包装实验(Molecular Therapy-Methods&Clinical Development,2016,3:16017),由此制备得到如下慢病毒载体:对照(CAR19-F2A-GFP)、样本1(CAR19-F2A-UCHT1 scfv-AEKDEL)、样本2(CAR19-F2A-OKT3 scfv-AEKDEL)、样本3(CAR19-F2A-CTAB5 scfv-AEKDEL)、样本4(CAR19-F2A-CTAB2 scfv-AEKDEL)、样本5(CAR19-F2A-CTAB3 scfv-AEKDEL)、样本6(CAR19-F2A-CTAB4 scfv-AEKDEL)、样本7(CTAB5scfv-AEKDEL)。
实施例3-PBMC以及T细胞的分离
外周血PBMC的分离、T细胞分离活化、慢病毒转导、体外培养
选择HBV、HCV和HIV检测阴性的健康供者,肘正中静脉抽血,Ficoll密度梯度离心分离PBMC白膜层,根据全血流式检测CD3+T细胞百分比,计算CD3+T细胞数,按DynaBeadsCD3/CD28与CD3+T细胞比例3:1,吸取使用量磁珠,与白膜层细胞孵育30min,分离CD3+T细胞,CD3+T细胞经Dynabeads CD3/CD28(Life Technology)活化24小时后流式检测CD25+CD69+T细胞比例。
实施例4-慢病毒转导和T细胞培养
CD3+T活化后,进行慢病毒转导。用Novonectin包被24孔板37℃孵育2小时,将细胞悬液与分别与前述制备得到的各种慢病毒(MOI=3)、Tscm(2U/ml,近岸蛋白)配置成转导体系置于包被的24孔板中,细胞密度调整至1.0E+06/ml,500g离心30min,离心后置于37℃和5%CO2的培养箱静置培养48小时。慢病毒转染完毕后,以含5%FBS的Xvivo15培养液培养,隔日补充Tscm(终浓度2U/ml),计数并调整细胞密度至0.5E+06/ml,培养至第8-10天收获细胞。
实施例5-CAR阳性率以及CAR-T细胞TCR或CD3平均荧光强度
计数并收集5.0E+05细胞,洗涤细胞2次后重悬于100ul含4%BSA的缓冲液中。每管细胞加入抗人TCR或CD3抗体8ul,旋涡混匀,4℃孵育30分钟。染色孵育完毕后,重复洗涤细胞,将荧光标记的抗CAR19抗体或Protein L稀释500x,重悬细胞,每管200ul,旋涡混匀,4℃孵育30分钟。重复洗涤细胞,重悬于500ul含4%BSA的缓冲液中,每管加入7AAD染料4ul,旋涡混匀,常温避光孵育10分钟。最后,将样品转移至流式管,在Calibr流式仪上检测CAR19转染效率以及CAR19+T细胞群体的TCR或CD3表面水平。
首先对两个广泛使用的抗人TCR/CD3鼠源抗体(OKT3和UCTH1)做了评估。为了避免临床应用中鼠源序列带来的排斥反应,将其做了人源化改造并开展了细胞水平的测试。结果如图1和表1所示,表达含有人源化UCHT1抗体序列的多肽具有一定下调细胞表面TCR/CD3复合物的活性,在转导阳性细胞中(CAR+),TCR-和CD3-群体的占比分别为48.22%和45.8%。专利US20180086831A1也测试了UCHT1抗体序列,其图5显示对于不同供者来源的T细胞,TCR/CD3复合物的表面下调水平差异较大。对供者1,转染阳性细胞中TCR-群体的占比为:17.1/(17.1+14.1)*100%=54.8%,与本发明得到的结果接近。然而对供者2,转染阳性细胞中TCR-群体的占比为42.5/(42.5+6.79)*100%=86.2%,展现出与供者1较大的差异。
含有人源化OKT3序列的多肽下调细胞表面TCR/CD3复合物的活性高于含有UCTH1序列的多肽(图1和表1)。CAR+细胞中,TCR-和CD3-群体的占比分别提高至70.62%和66.09%,但是TCR/CD3+群体的占比仍然较高,这将给CAR-T细胞的纯化带来极大挑战,也给临床应用带来极大的风险。含有另外三种抗TCR/CD3抗体序列的多肽(图2和表1)与含有OKT3序列的多肽活性接近,CAR+TCR-/CAR+的占比在48.81~68.95%之间。
意外地是,含有抗体CTAB5序列的多肽能够最有效地下调细胞表面TCR/CD3复合物的水平,高达88.09%的CAR+细胞都不表达表面TCR;高达85.89%的CAR+细胞都不表达表面CD3(图1和表1)。
表1
a:Q4的比例/Q2+Q4的比例
实施例6-不同供者T细胞的CAR阳性率以及CAR-T细胞的表面TCR或CD3蛋白水平
按照实施例3和实施例4的方法制备得到不同供者来源的含有CTAB5序列多肽的CAR-T细胞,并按照实施例5的方法流式检测CAR19转染效率以及CAR19+T细胞群体的TCR或CD3平均荧光强度。
结果如图3所示,表达CTAB5序列的多肽在不同供者CAR-T细胞中表现出稳定下调细胞表面TCR/CD3复合物的能力。计算结果如表2所示,转染阳性细胞(CAR+)中TCR阴性群体的占比在不同的供者间均不低于85%,显示含有CTAB5序列的多肽适用于广泛的供者T细胞。
表2
a:Q4的比例/Q2+Q4的比例
实施例7-表达含有CTAB5抗体序列的多肽能高效下调T细胞表面的TCR和CD3水平
为了确认含有CTAB5抗体序列的多肽的活性,按照实施例2制备得到仅仅表达含有CTAB5序列的多肽但不表达治疗用蛋白的慢病毒载体,按照实施例3和实施例4的方法制备得到对应的T细胞,并按照实施例5的方法流式检测其表面的TCR或CD3水平。
结果如图4所示,含有CTAB5抗体序列的多肽在单独表达时,仍然能够高效地抑制TCR和CD3的表面表达。
实施例8-细胞表型分析
计数各组CAR-T细胞,离心收集1.0E+06细胞,用无菌4%BSA重悬洗涤细胞2次,后用200ul 4%BSA重悬细胞。在每个样本中加入如下所需的抗人抗体:CD4(AmCyan),CD8(APC-Cy7),CD45RA(PE-Cy7)和CCR7(BV421)。每种抗体各加5ul,旋涡混匀仪混匀,4℃孵育30分钟。染色孵育完毕后,重复洗涤细胞,用500ul的含4%BSA缓冲液重悬细胞,每管加入7AAD染料4ul,旋涡混匀,常温避光孵育10分钟。转移样品至流式管,在FACS Calibr流式仪上检测各组T细胞的CCR7和CD45RA表达,分析T细胞免疫表型。
结果如图5a-5g所示。各组中的CAR+CD8+T和CAR+CD4+T的比例均正常而且组间均无明显差异,包括下调细胞表面TCR/CD3复合物最有效的含有CTAB5抗体序列的多肽细胞组。
实施例9-T细胞体外扩增分析
各组慢病毒载体转染的T细胞,隔日计数T细胞,体外培养T细胞至第8天,计算细胞增殖倍数(第8天的细胞数/用于转染的细胞数)。
结果如图6所示。各组TCR/CD3复合物表面表达下调的T细胞的扩增能力与对照相比不仅没有减弱,反而均有不同程度的提高。
实施例10-T细胞对肿瘤靶细胞的杀伤
计数并收集NC-T细胞(未进行慢病毒转染的T细胞)和各组CAR-T细胞,用T细胞培养液X-VIVO15(不含Tscm)调整细胞密度至5.0E+07/mL。计数并收集靶细胞,用RPMI 1640(不含FBS)将细胞密度调整至5.0E+06/mL。于1.5毫升离心管中将上述调整好密度的效应细胞分别与靶细胞按不同效靶比(1:1、2.5:1、5:1、10:1、20:1)混合,用X-VIVO15将总体积补足至200ul。移入96孔V型板中,在37℃和5%CO2下孵育24小时后,轻轻吹打混匀各孔细胞并转移100ul细胞悬液至白壁实心底的96孔板中。加入80μL ONE-GloTM Luciferase底物,吹吸混匀,室温避光孵育10分钟后上Luminoskan Ascent化学发光分析仪检测荧光强度。
结果如表3和图7所示。除表达含有CTAB3抗体序列多肽的细胞外,其它各组均具有高效的杀伤肿瘤靶细胞的能力。
表3
名称 | 1:1 | 2.5:1 | 5:1 | 10:1 | 20:1 |
对照 | 89.15% | 98.36% | 99.27% | 99.52% | 99.46% |
UCHT1 | 87.82% | 99.12% | 99.72% | 99.61% | 99.94% |
OKT3 | 91.74% | 98.51% | 99.51% | 99.50% | 99.72% |
CTAB5 | 98.32% | 99.52% | 99.81% | 99.85% | 99.56% |
CTAB2 | 87.81% | 99.16% | 99.61% | 99.64% | 99.84% |
CTAB3 | -19.07% | 55.03% | 74.29% | 89.55% | 66.60% |
CTAB4 | 69.40% | 99.17% | 99.68% | 99.82% | 99.65% |
实施例11-T细胞分泌IFN-γ的能力
各组慢病毒转染的T细胞体外培养至第8天,加入TCR依赖的T细胞激活抗体OKT3至终浓度分别为:50ng/ml,100ng/ml,150ng/ml,200ng/ml。用X-VIVO15培养液将各组CAR-T细胞样品稀释适当倍数,根据需要取出相应数量的条块,每孔加入100ul稀释液RD1-51,将稀释后的样品混匀,取100ul加入孔中(15分钟内完成);盖上封口膜,室温孵育2小时。孵育完成后,完全去除孔中溶液,加入洗涤液,静置1分钟,重复此步骤,总共清洗四次;每孔加200ul的人IFN-γ偶联试剂,盖上新的封口膜,室温孵育2小时;每孔加200ul底物溶液,室温避光孵育30分钟;孵育完成后,每孔加入50ul终止液,充分混合后上酶标仪检测(设置波长为450nm,校正波长570nm/540nm)。
结果如表4和图8所示。所有实验组与对照组相比,IFN-γ分泌均有所下调,其中含有CTAB5抗体序列的细胞IFN-γ分泌能力处于较低水平,表明该细胞的细胞表面不存在功能性的TCR/CD3复合物,这与前述实验结果完全一致。
表4
实施例12-突变文库的制备和筛选
1)选取目标TCR/CD3抗体序列进行氨基酸点突变以找寻更有效下调表面TCR/CD3复合物表达的、或消除其MHC-I表位的,或能促进T细胞扩增等应用优势的突变体。突变文库的区域1位于目标scfv的轻链(SEQ ID NO:43的第90-95位氨基酸),区域2位于目标scfv的重链(SEQ ID NO:42的第50-55位氨基酸),区域3位于目标scfv的重链(SEQ ID NO:42第97-101位氨基酸)。
2)设计NNK简并引物进行上述突变文库的构建。按照实施例1和实施例2的方法制备得到慢病毒目标突变体文库。
3)按照实施例3和实施例4的方法制备得到目标突变T细胞文库。
4)按照实施例5的方法检测目标突变T细胞文库的TCR和CD3的表达情况。结果如图9所示,目标突变文库细胞表现出下调TCR和CD3表达的能力。
5)流式分选出下调TCR能力最强的T细胞克隆亚群,并进行基因组高通量测序,表5展示了文库中示例性的23个突变体。随后挑选其中三个,确认它们能够下调细胞表面TCR/CD3复合物的表达,并能有效杀伤靶细胞。
6)所选的三个突变体为:突变体1,VL-CDR3(SEQ ID NO:23);突变体2,VL-CDR3(SEQ ID NO:24);突变体3,VH-CDR3(SEQ ID NO:17)。构建相应的点突变质粒。
表5
7)按照上述实施例的方法检测了所选3个突变体的相关CAR-T指标,结果如图10-12所示。
如图10所示,突变体1、突变体2和突变体3表现出和未突变对照相同程度的下调TCR和CD3在细胞表面表达的能力。如图11所示,突变体1、2、3均能提高CAR-T细胞的扩增效率,因此生产周期可以缩短,增加终产品的干性,增强体内杀瘤活性和持久性,降低药品的单位生产成本,并提高产品质量;如图12所示,突变体表现出与未突变对照等效的肿瘤细胞杀伤能力。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
本文序列
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<110> 苏州方德门达新药开发有限公司
<120> 工程改造的T细胞、其制备及应用
<130> 198068
<141> 2020-01-09
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<221> misc_feature
<222> (3)..(3)
<223> The 'Xaa' at location 3 stands for any amino acid.
<220>
<221> misc_feature
<222> (4)..(4)
<223> The 'Xaa' at location 4 stands for any amino acid.
<400> 37
Lys Lys Xaa Xaa
1
<210> 38
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<221> misc_feature
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for any amino acid.
<400> 38
Lys Xaa Asp
1
<210> 39
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<221> misc_feature
<222> (2)..(2)
<223> The 'Xaa' at location 2 stands for any amino acid.
<400> 39
Lys Xaa Glu
1
<210> 40
<211> 4
<212> PRT
<213> Artificial Sequence
<400> 40
Tyr Gln Arg Leu
1
<210> 41
<211> 20
<212> PRT
<213> Artificial Sequence
<400> 41
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 42
<211> 120
<212> PRT
<213> Artificial Sequence
<400> 42
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val His Tyr Cys
85 90 95
Ala Arg Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe Val Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 43
<211> 106
<212> PRT
<213> Artificial Sequence
<400> 43
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 44
<211> 804
<212> PRT
<213> Artificial Sequence
<400> 44
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
115 120 125
Lys Gly Ser Thr Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys
145 150 155 160
Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu
165 170 175
Ser Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu
180 185 190
Glu Trp Leu Ala Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser
195 200 205
Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln
210 215 220
Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr
225 230 235 240
Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr
245 250 255
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala
260 265 270
Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser
275 280 285
Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr
290 295 300
Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala
305 310 315 320
Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys
325 330 335
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
340 345 350
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
355 360 365
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg
370 375 380
Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn
385 390 395 400
Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg
405 410 415
Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro
420 425 430
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
435 440 445
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
450 455 460
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
465 470 475 480
Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Val Lys Gln
485 490 495
Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val Glu Ser Asn
500 505 510
Pro Gly Pro Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu
515 520 525
Leu Leu Trp Leu Arg Gly Ala Arg Cys Gln Ile Val Leu Thr Gln Ser
530 535 540
Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys
545 550 555 560
Ser Ala Thr Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Ser
565 570 575
Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser
580 585 590
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
595 600 605
Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
610 615 620
Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu
625 630 635 640
Glu Leu Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
645 650 655
Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro
660 665 670
Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr
675 680 685
Ser Tyr Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu
690 695 700
Trp Ile Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Asn Glu
705 710 715 720
Lys Phe Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr
725 730 735
Ala Tyr Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val His
740 745 750
Tyr Cys Ala Arg Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe Val Tyr Trp
755 760 765
Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly
770 775 780
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
785 790 795 800
Lys Asp Glu Leu
<210> 45
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 45
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 Arg Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Glu 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 Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 46
<211> 122
<212> PRT
<213> Artificial Sequence
<400> 46
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Leu Ile Asn Pro Tyr Lys Gly Val Thr Thr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 47
<211> 106
<212> PRT
<213> Artificial Sequence
<400> 47
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 Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr
85 90 95
Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr
100 105
<210> 48
<211> 119
<212> PRT
<213> Artificial Sequence
<400> 48
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 49
<211> 21
<212> DNA
<213> Artificial Sequence
<400> 49
tcaagcctca gacagtggtt c 21
<210> 50
<211> 24
<212> DNA
<213> Artificial Sequence
<400> 50
ccagtcaatc tttcacaaat tttg 24
<210> 51
<211> 2415
<212> DNA
<213> Artificial Sequence
<400> 51
atggatatga gggtgcctgc ccagctgctg ggcctgctgc tgctgtggct gaggggcgct 60
aggtgtgaca tccagatgac ccagagccct tcctccctga gcgcctccgt gggcgataga 120
gtgacaatca catgtagagc ctcccaggac atcagcaagt acctgaactg gtaccagcag 180
aagcccggca aggcccccaa gctgctgatc taccacacct ccagactgca cagcggcgtg 240
cctagcaggt tcagcggctc cggcagcggc accgacttta cactgaccat cagctccctg 300
cagcctgagg atttcgccac ctactactgt cagcagggca atacactgcc ctacaccttt 360
ggccagggca ccaagctgga gatcaaggga tccaccagcg gcggaggaag cggcggaggt 420
agcggaggag gcggaagctc ccaggtgaca ctgaaggaga gcggccctgc cctggtgaag 480
cctacacaga cactgacact gacgtgtacc ttctccggct tcagcctgtc cgattacggc 540
gtgagctgga tcagacagcc tcctggcaag gccctggagt ggctggccgt gatctggggc 600
agcgagacca cctactacaa ttccgccctg aagagcaggc tgaccatctc caaggacacc 660
tccaagaacc aggtggtgct gaccatgacc aatatggatc ctgtggacac cgccacatac 720
tactgtgcca agcactacta ctacggcggc agctacgcca tggattactg gggccagggc 780
accctggtga ccgtgagctc caccacgacg ccagcgccgc gaccaccaac accggcgccc 840
accatcgcgt cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcggggggc 900
gcagtgcaca cgagggggct ggacttcgcc tgtgatatct acatctgggc gcccttggcc 960
gggacttgtg gggtccttct cctgtcactg gttatcaccc tttactgcaa acggggcaga 1020
aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 1080
gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 1140
aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 1200
gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 1260
cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 1320
cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1380
ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1440
gcccttcaca tgcaggccct gccccctcgc ggctccggag taaagcaaac actgaacttt 1500
gaccttctca agttggctgg agacgttgag tccaatcctg ggcccatgga catgagagtg 1560
cccgctcaac tgctgggact gctgctgctt tggctgagag gcgccagatg ccaaattgtg 1620
ctgacacaga gccccgccat catgtctgct agccctggcg agaaagtgac catgacctgt 1680
agcgccacaa gcagcgtgtc ctacatgcac tggtatcagc agaagtccgg cacaagcccc 1740
aagcggtgga tctacgatac aagcaagctg gcctctggcg tgcccgctag attttctggc 1800
tctggcagcg gcaccagcta cagcctgaca atcagcagca tggaagccga ggatgccgcc 1860
acctactact gccagcagtg gtccagcaat cccctgacat ttggagccgg caccaagctg 1920
gaactgaaag gcggcggagg atctggcgga ggtggaagtg gcggaggcgg atctgaagtt 1980
cagctgcagc agagcggacc cgagcttgtg aaacctggcg cctctgtgaa gatgagctgc 2040
aaggccagcg gctacaagtt cacctcctac gtgatgcact gggtcaagca gaaaccaggc 2100
cagggcctcg agtggatcgg ctacatcaac ccctacaacg acgtgaccaa gtacaacgag 2160
aagttcaagg gcaaagccac actgaccagc gacaagagca gcagcaccgc ctacatggaa 2220
ctgagcagcc tgacctctga ggacagcgcc gtgcactatt gtgccagggg cagctactac 2280
gactacgacg gctttgtgta ttggggccag ggcaccctgg ttacagtttc tgctggtggc 2340
ggcggtagcg gaggtggtgg ttctggtggt ggtggatctg gcggcggagg ttctgccgag 2400
aaggatgaac tgtga 2415
Claims (25)
1.一种工程改造的T细胞,其特征在于,所述T细胞表达下调细胞表面TCR/CD3复合物的多肽,所述下调细胞表面TCR/CD3复合物的多肽包含一个重链可变区(VH),该重链可变区的氨基酸序列为SEQ ID NO:1或与SEQ ID NO:1具有95%以上相同性的氨基酸序列,和一个轻链可变区(VL),该轻链可变区的氨基酸序列为SEQ ID NO:2或与SEQ ID NO:2具有95%以上相同性的氨基酸序列。
2.如权利要求1所述的T细胞,其特征在于,
所述下调细胞表面TCR/CD3复合物的多肽的VH中包含序列如SEQ ID NO:9所示的HCDR2:INX1X2X3DVT,其中X1,X2,X3为任意氨基酸,或
所述下调细胞表面TCR/CD3复合物的多肽的VH中包含序列如SEQ ID NO:15所示的HCDR3:AX4GX5X6YDYDGFVY,其中X4,X5,X6为任意氨基酸;或
所述下调细胞表面TCR/CD3复合物的多肽的VL中包含序列如SEQ ID NO:22所示的LCDR3:QQWX7X8X9X10X11T,其中X7,X8,X9,X10,X11为任意氨基酸。
3.如权利要求2所述的T细胞,其特征在于,所述下调细胞表面TCR/CD3复合物的多肽具有选自以下的一个或多个特征:
所述序列SEQ ID NO:9所示的HCDR2中,X1氨基酸为脯氨酸、苏氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甲硫氨酸或色氨酸,X2氨基酸为酪氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、半胱氨酸、苯丙氨酸、色氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸或甲硫氨酸,X3氨基酸为天冬酰胺、甘氨酸、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、赖氨酸、精氨酸或组氨酸;
所述序列SEQ ID NO:15所示的HCDR3中,X4氨基酸为精氨酸、赖氨酸或组氨酸,X5氨基酸为丝氨酸、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸,X6氨基酸为酪氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、半胱氨酸、苯丙氨酸、色氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、甲硫氨酸、赖氨酸、精氨酸、天冬氨酸或谷氨酸;
所述序列SEQ ID NO:22所示的LCDR3中,X7氨基酸为丝氨酸、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、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、组氨酸、赖氨酸或精氨酸,X8氨基酸为丝氨酸、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、赖氨酸、精氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸,X9氨基酸为天冬酰胺、甘氨酸、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸或丝氨酸,X10氨基酸为脯氨酸、丙氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甲硫氨酸或色氨酸,X11氨基酸为亮氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、酪氨酸、半胱氨酸、丙氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸。
4.如权利要求1-3中任一项所述的T细胞,其特征在于,所述下调细胞表面TCR/CD3复合物的多肽包含以下各组中的一组或多组:
(1)以下的LCDR3序列之一:SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ IDNO:32、SEQ ID NO:33,SEQ ID NO:34,
(2)以下的HCDR2序列之一:SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14,
(3)以下的HCDR3序列之一:SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21。
5.如权利要求1-4中任一项所述的T细胞,其特征在于,所述多肽是单链抗体。
6.如权利要求1-5中任一项所述的T细胞,其特征在于,所述下调细胞表面TCR/CD3复合物的多肽包含定位序列和任选的信号肽,优选地,
所述定位序列选自内质网滞留序列,高尔基体滞留序列,E3泛素连接酶结合序列,蛋白酶体定位序列或溶酶体定位序列;优选地,所述内质网滞留序列包括SEQ ID NO:35-40中任一所示的序列或由其组成,其中X是任意氨基酸,
所述定位序列与抗体之间包含接头,所述接头优选如SEQ ID NO:41所示;
所述信号肽如SEQ ID NO:44第516-537位所示。
7.如权利要求1-6中任一项所述的T细胞,进一步表达治疗用蛋白,优选地,治疗用蛋白是嵌合抗原受体。
8.如权利要求7所述的T细胞,其特征在于,所述T细胞含有所述治疗用蛋白的表达框和所述下调细胞表面TCR/CD3复合物的多肽的表达框,或所述治疗用蛋白的编码序列和所述下调细胞表面TCR/CD3复合物的多肽的编码序列处于同一表达框内。
9.一种工程改造的T细胞,其特征在于,所述T细胞表达下调细胞表面TCR/CD3复合物的多肽,所述多肽包含:抗体或其抗原结合片段,或与所述抗体或其抗原结合片段具有至少90%序列相同性并保留所述抗体或抗原结合片段的抗原结合活性的突变体;其中,所述抗体包含重链可变区和轻链可变区,
所述重链可变区具有下述HCDR:
如SEQ ID NO:3所示的HCDR1:GYKFTSYV,
如SEQ ID NO:9所示的HCDR2:INX1X2X3DVT,其中X1,X2,X3为任意氨基酸,
如SEQ ID NO:15所示的HCDR3:AX4GX5X6YDYDGFVY,其中X4,X5,X6为任意氨基酸,
所述轻链可变区具有下述LCDR:
如SEQ ID NO:6所示的LCDR1:SSVSY,
如SEQ ID NO:7所示的LCDR2:DTS,
如SEQ ID NO:22所示的LCDR3:QQWX7X8X9X10X11T,其中X7,X8,X9,X10,X11为任意氨基酸。
10.如权利要求9所述的T细胞,其特征在于,所述下调细胞表面TCR/CD3复合物的多肽具有选自以下的一个或多个特征:
X1为脯氨酸、苏氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甲硫氨酸或色氨酸,
X2为酪氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、半胱氨酸、苯丙氨酸、色氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸或甲硫氨酸,
X3为天冬酰胺、甘氨酸、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、赖氨酸、精氨酸或组氨酸,
X4为精氨酸、赖氨酸或组氨酸,
X5为丝氨酸、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸,
X6为酪氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、半胱氨酸、苯丙氨酸、色氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、甲硫氨酸、赖氨酸、精氨酸、天冬氨酸或谷氨酸;
X7为丝氨酸、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、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、组氨酸、赖氨酸或精氨酸,
X8为丝氨酸、甘氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸、赖氨酸、精氨酸、组氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸,
X9为天冬酰胺、甘氨酸、谷氨酰胺、苏氨酸、酪氨酸、半胱氨酸或丝氨酸,
X10为脯氨酸、丙氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甲硫氨酸或色氨酸,
X11为亮氨酸、甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、酪氨酸、半胱氨酸、丙氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸或色氨酸。
11.如权利要求9或10所述的T细胞,其特征在于,所述下调细胞表面TCR/CD3复合物的多肽具有选自以下的一个或多个特征:
(1)LCDR3选自:SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ IDNO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32、SEQ IDNO:33,SEQ ID NO:34,
(2)HCDR2选自:SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ IDNO:14,
(3)HCDR3选自:SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ IDNO:20、SEQ ID NO:21。
12.如权利要求9-11中任一项所述的T细胞,其中,
重链可变区的氨基酸序列选自:
(1)SEQ ID NO:42,
(2)HCDR2和/或HCDR3的序列如权利要求10或11所示的SEQ ID NO:42变体,
(3)与(1)或(2)具有95%以上相同性的序列,和/或
轻链可变区的氨基酸序列选自:
(1)SEQ ID NO:43,
(2)LCDR3的序列如权利要求10或11所示的SEQ ID NO:43变体;
(3)与(1)或(2)具有95%以上相同性的序列。
13.如权利要求9-12中任一项所述的T细胞,其特征在于,所述抗体是单链抗体。
14.如权利要求9-12中任一项所述的T细胞,其特征在于,所述下调细胞表面TCR/CD3复合物的多肽包含定位序列和任选的信号肽,优选地,
所述定位序列选自内质网滞留序列,高尔基体滞留序列,E3泛素连接酶结合序列,蛋白酶体定位序列或溶酶体定位序列;优选地,所述内质网滞留序列包括SEQ ID NO:35-40中任一所示的序列或由其组成,其中X是任意氨基酸;
所述定位序列与抗体之间包含接头,优选地,所述接头如SEQ ID NO:41所示,
所述信号肽如SEQ ID NO:44第516-537位所示。
15.如权利要求9-14中任一项所述的T细胞,进一步表达治疗用蛋白;优选地,所述治疗用蛋白为嵌合抗原受体。
16.如权利要求15所述的T细胞,其特征在于,所述T细胞含有所述治疗用蛋白的表达框和所述下调细胞表面TCR/CD3复合物的多肽的表达框,或所述治疗用蛋白的编码序列和所述下调细胞表面TCR/CD3复合物的多肽的编码序列处于同一表达框内。
17.一种抗体或其抗原结合片段,其特征在于,所述抗体的HCDR1的氨基酸序列为GYKFTSYV,HCDR2的氨基酸序列为INX1X2X3DVT,HCDR3的氨基酸序列为AX4GX5X6YDYDGFVY,LCDR1的氨基酸序列为SSVSY,LCDR2的氨基酸序列为DTS,LCDR3的氨基酸序列为QQWX7X8X9X10X11T;其中,X1-X11如权利要求10所述,并且HCDR2不是INPYNDVT,HCDR3不是ARGSYYDYDGFVY,LCDR3不是QQWSSNPLT,
优选地,所述抗体的LCDR3、HCDR2和HCDR3如权利要求11所述。
18.如权利要求17所述的抗体或其抗原结合片段,其特征在于,
所述抗体的重链可变区的氨基酸序列如SEQ ID NO:42所示,但其HCDR2和/或HCDR3的序列如权利要求10或11所示;
所述抗体的轻链可变区的氨基酸序列如SEQ ID NO:43所示,但其LCDR3的序列如权利要求10或11所示。
19.一种融合蛋白,包含定位序列、下调细胞表面TCR/CD3复合物的多肽和任选的信号肽;优选地,所述下调细胞表面TCR/CD3复合物的多肽如权利要求9-18中任一项所述,优选地,
所述信号肽如SEQ ID NO:44第516-537位所示,
所述定位序列与下调细胞表面TCR/CD3复合物的多肽之间包含接头,优选地,所述接头如SEQ ID NO:41所示,
所述融合蛋白如SEQ ID NO:44第516-804位所示,或如SEQ ID NO:44第538-804位所示。
20.一种核酸分子,其特征在于,所述核酸分子选自:
(1)含治疗用蛋白的编码序列和下调细胞表面TCR/CD3复合物的多肽的编码序列的核酸分子;
(2)权利要求19所述的融合蛋白的编码序列;
(3)权利要求17或18所述的抗体或其抗原结合片段的编码序列;和
(4)(1)、(2)或(3)的互补序列或片段;
优选地,所述治疗用蛋白为嵌合抗原受体,所述下调细胞表面TCR/CD3 复合物的多肽如权利要求9-14中所述。
21.一种核酸构建物,其特征在于,所述核酸构建物包含权利要求20所述的核酸分子,
优选地,所述核酸构建物含有所述治疗用蛋白的表达框和所述下调细胞表面TCR/CD3复合物的多肽的表达框;或所述核酸构建物为一表达框,其中所述治疗用蛋白的编码序列和所述下调细胞表面TCR/CD3复合物的多肽的编码序列处于该表达框内;或
所述核酸构建物是克隆载体或表达载体。
22.一种慢病毒,其特征在于,所述慢病毒含有权利要求20所述的核酸分子或权利要求21所述的核酸构建物。
23.一种宿主细胞,其特征在于,所述宿主细胞包含、表达和/或分泌权利要求17或18所述的抗体或其抗原结合片段,或权利要求19所述的融合蛋白和任选的治疗用蛋白;优选地,所述宿主细胞包含权利要求20所述的核酸分子、权利要求21所述的核酸构建物和/或权利要求22所述的慢病毒。
24.一种药物组合物,含有权利要求9-16中任一项所述的T细胞、权利要求17或18所述的抗体或其抗原结合片段、权利要求19所述的融和蛋白、权利要求20所述的核酸分子、权利要求21所述的核酸构建物和/或权利要求22所述的慢病毒,以及药学上可接受的载体。
25.下调细胞表面TCR/CD3复合物的多肽或其编码序列、权利要求20所述的核酸分子、权利要求21所述的核酸构建物和/或权利要求22所述的慢病毒在制备细胞表面TCR下调的T细胞中的应用,或在制备癌症治疗用的T细胞中的应用,所述下调细胞表面TCR/CD3复合物的多肽如权利要求9-14中所述。
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