CN114907485A - 一种以内源性蛋白质分子替代单结构域抗体的嵌合抗原受体 - Google Patents
一种以内源性蛋白质分子替代单结构域抗体的嵌合抗原受体 Download PDFInfo
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Abstract
本发明涉及一种以内源性蛋白质分子替代单结构域抗体的嵌合抗原受体,具体地,本发明提供了一种内源性嵌合抗原受体CAR(ECAR),所述内源性嵌合抗原受体CAR(ECAR)包含抗原结合结构域,所述抗原结合结构域为内源性蛋白质分子。本发明的工程化免疫细胞可特异性、选择性地杀伤多种细胞,并且具有显著的杀伤效果。
Description
技术领域
本发明涉及免疫治疗领域,具体地,涉及一种以内源性蛋白质分子替代单结构域抗体的嵌合抗原受体。
背景技术
随着细胞免疫治疗的发展以及临床应用上的成功,嵌合抗原受体T细胞(ChimericAntigen Receptor T cell,CAR T)免疫治疗成为现今最有前景的肿瘤免疫治疗途径之一。嵌合抗原受体T细胞(CAR T)是指经基因修饰后的,在人体内能够特异性识别特定抗原,并杀伤特定抗原所在的靶细胞的一种T细胞。
嵌合抗原受体(CAR)可通过病毒感染等技术修饰T淋巴细胞,使其表达嵌合抗原受体,而这种经过嵌合抗原受体(CAR)改造的T细胞能够以MHC非限制性的方式特异性识别并结合目的抗原,并特异性杀伤目的细胞。嵌合抗原受体(CAR)包含胞外抗原结合结构域、跨膜结构域和细胞内信号传导结构域。而胞外抗原结合结构域目前以单结构域抗体为主,并针对特定的目的抗原设计并制备特定的单结构域抗体,原因之一为这些目的抗原主要为肿瘤表面特异性标志物,在体内缺乏相应的配体。
并且靶向间皮素(mesothelin)CAR T的临床研究(2013年)发现嵌合抗原受体上的鼠源抗体单结构域能够引发过敏反应,并使得其中一名受试者死亡。这也说明了以单结构域抗体为胞外结合域的嵌合抗原受体在临床上存在的排异问题。此外,以抗体单链可变片段(scFv)为胞外抗原结合结构域的嵌合抗原受体的制备过程耗时长,具有时间成本高,经济成本高以及抗体筛选难度大等问题。
因此,本领域迫切需要开发一种能避免排异反应而具有良好的耐受性的新的嵌合抗原受体。
发明内容
本发明的目的是提供一种能避免排异反应而具有良好的耐受性的新的嵌合抗原受体。
本发明第一方面提供了一种内源性嵌合抗原受体CAR(ECAR),所述内源性嵌合抗原受体CAR(ECAR)包含抗原结合结构域,所述抗原结合结构域为内源性蛋白质分子。
在另一优选例中,所述内源性蛋白质分子选自下组:白细胞介素家族、趋化因子家族、集落刺激因子、生长因子、肿瘤坏死因子超家族、干扰素家族、肿瘤标志物、衰老细胞相关性因子、或其组合。
在另一优选例中,所述白细胞介素家族选自下组:IL1α(白细胞介素1α)、IL1β(白细胞介素1β)、IL2(白细胞介素2)、IL3(白细胞介素3)、IL4(白细胞介素4)、IL5(白细胞介素5)、IL6(白细胞介素6)、IL9(白细胞介素9)、IL10(白细胞介素10)、IL12(白细胞介素12)、IL13(白细胞介素13)、IL14(白细胞介素14)、IL17A(白细胞介素17A)、IL17B(白细胞介素17B)、IL17C(白细胞介素17C)、IL17E(白细胞介素17E)、IL17F(白细胞介素17F)、IL33(白细胞介素33)、或其组合。
在另一优选例中,所述趋化因子家族选自下组:CCL1、CCL2、CCL3、CCL4、CCL5、CCL6、CCL7、CCL8、CCL9、CCL10、CCL11、CCL12、CCL13、CCL14、CCL15、CCL16、CCL17、CCL18、CCL19、CCL20、CCL21、CCL22、CCL23、CCL24、CCL25、CCL26、CCL27、CCL28、CXCL1、CXCL2、CXCL3、CXCL4、CXCL5、CXCL6、CXCL7、CXCL8、CXCL9、CXCL10、CXCL11、CXCL12、CXCL13、CXCL14、CXCL15、CXCL16、CXCL17、XCL1、XCL2、CX3CL1、GRO/MGSA(黑素瘤细胞生长刺激活性)、PF-4(血小板因子-4)、血小板碱性蛋白、IP-10(炎症蛋白10)、ENA-78、MIP-1α(巨噬细胞炎症蛋白1α)、MIP-1β、MCP-1/MCAF(单核细胞趋化蛋白-1)、MCP-2、MCP-3、或其组合。
在另一优选例中,所述集落刺激因子选自下组:G-CSF、M-CSF、GM-CSF、或其组合。
在另一优选例中,所述生长因子选自下组:EGF(表皮生长因子)、VEGF(血管内皮细胞生长因子)、FGF(成纤维细胞生长因子)、PDGF(血小板衍生的内皮细胞生长因子)、HGF(肝细胞生长因子)、IGF-Ⅰ(胰岛素样生长因子)、IGF-Ⅱ、LIF(白血病抑制因子)、NGF(神经生长因子)、TGF-α(转化生长因子)、TGF-β1、TGF-β2、TGF-β3、TGFβ1β2、BMP(骨形成蛋白)、或其组合。
在另一优选例中,所述肿瘤坏死因子选自下组:TNF-α、TNF-β、或其组合。
在另一优选例中,所述干扰素家族选自下组:IFN-α(α型干扰素)、IFN-β(β型干扰素)、IFN-γ(γ型干扰素)、或其组合。
在另一优选例中,所述肿瘤标志物选自下组:CEA(血清癌胚抗原)、AFP(甲胎蛋白)、PSA(前列腺特异性抗原)、或其组合。
在另一优选例中,所述衰老细胞相关性因子包括Plau(尿激酶型纤溶酶原激活因子)。
在另一优选例中,所述内源性蛋白质分子包括野生型的内源性蛋白质分子和突变型的内源性蛋白质分子。
在另一优选例中,所述的突变型包括突变后编码蛋白的功能未发生改变(即功能与野生型编码蛋白相同或基本相同)和功能增强的突变形式
在另一优选例中,所述的内源性蛋白质分子包括全长蛋白或蛋白片段。
在另一优选例中,所述的内源性蛋白质分子蛋白来源于哺乳动物,更佳地来源于啮齿动物(如小鼠、大鼠)、灵长动物和人。
在另一优选例中,所述内源性蛋白质分子还包括内源性蛋白质分子的衍生物。
在另一优选例中,所述内源性蛋白质分子的衍生物包括经修饰的内源性蛋白质分子、氨基酸序列与天然内源性蛋白质分子同源蛋白质分子的蛋白分子、内源性蛋白质分子的二聚体或多聚体、含有内源性蛋白质分子氨基酸序列的融合蛋白。
在另一优选例中,所述经修饰的内源性蛋白质分子是PEG化的内源性蛋白质分子。
在另一优选例中,所述“氨基酸序列与天然内源性蛋白质分子同源且具有天然内源性蛋白肽活性的蛋白分子”是指其氨基酸序列与内源性蛋白质分子相比具有≥85%的同源性,较佳地≥90%的同源性,更佳地≥95%的同源性,最佳地≥98%同源性;并且具有天然内源性蛋白肽活性的蛋白分子。
在另一优选例中,所述的突变型的内源性蛋白质分子的基因编码的多肽与野生型内源性蛋白质分子的基因所编码的多肽相同或基本相同。
在另一优选例中,所述的突变型的内源性蛋白质分子基因包括与野生型内源性蛋白质分子的基因相比,同源性≥80%(较佳地≥90%,更佳地≥95%,更佳地,≥98%或99%)的多核苷酸。
在另一优选例中,所述的突变型内源性蛋白质分子的基因包括在野生型内源性蛋白质分子的基因的5'端和/或3'端截短或添加1-60个(较佳地1-30,更佳地1-10个)核苷酸的多核苷酸。
在另一优选例中,所述内源性蛋白质分子的氨基酸序列选自下组:
(i)具有SEQ ID NO.:1-5中任一所示的氨基酸序列;
(ii)将如SEQ ID NO.:1-5中任一所示的氨基酸序列经过一个或几个(如1-10个)氨基酸残基的取代、缺失或添加而形成的,具有所述内源性蛋白肽活性的由(i)衍生的多肽;或
(iii)氨基酸序列与SEQ ID NO.:1-5中任一所示氨基酸序列的同源性≥80%(较佳地≥90%,更佳地≥95%或≥98%),具有所述内源性蛋白肽活性的,由(i)衍生的多肽。
在另一优选例中,所述的内源性嵌合抗原受体CAR(ECAR)的结构如式I所示:
L-Z1-Z2-TM-C-CD3ζ (I)
式中,
各“-”独立地为连接肽或肽键;
L为任选的信号肽序列;
Z1为抗原结合结构域,所述抗原结合域为内源性蛋白质分子;和
Z2为无或绞链区;
TM为跨膜结构域;
C为共刺激信号分子;
CD3ζ为源于CD3ζ的胞浆信号传导序列。
在另一优选例中,所述L为选自下组的蛋白的信号肽:CD8、CD8α、CD28、GM-CSF、CD4、CD137、FcRγ、FcRβ、CD3ζ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD20、CD79a、CD79b、CD278(ICOS)、FcERI、CD66d、DAP10、DAP12、或其组合。
在另一优选例,所述L的信号肽为人源CD8的信号肽,氨基酸序列为MALPVTALLLPLALLLHAARP(SEQ ID NO.:16)。
在另一优选例,所述L的信号肽为鼠源CD8的信号肽,氨基酸序列为MASPLTRFLSLNLLLLGESIILGSGEA(SEQ ID NO.:17)。
在另一优选例中,所述Z2为选自下组的蛋白的绞链区:CD8、CD8α、CD28、CD137、Ig(免疫球蛋白)铰链、或其组合。
在另一优选例中,所述Z2包括野生型的铰链区和突变型的铰链区。
在另一优选例中,所述的突变型包括在上述蛋白铰链区中缺失、添加或替换一个或几个氨基酸后的融合铰链区、或其组合。
在另一优选例中,所述Z2为人源CD28铰链区,氨基酸序列为:IEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP(SEQ ID NO.:18)。
在另一优选例中,所述Z2为人源CD8α铰链区,氨基酸序列为:TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD(SEQ ID NO.:19)。
在另一优选例中,所述Z2为鼠源CD8α铰链区,氨基酸序列为:STTTKPVLRTPSPVHPTGTSQPQRPEDCRPRGSVKGTGLDFACDIY(SEQ ID NO.:20)。
在另一优选例中,所述的TM为选自下组的蛋白的跨膜区:CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、CD8α、ICOS、CD19、CD45、或其组合。
在另一优选例中,所述TM跨膜区包括野生型的蛋白跨膜区和突变型的蛋白跨膜区。
在另一优选例中,所述的突变型包括在上述蛋白跨膜区中缺失、添加或替换一个或几个氨基酸后的融合蛋白跨膜区、或其组合。
在另一优选例中,所述TM为选自人源CD28蛋白的跨膜区,氨基酸序列为:FWVLVVVGGVLACYSLLVTVAFIIFWV(SEQ ID NO.:21)。
在另一优选例中,所述TM为选自人源CD8蛋白的跨膜区,氨基酸序列为:IYIWAPLAGTCGVLLLSLVIT(SEQ ID NO.:22)。
在另一优选例中,所述TM为选自鼠源CD8蛋白的跨膜区,氨基酸序列为:IWAPLAGICVALLLSLIITLI(SEQ ID NO.:23)。
在另一优选例中,所述C为选自下组的蛋白的共刺激信号分子:CD28、CD27、CD3ζ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD79a、CD79b、CD66d、CD2、CD4、CD5、CD30、CD40、CD134、CD137、ICOS、CD154、4-1BB、OX40、CD7、LIGHT、NKG2C、B7-H3、OX40、活化NK细胞受体、BTLA、Toll配体受体、CD2、CD7、CD27、CD30、CD40、CDS、ICAM-L LFA-1(CD11a/CD18)、B7-H3、CDS、ICAM-1、ICOS(CD278)、GITR、BAFFR、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL2Rβ、IL2Rγ、IL7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD11a、LFA-1、ITGAM、CD11b、ITGAX、CD11c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、NKG2C、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(触觉)、CEACAM1、CRTAM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTBA、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、DAP10、DAP12、CD83的配体、MHC I类分子、TNF受体蛋白、免疫球蛋白样蛋白质、细胞因子受体、整合素、信号传导淋巴细胞活化分子、或其组合。
在另一优选例中,所述的C为人源CD28来源的共刺激信号分子,氨基酸序列为:RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS(SEQ ID NO.:24)。
在另一优选例中,所述的C为人源4-1BB来源的共刺激信号分子,氨基酸序列为:KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(SEQ ID NO.:25)。
在另一优选例中,所述的C为鼠源CD28来源的共刺激信号分子,氨基酸序列为:NSRRNRLLQSDYMNMTPRRPGLTRKPYQPYAPARDFAAYRP(SEQ ID NO.:26)。
在另一优选例中,所述CD3ζ为CD3ζ蛋白分子的胞内区域。
在另一优选例中,所述CD3ζ包括野生型的CD3ζ蛋白分子的胞内区域和突变型的CD3ζ蛋白分子的胞内区域。
在另一优选例中,所述的突变型的氨基酸序列包括在上述CD3ζ蛋白分子的胞内区域的氨基酸序列中缺失、添加或替换一个或几个氨基酸后的融合氨基酸序列或其组合。
在另一优选例中,所述CD3ζ为人源CD3ζ蛋白分子的胞内区域,氨基酸序列为:RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO.:27)。
在另一优选例中,所述CD3ζ为鼠源CD3ζ蛋白分子的胞内区域,氨基酸序列为:RAKFSRSAETAANLQDPNQLYNELNLGRREEYDVLEKKRARDPEMGGKQQRRRNPQEGVYNALQKDKMAEAYSEIGTKGERRRGKGHDGLYQGLSTATKDTYDALHMQTLAPR(SEQ ID NO.:28)。
在另一优选例中,所述内源性嵌合抗原受体CAR(ECAR)的氨基酸序列如SEQ IDNO.:6-10中任一所示。
本发明第二方面提供了一种核酸分子,所述核酸分子编码本发明第一方面所述的内源性嵌合抗原受体CAR(ECAR)。
在另一优选例中,所述核酸分子选自下组:
(a)编码如SEQ ID NO:1-5中任一所示多肽的多核苷酸;
(b)序列如SEQ ID NO:11-15中任一所示的多核苷酸;
(c)核苷酸序列与(b)所示序列的同源性≥75%(较佳地≥80%,更佳地,90%,更佳地,95%,更佳地,98%,更佳地,99%)的多核苷酸;
(d)如(b)所示多核苷酸的5’端和/或3’端截短或添加1-60个(较佳地1-30,更佳地1-10个)核苷酸的多核苷酸;
(e)与(a)-(d)任一所述的多核苷酸互补的多核苷酸。
在另一优选例中,所述的核酸分子的核苷酸序列如SEQ ID NO:11-15中任一所示。
在另一优选例中,所述的核酸分子为多核苷酸。
本发明第三方面提供了一种载体,所述的载体含有本发明第二方面所述的核酸分子。
在另一优选例中,所述的载体选自下组:质粒、慢病毒载体、腺病毒载体、逆转录病毒载体、或其组合。
在另一优选例中,所述载体为慢病毒载体。
在另一优选例中,所述载体为逆转录病毒载体。
本发明第四方面提供了一种宿主细胞,所述的宿主细胞含有本发明第三方面所述的载体或染色体中整合有外源的本发明第二方面所述的核酸分子或表达本发明第一方面所述的ECAR。
在另一优选例中,所述细胞为分离的细胞,和/或所述细胞为基因工程化的细胞。
在另一优选例中,所述细胞为哺乳动物细胞。
在另一优选例中,所述细胞为巨噬细胞、T细胞或NK细胞。
在另一优选例中,所述的宿主细胞为工程化的免疫细胞。
在另一优选例中,所述的工程化的免疫细胞包括巨噬细胞、T细胞或NK细胞,较佳地为(i)内源性嵌合抗原受体T细胞(ECAR-T细胞);(i i)内源性嵌合抗原受体NK细胞(ECAR-NK细胞);(iii)外源T细胞受体(TCR)T细胞(TCR-T细胞)或(iv)内源性嵌合抗原受体巨噬细胞(ECAR-巨噬细胞)。
在另一优选例中,所述免疫细胞为自体的。
在另一优选例中,所述免疫细胞为非自体的。
在另一优选例中,所述免疫细胞靶向表达与内源性蛋白质分子相匹配的受体的靶细胞。
本发明第五方面提供了一种制备工程化免疫细胞的方法,所述的工程化免疫细胞表达本发明第一方面所述的ECAR,包括以下步骤:将本发明第二方面所述的核酸分子或本发明第三方面所述的载体转导入巨噬细胞、T细胞或NK细胞内,从而获得所述工程化免疫细胞。
在另一优选例中,所述导入包括同时、先后、或依次导入。
在另一优选例中,所述的细胞为ECAR-巨噬细胞、ECAR-T细胞或ECAR-NK细胞。
在另一优选例中,所述的方法还包括对获得的工程化免疫细胞进行功能和有效性检测的步骤。
本发明第六方面提供了一种药物组合物,所述药物组合物含有本发明第一方面所述的ECAR、本发明第二方面所述的核酸分子、本发明第三方面所述的载体、或本发明第四方面所述的宿主细胞,以及药学上可接受的载体、稀释剂或赋形剂。
在另一优选例中,所述药物组合物为液态制剂。
在另一优选例中,所述药物组合物的剂型为注射剂。
在另一优选例中,所述药物组合物中,所述细胞的浓度为1×105-1×108个细胞/ml,较佳地为1×106-1×107个细胞/ml,更佳地为1×106-5×106个细胞/ml。
在另一优选例中,所述药物组合物还含有杀伤细胞的其他药物(如抗体药物、其他CAR-T药物或化疗药物)。
在另一优选例中,所述药物组合物还含有调控本发明第一方面所述的ECAR的表达的药物、调控本发明第四方面所述的宿主细胞的杀伤功能和细胞活性的药物、调控宿主体内免疫反应的药物、调控副反应的药物(比如,T细胞凋亡信号通路抑制剂、抗细胞因子风暴的中和抗体)。
本发明第七方面提供了一种如本发明第一方面所述的ECAR、本发明第二方面所述的核酸分子、本发明第三方面所述的载体、本发明第四方面所述宿主细胞、或本发明第六方面所述的药物组合物的用途,用于制备药物或制剂,所述药物或制剂用于(a)选择性杀伤细胞;和/或(b)治疗疾病。
在另一优选例中,所述细胞含有与内源性蛋白质分子相匹配的受体。
在另一优选例中,所述细胞选自下组:炎症细胞、衰老细胞、肿瘤细胞、自身免疫性细胞、或其组合。
在另一优选例中,所述疾病选自下组:肿瘤疾病、过敏性疾病、自身免疫性疾病、衰老细胞相关性疾病、或其组合。
在另一优选例中,所述肿瘤疾病选自下组:上皮细胞来源的恶性/良性肿瘤、间叶细胞来源的恶性/良性肿瘤、血液干细胞来源的恶性/良性肿瘤、神经上皮细胞来源的恶性/良性肿瘤。
在另一优选例中,所述过敏性疾病选自下组:皮肤过敏性疾病、呼吸道过敏性疾病、消化道过敏性疾病、过敏性休克、或其组合。
在另一优选例中,所述自身免疫性疾病选自下组:类风湿性关节炎、全身性红斑狼疮、银屑病、Ⅰ型糖尿病、炎症性肠病、乳糜泻、多发性硬化症、再生不良性贫血、弥漫性毒性甲状腺肿、或其组合。
在另一优选例中,所述衰老相关性疾病选自下组:衰老相关性肝纤维化、衰老相关性肺纤维化、衰老相关性动脉粥样硬化、衰老相关性糖尿病、衰老相关性骨关节炎、衰老相关性肌肉减少症、衰老相关性肥胖症、衰老相关性青光眼。
本发明第八方面提供了一种用于选择性杀伤细胞的试剂盒,所述试剂盒含有容器,以及位于容器内的本发明第一方面所述的ECAR、本发明第二方面所述的核酸分子、本发明第三方面所述的载体、本发明第四方面所述的宿主细胞或本发明第六方面所述的药物组合物。
在另一优选例中,所述试剂盒还含有标签或使用说明书。
本发明第九方面提供了一种选择性杀伤细胞的方法,包括:
给需要治疗的对象施用安全有效量的本发明第一方面所述的ECAR、本发明第四方面所述的宿主细胞、或本发明第六方面所述的药物组合物。
在另一优选例中,所述对象包括人或非人哺乳动物。
在另一优选例中,所述非人哺乳动物包括啮齿类动物(如小鼠、大鼠、兔)、灵长类动物(如猴)、猪科动物。
在另一优选例中,所述方法为非治疗性和非诊断性的。
本发明第十方面提供了一种治疗疾病的方法,包括给需要治疗的对象施用安全有效量的本发明第一方面所述的ECAR、本发明第四方面所述的宿主细胞或本发明第六方面所述的药物组合物。
在另一优选例中,所述方法还包括给需要治疗的对象施用治疗肿瘤疾病、过敏性疾病、自身免疫性疾病、衰老细胞相关性疾病的其他药物。
在另一优选例中,所述其他药物包括杀伤细胞的其他药物(如抗体药物、其他CAR-T药物或化疗药物)、调控内源性嵌合抗原受体的表达的药物、调控宿主细胞的杀伤功能和细胞活性的药物、调控宿主体内免疫反应的药物、调控副反应的药物、CAR-T药物。
在另一优选例中,所述疾病选自下组:肿瘤疾病、过敏性疾病、自身免疫性疾病、衰老细胞相关性疾病、或其组合。
在另一优选例中,所述肿瘤疾病选自下组:上皮细胞来源的恶性/良性肿瘤、间叶细胞来源的恶性/良性肿瘤、血液干细胞来源的恶性/良性肿瘤、神经上皮细胞来源的恶性/良性肿瘤。
在另一优选例中,所述过敏性疾病选自下组:皮肤过敏性疾病、呼吸道过敏性疾病、消化道过敏性疾病、过敏性休克、或其组合。
在另一优选例中,所述自身免疫性疾病选自下组:类风湿性关节炎、全身性红斑狼疮、银屑病、Ⅰ型糖尿病、炎症性肠病、乳糜泻、多发性硬化症、再生不良性贫血、弥漫性毒性甲状腺肿、或其组合。
在另一优选例中,所述衰老相关性疾病选自下组:衰老相关性肝纤维化、衰老相关性肺纤维化、衰老相关性动脉粥样硬化、衰老相关性糖尿病、衰老相关性骨关节炎、衰老相关性肌肉减少症、衰老相关性肥胖症、衰老相关性青光眼。
应理解,在本发明范围内中,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构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1为hIL5-ECAR质粒图。
图2为hIL5-ECAR Jurkat细胞系与hIL5Ra表达的靶细胞共培养后的激活检测。
图3为hIL5-ECAR T细胞慢病毒离心感染人T细胞72小时后的CAR表达效率。
图4为hIL5-ECAR T与hIL5Ra表达的靶细胞共培养后的特异性杀伤效果。
图5为mIL5-ECAR质粒图。
图6为mIL5-ECAR逆转录病毒离心感染小鼠T细胞48小时后的CAR表达效率。
图7为mIL5-ECAR T回输小鼠哮喘模型后对嗜酸性粒细胞的杀伤作用。
图8为mIL5-ECAR T回输小鼠哮喘模型后对炎症的缓解作用。
图9为hPlau-ECAR质粒图。
图10为hPlau-ECAR T与hPlauR表达的靶细胞共培养后的特异性杀伤效果。
图11为hCCL11-ECAR质粒图。
图12为hCCL11-ECAR T与hCCR3表达的靶细胞共培养后的特异性杀伤效果。
图13为hCCL24-ECAR质粒图。
图14为hCCL24-ECAR T与hCCR3表达的靶细胞共培养后的特异性杀伤效果。
具体实施方式
本发明人经过广泛而深入地研究,经过大量的筛选,首次意外地发现以内源性蛋白质分子代替抗体单结构域片段作为CAR胞外的抗原结合结构域,设计内源性嵌合抗原受体(Endogenous CAR,ECAR),其在T细胞、NK细胞、巨噬细胞等内表达并上膜后,能够使上述细胞特异性、选择性地杀伤靶细胞,并且具有显著的杀伤效果,并且还可治疗疾病,比如肿瘤疾病、过敏性疾病、自身免疫性疾病、衰老细胞相关性疾病。在此基础上,本发明人完成了本发明。
本发明以ECAR-T细胞为例,代表性地对本发明的工程化的免疫细胞进行详细说明。本发明的工程化的免疫细胞不限于上下文所述的ECAR-T细胞,本发明的工程化的免疫细胞具有与上下文所述的ECAR-T细胞相同或类似的技术特征和有益效果。具体地,当免疫细胞表达内源性嵌合抗原受体ECAR时,巨噬细胞、NK细胞等同于T细胞(或T细胞可替换NK细胞、巨噬细胞);当免疫细胞为T细胞时,TCR等同于ECAR(或ECAR可替换为TCR)。
内源性蛋白质分子
在本发明中,内源性蛋白质分子指的是以人基因组为翻译模板的,在人体内能够转录并翻译的由氨基酸以“脱水缩合”的方式组成的肽链或蛋白质分子。这种蛋白质分子是由20种不同的氨基酸连接而成的多聚体,并具有三维空间结构。在生理状态下,大多数蛋白质分子都具有能够和其他蛋白质分子特异性结合的能力,这在蛋白质交互过程发挥重要的作用。而在病理状态下,促进病理过程发生的细胞表面表达着特异性的蛋白质受体。基于此,我们设计了连接内源性蛋白质分子的嵌合抗原受体(ECAR),并将其表达在杀伤细胞,如T细胞中,以促使ECAR杀伤细胞发挥对这些促进病理过程发生的有害细胞的特异性杀伤与清除。
在本发明的一个优选实施方式中,本发明的内源性蛋白质分子优选为白细胞介素家族、趋化因子家族、集落刺激因子、生长因子、肿瘤坏死因子超家族、干扰素家族、肿瘤标志物、衰老细胞相关性因子等类型。
本发明涉及一种内源性蛋白质分子及其变体。
在本发明的一优选实施方式中,本发明的内源性蛋白质分子的氨基酸序列如SEQID NO.:1-5中任一所示。
IPTEIPTSALVKETLALLSTHRTLLIANETLRIPVPVHKNHQLCTEEIFQGIGTLESQTVQGGTVERLFKNLSLIKKYIDGQKKKCGEERRRVNQFLDYLQEFLGVMNTEWIIES(SEQ ID NO.:1,来自人源白介素5因子IL5);
MEIPMSTVVKETLTQLSAHRALLTSNETMRLPVPTHKNHQLCIGEIFQGLDILKNQTVRGGTVEMLFQNLSLIKKYIDRQKEKCGEERRRTRQFLDYLQEFLGVMSTEWAMEG(SEQ ID NO.:2,来自小鼠源白介素5因子IL5)
SNELHQVPSNCDCLNGGTCVSNKYFSNIHWCNCPKKFGGQHCEIDKSKTCYEGNGHFYRGKASTDTMGRPCLPWNSATVLQQTYHAHRSDALQLGLGKHNYCRNPDNRRRPWCYVQVGLKLLVQECMVHDCADGKKPSSPPEELKFQCGQKTLRPRFKIIGGEFTTIENQPWFAAIYRRHRGGSVTYVCGGSLISPCWVISATHCFIDYPKKEDYIVYLGRSRLNSNTQGEMKFEVENLILHKDYSADTLAHHNDIALLKIRSKEGRCAQPSRTIQTICLPSMYNDPQFGTSCEITGFGKENSTDYLYPEQLKMTVVKLISHRECQQPHYYGSEVTTKMLCAADPQWKTDSCQGDSGGPLVCSLQGRMTLTGIVSWGRGCALKDKPGVYTRVSHFLPWIRSHTKEENGLAL(SEQ ID NO.:3,来自人源尿激酶型纤溶酶原激活因子Plau)
GPASVPTTCCFNLANRKIPLQRLESYRRITSGKCPQKAVIFKTKLAKDICADPKKKWVQDSMKYLDQKSPTPKP(SEQ ID NO.:4,来自人源CCL11因子);
VVIPSPCCMFFVSKRIPENRVVSYQLSSRSTCLKAGVIFTTKKGQQFCGDPKQEWVQRYMKNLDAKQKKASPRARAVAVKGPVQRYPGNQTTC(SEQ ID NO.:5,来自人源CCL24因子)
本发明还包括与本发明的SEQ ID NO.:1-5中任一所示序列具有50%或以上(优选60%以上,70%以上,80%以上,更优选90%以上,更优选95%以上,最优选98%以上,如99%)同源性的具有相同或相似功能的多肽或蛋白。
本发明的蛋白可以是重组蛋白、天然蛋白、合成蛋白。本发明的蛋白可以是天然纯化的产物,或是化学合成的产物,或使用重组技术从原核或真核宿主(例如,细菌、酵母、高等植物、昆虫和哺乳动物细胞)中产生。根据重组生产方案所用的宿主,本发明的蛋白可以是糖基化的,或可以是非糖基化的。本发明的蛋白还可包括或不包括起始的甲硫氨酸残基。
本发明还包括具有内源性蛋白质分子活性的内源性蛋白质分子片段和类似物。如本文所用,术语“片段”和“类似物”是指基本上保持本发明的天然内源性蛋白质分子相同的生物学功能或活性的蛋白。
本发明的突变蛋白片段、衍生物或类似物可以是(i)有一个或多个保守或非保守性氨基酸残基(优选保守性氨基酸残基)被取代的突变蛋白,而这样的取代的氨基酸残基可以是也可以不是由遗传密码编码的,或(ii)在一个或多个氨基酸残基中具有取代基团的突变蛋白,或(iii)成熟突变蛋白与另一个化合物(比如延长突变蛋白半衰期的化合物,例如聚乙二醇)融合所形成的突变蛋白,或(iv)附加的氨基酸序列融合到此突变蛋白序列而形成的突变蛋白(如前导序列或分泌序列或用来纯化此突变蛋白的序列或蛋白原序列,或与抗原IgG片段的形成的融合蛋白)。根据本文的教导,这些片段、衍生物和类似物属于本领域熟练技术人员公知的范围。本发明中,保守性替换的氨基酸最好根据表I进行氨基酸替换而产生。
表I
最初的残基 | 代表性的取代 | 优选的取代 |
Ala(A) | Val;Leu;Ile | Val |
Arg(R) | Lys;Gln;Asn | Lys |
Asn(N) | Gln;His;Lys;Arg | Gln |
Asp(D) | Glu | Glu |
Cys(C) | Ser | Ser |
Gln(Q) | Asn | Asn |
Glu(E) | Asp | Asp |
Gly(G) | Pro;Ala | Ala |
His(H) | Asn;Gln;Lys;Arg | Arg |
Ile(I) | Leu;Val;Met;Ala;Phe | Leu |
Leu(L) | Ile;Val;Met;Ala;Phe | Ile |
Lys(K) | Arg;Gln;Asn | Arg |
Met(M) | Leu;Phe;Ile | Leu |
Phe(F) | Leu;Val;Ile;Ala;Tyr | Leu |
Pro(P) | Ala | Ala |
Ser(S) | Thr | Thr |
Thr(T) | Ser | Ser |
Trp(W) | Tyr;Phe | Tyr |
Tyr(Y) | Trp;Phe;Thr;Ser | Phe |
Val(V) | Ile;Leu;Met;Phe;Ala | Leu |
本发明还包括与本发明的天然内源性蛋白质分子具有50%或以上(优选60%以上,70%以上,80%以上,更优选90%以上,更优选95%以上,最优选98%以上,如99%)同源性的具有相同或相似功能的多肽或蛋白。在蛋白质变体可以经过若干个(通常为1-60个,较佳地1-30个,更佳地1-20个,最佳地1-10个)取代、缺失或添加至少一个氨基酸所得的衍生序列,以及在C末端和/或N末端添加一个或数个(通常为20个以内,较佳地为10个以内,更佳地为5个以内)氨基酸。例如,在所述蛋白中,用性能相近或相似的氨基酸进行取代时,通常不会改变蛋白质的功能,在C末端和/或\末端添加一个或数个氨基酸通常也不会改变蛋白质的功能。本发明包括天然内源性蛋白质分子类似物与天然内源性蛋白质分子的差别可以是氨基酸序列上的差异,也可以是不影响序列的修饰形式上的差异,或者兼而有之。这些蛋白的类似物包括天然或诱导的遗传变异体。诱导变异体可以通过各种技术得到,如通过辐射或暴露于诱变剂而产生随机诱变,还可通过定点诱变法或其他已知分了生物学的技术。类似物还包括具有不同于天然L-氨基酸的残基(如D-氨基酸)的类似物,以及具有非天然存在的或合成的氨基酸(如β、γ-氨基酸)的类似物。应理解,本发明的蛋白并不限于上述例举的代表性蛋白。
修饰(通常不改变一级结构)形式包括:体内或体外蛋白的化学衍生形式如乙酸化或羧基化。修饰还包括糖基化,如那些在蛋白质合成和加工中进行糖基化修饰。这种修饰可以通过将蛋白暴露于进行糖基化的酶(如哺乳动物的糖基化酶或去糖基化酶)而完成。修饰形式还包括具有磷酸化氨基酸残基(如磷酸酪氨酸,磷酸丝氨酸,磷酸苏氨酸)的序列。此外,还可以对本发明突变蛋白进行修饰。修饰(通常不改变一级结构)形式包括:体内或体外的突变蛋白的化学衍生形式如乙酰化或羧基化。修饰还包括糖基化,如那些在突变蛋白的合成和加工中或进一步加工步骤中进行糖基化修饰而产生的突变蛋白。这种修饰可以通过将突变蛋白暴露于进行糖基化的酶(如哺乳动物的糖基化酶或去糖基化酶)而完成。修饰形式还包括具有磷酸化氨基酸残基(如磷酸酪氨酸,磷酸丝氨酸,磷酸苏氨酸)的序列。还包括被修饰从而提高了其抗蛋白水解性能或优化了溶解性能的突变蛋白。
本发明还提供了编码内源性蛋白质分子的多核苷酸序列。本发明的多核苷酸可以是DNA形式或RNA形式。DNA形式包括:DNA、基因组DNA或人工合成的DNA,DNA可以是单链的或是双链的。编码成熟多肽的多核苷酸包括:只编码成熟多肽的编码序列;成熟多肽的编码序列和各种附加编码序列;成熟多肽的编码序列(和任选的附加编码序列)以及非编码序列。术语“编码多肽的多核苷酸”可以是包括编码此多肽的多核苷酸,也可以是还包括附加编码和/或非编码序列的多核苷酸。本发明还涉及上述多核苷酸的变异体,其编码与本发明有相同的氨基酸序列的多肽的片段、类似物和衍生物。此多核苷酸的变异体可以是天然发生的等位变异体或非天然发生的变异体。这些核苷酸变异体包括取代变异体、缺失变异体和插入变异体。如本领域所知的,等位变异体是一个多核苷酸的替换形式,它可能是一个或多个核苷酸的取代、缺失或插入,但不会从实质上改变其编码的多肽的功能。
根据本文所述的核苷酸序列,本技术领域人员可方便地用各种已知方法制得本发明的编码核酸。这些方法例如但不限于:PCR,DNA人工合成等,具体的方法可参见J.萨姆布鲁克,《分子克隆实验指南》。作为本发明的一种实施方式,可通过分段合成核苷酸序列再进行重叠延伸PCR的方法来构建本发明的编码核酸序列。
本发明还涉及与上述的序列杂交且两个序列之间具有至少50%,较佳地至少70%,更佳地至少80%相同性的多核苷酸。本发明特别涉及在严格条件(或严紧条件)下与本发明所述多核苷酸可杂交的多核苷酸。在本发明中,“严格条件”是指:(1)在较低离子强度和较高温度下的杂交和洗脱,如0.2×SSC,0.1%SDS,60℃;或(2)杂交时加有变性剂,如50%(v/v)甲酰胺,0.1%小牛血清/0.1%Ficoll,42℃等;或(3)仅在两条序列之间的相同性至少在90%以上,更好是95%以上时才发生杂交。
本发明的蛋白和多核苷酸优选以分离的形式提供,更佳地,被纯化至均质。
本发明多核苷酸全长序列通常可以通过PCR扩增法、重组法或人工合成的方法获得。对于PCR扩增法,可根据本发明所公开的有关核苷酸序列,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。
一旦获得了有关的序列,就可以用重组法来大批量地获得有关序列。这通常是将其克隆入载体,再转入细胞,然后通过常规方法从增殖后的宿主细胞中分离得到有关序列。
此外,还可用人工合成的方法来合成有关序列,尤其是片段长度较短时。通常,通过先合成多个小片段,然后再进行连接可获得序列很长的片段。
目前,已经可以完全通过化学合成来得到编码本发明蛋白(或其片段,或其衍生物)的DNA序列。然后可将该DNA序列引入本领域中已知的各种现有的DNA分子(或如载体)和细胞中。此外,还可通过化学合成将突变引入本发明蛋白序列中。
应用PCR技术扩增DNA/RNA的方法被优选用于获得本发明的多核苷酸。特别是很难从文库中得到全长的cDNA时,可优选使用RACE法(RACE-cDNA末端快速扩增法),用于PCR的引物可根据本文所公开的本发明的序列信息适当地选择,并可用常规方法合成。可用常规方法如通过凝胶电泳分离和纯化扩增的DNA/RNA片段。
抗原结合结构域
在本发明中,嵌合抗原受体CAR的抗原结合结构域特异性结合于细胞表面上可与内源性蛋白质分子相匹配的受体(比如IL-5,IL-17的受体)。
铰链区和跨膜区
对于铰链区和跨膜区(跨膜结构域),CAR可被设计以包括融合至CAR的胞外结构域的跨膜结构域。在一个实施方式中,使用天然与CAR中的结构域之一相关联的跨膜结构域。在一些例子中,可选择跨膜结构域,或通过氨基酸置换进行修饰,以避免将这样的结构域结合至相同或不同的表面膜蛋白的跨膜结构域,从而最小化与受体复合物的其他成员的相互作用。
跨膜结构域可源于天然来源或合成来源。在天然来源中,该结构域可源于任何膜结合蛋白或跨膜蛋白。优选地,本发明的CAR中的铰链区为CD8α的铰链区或者CD28长度铰链区,本发明的跨膜区为CD8α的跨膜区或者CD28的跨膜区。
胞内结构域
本发明的CAR的胞内结构域或另外的细胞内信号传导结构域是造成其中已放置CAR的免疫细胞的至少一种正常效应子功能的活化的原因。术语“效应子功能”指的是细胞的专有功能。例如,T细胞的效应子功能可为包括细胞因子分泌的细胞溶解活性或辅助活性。因此术语“细胞内信号传导结构域”指的是转导效应子功能信号并指导细胞实施专有功能的蛋白部分。尽管通常可使用整个细胞内信号传导结构域,但在很多例子中,不必使用整个链。就使用细胞内信号传导结构域的截短部分而言,这种截短部分可用于代替完整的链,只要它转导效应子功能信号。术语细胞内信号传导结构域因此指包括足以转导效应子功能信号的细胞内信号传导结构域的任何截短部分。
用于本发明的CAR的细胞内信号传导结构域的优选例子包括T细胞受体(TCR)的胞浆序列和协同行动以在抗原受体结合后开始信号转导的共受体,以及这些序列的任何衍生物或变体和具有相同的功能能力的任何合成序列。
在优选的实施方式中,CAR的胞浆结构域可被设计以本身包括CD3-ζ信号传导结构域,或可与在本发明的CAR的内容中有用的任何其他期望的胞浆结构域(一个或多个)联合。例如,CAR的胞浆结构域可包括CD3ζ链部分和共刺激信号传导区。共刺激信号传导区指的是包括共刺激分子的细胞内结构域的一部分CAR。共刺激分子是淋巴细胞对抗原的有效应答所需的细胞表面分子,而不是抗原受体或它们的配体。优选地,包括CD28、4-1BB等。
本发明的CAR的胞浆信号传导部分内的胞浆信号传导序列可以随机或以规定的顺序相互连接。任选地,短的寡肽或多肽连接体,优选长度在2和10个氨基酸,可形成该连接。甘氨酸-丝氨酸双联体提供了特别合适的连接体。
在一个实施方式中,本发明的CAR中的胞浆结构域被设计以包括CD28的信号传导结构域(共刺激分子)以及CD3ζ的信号传导结构域。
嵌合抗原受体(CAR)
嵌合免疫抗原受体(Chimeric antigen receptors,CARs)由胞外抗原识别区域,通常是scFv(single-chain variable fragment),跨膜区以及胞内共刺激信号区域组成。CARs的设计经历了以下过程:第一代CAR只有一个胞内信号组份CD3ζ或者FcγRI分子,由于胞内只有一个活化结构域,因此它只能引起短暂的T细胞增殖和较少的细胞因子分泌,而并不能提供长时间的T细胞增殖信号和持续的体内抗肿瘤效应,所以并没有取得很好地临床疗效。第二代CARs在原有结构基础上引入一个共刺激分子,如CD28、4-1BB、OX40、ICOS,与一代CARs相比功能有很大提高,进一步加强CAR-T细胞的持续性和对肿瘤细胞的杀伤能力。在二代CARs基础上串联一些新的免疫共刺激分子如CD27、CD134,发展成为三代和四代CARs。
CARs的胞外段可识别一个特异的抗原,随后通过胞内结构域转导该信号,引起细胞的活化增殖、细胞溶解毒性和分泌细胞因子,进而清除靶细胞。首先分离病人自体细胞(或者异源供体),激活并进行基因改造产生CAR的免疫细胞,随后注入同一病人体内。这种方式患移植物抗宿主病概率极低,抗原被免疫细胞以非MHC限制方式识别。
CAR-免疫细胞治疗在血液恶性肿瘤治疗中取得了非常高的临床反应率,这样的高反应率是以往任何一种治疗手段都无法达到的,在世界各引发了临床研究的热潮。
具体地,本发明的内源性嵌合抗原受体(ECAR)包括细胞外结构域、跨膜结构域、和细胞内结构域。胞外结构域包括靶点特异性结合元件(也称为抗原结合结构域)。细胞内结构域包括共刺激信号传导区和/或ζ链部分。共刺激信号传导区指包括共刺激分子的细胞内结构域的一部分。共刺激分子为淋巴细胞对抗原的有效应答所需要的细胞表面分子,而不是抗原受体或它们的配体。
在CAR的胞外结构域和跨膜结构域之间,或在CAR的胞浆结构域和跨膜结构域之间,可并入接头。如本文所用的,术语“接头”通常指起到将跨膜结构域连接至多肽链的胞外结构域或胞浆结构域作用的任何寡肽或多肽。接头可包括0-300个氨基酸,优选地2至100个氨基酸和最优选地3至50个氨基酸。
本发明的ECAR当在T细胞中表达时,能够基于抗原结合特异性进行抗原识别。当ECAR结合靶细胞表面特异性的抗原时,能够激活ECAR T细胞,并使ECAR T细胞对靶细胞进行杀伤。抗原结合结构域优选与来自共刺激分子和/或ζ链中的一个或多个的细胞内结构域融合。优选地,抗原结合结构域与CD28信号传导结构域和/或CD3ζ信号结构域组合的细胞内结构域融合。
在一优选实施方式中,本发明ECAR的抗原结合部分靶向内源性蛋白质分子相对应(相匹配)的受体。在一优选实施方式中,本发明的ECAR的抗原结合部分是靶向内源性蛋白质分子相匹配的受体的内源性蛋白质分子。
在一优选实施方式中,内源性蛋白质分子包含变体形式,所述变体与其野生型的内源性蛋白质分子的蛋白序列表具有≥80%、≥85%、≥90%、≥95%、≥98%或≥99%的同源性。
在本发明中,本发明的内源性蛋白质分子还包括其保守性变异体,指与本发明内源性蛋白质分子的氨基酸序列相比,有至多10个,较佳地至多8个,更佳地至多5个,最佳地至多3个氨基酸被性质相似或相近的氨基酸所替换而形成多肽。
在本发明中,所述添加、缺失、修饰和/或取代的氨基酸数量,优选为不超过初始氨基酸序列总氨基酸数量的40%,更优选为不超过35%,更优选为1-33%,更优选为5-30%,更优选为10-25%,更优选为15-20%。
在本发明中,所述添加、缺失、修饰和/或取代的氨基酸数量通常是1、2、3、4或5个,较佳地为1-3个,更佳地为1-2个,最佳地为1个。
对于绞链区和跨膜区(跨膜结构域),CAR可被设计以包括融合至CAR的胞外结构域的跨膜结构域。在一个实施方式中,使用天然与CAR中的结构域之一相关联的跨膜结构域。在一些例子中,可选择跨膜结构域,或通过氨基酸置换进行修饰,以避免将这样的结构域结合至相同或不同的表面膜蛋白的跨膜结构域,从而最小化与受体复合物的其他成员的相互作用。
本发明的ECAR的胞外结构域包括内源性蛋白质分子,优选具有特定序列的内源性蛋白质分子。
在本发明中,本发明的ECAR中的胞内结构域包括CD28的跨膜区、CD28的共刺激因子、CD3ζ的信号传导结构域。
在本发明的一优选实施方式中,所述ECAR的氨基酸序列如SEQ ID NO.:6-10中任一所示。
MALPVTALLLPLALLLHAIPTEIPTSALVKETLALLSTHRTLLIANETLRIPVPVHKNHQLCTEEIFQGIGTLESQTVQGGTVERLFKNLSLIKKYIDGQKKKCGEERRRVNQFLDYLQEFLGVMNTEWIIESRAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO.:6,内源性嵌合抗原受体CAR(ECAR)hCD28信号肽-hIL5-hCD28铰链区-hCD28跨膜区-hCD28共刺激分子-CD3ζ胞浆信号传导序列,hIL5-ECAR)
MASPLTRFLSLNLLLLGESIILGSGEAMEIPMSTVVKETLTQLSAHRALLTSNETMRLPVPTHKNHQLCIGEIFQGLDILKNQTVRGGTVEMLFQNLSLIKKYIDRQKEKCGEERRRTRQFLDYLQEFLGVMSTEWAMEGRAAASTTTKPVLRTPSPVHPTGTSQPQRPEDCRPRGSVKGTGLDFACDIYIWAPLAGICVALLLSLIITLICYNSRRNRLLQSDYMNMTPRRPGLTRKPYQPYAPARDFAAYRPRAKFSRSAETAANLQDPNQLYNELNLGRREEYDVLEKKRARDPEMGGKQQRRRNPQEGVYNALQKDKMAEAYSEIGTKGERRRGKGHDGLYQGLSTATKDTYDALHMQTLAPRGSG(SEQ ID NO.:7,mCD8α信号肽-mIL5-mCD8α铰链区-mCD8α跨膜区-mCD28共刺激分子-CD3ζ胞浆信号传导序列,mIL5-ECAR)
MALPVTALLLPLALLLHAYPYDVPDYASNELHQVPSNCDCLNGGTCVSNKYFSNIHWCNCPKKFGGQHCEIDKSKTCYEGNGHFYRGKASTDTMGRPCLPWNSATVLQQTYHAHRSDALQLGLGKHNYCRNPDNRRRPWCYVQVGLKLLVQECMVHDCADGKKPSSPPEELKFQCGQKTLRPRFKIIGGEFTTIENQPWFAAIYRRHRGGSVTYVCGGSLISPCWVISATHCFIDYPKKEDYIVYLGRSRLNSNTQGEMKFEVENLILHKDYSADTLAHHNDIALLKIRSKEGRCAQPSRTIQTICLPSMYNDPQFGTSCEITGFGKENSTDYLYPEQLKMTVVKLISHRECQQPHYYGSEVTTKMLCAADPQWKTDSCQGDSGGPLVCSLQGRMTLTGIVSWGRGCALKDKPGVYTRVSHFLPWIRSHTKEENGLALRAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO.:8,hCD28信号肽-hPlau-hCD28铰链区-hCD28跨膜区-hCD28共刺激分子-CD3ζ胞浆信号传导序列,hPLau-ECAR)
MALPVTALLLPLALLLHAYPYDVPDYAGPASVPTTCCFNLANRKIPLQRLESYRRITSGKCPQKAVIFKTKLAKDICADPKKKWVQDSMKYLDQKSPTPKPRAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFI IFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO.:9,hCD28信号肽-hCCL11-hCD28铰链区-hCD28跨膜区-hCD28共刺激分子-CD3ζ胞浆信号传导序列,hCCL11-ECAR)
MALPVTALLLPLALLLHAYPYDVPDYAVVIPSPCCMFFVSKRIPENRVVSYQLSSRSTCLKAGVIFTTKKGQQFCGDPKQEWVQRYMKNLDAKQKKASPRARAVAVKGPVQRYPGNQTTCRAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO.:10,hCD28信号肽-hCCL24-hCD28铰链区-hCD28跨膜区-hCD28共刺激分子-CD3ζ胞浆信号传导序列,hCCL24-ECAR)
在本发明的一优选实施方式中,所述ECAR的核苷酸序列如SEQ ID NO.:11-15中任一所示。
其中,在SEQ ID NO.:6中第1-54位为信号肽;第55-399位为内源性蛋白质分子(如人IL5);第412-528位为绞链区(如人CD28的绞链区);第529-609位为跨膜区(如人CD28的跨膜区);第610-732位为共刺激元件(如人CD28的共刺激元件);第733-1068位为CD3ζ。
其中,在SEQ ID NO.:7中第1-81位为信号肽;第82-420位为内源性蛋白质分子(如鼠IL5);第433-570位为绞链区(如鼠CD8α的绞链区);第571-633位为跨膜区(如鼠CD8α的跨膜区);第640-762位为共刺激元件(如鼠CD28的共刺激元件);第763-1101位为CD3ζ。
其中,在SEQ ID NO.:8中第1-54位为信号肽;第82-1314位为内源性蛋白质分子(如人Plau);第1327-1443位为绞链区(如人CD28的绞链区);第1444-1524位为跨膜区(如人CD28的跨膜区);第1525-1647位为共刺激元件(如人CD28的共刺激元件);第1648-1983位为CD3ζ。
其中,在SEQ ID NO.:9中第1-54位为信号肽;第82-303位为内源性蛋白质分子(如人CCL11);第316-432位为绞链区(如人CD28的绞链区);第433-513位为跨膜区(如人CD28的跨膜区);第514-636位为共刺激元件(如人CD28的共刺激元件);第637-972位为CD3ζ。
其中,在SEQ ID NO.:10中第1-54位为信号肽;第82-360位为内源性蛋白质分子(如人CCL24);第373-489位为绞链区(如人CD28的绞链区);第490-570位为跨膜区(如人CD28的跨膜区);第571-693位为共刺激元件(如人CD28的共刺激元件);第694-1029位为CD3ζ。
嵌合抗原受体T细胞(CAR-T细胞)
如本文所用,术语“CAR-T细胞”、“CAR-T”、“本发明CAR-T细胞”、“本发明CAR-T细胞”、“抗原受体T细胞”、“ECAR-T细胞”、“ECAR-T”、“本发明ECAR-T细胞”、“本发明ECAR-T细胞”、“内源性抗原受体T细胞”均指本发明第六方面所述的ECAR-T细胞,本发明ECAR-T细胞可靶向内源性蛋白质分子相对应(相匹配)的受体,用来杀伤或杀灭细胞(比如炎症细胞、衰老细胞、肿瘤细胞、自身免疫性细胞)或治疗疾病(比如,肿瘤疾病、过敏性疾病、自身免疫性疾病、衰老细胞相关性疾病)。
CAR-T细胞较其它基于T细胞的治疗方式存在以下优势:(1)CAR-T细胞的作用过程不受MHC的限制;(2)鉴于很多细胞表达相同的抗原,针对某一种抗原的CAR基因构建一旦完成,便可以被广泛利用;(3)CAR既可以利用蛋白质抗原,又可利用糖脂类非蛋白质抗原,扩大了抗原的靶点范围;(4)使用患者自体细胞降低了排异反应的风险;(5)CAR-T细胞具有免疫记忆功能,可以长期在体内存活。
在本发明中,本发明的CAR包含(i)胞外结构域,其为内源性蛋白质分子;(ii)任选的绞链区;(ii i)跨膜域;(iv)共刺激因子;和(v)CD3ζ的信号传导结构域。
嵌合抗原受体NK细胞(CAR-NK细胞)
如本文所用,术语“CAR-NK细胞”、“CAR-NK”、“本发明CAR-NK细胞”、“本发明CAR-NK细胞”、“抗原受体NK细胞”、“ECAR-NK细胞”、“ECAR-NK”、“本发明ECAR-NK细胞”、“本发明ECAR-NK细胞”、“内源性抗原受体NK细胞”均指本发明第一方面所述的ECAR-NK细胞。本发明CAR-NK细胞可靶向内源性蛋白质分子相对应(相匹配)的受体,用于杀伤或杀灭细胞(比如炎症细胞、衰老细胞、肿瘤细胞、自身免疫性细胞)。
自然杀伤(NK)细胞是一类主要的免疫效应细胞,通过非抗原特异性途径去保护机体免受病毒感染和肿瘤细胞的侵袭。通过工程化(基因修饰)的NK细胞可能获得新的功能,包括特异性识别细胞抗原的能力及具有增强的杀伤或杀灭细胞的作用。
与自体CAR-T细胞相比,CAR-NK细胞还具有一下优点,例如:(1)通过释放穿孔素和颗粒酶直接杀伤细胞,而对机体正常的细胞没有杀伤作用;(2)它们释放很少量的细胞因子从而降低了细胞因子风暴的危险;(3)体外极易扩增及发展为“现成的”产品。除此之外,与CAR-T细胞治疗类似。
嵌合抗原受体巨噬细胞(CAR-巨噬细胞)
如本文所用,术语“CAR-巨噬细胞”、“CAR-巨噬”、“本发明CAR-巨噬细胞”、“本发明CAR-巨噬细胞”、“抗原受体巨噬细胞”、“ECAR-巨噬细胞”、“ECAR-巨噬”、“本发明ECAR-巨噬细胞”、“本发明ECAR-巨噬细胞”、“内源性抗原受体巨噬细胞”均指本发明第一方面所述的ECAR-巨噬细胞。本发明CAR-巨噬细胞可靶向内源性蛋白质分子相匹配的受体,用于杀伤或杀灭细胞(比如炎症细胞、衰老细胞、肿瘤细胞、自身免疫性细胞)或治疗疾病(比如炎症细胞、衰老细胞、肿瘤细胞、自身免疫性细胞)。
外源T细胞抗原受体
如本文所用,外源T细胞抗原受体(T cell receptor,TCR)为通过基因转移技术从肿瘤反应性T细胞中克隆出TCR的α链和β链,通过基因工程的手段,以慢病毒或逆转录病毒为载体,外源性转入到T细胞内的TCR。
外源TCR修饰的T细胞能够特异性识别和杀伤细胞,并通过优化TCR与特异性抗原的亲和力,可以提高T细胞与待杀伤细胞的亲和力,提高杀伤或杀灭细胞的效果。
载体
编码期望分子的核酸序列可利用在本领域中已知的重组方法获得,诸如例如通过从表达基因的细胞中筛选文库,通过从已知包括该基因的载体中得到该基因,或通过利用标准的技术,从包含该基因的细胞和组织中直接分离。可选地,感兴趣的基因可被合成生产。
本发明也提供了其中插入本发明的表达盒的载体。源于逆转录病毒诸如慢病毒的载体是实现长期基因转移的合适工具,因为它们允许转基因长期、稳定的整合并且其在子细胞中增殖。慢病毒载体具有超过源自致癌逆转录病毒诸如鼠科白血病病毒的载体的优点,因为它们可转导非增殖的细胞,诸如肝细胞。它们也具有低免疫原性的优点。
简单概括,通常可操作地连接本发明的表达盒或核酸序列至启动子,并将其并入表达载体。该载体适合于复制和整合真核细胞。典型的克隆载体包含可用于调节期望核酸序列表达的转录和翻译终止子、初始序列和启动子。
本发明的表达构建体也可利用标准的基因传递方案,用于核酸免疫和基因疗法。基因传递的方法在本领域中是已知的。见例如美国专利号5,399,346、5,580,859、5,589,466,在此通过引用全文并入。在另一个实施方式中,本发明提供了基因疗法载体。
该核酸可被克隆入许多类型的载体。例如,该核酸可被克隆入如此载体,其包括但不限于质粒、噬菌粒、噬菌体衍生物、动物病毒和粘粒。特定的感兴趣载体包括表达载体、复制载体、探针产生载体和测序载体。
进一步地,表达载体可以以病毒载体形式提供给细胞。病毒载体技术在本领域中是公知的并在例如Sambrook等(2001,Molecular Cloning:A Laboratory Manual,ColdSpring Harbor Laboratory,New York)和其他病毒学和分子生物学手册中进行了描述。可用作载体的病毒包括但不限于逆转录病毒、腺病毒、腺伴随病毒、疱疹病毒和慢病毒。通常,合适的载体包含在至少一种有机体中起作用的复制起点、启动子序列、方便的限制酶位点和一个或多个可选择的标记(例如,WO01/96584;WO01/29058;和美国专利号6,326,193)。
已经开发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。可利用在本领域中已知的技术将选择的基因插入载体并包装入逆转录病毒颗粒。该重组病毒可随后被分离和传递至体内或离体的对象细胞。许多逆转录病毒系统在本领域中是已知的。在一些实施方式中,使用腺病毒载体。许多腺病毒载体在本领域中是已知的。在一个实施方式中,使用慢病毒载体。
额外的启动子元件,例如增强子,可以调节转录开始的频率。通常地,这些位于起始位点上游的30-110bp区域中,尽管最近已经显示许多启动子也包含起始位点下游的功能元件。启动子元件之间的间隔经常是柔性的,以便当元件相对于另一个被倒置或移动时,保持启动子功能。在胸苷激酶(tk)启动子中,启动子元件之间的间隔可被增加隔开50bp,活性才开始下降。取决于启动子,表现出单个元件可合作或独立地起作用,以起动转录。
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。该启动子序列为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、艾伯斯坦-巴尔(Epstein-Barr)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。进一步地,本发明不应被限于组成型启动子的应用。诱导型启动子也被考虑为本发明的一部分。诱导型启动子的使用提供了分子开关,其能够当这样的表达是期望的时,打开可操作地连接诱导型启动子的多核苷酸序列的表达,或当表达是不期望的时关闭表达。诱导型启动子的例子包括但不限于金属硫蛋白启动子、糖皮质激素启动子、孕酮启动子和四环素启动子。
为了评估CAR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。通常地,报道基因为以下基因:其不存在于受体有机体或组织或由受体有机体或组织进行表达,并且其编码多肽,该多肽的表达由一些可容易检测的性质例如酶活性清楚表示。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的基因(例如,Ui-Tei等,2000FEBS Letters479:79-82)。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。通常,显示最高水平的报道基因表达的具有最少5个侧翼区的构建体被鉴定为启动子。这样的启动子区可被连接至报道基因并用于评价试剂调节启动子-驱动转录的能力。
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。在表达载体的内容中,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。生产包括载体和/或外源核酸的细胞的方法在本领域中是公知的。见例如Sambrook等(2001,Molecular Cloning:A Laboratory Manual,Cold Spring HarborLaboratory,New York)。将多核苷酸引入宿主细胞的优选方法为磷酸钙转染。
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。病毒载体,特别是逆转录病毒载体,已经成为最广泛使用的将基因插入哺乳动物例如人细胞的方法。其他病毒载体可源自慢病毒、痘病毒、单纯疱疹病毒I、腺病毒和腺伴随病毒等等。见例如美国专利号5,350,674和5,585,362。
将多核苷酸引入宿主细胞的化学手段包括胶体分散系统,诸如大分子复合物、纳米胶囊、微球、珠;和基于脂质的系统,包括水包油乳剂、胶束、混合胶束和脂质体。用作体外和体内传递工具(delivery vehicle)的示例性胶体系统为脂质体(例如,人造膜囊)。
在使用非病毒传递系统的情况下,示例性传递工具为脂质体。考虑使用脂质制剂,以将核酸引入宿主细胞(体外、离体(ex vivo)或体内)。在另一方面,该核酸可与脂质相关联。与脂质相关联的核酸可被封装入脂质体的水性内部中,散布在脂质体的脂双层内,经与脂质体和寡核苷酸两者都相关联的连接分子附接至脂质体,陷入脂质体,与脂质体复合,分散在包含脂质的溶液中,与脂质混合,与脂质联合,作为悬浮液包含在脂质中,包含在胶束中或与胶束复合,或以其他方式与脂质相关联。与组合物相关联的脂质、脂质/DNA或脂质/表达载体不限于溶液中的任何具体结构。例如,它们可存在于双分子层结构中,作为胶束或具有“坍缩的(collapsed)”结构。它们也可简单地被散布在溶液中,可能形成大小或形状不均一的聚集体。脂质为脂肪物质,其可为天然发生或合成的脂质。例如,脂质包括脂肪小滴,其天然发生在细胞质以及包含长链脂肪族烃和它们的衍生物诸如脂肪酸、醇类、胺类、氨基醇类和醛类的该类化合物中。
在本发明的一个优选地实施方式中,所述载体为慢病毒载体。
制剂
本发明提供了一种本发明第一方面所述的CAR、本发明第二方面所述的核酸分子、本发明第三方面所述的载体、或本发明第四方面所述的宿主细胞,以及药学上可接受的载体、稀释剂或赋形剂。在一个实施方式中,所述制剂为液态制剂。优选地,所述制剂为注射剂。优选地,所述制剂中所述CAR-T细胞的浓度为1×105-1×108个细胞/ml,较佳地为1×106-1×107个细胞/ml,更佳地为1×106-5×106个细胞/ml。在一个实施方式中,所述制剂可包括缓冲液诸如中性缓冲盐水、硫酸盐缓冲盐水等等;碳水化合物诸如葡萄糖、甘露糖、蔗糖或葡聚糖、甘露醇;蛋白质;多肽或氨基酸诸如甘氨酸;抗氧化剂;螯合剂诸如EDTA或谷胱甘肽;佐剂(例如,氢氧化铝);和防腐剂。本发明的制剂优选配制用于静脉内施用。
治疗性应用
本发明包括用编码本发明表达盒的慢病毒载体(LV)转导的细胞(例如,T细胞)进行的治疗性应用。转导的T细胞可靶向内源性蛋白质分子相对应(相匹配)的受体,协同激活T细胞,引起细胞免疫应答,从而显著提高其对细胞的杀伤或杀灭效率。
因此,本发明也提供了刺激对哺乳动物的靶细胞群或组织的T细胞-介导的免疫应答的方法,其包括以下步骤:给哺乳动物施用本发明的CAR-T细胞。
在一个实施方式中,本发明包括一类细胞疗法,分离病人自体T细胞(或者异源供体),激活并进行基因改造产生ECAR-T细胞,随后注入同一病人体内。这种方式患移植物抗宿主病概率极低,抗原被T细胞以无MHC限制方式识别。此外,一种ECAR-T就可以治疗表达该内源性蛋白质分子相对应受体的所有疾病。不像抗体疗法,ECAR-T细胞能够体内复制,产生可导致持续细胞杀伤或杀灭控制的长期持久性。
在一个实施方式中,本发明的ECAR-T细胞可经历稳固的体内T细胞扩展并可持续延长的时间量。另外,ECAR介导的免疫应答可为过继免疫疗法步骤的一部分,其中ECAR-修饰T细胞,并诱导T细胞对靶细胞进行特异性的免疫应答。
尽管本文公开的数据具体公开了包括内源性蛋白质分子、铰链和跨膜区、和CD28和CD3ζ信号传导结构域的慢病毒载体,但本发明应被解释为包括对构建体组成部分中的每一个的任何数量的变化。
可治疗的疾病包括肿瘤疾病、过敏性疾病、自身免疫性疾病、衰老细胞相关性疾病。
本发明的CAR-修饰T细胞也可用作对哺乳动物离体免疫和/或体内疗法的疫苗类型。优选地,哺乳动物为人。
对于离体免疫,以下中的至少一项在将细胞施用进入哺乳动物前在体外发生:i)扩增细胞,ii)将编码CAR的核酸引入细胞,和/或i ii)冷冻保存细胞。
离体程序在本领域中是公知的,并在以下更完全地进行讨论。简单地说,细胞从哺乳动物(优选人)中分离并用表达本文公开的CAR的载体进行基因修饰(即,体外转导或转染)。CAR-修饰的细胞可被施用给哺乳动物接受者,以提供治疗益处。哺乳动物接受者可为人,和CAR-修饰的细胞可相对于接受者为自体的。可选地,细胞可相对于接受者为同种异基因的、同基因的(syngeneic)或异种的。
除了就离体免疫而言使用基于细胞的疫苗之外,本发明也提供了体内免疫以引起针对患者中抗原的免疫应答的组合物和方法。
本发明提供了治疗疾病的方法,其包括施用给需要其的对象治疗有效量的本发明的CAR-修饰的T细胞。
本发明的CAR-修饰的T细胞可被单独施用或作为药物组合物与稀释剂和/或与其他组分或其他细胞因子或细胞群结合施用。简单地说,本发明的药物组合物可包括如本文所述的靶细胞群,与一种或多种药学或生理学上可接受载体、稀释剂或赋形剂结合。这样的组合物可包括缓冲液诸如中性缓冲盐水、硫酸盐缓冲盐水等等;碳水化合物诸如葡萄糖、甘露糖、蔗糖或葡聚糖、甘露醇;蛋白质;多肽或氨基酸诸如甘氨酸;抗氧化剂;螯合剂诸如EDTA或谷胱甘肽;佐剂(例如,氢氧化铝);和防腐剂。本发明的组合物优选配制用于静脉内施用。
本发明的药物组合物可以以适于待治疗(或预防)的疾病的方式施用。施用的数量和频率将由这样的因素确定,如患者的病症、和患者疾病的类型和严重度——尽管适当的剂量可由临床试验确定。
当指出“免疫学上有效量”或“治疗量”时,待施用的本发明组合物的精确量可由医师确定,其考虑患者(对象)的年龄、重量、感染或转移程度和病症的个体差异。可通常指出:包括本文描述的T细胞的药物组合物可以以104至109个细胞/kg体重的剂量,优选105至106个细胞/kg体重的剂量(包括那些范围内的所有整数值)施用。T细胞组合物也可以以这些剂量多次施用。细胞可通过使用免疫疗法中公知的注入技术(见例如Rosenberg等,NewEng.J.of Med.319:1676,1988)施用。对于具体患者的最佳剂量和治疗方案可通过监测患者的疾病迹象并因此调节治疗由医学领域技术人员容易地确定。
对象组合物的施用可以以任何方便的方式进行,包括通过喷雾法、注射、吞咽、输液、植入或移植。本文描述的组合物可被皮下、皮内、瘤内、结内、脊髓内、肌肉内、通过静脉内(i.v.)注射或腹膜内施用给患者。在一个实施方式中,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。在另一个实施方式中,本发明的T细胞组合物优选通过i.v.注射施用。T细胞的组合物可被直接注入待杀伤的细胞、肿瘤、淋巴结或感染位置。
在本发明的某些实施方式中,利用本文描述的方法或本领域已知的其他将T细胞扩展至治疗性水平的方法活化和扩展的细胞,与任何数量的有关治疗形式结合(例如,之前、同时或之后)施用给患者,所述治疗形式包括但不限于用以下试剂进行治疗:所述试剂诸如抗病毒疗法、西多福韦和白细胞介素-2、阿糖胞苷(也已知为ARA-C)或对MS患者的那他珠单抗治疗或对牛皮癣患者的厄法珠单抗治疗或对PML患者的其他治疗。在进一步的实施方式中,本发明的T细胞可与以下结合使用:化疗、辐射、免疫抑制剂,诸如,环孢菌素、硫唑嘌呤、甲氨喋呤、麦考酚酯和FK506,抗体或其他免疫治疗剂。在进一步的实施方式中,本发明的细胞组合物与骨髓移植、利用化疗剂诸如氟达拉滨、外部光束放射疗法(XRT)、环磷酰胺结合(例如,之前、同时或之后)而施用给患者。例如,在一个实施方式中,对象可经历高剂量化疗的标准治疗,之后进行外周血干细胞移植。在一些实施方式中,在移植后,对象接受本发明的扩展的免疫细胞的注入。在一个额外的实施方式中,扩展的细胞在外科手术前或外科手术后施用。
施用给患者的以上治疗的剂量将随着治疗病症的精确属性和治疗的接受者而变化。人施用的剂量比例可根据本领域接受的实践实施。通常,每次治疗或每个疗程,可将1×106个至1×1010个本发明经修饰的T细胞,通过例如静脉回输的方式,施用于患者。
本发明的主要优点包括:
(1)本发明首次发现以内源性蛋白质分子代替抗体单结构域片段作为CAR胞外的抗原结合结构域,设计内源性嵌合抗原受体(endogenous CAR,ECAR),可特异性、选择性地杀伤多种细胞,并且具有显著的杀伤效果。
(2)本发明首次将内源性蛋白质分子作为嵌合抗原受体的胞外结合域,构建一种新的内源性嵌合抗原受体(Endogenous Chimeric Antigen Receptor,eCAR),其胞外结构域的基因序列选自人体存在的蛋白质分子链,因此在人体内能避免排异反应而具有良好的耐受性。
(3)本发明针对在体内已发现具有配体的抗原为靶点,以内源性蛋白质分子代替抗体单结构域片段作为CAR胞外的抗原结合结构域,设计内源性嵌合抗原受体(endogenousCAR)。本发明的方法大大缩短了时间成本,缩短了经济成本,并且避免了抗体制备与筛选的过程。
(4)本发明设计的内源性嵌合抗原受体,完全由内源的蛋白质分子链组成,因此不同于传统的携带外源单结构域抗体的嵌合抗原受体,不会在人体内造成排异反应。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring HarborLaboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
除非特别说明,否则本发明实施例中所用材料和试剂均为市售产品。
实施例1:hCD8α信号肽-hIL5(内源性蛋白分子)-hCD28铰链区-hCD28跨膜区-hCD28胞内域(共刺激分子)-hCD3ζ基因序列的确认及慢病毒载体构建。
从NCBI数据库检索到人CD8α信号肽基因序列,人IL5基因序列,人CD28铰链区基因序列,人CD28跨膜区基因序列,人CD28胞内域基因序列以及人CD3ζ胞内区的基因序列。
委托擎科生物科技有限公司按人CD8α信号肽基因编码区序列,人IL5基因编码区序列,人CD28铰链区基因编码区序列,人CD28跨膜区基因编码区序列,人CD28胞内域基因编码区序列以及人CD3ζ胞内区的基因编码区序列顺序合成完整的hIL5-ECAR基因序列,并通过PCR法和诺唯赞生物科技股份有限公司的非连接酶依赖型单片段快速克隆试剂盒将hIL5-ECAR连接到PHAGE慢病毒质粒上。将连接产物转化到感受态(DH5α)中,涂板过夜,挑单克隆,并送擎科生物科技有限公司进行测序,并比对测序结果,确认质粒是否构建成功。
使用康为世纪公司的质粒大提试剂盒提出纯化的hIL5-ECAR慢病毒质粒(质粒图例如图1所示)。
实施例2:hIL5-ECAR慢病毒包装与浓缩
将实施例1得到的hIL5-ECAR质粒采用PEI法转染293T来包装病毒,并通过超速离心来浓缩病毒,具体步骤如下:
第1天:选取代数小于20代且细胞密度约为90%的293T细胞,以30%的细胞密度铺板于含有30mL DMEM完全培养基的15cm皿中,充分混匀细胞,于37℃、5%CO2培养箱中过夜培养。
第2天:观察293T细胞密度达到70%-90%,弃去培养基,加入27ml新鲜含10%血清的DMEM培养基,准备进行转染;准备质粒混合物,各种质粒的量为:于洁净15ml离心管中加入DMEM培养基1500uL,并加入实施例1得到的hIL5-ECAR慢病毒质粒22.5ug,psPAX216.875ug和pMD2.G 5.625ug,充分混匀;另取洁净15ml离心管,加入DMEM培养基1500uL,并加入上海翊圣生物科技有限公司的PEI 40000转染试剂112.5uL,充分混匀;将PEI混合物滴入到质粒混合物中,充分混匀,静置20分钟。将3ml混合物沿培养皿壁加入到293T细胞皿中,37℃培养8h,吸弃培养基,轻柔沿培养皿壁重新加入预热的新鲜的含10%血清的DMEM完全培养基。
第4天:转染48h后收集病毒上清并用0.45um滤器过滤。过滤后的上清转移到超速离心管并配平,于4℃条件下在超速离心机中离心90分钟,转速35000rpm。离心结束,吸弃上清,每30ml病毒原液所得沉淀用300uL DMEM培养基重悬,所得浓缩好的hIL5-ECAR慢病毒液24h内用于感染或者于-80℃保存。
实施例3:hIL5-ECAR Jurkat与hIL5Ra靶细胞共培养后CD69表达检测
将实施例2浓缩的hIL5-ECAR病毒感染Jurkat细胞系得到hIL5-ECAR Jurkat稳转细胞系。实验组每孔含hIL5-ECAR Jurkat细胞1*10^5个,含hIL5Ra靶细胞(U2OS细胞系)1*10^5个;阴性对照组每孔含hIL5-ECAR Jurkat细胞1*10^5个,含不带hIL5Ra的靶细胞(U2OS细胞系)1*10^5个;空白组每孔仅含hIL5-ECAR Jurkat细胞1*10^5个。总体系为200ul含10%血清的1640完全培养基,两种细胞充分混匀之后加入96孔板中共培养。
培养箱中分别孵育24小时后收集细胞,每管细胞用1ml PBS清洗1次,400g离心5分钟,去上清。加入100ul PBS和0.5ul Biolegend公司的人CD69流式抗体(PE荧光),4℃,避光染色30分钟。每管细胞用1ml PBS清洗1次,400g离心5分钟,去上清。加入200ul PBS重悬,利用流式细胞仪检测hIL5-ECAR Jurkat细胞表面CD69的表达。
图2显示了共培养后hIL5-ECAR Jurkat被hIL5Ra靶细胞(模拟炎症细胞(嗜酸性粒细胞))显著激活。
实施例4:人T细胞的纯化与培养
利用达优的淋巴分离液获得人外周血单核细胞,利用Biolegend公司的CD3T淋巴细胞阴选试剂盒分离纯化T淋巴细胞。用LONZA的X-VIVO 15培养基调整细胞密度至1*10^6/ml,并加入1*10^6数量的CD3/CD28磁珠(Gibco),刺激培养48小时。
实施例5:hIL5-ECAR慢病毒感染人T细胞与流式检测病毒感染效率
利用实施例3得到的hIL5-ECAR浓缩病毒并采用离心感染法感染人T细胞来制备CART细胞,并通过流式细胞术检测hIL5-eCAR的表达情况,具体步骤如下:
T细胞活化培养两天后,进行细胞计数并调整T细胞密度至1*10^6/孔,每孔加入500ul新鲜的X-VIVO 15,接种到新的24孔板中。
配制病毒液:每孔加入实施例2的病毒浓缩液100ul,6ug/mL Polybrene,400ul X-VIVO 15培养基。
离心感染T细胞:将24孔板置于离心机中,32℃,1500g,离心2h。
离心完毕后,感染好的T细胞于1600rpm条件下离心5分钟,吸弃上清,每孔用1ml新鲜X-VIVO培养基种于新的24孔板。于37℃,5%CO2的培养箱中培养。
培养72h后,分别收集5*105CAR T细胞和T细胞(对照组)于流式管,PBS洗涤1次后弃上清,加入Biolegend公司的hIL5的流式抗体避光染色30分钟,随后PBS洗涤,200ul PBS重悬,流式细胞仪检测。结果如图3所示,实施例2得到的hIL5-ECAR慢病毒感染T细胞72h后,hIL5-ECAR的表达效率为13%。
实施例6:hIL5-ECAR T与hIL5Ra表达的靶细胞共培养后的杀伤检测(荧光素酶检测法)。
通过慢病毒感染法构建带有荧光素酶的hIL5Ra-U2OS靶细胞,并通过荧光素酶发光强度检测hIL5-eCAR T细胞杀伤能力,具体步骤如下:
准备WHB的全白色96孔板,用100ul X-VIVO 15培养基重悬hIL5Ra-U2OS-Luciferase靶细胞、U2OS-Luciferase细胞,调整细胞密度为1*10^4/孔。
用50ul X-VIVO 15培养基重悬实施例5制备好的hIL5-ECAR T细胞,调整细胞密度为2*106/mL,梯度稀释并以1*10^5/孔、5*10^4/孔、2.5*10^4/孔、1.25*10^4/孔的细胞密度种板,每孔100ul。
实验组96孔板中每孔加入100uL hIL5Ra-U2OS-Luciferase靶细胞,100uL不同细胞密度hIL5-ECAR T细胞;阴性对照组96孔板中每孔加入100uL hIL5Ra-U2OS-Luciferase细胞,100uL不同细胞密度未感染的T细胞;空白对照组和阳性对照组96孔板中每孔加入100uL hIL5Ra-U2OS-Luciferase和100uL X-VIVO培养基,充分混匀后,于37℃,5%CO2的培养箱中培养24小时。
24小时后,取出96孔板。阳性对照组每孔加入1uL NP40,充分混匀。5分钟后,倒弃孔板里的培养基,每孔加入1uL辅酶A和1uL D-荧光素以及100ul PBS,避光10分钟,利用M5酶标仪检测其化学发光强度。
结果如图4所示,hIL5-ECAR T细胞与hIL5R-U2OS-Luciferase靶细胞共培养后,随着效靶比的增加,其杀伤能力也增强,并呈现剂量依赖性。细胞裂解率(Lysis)定义为(1-(RLUsample)/(RLUmax))*100。RLUsample是指酶标仪检测到的样本的相对光强度,RLUmax是指酶标仪检测到的未加入杀伤细胞的靶细胞对照组的相对光强度。
实施例7:mCD8α信号肽-mIL5(内源性蛋白分子)-mCD8a铰链区-mCD8a跨膜区-mCD28胞内域(共刺激分子)-mCD3ζ基因序列的确认及慢病毒载体构建。
从NCBI数据库检索到小鼠源CD8α信号肽基因序列,小鼠源IL5基因序列,小鼠源CD8a铰链区基因序列,小鼠源CD8a跨膜区基因序列,小鼠源CD28胞内域基因序列以及小鼠源CD3ζ胞内区的基因序列。
委托擎科生物科技有限公司按小鼠源CD8α信号肽基因编码区序列,小鼠源IL5基因编码区序列,小鼠源CD28铰链区基因编码区序列,小鼠源CD28跨膜区基因编码区序列,小鼠源CD28胞内域基因编码区序列以及小鼠源CD3ζ胞内区的基因编码区序列顺序合成完整的mIL5-ECAR基因序列,并通过PCR法和诺唯赞生物科技股份有限公司的非连接酶依赖型单片段快速克隆试剂盒将mIL5-ECAR连接到PMX逆转录病毒质粒上。将连接产物转化到感受态(DH5α)中,涂板过夜,挑单克隆,并送擎科生物科技有限公司进行测序,并比对测序结果,确认质粒是否构建成功。
使用康为世纪公司的质粒大提试剂盒提出纯化的mIL5-ECAR慢病毒质粒(质粒图例如图5所示)。
实施例8:mIL5-ECAR逆转录病毒包装与浓缩
将实施例1得到的mIL5-ECAR质粒采用PEI法转染Plat-E细胞系来包装病毒,并通过超速离心来浓缩病毒,具体步骤如下:
第1天:选取代数小于20代且细胞密度约为90%的Plat-E细胞,以30%的细胞密度铺板于含有30mL DMEM完全培养基的15cm皿中,充分混匀细胞,于37℃、5%CO2培养箱中过夜培养。
第2天:观察Plat-E细胞密度达到70%-90%,弃去培养基,加入27ml新鲜含10%血清的DMEM培养基,准备进行转染;准备质粒混合物,各种质粒的量为:于洁净15ml离心管中加入DMEM培养基1500uL,并加入实施例1得到的mIL5-ECAR慢病毒质粒45ug,充分混匀;另取洁净15ml离心管,加入DMEM培养基1500uL,并加入转染试剂PEI 112.5uL,充分混匀;将PEI混合物滴入到质粒混合物中,充分混匀,静置20分钟。将3ml混合物沿培养皿壁加入到Plat-E细胞皿中,37℃培养8h,吸弃培养基,轻柔沿培养皿壁重新加入预热的新鲜的含10%血清的DMEM完全培养基。
第4天:转染48h后收集病毒上清并用0.45um滤器过滤。过滤后的上清转移到超速离心管并配平,于4℃条件下在超速离心机中离心90分钟,转速35000rpm。离心结束,吸弃上清,每30ml病毒原液所得沉淀用300uL DMEM培养基重悬,所得浓缩好的mIL5-ECAR逆转录病毒液24h内用于感染或者于-80℃保存。
实施例9:鼠T细胞的纯化与培养
将biolegend品牌的anti-mouse CD3因子和anti-mouse CD28因子用PBS稀释到1ug/ml,并加入到24孔板中,每孔加入500ul,于37摄氏度孵育箱孵育2hr,待用。通过颈椎离断方式处死一只Balb/c品系小鼠,在超净台中取出脾脏并研磨,用红细胞裂解液裂红,用滤网过滤得到脾脏单细胞悬液。利用Biolegend品牌的小鼠CD3 T淋巴细胞阴选试剂盒分离纯化T淋巴细胞。用1640完全培养基调整细胞密度至1*10^6/ml。取出在37摄氏度孵育箱孵育的24孔板,吸去液体,每孔加入1*10^6的T淋巴细胞,于37摄氏度孵育箱孵育48小时。
实施例10:mIL5-ECAR逆转录病毒感染鼠T细胞与流式检测病毒感染效率
利用实施例8得到的mIL5-ECAR浓缩病毒并采用离心感染法感染鼠T细胞来制备CART细胞,并通过流式细胞术检测mIL5-ECAR的表达情况,具体步骤如下:
T细胞活化培养两天后,进行细胞计数并调整T细胞密度至1*10^6/孔,每孔加入500ul新鲜的1640完全培养基,接种到新的24孔板中。
配制病毒液:每孔加入实施例2的病毒浓缩液100ul,6ug/mL Polybrene,400ul1640完全培养基。
离心感染T细胞:将24孔板置于离心机中,32℃,1500g,离心2h。
离心完毕后,感染好的T细胞于1600rpm条件下离心5分钟,吸弃上清,每孔用1ml新鲜1640完全培养基种于新的24孔板。于37℃,5%CO2的培养箱中培养。
培养72h后,分别收集5*105mIL5-ECAR T细胞和T细胞(对照组)于流式管,PBS洗涤1次后弃上清,加入Biolegend公司的mIL5的流式抗体避光染色30分钟,随后PBS洗涤,200ulPBS重悬,流式细胞仪检测。结果如图6所示,实施例8得到的mIL5-ECAR逆转录感染T细胞72h后,mIL5-ECAR的表达效率为55%。
实施例11:mIL5-ECAR T回输小鼠哮喘模型后对嗜酸性粒细胞的杀伤作用检测。
取6-8周SPF级别的雄性Balb/C小鼠,饲养在浙江大学动物中心,尾静脉注射mIL5-ECAR T细胞,细胞用量为3×10^6每只小鼠,每只小鼠注射体积为200ul的生理盐水,对照组注射同样体积的生理盐水。
配制致敏液(即配即用):称取卵清蛋白(Ovalbumin,OVA)20mg,用1ml生理盐水溶解,称A液;从A液中取出0.4ml到15ml无菌离心管中,加入9.6ml无菌生理盐水混匀,称B液;从B液中取出2ml到新的15ml离心管中,加入2ml铝剂,充分混合,即为致敏液,待用。
致敏:mIL5-ECART细胞回输一周后,每只小鼠腹腔注射200ul致敏液,此时标记为第1天;在第14天,以相同的溶剂和体积,进行第二次致敏。
雾化:之后分别在第27,28,29天每天进行OVA雾化(雾化液体积为10ml,以生理盐水为溶剂,含有130mg的OVA)。
小鼠处理:在第30天处理小鼠。每只小鼠腹腔注射1.5%戊巴比妥钠200ul,待小鼠麻醉后,剪开小鼠胸腔,并从心脏取血,装入1.5ml EDTA抗凝管中,并置于冰上;暴露气道与两侧肺叶,用细线在右侧肺近肺门处结扎右肺在气道远端剪开一个小口子,准备好注射器(20ml手动磨钝的注射器针头和1ml注射器的针筒)。注射器从小孔处插入气道,针头留于气道内,拔出针筒,并吸取干净的PBS 400ul,之后缓慢从气道推入肺中,反复推拉2-3次,最后把抽出的液体打入到1.5ml EP管中并置于冰上,总液体即为支气管肺泡灌洗液(BALF)。以上步骤,重复三次,共得到约1ml BALF。最后抽取400ul 4%甲醛溶液灌入左肺中,并结扎气道防止甲醛漏出。剪下右侧四叶肺,分别装入组织匀浆管中,投入液氮中保存;提起结扎气道的线,往下剪出左侧整叶肺,连同心脏一起放入装有13ml 4%甲醛的15ml离心管中。
BALF液混匀后,取20ul于PCR管中,加入20ul裂红液,混匀后,等待一分钟,镜下计数;剩余BALF液离心,6000rpm,4℃,15分钟,收集上清,-80℃保存;细胞沉淀用200ul预冷PBS稀释(OVA组加300ul);取100ul细胞悬液于装有1ml PBS的流式管中(包括1管blank组,6管单标管),400g,4℃,离心5分钟,另100ul等待甩片;离心后,弃去上清,加入80ul预冷PBS(含0.5ul流式抗体,包括CD45(PE-CY7,biolegend),SiglecF(PE,biolegend),F4/80(APC-CY7,biolegend),CD11b(FITC,biolegend),CD11c(APC,biolegend)以及DAPI(PB450)),吹匀后,避光,4℃冰箱孵育30分钟;每管加入1ml预冷PBS,400g,4℃,离心5分钟,弃上清之后,加入200ul预冷PBS,上机检测嗜酸粒细胞表达。
结果如图7所示,用mIL5-ECAR T治疗OVA哮喘模型(如图7左图的造模流程图)的Balb/c小鼠后,其BALF液中嗜酸粒细胞比例(如图7右图柱状图中由左至右第四组)较注射生理盐水的OVA哮喘模型组(如图7右图柱状图中由左至右第三组)明显减少。
实施例12:mIL5-ECAR T回输小鼠哮喘模型后对炎症的缓解作用检测。
提取肺组织RNA:选取处理好的小鼠肺组织一叶,加入研磨珠,加入1ml Trizol。在研磨机中以60Hz速度,研磨一分钟,重复一次。室温静置5分钟,吹打并收集裂解液至1.5mlEP管中;每管加入0.2ml三氯甲烷,充分震荡混匀,室温静置5分钟;12000g×15分钟,4℃离心;离心后分3层,RNA分布于上层水相中,吸取400ul上层液体至新的EP管中;每管RNA液体里加入0.5ml异丙醇,上下倒置轻柔混匀,室温静置5分钟;12000g×10分钟,4℃离心;弃上清,留沉淀;每管加入1ml预冷好的75%乙醇,上下轻轻颠倒,使沉淀飘起,不要用力过猛导致沉淀碎裂;9000g×5分钟,4℃离心;用吸水纸吸净残液,于室温下干燥5分钟;加入适量DEPC水,轻柔吹打至RNA溶解;使用Nanodrop测定RNA的浓度及质量。
RNA反转录:使用Takara公司的反转录试剂盒,反应体系如下,得到cDNA。
反应条件:37℃15分钟
85℃5sec
使用Takara公司的荧光定量PCR试剂盒,利用荧光定量PCR法(RT-PCR)定量检测IL4,IL25炎症因子的MRNA水平,反应体系如下,
反应程序如下:
94℃2min
94℃15sec,60℃30sec,72℃30sec,for 40cycle
72℃10min
4℃forever
数据处理与分析后,结果如图8所示,在用mIL5-ECAR T治疗OVA模型的Balb/c小鼠(如图8柱状图中由左至右第四组)后,其肺组织中的炎症相关因子(IL4,IL25)的mRNA水平较单纯注射生理盐水的OVA模型组(如图8柱状图中由左至右第三组)显著降低;且较未经处理组(如图8柱状图中由左至右第一组)及单纯注射mIL5-ECAR T组(如图8柱状图中由左至右第二组)无明显区别,结果显示出气道炎症的明显缓解。
实施例13:构建hPlau-ECAR T源代小鼠细胞。
从NCBI数据库检索到人源Plau基因序列。
委托擎科生物科技有限公司合成人源Plau基因编码区片段。并通过PCR法和诺唯赞生物科技股份有限公司的非连接酶依赖型单片段快速克隆试剂盒按小鼠CD8α信号肽基因编码区序列,人Plau基因编码区序列,小鼠CD28铰链区基因编码区序列,小鼠CD28跨膜区基因编码区序列,小鼠CD28胞内域基因编码区序列以及小鼠CD3ζ胞内区的基因编码区序列顺序,将hPlau-ECAR基因序列连接到PMX逆转录病毒质粒上。将连接产物转化到感受态(DH5α)中,涂板过夜,挑单克隆,并送擎科生物科技有限公司进行测序,并比对测序结果,确认质粒是否构建成功。
使用康为世纪公司的质粒大提试剂盒提出纯化的hPlau-ECAR逆转录质粒(质粒图例如图9所示)。
按照实施例8进行hPlau-ECAR逆转录病毒的包装与浓缩。
按照实施例9进行鼠T淋巴细胞的获取、激活与培养。
按照实施例10进行hPlau-ECAR T细胞的构建。
实施例14:hPlau-ECAR T与人源Plau受体(hPlauR)表达的靶细胞(模拟衰老细胞)共培养后的杀伤检测(荧光素酶检测法)。
通过慢病毒感染法构建带有荧光素酶的hPlauR-293T靶细胞,并通过荧光素酶发光强度检测hPlau-ECAR T细胞杀伤能力,具体步骤如下:
准备WHB品牌的全白色96孔板,用100ul 1640完全培养基重悬hPlauR-293T-Luciferase靶细胞、293T-Luciferase细胞,调整细胞密度为1*10^4/孔。
用50ul 1640完全培养基培养基重悬实施例13制备好的hPlau-ECAR T细胞,调整细胞密度为2*106/mL,梯度稀释并以1*10^5/孔、5*10^4/孔、2.5*10^4/孔的细胞密度种板,每孔100ul。
实验组96孔板中每孔加入100uL hPlauR-293T-Luciferase靶细胞,100uL不同细胞密度hPlau-ECAR T细胞;阴性对照组96孔板中每孔加入100uL293T-Luciferase靶细胞,100uL不同细胞密度hPlau-ECAR T细胞;空白对照组和阳性对照组96孔板中每孔加入100uLhPlauR-293T-Luciferase和100uL1640完全培养基,充分混匀后,于37℃,5%CO2的培养箱中培养12小时。
在12小时后取出96孔板。阳性对照组每孔加入1uL NP40,充分混匀。5分钟后,倒弃孔板里的培养基,每孔加入1uL辅酶A和1uL D-荧光素以及100ul PBS,避光10分钟,利用M5酶标仪检测其化学发光强度。
结果如图10所示,hPlau-ECAR T细胞与hPlauR-293T-Luciferase靶细胞共培养后,随着效靶比的增加,其杀伤能力也增强,并呈现剂量依赖性。
实施例15:构建hCCL11-ECAR T源代小鼠细胞。
从NCBI数据库检索到人源CCL11基因序列。
委托擎科生物科技有限公司合成人源CCL11基因编码区片段。并通过PCR法和诺唯赞生物科技股份有限公司的非连接酶依赖型单片段快速克隆试剂盒按小鼠CD8α信号肽基因编码区序列,人CCL11基因编码区序列,小鼠CD28铰链区基因编码区序列,小鼠CD28跨膜区基因编码区序列,小鼠CD28胞内域基因编码区序列以及小鼠CD3ζ胞内区的基因编码区序列顺序,将hCCL11-ECAR基因序列连接到PMX逆转录病毒质粒上。将连接产物转化到感受态(DH5α)中,涂板过夜,挑单克隆,并送擎科生物科技有限公司进行测序,并比对测序结果,确认质粒是否构建成功。
使用康为世纪公司的质粒大提试剂盒提出纯化的hCCL11-ECAR逆转录质粒(质粒图例如图11所示)。
按照实施例8进行hCCL11-ECAR逆转录病毒的包装与浓缩。
按照实施例9进行鼠T淋巴细胞的获取、激活与培养。
按照实施例10进行hCCL11-ECAR T细胞的构建。
实施例16:hCCL11-ECAR T与人源CCR3受体表达的靶细胞(模拟炎症细胞(嗜酸性粒细胞))共培养后的杀伤检测(荧光素酶检测法)。
通过慢病毒感染法构建带有荧光素酶的hCCR3-U2OS靶细胞,并通过荧光素酶发光强度检测hCCl 11-ECAR T细胞杀伤能力,具体步骤如下:
准备WHB的全白色96孔板,用100ul 1640完全培养基重悬hCCR3-U2OS-Luciferase靶细胞,调整细胞密度为1*10^4/孔。
用50ul 1640完全培养基培养基重悬实施例15制备好的hCCL11-ECAR T细胞,调整细胞密度为2*106/mL,梯度稀释并以2*10^5/孔、1*10^5/孔、5*10^4/孔、2.5*10^4/孔的细胞密度种板,每孔100ul。
实验组96孔板中每孔加入100uL hCCR3-U2OS-Luciferase靶细胞,100uL不同细胞密度hCCL11-ECAR T细胞;空白对照组和阳性对照组96孔板中每孔加入100uL hCCR3-U2OS-Luciferase靶细胞和100uL 1640完全培养基,充分混匀后,于37℃,5%CO2的培养箱中培养12小时。
在12小时后取出96孔板。阳性对照组每孔加入1uL NP40,充分混匀。5分钟后,倒弃孔板里的培养基,每孔加入1uL辅酶A和1uL D-荧光素以及100ul PBS,避光10分钟,利用M5酶标仪检测其化学发光强度。
结果如图12所示,hCCL11-ECAR T细胞与hCCR3-U2OS-Luciferase靶细胞共培养后,随着效靶比的增加,其杀伤能力也增强,并呈现剂量依赖性。
实施例17:构建hCCL24-ECAR T源代小鼠细胞。
从NCBI数据库检索到人源CCL24基因序列。
委托擎科生物科技有限公司合成人源CCL24基因编码区片段。并通过PCR法和诺唯赞生物科技股份有限公司的非连接酶依赖型单片段快速克隆试剂盒按小鼠CD8α信号肽基因编码区序列,人CCL24基因编码区序列,小鼠CD28铰链区基因编码区序列,小鼠CD28跨膜区基因编码区序列,小鼠CD28胞内域基因编码区序列以及小鼠CD3ζ胞内区的基因编码区序列顺序,将hCCL24-ECAR基因序列连接到PMX逆转录病毒质粒上。将连接产物转化到感受态(DH5α)中,涂板过夜,挑单克隆,并送擎科生物科技有限公司进行测序,并比对测序结果,确认质粒是否构建成功。
使用康为世纪公司的质粒大提试剂盒提出纯化的hCCL24-ECAR逆转录质粒(质粒图例如图13所示)。
按照实施例8进行hCCL24-ECAR逆转录病毒的包装与浓缩。
按照实施例9进行鼠T淋巴细胞的获取、激活与培养。
按照实施例10进行hCCL24-ECAR T细胞的构建。
实施例18:hCCL24-ECAR T与人源CCR3受体表达的靶细胞共培养后的杀伤检测(荧光素酶检测法)。
通过慢病毒感染法构建带有荧光素酶的hCCR3-U2OS靶细胞,并通过荧光素酶发光强度检测hCCl24-ECAR T细胞杀伤能力,具体步骤如下:
准备WHB的全白色96孔板,用100ul 1640完全培养基重悬hCCR3-U2OS-Luciferase靶细胞,调整细胞密度为1*10^4/孔。
用50ul 1640完全培养基培养基重悬实施例17制备好的hCCL24-ECAR T细胞,调整细胞密度为2*106/mL,梯度稀释并以2*10^5/孔、1*10^5/孔、5*10^4/孔、2.5*10^4/孔的细胞密度种板,每孔100ul。
实验组96孔板中每孔加入100uL hCCR3-U2OS-Luciferase靶细胞,100uL不同细胞密度hCCL24-ECAR T细胞;空白对照组和阳性对照组96孔板中每孔加入100uL hCCR3-U2OS-Luciferase靶细胞和100uL 1640完全培养基,充分混匀后,于37℃,5%CO2的培养箱中培养12小时。
在12小时取出96孔板。阳性对照组每孔加入1uL NP40,充分混匀。5分钟后,倒弃孔板里的培养基,每孔加入1uL辅酶A和1uL D-荧光素以及100ul PBS,避光10分钟,利用M5酶标仪检测其化学发光强度。
结果如图14所示,hCCL24-ECAR T细胞与hCCR3-U2OS-Luciferase靶细胞共培养后,随着效靶比的增加,其杀伤能力也增强,并呈现剂量依赖性。
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。
序列表
<110> 浙江大学
<120> 一种以内源性蛋白质分子替代单结构域抗体的嵌合抗原受体
<130> P2020-2625
<160> 28
<170> PatentIn version 3.5
<210> 1
<211> 115
<212> PRT
<213> 智人(Homo sapiens)
<400> 1
Ile Pro Thr Glu Ile Pro Thr Ser Ala Leu Val Lys Glu Thr Leu Ala
1 5 10 15
Leu Leu Ser Thr His Arg Thr Leu Leu Ile Ala Asn Glu Thr Leu Arg
20 25 30
Ile Pro Val Pro Val His Lys Asn His Gln Leu Cys Thr Glu Glu Ile
35 40 45
Phe Gln Gly Ile Gly Thr Leu Glu Ser Gln Thr Val Gln Gly Gly Thr
50 55 60
Val Glu Arg Leu Phe Lys Asn Leu Ser Leu Ile Lys Lys Tyr Ile Asp
65 70 75 80
Gly Gln Lys Lys Lys Cys Gly Glu Glu Arg Arg Arg Val Asn Gln Phe
85 90 95
Leu Asp Tyr Leu Gln Glu Phe Leu Gly Val Met Asn Thr Glu Trp Ile
100 105 110
Ile Glu Ser
115
<210> 2
<211> 113
<212> PRT
<213> 小鼠(Mus musculus)
<400> 2
Met Glu Ile Pro Met Ser Thr Val Val Lys Glu Thr Leu Thr Gln Leu
1 5 10 15
Ser Ala His Arg Ala Leu Leu Thr Ser Asn Glu Thr Met Arg Leu Pro
20 25 30
Val Pro Thr His Lys Asn His Gln Leu Cys Ile Gly Glu Ile Phe Gln
35 40 45
Gly Leu Asp Ile Leu Lys Asn Gln Thr Val Arg Gly Gly Thr Val Glu
50 55 60
Met Leu Phe Gln Asn Leu Ser Leu Ile Lys Lys Tyr Ile Asp Arg Gln
65 70 75 80
Lys Glu Lys Cys Gly Glu Glu Arg Arg Arg Thr Arg Gln Phe Leu Asp
85 90 95
Tyr Leu Gln Glu Phe Leu Gly Val Met Ser Thr Glu Trp Ala Met Glu
100 105 110
Gly
<210> 3
<211> 411
<212> PRT
<213> 智人(Homo sapiens)
<400> 3
Ser Asn Glu Leu His Gln Val Pro Ser Asn Cys Asp Cys Leu Asn Gly
1 5 10 15
Gly Thr Cys Val Ser Asn Lys Tyr Phe Ser Asn Ile His Trp Cys Asn
20 25 30
Cys Pro Lys Lys Phe Gly Gly Gln His Cys Glu Ile Asp Lys Ser Lys
35 40 45
Thr Cys Tyr Glu Gly Asn Gly His Phe Tyr Arg Gly Lys Ala Ser Thr
50 55 60
Asp Thr Met Gly Arg Pro Cys Leu Pro Trp Asn Ser Ala Thr Val Leu
65 70 75 80
Gln Gln Thr Tyr His Ala His Arg Ser Asp Ala Leu Gln Leu Gly Leu
85 90 95
Gly Lys His Asn Tyr Cys Arg Asn Pro Asp Asn Arg Arg Arg Pro Trp
100 105 110
Cys Tyr Val Gln Val Gly Leu Lys Leu Leu Val Gln Glu Cys Met Val
115 120 125
His Asp Cys Ala Asp Gly Lys Lys Pro Ser Ser Pro Pro Glu Glu Leu
130 135 140
Lys Phe Gln Cys Gly Gln Lys Thr Leu Arg Pro Arg Phe Lys Ile Ile
145 150 155 160
Gly Gly Glu Phe Thr Thr Ile Glu Asn Gln Pro Trp Phe Ala Ala Ile
165 170 175
Tyr Arg Arg His Arg Gly Gly Ser Val Thr Tyr Val Cys Gly Gly Ser
180 185 190
Leu Ile Ser Pro Cys Trp Val Ile Ser Ala Thr His Cys Phe Ile Asp
195 200 205
Tyr Pro Lys Lys Glu Asp Tyr Ile Val Tyr Leu Gly Arg Ser Arg Leu
210 215 220
Asn Ser Asn Thr Gln Gly Glu Met Lys Phe Glu Val Glu Asn Leu Ile
225 230 235 240
Leu His Lys Asp Tyr Ser Ala Asp Thr Leu Ala His His Asn Asp Ile
245 250 255
Ala Leu Leu Lys Ile Arg Ser Lys Glu Gly Arg Cys Ala Gln Pro Ser
260 265 270
Arg Thr Ile Gln Thr Ile Cys Leu Pro Ser Met Tyr Asn Asp Pro Gln
275 280 285
Phe Gly Thr Ser Cys Glu Ile Thr Gly Phe Gly Lys Glu Asn Ser Thr
290 295 300
Asp Tyr Leu Tyr Pro Glu Gln Leu Lys Met Thr Val Val Lys Leu Ile
305 310 315 320
Ser His Arg Glu Cys Gln Gln Pro His Tyr Tyr Gly Ser Glu Val Thr
325 330 335
Thr Lys Met Leu Cys Ala Ala Asp Pro Gln Trp Lys Thr Asp Ser Cys
340 345 350
Gln Gly Asp Ser Gly Gly Pro Leu Val Cys Ser Leu Gln Gly Arg Met
355 360 365
Thr Leu Thr Gly Ile Val Ser Trp Gly Arg Gly Cys Ala Leu Lys Asp
370 375 380
Lys Pro Gly Val Tyr Thr Arg Val Ser His Phe Leu Pro Trp Ile Arg
385 390 395 400
Ser His Thr Lys Glu Glu Asn Gly Leu Ala Leu
405 410
<210> 4
<211> 74
<212> PRT
<213> 智人(Homo sapiens)
<400> 4
Gly Pro Ala Ser Val Pro Thr Thr Cys Cys Phe Asn Leu Ala Asn Arg
1 5 10 15
Lys Ile Pro Leu Gln Arg Leu Glu Ser Tyr Arg Arg Ile Thr Ser Gly
20 25 30
Lys Cys Pro Gln Lys Ala Val Ile Phe Lys Thr Lys Leu Ala Lys Asp
35 40 45
Ile Cys Ala Asp Pro Lys Lys Lys Trp Val Gln Asp Ser Met Lys Tyr
50 55 60
Leu Asp Gln Lys Ser Pro Thr Pro Lys Pro
65 70
<210> 5
<211> 93
<212> PRT
<213> 智人(Homo sapiens)
<400> 5
Val Val Ile Pro Ser Pro Cys Cys Met Phe Phe Val Ser Lys Arg Ile
1 5 10 15
Pro Glu Asn Arg Val Val Ser Tyr Gln Leu Ser Ser Arg Ser Thr Cys
20 25 30
Leu Lys Ala Gly Val Ile Phe Thr Thr Lys Lys Gly Gln Gln Phe Cys
35 40 45
Gly Asp Pro Lys Gln Glu Trp Val Gln Arg Tyr Met Lys Asn Leu Asp
50 55 60
Ala Lys Gln Lys Lys Ala Ser Pro Arg Ala Arg Ala Val Ala Val Lys
65 70 75 80
Gly Pro Val Gln Arg Tyr Pro Gly Asn Gln Thr Thr Cys
85 90
<210> 6
<211> 356
<212> PRT
<213> 人工序列(artificial sequence)
<400> 6
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ile Pro Thr Glu Ile Pro Thr Ser Ala Leu Val Lys Glu Thr
20 25 30
Leu Ala Leu Leu Ser Thr His Arg Thr Leu Leu Ile Ala Asn Glu Thr
35 40 45
Leu Arg Ile Pro Val Pro Val His Lys Asn His Gln Leu Cys Thr Glu
50 55 60
Glu Ile Phe Gln Gly Ile Gly Thr Leu Glu Ser Gln Thr Val Gln Gly
65 70 75 80
Gly Thr Val Glu Arg Leu Phe Lys Asn Leu Ser Leu Ile Lys Lys Tyr
85 90 95
Ile Asp Gly Gln Lys Lys Lys Cys Gly Glu Glu Arg Arg Arg Val Asn
100 105 110
Gln Phe Leu Asp Tyr Leu Gln Glu Phe Leu Gly Val Met Asn Thr Glu
115 120 125
Trp Ile Ile Glu Ser Arg Ala Ala Ala Ile Glu Val Met Tyr Pro Pro
130 135 140
Pro Tyr Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His Val Lys
145 150 155 160
Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys Pro
165 170 175
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
180 185 190
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser
195 200 205
Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly
210 215 220
Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala
225 230 235 240
Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala
245 250 255
Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
260 265 270
Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu
275 280 285
Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
290 295 300
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
305 310 315 320
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
325 330 335
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
340 345 350
Leu Pro Pro Arg
355
<210> 7
<211> 370
<212> PRT
<213> 人工序列(artificial sequence)
<400> 7
Met Ala Ser Pro Leu Thr Arg Phe Leu Ser Leu Asn Leu Leu Leu Leu
1 5 10 15
Gly Glu Ser Ile Ile Leu Gly Ser Gly Glu Ala Met Glu Ile Pro Met
20 25 30
Ser Thr Val Val Lys Glu Thr Leu Thr Gln Leu Ser Ala His Arg Ala
35 40 45
Leu Leu Thr Ser Asn Glu Thr Met Arg Leu Pro Val Pro Thr His Lys
50 55 60
Asn His Gln Leu Cys Ile Gly Glu Ile Phe Gln Gly Leu Asp Ile Leu
65 70 75 80
Lys Asn Gln Thr Val Arg Gly Gly Thr Val Glu Met Leu Phe Gln Asn
85 90 95
Leu Ser Leu Ile Lys Lys Tyr Ile Asp Arg Gln Lys Glu Lys Cys Gly
100 105 110
Glu Glu Arg Arg Arg Thr Arg Gln Phe Leu Asp Tyr Leu Gln Glu Phe
115 120 125
Leu Gly Val Met Ser Thr Glu Trp Ala Met Glu Gly Arg Ala Ala Ala
130 135 140
Ser Thr Thr Thr Lys Pro Val Leu Arg Thr Pro Ser Pro Val His Pro
145 150 155 160
Thr Gly Thr Ser Gln Pro Gln Arg Pro Glu Asp Cys Arg Pro Arg Gly
165 170 175
Ser Val Lys Gly Thr Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp
180 185 190
Ala Pro Leu Ala Gly Ile Cys Val Ala Leu Leu Leu Ser Leu Ile Ile
195 200 205
Thr Leu Ile Cys Tyr Asn Ser Arg Arg Asn Arg Leu Leu Gln Ser Asp
210 215 220
Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Leu Thr Arg Lys Pro Tyr
225 230 235 240
Gln Pro Tyr Ala Pro Ala Arg Asp Phe Ala Ala Tyr Arg Pro Arg Ala
245 250 255
Lys Phe Ser Arg Ser Ala Glu Thr Ala Ala Asn Leu Gln Asp Pro Asn
260 265 270
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
275 280 285
Leu Glu Lys Lys Arg Ala Arg Asp Pro Glu Met Gly Gly Lys Gln Gln
290 295 300
Arg Arg Arg Asn Pro Gln Glu Gly Val Tyr Asn Ala Leu Gln Lys Asp
305 310 315 320
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Thr Lys Gly Glu Arg Arg
325 330 335
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
340 345 350
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Thr Leu Ala Pro Arg Gly
355 360 365
Ser Gly
370
<210> 8
<211> 661
<212> PRT
<213> 人工序列(artificial sequence)
<400> 8
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Ser Asn Glu Leu His
20 25 30
Gln Val Pro Ser Asn Cys Asp Cys Leu Asn Gly Gly Thr Cys Val Ser
35 40 45
Asn Lys Tyr Phe Ser Asn Ile His Trp Cys Asn Cys Pro Lys Lys Phe
50 55 60
Gly Gly Gln His Cys Glu Ile Asp Lys Ser Lys Thr Cys Tyr Glu Gly
65 70 75 80
Asn Gly His Phe Tyr Arg Gly Lys Ala Ser Thr Asp Thr Met Gly Arg
85 90 95
Pro Cys Leu Pro Trp Asn Ser Ala Thr Val Leu Gln Gln Thr Tyr His
100 105 110
Ala His Arg Ser Asp Ala Leu Gln Leu Gly Leu Gly Lys His Asn Tyr
115 120 125
Cys Arg Asn Pro Asp Asn Arg Arg Arg Pro Trp Cys Tyr Val Gln Val
130 135 140
Gly Leu Lys Leu Leu Val Gln Glu Cys Met Val His Asp Cys Ala Asp
145 150 155 160
Gly Lys Lys Pro Ser Ser Pro Pro Glu Glu Leu Lys Phe Gln Cys Gly
165 170 175
Gln Lys Thr Leu Arg Pro Arg Phe Lys Ile Ile Gly Gly Glu Phe Thr
180 185 190
Thr Ile Glu Asn Gln Pro Trp Phe Ala Ala Ile Tyr Arg Arg His Arg
195 200 205
Gly Gly Ser Val Thr Tyr Val Cys Gly Gly Ser Leu Ile Ser Pro Cys
210 215 220
Trp Val Ile Ser Ala Thr His Cys Phe Ile Asp Tyr Pro Lys Lys Glu
225 230 235 240
Asp Tyr Ile Val Tyr Leu Gly Arg Ser Arg Leu Asn Ser Asn Thr Gln
245 250 255
Gly Glu Met Lys Phe Glu Val Glu Asn Leu Ile Leu His Lys Asp Tyr
260 265 270
Ser Ala Asp Thr Leu Ala His His Asn Asp Ile Ala Leu Leu Lys Ile
275 280 285
Arg Ser Lys Glu Gly Arg Cys Ala Gln Pro Ser Arg Thr Ile Gln Thr
290 295 300
Ile Cys Leu Pro Ser Met Tyr Asn Asp Pro Gln Phe Gly Thr Ser Cys
305 310 315 320
Glu Ile Thr Gly Phe Gly Lys Glu Asn Ser Thr Asp Tyr Leu Tyr Pro
325 330 335
Glu Gln Leu Lys Met Thr Val Val Lys Leu Ile Ser His Arg Glu Cys
340 345 350
Gln Gln Pro His Tyr Tyr Gly Ser Glu Val Thr Thr Lys Met Leu Cys
355 360 365
Ala Ala Asp Pro Gln Trp Lys Thr Asp Ser Cys Gln Gly Asp Ser Gly
370 375 380
Gly Pro Leu Val Cys Ser Leu Gln Gly Arg Met Thr Leu Thr Gly Ile
385 390 395 400
Val Ser Trp Gly Arg Gly Cys Ala Leu Lys Asp Lys Pro Gly Val Tyr
405 410 415
Thr Arg Val Ser His Phe Leu Pro Trp Ile Arg Ser His Thr Lys Glu
420 425 430
Glu Asn Gly Leu Ala Leu Arg Ala Ala Ala Ile Glu Val Met Tyr Pro
435 440 445
Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His Val
450 455 460
Lys Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys
465 470 475 480
Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser
485 490 495
Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg
500 505 510
Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro
515 520 525
Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe
530 535 540
Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro
545 550 555 560
Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly
565 570 575
Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro
580 585 590
Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr
595 600 605
Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly
610 615 620
Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln
625 630 635 640
Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln
645 650 655
Ala Leu Pro Pro Arg
660
<210> 9
<211> 324
<212> PRT
<213> 人工序列(artificial sequence)
<400> 9
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Gly Pro Ala Ser Val
20 25 30
Pro Thr Thr Cys Cys Phe Asn Leu Ala Asn Arg Lys Ile Pro Leu Gln
35 40 45
Arg Leu Glu Ser Tyr Arg Arg Ile Thr Ser Gly Lys Cys Pro Gln Lys
50 55 60
Ala Val Ile Phe Lys Thr Lys Leu Ala Lys Asp Ile Cys Ala Asp Pro
65 70 75 80
Lys Lys Lys Trp Val Gln Asp Ser Met Lys Tyr Leu Asp Gln Lys Ser
85 90 95
Pro Thr Pro Lys Pro Arg Ala Ala Ala Ile Glu Val Met Tyr Pro Pro
100 105 110
Pro Tyr Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His Val Lys
115 120 125
Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys Pro
130 135 140
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
145 150 155 160
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser
165 170 175
Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly
180 185 190
Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala
195 200 205
Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala
210 215 220
Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
225 230 235 240
Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu
245 250 255
Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
260 265 270
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
275 280 285
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
290 295 300
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
305 310 315 320
Leu Pro Pro Arg
<210> 10
<211> 343
<212> PRT
<213> 人工序列(artificial sequence)
<400> 10
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Val Val Ile Pro Ser
20 25 30
Pro Cys Cys Met Phe Phe Val Ser Lys Arg Ile Pro Glu Asn Arg Val
35 40 45
Val Ser Tyr Gln Leu Ser Ser Arg Ser Thr Cys Leu Lys Ala Gly Val
50 55 60
Ile Phe Thr Thr Lys Lys Gly Gln Gln Phe Cys Gly Asp Pro Lys Gln
65 70 75 80
Glu Trp Val Gln Arg Tyr Met Lys Asn Leu Asp Ala Lys Gln Lys Lys
85 90 95
Ala Ser Pro Arg Ala Arg Ala Val Ala Val Lys Gly Pro Val Gln Arg
100 105 110
Tyr Pro Gly Asn Gln Thr Thr Cys Arg Ala Ala Ala Ile Glu Val Met
115 120 125
Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile
130 135 140
His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro
145 150 155 160
Ser Lys Pro Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys
165 170 175
Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser
180 185 190
Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg
195 200 205
Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg
210 215 220
Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp
225 230 235 240
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
245 250 255
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
260 265 270
Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly
275 280 285
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
290 295 300
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
305 310 315 320
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
325 330 335
Met Gln Ala Leu Pro Pro Arg
340
<210> 11
<211> 1068
<212> DNA
<213> 人工序列(artificial sequence)
<400> 11
atggctctcc cagtgactgc cctactgctt cccctagcgc ttctcctgca tgcaatcccc 60
acagaaattc ccacaagtgc attggtgaaa gagaccttgg cactgctttc tactcatcga 120
actctgctga tagccaatga gactctgagg attcctgttc ctgtacataa aaatcaccaa 180
ctgtgcactg aagaaatctt tcagggaata ggcacactgg agagtcaaac tgtgcaaggg 240
ggtactgtgg aaagactatt caaaaacttg tccttaataa agaaatacat tgacggccaa 300
aaaaaaaagt gtggagaaga aagacggaga gtaaaccaat tcctagacta cctgcaagag 360
tttcttggtg taatgaacac cgagtggata atagaaagtc gggcggccgc aattgaagtt 420
atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 480
gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 540
gtggtggttg gtggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 600
ttctgggtga ggagtaagag gagcaggctc ctgcacagtg actacatgaa catgactccc 660
cgccgccccg ggcccacccg caagcattac cagccctatg ccccaccacg cgacttcgca 720
gcctatcgct ccagagtgaa gttcagcagg agcgcagacg cccccgcgta ccagcagggc 780
cagaaccagc tctataacga gctcaatcta ggacgaagag aggagtacga tgttttggac 840
aagagacgtg gccgggaccc tgagatgggg ggaaagccga gaaggaagaa ccctcaggaa 900
ggcctgtaca atgaactgca gaaagataag atggcggagg cctacagtga gattgggatg 960
aaaggcgagc gccggagggg caaggggcac gatggccttt accagggtct cagtacagcc 1020
accaaggaca cctacgacgc ccttcacatg caggccctgc cccctcgc 1068
<210> 12
<211> 1110
<212> DNA
<213> 人工序列(artificial sequence)
<400> 12
atggcctcac cgttgacccg ctttctgtcg ctgaacctgc tgctgctggg tgagtcgatt 60
atcctgggga gtggagaagc tatggagatt cccatgagca cagtggtgaa agagaccttg 120
acacagctgt ccgctcaccg agctctgttg acaagcaatg agacgatgag gcttcctgtc 180
cctactcata aaaatcacca gctatgcatt ggagaaatct ttcaggggct agacatactg 240
aagaatcaaa ctgtccgtgg gggtactgtg gaaatgctat tccaaaacct gtcattaata 300
aagaaataca ttgaccgcca aaaagagaag tgtggcgagg agagacggag gacgaggcag 360
ttcctggatt acctgcaaga gttccttggt gtgatgagta cagagtgggc aatggaaggc 420
cgggcggccg catctactac taccaagcca gtgctgcgaa ctccctcacc tgtgcaccct 480
accgggacat ctcagcccca gagaccagaa gattgtcggc cccgtggctc agtgaagggg 540
accggattgg acttcgcctg tgatatttac atctgggcac ccttggccgg aatctgcgtg 600
gcccttctgc tgtccttgat catcactctc atctgctaca atagtagaag gaacagactc 660
cttcaaagtg actacatgaa catgactccc cggaggcctg ggctcactcg aaagccttac 720
cagccctacg cccctgccag agactttgca gcgtaccgcc ccagagcaaa attcagcagg 780
agtgcagaga ctgctgccaa cctgcaggac cccaaccagc tctacaatga gctcaatcta 840
gggcgaagag aggaatatga cgtcttggag aagaagcggg ctcgggatcc agagatggga 900
ggcaaacagc agaggaggag gaacccccag gaaggcgtat acaatgcact gcagaaagac 960
aagatggcag aagcctacag tgagatcggc acaaaaggcg agaggcggag aggcaagggg 1020
cacgatggcc tttaccaggg tctcagcact gccaccaagg acacctatga tgccctgcat 1080
atgcagaccc tggcccctcg cggatctgga 1110
<210> 13
<211> 1983
<212> DNA
<213> 人工序列(artificial sequence)
<400> 13
atggctctcc cagtgactgc cctactgctt cccctagcgc ttctcctgca tgcatatcca 60
tacgacgttc cggactacgc aagcaatgaa cttcatcaag ttccatcgaa ctgtgactgt 120
ctaaatggag gaacatgtgt gtccaacaag tacttctcca acattcactg gtgcaactgc 180
ccaaagaaat tcggagggca gcactgtgaa atagataagt caaaaacctg ctatgagggg 240
aatggtcact tttaccgagg aaaggccagc actgacacca tgggccggcc ctgcctgccc 300
tggaactctg ccactgtcct tcagcaaacg taccatgccc acagatctga tgctcttcag 360
ctgggcctgg ggaaacataa ttactgcagg aacccagaca accggaggcg accctggtgc 420
tatgtgcagg tgggcctaaa gctgcttgtc caagagtgca tggtgcatga ctgcgcagat 480
ggaaaaaagc cctcctctcc tccagaagaa ttaaaatttc agtgtggcca aaagactctg 540
aggccccgct ttaagattat tgggggagaa ttcaccacca tcgagaacca gccctggttt 600
gcggccatct acaggaggca ccgggggggc tctgtcacct acgtgtgtgg aggcagcctc 660
atcagccctt gctgggtgat cagcgccaca cactgcttca ttgattaccc aaagaaggag 720
gactacatcg tctacctggg tcgctcaagg cttaactcca acacgcaagg ggagatgaag 780
tttgaggtgg aaaacctcat cctacacaag gactacagcg ctgacacgct tgctcaccac 840
aacgacattg ccttgctgaa gatccgttcc aaggagggca ggtgtgcgca gccatcccgg 900
actatacaga ccatctgcct gccctcgatg tataacgatc cccagtttgg cacaagctgt 960
gagatcactg gctttggaaa agagaattct accgactatc tctatccgga gcagctgaaa 1020
atgactgttg tgaagctgat ttcccaccgg gagtgtcagc agccccacta ttacggctct 1080
gaagtcacca ccaaaatgct gtgtgctgct gacccacagt ggaaaacaga ttcctgccag 1140
ggagactcag ggggacccct cgtctgttcc ctccaaggcc gcatgacttt gactggaatt 1200
gtgagctggg gccgtggatg tgccctgaag gacaagccag gcgtctacac gagagtctca 1260
cacttcttac cctggatccg cagtcacacc aaggaagaga atggcctggc cctccgggcg 1320
gccgcaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 1380
attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 1440
cccttttggg tgctggtggt ggttggtgga gtcctggctt gctatagctt gctagtaaca 1500
gtggccttta ttattttctg ggtgaggagt aagaggagca ggctcctgca cagtgactac 1560
atgaacatga ctccccgccg ccccgggccc acccgcaagc attaccagcc ctatgcccca 1620
ccacgcgact tcgcagccta tcgctccaga gtgaagttca gcaggagcgc agacgccccc 1680
gcgtaccagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1740
tacgatgttt tggacaagag acgtggccgg gaccctgaga tggggggaaa gccgagaagg 1800
aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1860
agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1920
ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1980
cgc 1983
<210> 14
<211> 972
<212> DNA
<213> 人工序列(artificial sequence)
<400> 14
atggctctcc cagtgactgc cctactgctt cccctagcgc ttctcctgca tgcatatcca 60
tacgacgttc cggactacgc agggccagct tctgtcccaa ccacctgctg ctttaacctg 120
gccaatagga agatacccct tcagcgacta gagagctaca ggagaatcac cagtggcaaa 180
tgtccccaga aagctgtgat cttcaagacc aaactggcca aggatatctg tgccgacccc 240
aagaagaagt gggtgcagga ttccatgaag tatctggacc aaaaatctcc aactccaaag 300
ccacgggcgg ccgcaattga agttatgtat cctcctcctt acctagacaa tgagaagagc 360
aatggaacca ttatccatgt gaaagggaaa cacctttgtc caagtcccct atttcccgga 420
ccttctaagc ccttttgggt gctggtggtg gttggtggag tcctggcttg ctatagcttg 480
ctagtaacag tggcctttat tattttctgg gtgaggagta agaggagcag gctcctgcac 540
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 600
tatgccccac cacgcgactt cgcagcctat cgctccagag tgaagttcag caggagcgca 660
gacgcccccg cgtaccagca gggccagaac cagctctata acgagctcaa tctaggacga 720
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 780
ccgagaagga agaaccctca ggaaggcctg tacaatgaac tgcagaaaga taagatggcg 840
gaggcctaca gtgagattgg gatgaaaggc gagcgccgga ggggcaaggg gcacgatggc 900
ctttaccagg gtctcagtac agccaccaag gacacctacg acgcccttca catgcaggcc 960
ctgccccctc gc 972
<210> 15
<211> 1029
<212> DNA
<213> 人工序列(artificial sequence)
<400> 15
atggctctcc cagtgactgc cctactgctt cccctagcgc ttctcctgca tgcatatcca 60
tacgacgttc cggactacgc agtggtcatc ccctctccct gctgcatgtt ctttgtttcc 120
aagagaattc ctgagaaccg agtggtcagc taccagctgt ccagcaggag cacatgcctc 180
aaggcaggag tgatcttcac caccaagaag ggccagcagt tctgtggcga ccccaagcag 240
gagtgggtcc agaggtacat gaagaacctg gacgccaagc agaagaaggc ttcccctagg 300
gccagggcag tggctgtcaa gggccctgtc cagagatatc ctggcaacca aaccacctgc 360
cgggcggccg caattgaagt tatgtatcct cctccttacc tagacaatga gaagagcaat 420
ggaaccatta tccatgtgaa agggaaacac ctttgtccaa gtcccctatt tcccggacct 480
tctaagccct tttgggtgct ggtggtggtt ggtggagtcc tggcttgcta tagcttgcta 540
gtaacagtgg cctttattat tttctgggtg aggagtaaga ggagcaggct cctgcacagt 600
gactacatga acatgactcc ccgccgcccc gggcccaccc gcaagcatta ccagccctat 660
gccccaccac gcgacttcgc agcctatcgc tccagagtga agttcagcag gagcgcagac 720
gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 780
gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 840
agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 900
gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 960
taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1020
ccccctcgc 1029
<210> 16
<211> 21
<212> PRT
<213> 智人(Homo sapiens)
<400> 16
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> 17
<211> 27
<212> PRT
<213> 小鼠(Mus musculus)
<400> 17
Met Ala Ser Pro Leu Thr Arg Phe Leu Ser Leu Asn Leu Leu Leu Leu
1 5 10 15
Gly Glu Ser Ile Ile Leu Gly Ser Gly Glu Ala
20 25
<210> 18
<211> 39
<212> PRT
<213> 智人(Homo sapiens)
<400> 18
Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn
1 5 10 15
Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu
20 25 30
Phe Pro Gly Pro Ser Lys Pro
35
<210> 19
<211> 45
<212> PRT
<213> 智人(Homo sapiens)
<400> 19
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> 20
<211> 46
<212> PRT
<213> 小鼠(Mus musculus)
<400> 20
Ser Thr Thr Thr Lys Pro Val Leu Arg Thr Pro Ser Pro Val His Pro
1 5 10 15
Thr Gly Thr Ser Gln Pro Gln Arg Pro Glu Asp Cys Arg Pro Arg Gly
20 25 30
Ser Val Lys Gly Thr Gly Leu Asp Phe Ala Cys Asp Ile Tyr
35 40 45
<210> 21
<211> 27
<212> PRT
<213> 智人(Homo sapiens)
<400> 21
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 22
<211> 21
<212> PRT
<213> 智人(Homo sapiens)
<400> 22
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
20
<210> 23
<211> 21
<212> PRT
<213> 小鼠(Mus musculus)
<400> 23
Ile Trp Ala Pro Leu Ala Gly Ile Cys Val Ala Leu Leu Leu Ser Leu
1 5 10 15
Ile Ile Thr Leu Ile
20
<210> 24
<211> 41
<212> PRT
<213> 智人(Homo sapiens)
<400> 24
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 25
<211> 42
<212> PRT
<213> 智人(Homo sapiens)
<400> 25
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 26
<211> 41
<212> PRT
<213> 小鼠(Mus musculus)
<400> 26
Asn Ser Arg Arg Asn Arg Leu Leu Gln Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Leu Thr Arg Lys Pro Tyr Gln Pro Tyr Ala Pro
20 25 30
Ala Arg Asp Phe Ala Ala Tyr Arg Pro
35 40
<210> 27
<211> 112
<212> PRT
<213> 智人(Homo sapiens)
<400> 27
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 28
<211> 113
<212> PRT
<213> 小鼠(Mus musculus)
<400> 28
Arg Ala Lys Phe Ser Arg Ser Ala Glu Thr Ala Ala Asn Leu Gln Asp
1 5 10 15
Pro Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Glu Lys Lys Arg Ala Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Gln Gln Arg Arg Arg Asn Pro Gln Glu Gly Val Tyr Asn Ala Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Thr 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 Thr Leu Ala Pro
100 105 110
Arg
Claims (10)
1.一种内源性嵌合抗原受体CAR(ECAR),其特征在于,所述内源性嵌合抗原受体CAR(ECAR)包含抗原结合结构域,所述抗原结合结构域为内源性蛋白质分子。
2.如权利要求1所述的ECAR,其特征在于,所述内源性蛋白质分子选自下组:白细胞介素家族、趋化因子家族、集落刺激因子、生长因子、肿瘤坏死因子超家族、干扰素家族、肿瘤标志物、衰老细胞相关性因子、或其组合。
3.如权利要求1所述的ECAR,其特征在于,所述的内源性嵌合抗原受体CAR(ECAR)的结构如式I所示:
L-Z1-Z2-TM-C-CD3ζ(I)
式中,
各“-”独立地为连接肽或肽键;
L为任选的信号肽序列;
Z1为抗原结合结构域,所述抗原结合域为内源性蛋白质分子;和
Z2为无或绞链区;
TM为跨膜结构域;
C为共刺激信号分子;
CD3ζ为源于CD3ζ的胞浆信号传导序列。
4.一种核酸分子,其特征在于,所述核酸分子编码权利要求1所述的内源性嵌合抗原受体CAR(ECAR)。
5.一种载体,其特征在于,所述的载体含有权利要求4所述的核酸分子。
6.一种宿主细胞,其特征在于,所述的宿主细胞含有权利要求5所述的载体或染色体中整合有外源的权利要求4所述的核酸分子或表达权利要求1所述的ECAR。
7.一种制备工程化免疫细胞的方法,其特征在于,所述的工程化免疫细胞表达权利要求1所述的ECAR,包括以下步骤:将权利要求4所述的核酸分子或权利要求5所述的载体转导入巨噬细胞、T细胞或NK细胞内,从而获得所述工程化免疫细胞。
8.一种药物组合物,其特征在于,所述药物组合物含有权利要求1所述的ECAR、权利要求4所述的核酸分子、权利要求5所述的载体、或权利要求6所述的宿主细胞,以及药学上可接受的载体、稀释剂或赋形剂。
9.一种如权利要求1所述的ECAR、权利要求4所述的核酸分子、权利要求5所述的载体、权利要求6所述宿主细胞、或权利要求8所述的药物组合物的用途,其特征在于,用于制备药物或制剂,所述药物或制剂用于(a)选择性杀伤细胞;和/或(b)治疗疾病。
10.一种用于选择性杀伤细胞的试剂盒,其特征在于,所述试剂盒含有容器,以及位于容器内的权利要求1所述的ECAR、权利要求4所述的核酸分子、权利要求5所述的载体、权利要求6所述的宿主细胞或权利要求8所述的药物组合物。
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