CN113248620A - 一种嵌合抗原受体的共刺激信号结构域及其应用 - Google Patents
一种嵌合抗原受体的共刺激信号结构域及其应用 Download PDFInfo
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Abstract
本发明属于基因工程与生物免疫治疗技术领域，构建了一种新的嵌合抗原受体(CAR)，其共刺激信号结构域包含新的共刺激分子，即反向的Dectin‑1(RD‑1)胞内区。新构建的嵌合抗原受体与T细胞结合形成的CAR‑T能够更高水平地分泌细胞因子，具有更好的抗肿瘤活性。
Description
技术领域
本发明属于基因工程与生物免疫治疗技术领域，构建一种新的嵌合抗原受体，包含一种新的共刺激分子RD-1的跨膜区和胞内信号传导结构域。
背景技术
嵌合抗原受体(Chimeric Antigen Receptor，CAR)T细胞免疫疗法，经历一系演化过程。第一代CAR介导的T细胞激活是通过CD3ζ上的酪氨酸激活基序完成的。CD3ζ能够激活T细胞、裂解靶细胞、调节IL-2分泌以及能在体内发挥抗肿瘤活性所需的信号。但第一代CAR改造T细胞的抗肿瘤活性在体内受到了限制，会因T细胞增殖减少而最终导致T细胞的凋亡。第二代CAR在胞内增加了一个新的共刺激信号CD28或者4-1BB(CD137)，与第一代CAR相比，抗原特异性不变，但T细胞增殖、细胞因子分泌增加，抗细胞凋亡蛋白分泌增加，细胞死亡延迟。在此基础上还发展了第三代乃至第四代CAR T细胞，通过添加两个共刺激分子或者增加其它多靶点来增强抗肿瘤作用，但其疗效参差不齐，尤其是在实体瘤治疗中的敏感性普遍较低。
因此在本技术领域中，还需要继续优化CAR结构来调节T细胞的功能，增强T细胞的增殖功能，以增强其杀伤肿瘤的作用。
发明内容
有鉴于此，本发明目的在于提供一种嵌合抗原受体的共刺激信号结构域，所述共刺激信号结构域包含RD-1胞内区。
进一步，所述共刺激信号结构域包含CD3ζ。
进一步，所述RD-1胞内区包含含有SEQ No.1的氨基酸序列或与所述SEQ No.1不低于90％同一性的氨基酸序列。
进一步，所述共刺激信号结构域还包含CD3,CD4,CD8,FcR,DAP10,DAP12,CD27,CD28,CD137,CD134,ICOS,OX40,CD30,CD40,PD-1,LFA-1,CD2,CD7,LIGHI,NKG2C,B7-H3,特异结合CD83的配体，CDS,ICAM-1,GITR,BAFFR,HVEM(IGHTR),SLAMF7,NKp80 KLRE1,CD160,CD19,CD83,IL-2Rβ,IL-Rγ,IL-7Rα,ITGA4,VLA1,CD49α,ITGA4,IA4,CD49D,ITGA6,LA-6,CD49f,ITGAD,CD11d,ITGAE,CD103,ITGAL,CD11α,LFA-1,ITGAM,CDIIB,ITGAX,CD11c,ITGB1,CD29,ITGB2,CD18,LFA-1.ITGB7 TAFR2,TRANCE/RANKL,DNAM1(CD226),SLAMF4(CD244,2B4),CD84,CD96(Tactile),CEACAM1 CRTAM,Ly9(CD229),D160(BY55),PSGL1,CD100(SEMA4D),CD69,SLAMF6(NTB-A,Ly108 SLAM(SLAMF1,CD150,IPO-3),BLAME(SLAME8),SELPLG(CD162),LTBR,LAT,GADS,SLP-76PAG/Cbp,NKp4,NWKp30,NKp46,NKG2D中的一种或多种。
本发明目的在于还提供一种包含前述的共刺激信号结构域的嵌合抗原受体。
进一步，所述嵌合抗原受体包括依次连接的抗原识别域、CD8α铰链区、跨膜区、RD-1胞内区和CD3ζ。
进一步，所述跨膜区包含的氨基酸序列能够将所述嵌合抗原受体锚定在细胞膜上。
进一步，所述跨膜区包含RD-1跨膜区。
进一步，所述RD-1跨膜区包含含有SEQ No.2氨基酸序列或与所述SEQ No.2不低于90％同一性的氨基酸序列。
优选地，所述抗原识别域是HER2结合域。
进一步，所述嵌合抗原受体包含含有SEQ No.5的氨基酸序列。
优选地，所述抗原识别域是CD19结合域。
进一步，所述的嵌合抗原受体包含含有SEQ No.6的氨基酸序列。
本发明目的在于还提供一种前述的嵌合抗原受体的合成方法，所述方法包括以下步骤：步骤(1)合成RD-1-CD3ζ基因序列；步骤(2)合成嵌合抗原受体基因序列。
进一步，所述步骤(2)具体包括：先用引物F1、R1扩增抗原识别域和CD8α铰链区结合的基因序列，然后再用引物F2、R2扩增所述RD-1-CD3ζ基因序列，最后以所述抗原识别域和CD8α铰链区结合的基因序列和所述RD-1-CD3ζ基因序列为模板，以F1、R2为引物，合成所述嵌合抗原受体的基因序列。
进一步，所述引物F1如SEQ No.7所示，R1如SEQ No.8所示，F2如SEQ No.9所示，R2如SEQ No.10所示。
本发明目的在于还提供一种前述的嵌合抗原受体与表达载体构建的重组质粒载体。
进一步，所述表达载体为pCLK载体。
本发明目的在于还提供了前述的重组质粒载体的构建方法，所述构建方法包括以Mlu I和Spe I为酶切位点，连接所述抗原受体基因与所述表达载体，从而获得所述重组质粒载体。
本发明目的在于还提供了一种前述嵌合抗原受体修饰的免疫细胞。
进一步，所述免疫细胞为T淋巴细胞。
进一步，所述免疫细胞还包括B淋巴细胞、K淋巴细胞和NK淋巴细胞中的一种或多种。
本发明目的在于还提供了一种获取前述的免疫细胞的方法，所述方法包括以下步骤：以Mlu I和Spe I为酶切位点，连接所述嵌合抗原受体基因与表达载体，得重组质粒载体；将所述重组质粒载体与包装质粒共同转入培养细胞中培养，获得重组病毒颗粒；再用所述重组病毒颗粒对免疫细胞进行修饰。
进一步，所述修饰的方法包括采用病毒载体或非病毒载体系统。
进一步，所述病毒载体系统包括逆转录病毒载体、慢病毒载体、腺病毒载体、腺相关病毒载体和仙台病毒载体中的一种或多种。
进一步，所述非病毒载体系统包括转座子系统、CRISPR基因编辑系统、TALEN系统、脂质体转染系统和电转染系统中的一种或多种。
本发明目的在于还提供一种前述免疫细胞在制备抗肿瘤药物中的应用。
本发明目的在于还提供一种包含前述的免疫细胞的抗肿瘤药物组合物。
进一步，所述抗肿瘤药物组合物，其特征在于，还包括化学药物。
进一步，所述化学药物包括环磷酰胺和/或氟达拉滨。
进一步，所述抗肿瘤药物组合物为抗乳腺癌和/或抗卵巢癌药物。
本发明目的在于还提供了一种包含前述嵌合抗原受体的组合物，所述组合物还包括与所述共刺激信号结构域结合的β-葡聚糖受体、Syk、CR3和CD11b中的一种或多种。
本发明的有益效果在于：
实验证明，本发明提供的CAR比现有的传统的二代CAR刺激免疫细胞分泌细胞因子的能力更强，免疫细胞增殖的时间比传统二代CAR要长，对肿瘤细胞的杀伤力更大。
附图说明
图1为抗原为HER2二代嵌合抗原受体的结构示意图。
图2为传统二代CAR基因转染人T细胞的表达检测图。
图3为新二代CAR基因转染人T细胞的表达检测图。
图4为CAR T细胞靶向HER2阳性细胞SKOV3肿瘤细胞RTCA检测图。
图5为CAR T细胞靶向HER2阳性肿瘤细胞SKOV3和HER2阴性肿瘤细胞MDA-MB-468分泌IFN-γ的检测图。
具体实施方式
所举实施例是为了更好地对本发明进行说明，但并不是本发明的内容仅局限于所举实施例。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。
除非另外指定，否则术语“包含有”和“包含”及其在语法上的变化是用来表示“开放式”或者“包括”的语言，从而它们包括列举的技术特征但也允许包括另外的没有列举的技术特征。
如在本说明书中使用的，术语“大约”，典型地表示为所述值的+/-5％，更典型的是所述值的+/-4％，更典型的是所述值的+/-3％，更典型的是所述值的+/-2％，甚至更典型的是所述值的+/-1％，甚至更典型的是所述值的+/-0.5％。
在本说明书中，某些实施方式可能以一种处于某个范围的格式公开。应该理解，这种“处于某个范围”的描述仅仅是为了方便和简洁，且不应该被解释为对所公开范围的僵化限制。因此，范围的描述应该被认为是已经具体地公开了所有可能的子范围以及在此范围内的独立数字值。例如，范围1-6的描述应该被看作已经具体地公开了子范围如从1到3，从1到4，从1到5，从2到4，从2到6，从3到6等，以及此范围内的单独数字，例如1，2，3，4，5和6。无论该范围的广度如何，均适用以上规则。
在本申请文件中，Dectin 1，即CLEC7A是C型凝集素家族中最重要的受体，是一个II型跨膜的细胞表面受体，能够介导β-葡聚糖的识别和内化。Dectin 1主要表达在树突细胞，巨噬细胞和中性粒细胞等细胞表面。有研究报道，还能识别T细胞表面的内源性配体，促进T细胞的增殖，并且这种识别不能被酵母聚糖所抑制。“RD-1”即为反向Dectin-1(ReverseDection-1)其氨基酸序列为“GLVVAIVLIVLCLIGLIVAILRWPPSAACSGKESVVAIRTNSQSDFHLQTYGDEDLNELDPHYEM”如SEQ NO 3所示；Dectin-1的氨基酸序列为“MEYHPDLENLDEDGYTQLHFDSQSNTRTAVVSEKGSCAASPPWRLIAVILGILCLVILVIAVVLG”，如SEQ NO 4所示。“RD-1胞内区”氨基酸序列为“RWPPSAACSGKESVVAIRTNSQSDFHLQTYGDEDLNELDPHYEM”，如SEQ NO 1所示；“RD-1跨膜区”氨基酸序列为“GLVVAIVLIVLCLIGLIVAIL”，如SEQ NO 2所示。
实施例中获得CAR基因所用的引物情况如表1：
表1获得CAR基因所用的引物
实施例1PCR获得全长抗原为HER2的CAR基因
(1)第一步，基因合成：合成RD-1(TM+cytoplasmic)-CD3ζ片段全长。
(2)第二步，合成引物，并利用重叠PCR方法得到(anti-HER2 scFV)-(CD8αhinge)-(RD-1TM+Cytoplasmic)-(CD3ζ)融合片段，其中具体包括以下两个步骤：
(2.1)利用引物F1、R1扩增(anti-HER2 scFV)-(CD8αhinge)；利用F2、R2扩增(RD-1TM+Cytoplasmic)-(CD3ζ)。
(2.2)再以(anti-HER2 scFV)-(CD8αhinge)和(RD-1TM+Cytoplasmic)-(CD3ζ)为模版，F1、R2为引物，通过PCR获得全长CAR基因。
合成的(anti-HER2 scFV)-(CD8αhinge)-(RD-1TM+Cytoplasmic)-(CD3ζ)的氨基酸序列为SEQ NO 5。
实施例2抗原为HER2的CAR的重组质粒载体的构建
(1)第一步，基因合成：合成RD-1(TM+cytoplasmic)-CD3ζ片段全长。
(2)第二步，设计引物，并利用重叠PCR方法得到(anti-HER2 scFV)-(CD8αhinge)-(RD-1TM+Cytoplasmic)-(CD3ζ)融合片段，其中具体包括以下两个步骤：
(2.1)利用引物F1、R1扩增(anti-HER2 scFV)-(CD8αhinge)；利用F2、R2扩增(RD-1TM+Cytoplasmic)-(CD3ζ)；
(2.2)以(anti-HER2 scFV)-(CD8αhinge)和(RD-1TM+Cytoplasmic)-(CD3ζ)为模版，F1、R2为引物，PCR获得全长CAR基因。
(3)以Mlu I和Spe I为酶切位点，连接通过上述步骤合成的CAR基因及PCLK载体，获得CAR-PCLK质粒载体。
实施例3T淋巴细胞的病毒转染及目的基因的表达检测
(1)将具有嵌合抗原受体基因新的二代CAR基因(anti-HER2 scFV)-(CD8αhinge)-(RD-1TM+Cytoplasmic)-(CD3ζ)(结构示意图如图1)，传统二代CAR基因(anti-HER2 scFV)-(CD8αhinge+TM)-(4-1BB)-(CD3ζ)(结构示意图如图1)分别装入慢病毒载体PCLK中，并与两个辅助载体psPAX2和pMD2.G共同转染T细胞，分别包装获得病毒颗粒，经离心浓缩后获得高浓度的慢病毒载体。
(2)利用密度梯度离心法，分离得到淋巴细胞，以CD3抗体(1ug/ml)和IL-2(100IU/ml)刺激淋巴细胞。一天后收集淋巴细胞进行病毒转染，培养淋巴细胞48小时，收集转染的淋巴细胞。
(3)收集到的经过病毒转染的淋巴细胞，用识别抗体Fab片段的特异性抗体，进行流式检测。
如图2为传统二代CAR基因转染人T细胞的表达检测，一抗为生物素标记的山羊抗小鼠Fab单克隆抗体，二抗为PE标记的抗streptavidin流式抗体。第一泳道为转染空载病毒的T细胞，第二泳道为转染CAR基因的T细胞。(图2中hH8-BBz为传统二代CAR基因(anti-HER2scFV)-(CD8αhinge+TM)-(4-1BB)-(CD3ζ)；)。
如图3为新二代CAR基因转染人T细胞的表达检测，一抗为生物素标记的山羊抗小鼠Fab单克隆抗体，二抗为PE标记的抗streptavidin流式抗体。第一泳道为转染空载病毒的T细胞，第二泳道为转染CAR基因的T细胞。(图3中hHD-Dz为新二代CAR基因(anti-HER2scFV)-(CD8αhinge)-(RD-1TM+Cytoplasmic)-(CD3ζ))。
在相同MOI(感染复数)病毒转染效力下，经流式细胞仪检测证实，新的二代CAR分子和传统二代CAR分子在淋巴细胞表面均高效表达。
实施例4对表达HER2的肿瘤细胞的杀伤作用
传统二代CAR-T细胞：(anti-HER2 scFV)-(CD8αhinge+TM)-(4-1BB)-(CD3ζ)-T细胞
新二代CAR-T细胞：(anti-HER2 scFV)-(CD8αhinge)-(RD-1TM+Cytoplasmic)-(CD3ζ)-T细胞
(1)利用RTCA(RealTime Cellular Analysis,实时无标记细胞分析技术)分别检测两种T细胞对HER2阳性细胞SKOV3(人卵巢癌细胞)肿瘤细胞杀伤效力检测，其检测结果如图4。(图4中hH8-BBz为传统二代CAR-T细胞；hHD-Dz为新二代CAR-T细胞)。
(2)利用ELISA分别检测两种CAR T细胞向HER2阳性肿瘤细胞SKOV3(人卵巢癌细胞)和HER2阴性肿瘤细胞MDA-MB-468(人乳腺癌细胞)分泌细胞因子情况,其检测分析结果如图5。图5清晰显示，新二代CAR T比传统二代CAR T向HER2阳性肿瘤细胞SKOV3分泌的细胞因子((IFNγ)情况要更多。(图5中hH8-BBz为传统二代CAR基因(anti-HER2 scFV)-(CD8αhinge+TM)-(4-1BB)-(CD3ζ)；hHD-Dz为新二代CAR基因(anti-HER2scFV)-(CD8αhinge)-(RD-1TM+Cytoplasmic)-(CD3ζ))。
最后说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的宗旨和范围，其均应涵盖在本发明的权利要求范围当中。
序列表
<110> 四川大学
<120> 一种嵌合抗原受体的共刺激信号结构域及其应用
<130> 2020.1.9
<160> 10
<170> SIPOSequenceListing 1.0
<210> 1
<211> 44
<212> PRT
<213> Artificial Sequence
<400> 1
Arg Trp Pro Pro Ser Ala Ala Cys Ser Gly Lys Glu Ser Val Val Ala
1 5 10 15
Ile Arg Thr Asn Ser Gln Ser Asp Phe His Leu Gln Thr Tyr Gly Asp
20 25 30
Glu Asp Leu Asn Glu Leu Asp Pro His Tyr Glu Met
35 40
<210> 2
<211> 21
<212> PRT
<213> Artificial Sequence
<400> 2
Gly Leu Val Val Ala Ile Val Leu Ile Val Leu Cys Leu Ile Gly Leu
1 5 10 15
Ile Val Ala Ile Leu
20
<210> 3
<211> 65
<212> PRT
<213> Artificial Sequence
<400> 3
Gly Leu Val Val Ala Ile Val Leu Ile Val Leu Cys Leu Ile Gly Leu
1 5 10 15
Ile Val Ala Ile Leu Arg Trp Pro Pro Ser Ala Ala Cys Ser Gly Lys
20 25 30
Glu Ser Val Val Ala Ile Arg Thr Asn Ser Gln Ser Asp Phe His Leu
35 40 45
Gln Thr Tyr Gly Asp Glu Asp Leu Asn Glu Leu Asp Pro His Tyr Glu
50 55 60
Met
65
<210> 4
<211> 65
<212> PRT
<213> Artificial Sequence
<400> 4
Met Glu Tyr His Pro Asp Leu Glu Asn Leu Asp Glu Asp Gly Tyr Thr
1 5 10 15
Gln Leu His Phe Asp Ser Gln Ser Asn Thr Arg Thr Ala Val Val Ser
20 25 30
Glu Lys Gly Ser Cys Ala Ala Ser Pro Pro Trp Arg Leu Ile Ala Val
35 40 45
Ile Leu Gly Ile Leu Cys Leu Val Ile Leu Val Ile Ala Val Val Leu
50 55 60
Gly
65
<210> 5
<211> 477
<212> PRT
<213> Artificial Sequence
<400> 5
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 Met Gln Val Gln Leu Gln Gln Ser Gly Pro Glu
20 25 30
Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly
35 40 45
Tyr Pro Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly
50 55 60
Gln Gly Leu Lys Trp Met Gly Trp Ile Asn Thr Ser Thr Gly Glu Ser
65 70 75 80
Thr Phe Ala Asp Asp Phe Lys Gly Arg Phe Asp Phe Ser Leu Glu Thr
85 90 95
Ser Ala Asn Thr Ala Tyr Leu Gln Ile Asn Asn Leu Lys Ser Glu Asp
100 105 110
Ser Ala Thr Tyr Phe Cys Ala Arg Trp Glu Val Tyr His Gly Tyr Val
115 120 125
Pro Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu
145 150 155 160
Thr Gln Ser His Lys Phe Leu Ser Thr Ser Val Gly Asp Arg Val Ser
165 170 175
Ile Thr Cys Lys Ala Ser Gln Asp Val Tyr Asn Ala Val Ala Trp Tyr
180 185 190
Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Ser Ala Ser
195 200 205
Ser Arg Tyr Thr Gly Val Pro Ser Arg Phe Thr Gly Ser Gly Ser Gly
210 215 220
Pro Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala
225 230 235 240
Val Tyr Phe Cys Gln Gln His Phe Arg Thr Pro Phe Thr Phe Gly Ser
245 250 255
Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro
260 265 270
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
275 280 285
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
290 295 300
Phe Ala Cys Asp Gly Leu Val Val Ala Ile Val Leu Ile Val Leu Cys
305 310 315 320
Leu Ile Gly Leu Ile Val Ala Ile Leu Arg Trp Pro Pro Ser Ala Ala
325 330 335
Cys Ser Gly Lys Glu Ser Val Val Ala Ile Arg Thr Asn Ser Gln Ser
340 345 350
Asp Phe His Leu Gln Thr Tyr Gly Asp Glu Asp Leu Asn Glu Leu Asp
355 360 365
Pro His Tyr Glu Met Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
370 375 380
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
385 390 395 400
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
405 410 415
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
420 425 430
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
435 440 445
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
450 455 460
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
465 470 475
<210> 6
<211> 493
<212> PRT
<213> Artificial Sequence
<400> 6
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Ala Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu
20 25 30
Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val
35 40 45
Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys
50 55 60
Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr
65 70 75 80
Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys
85 90 95
Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala
100 105 110
Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met
115 120 125
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
145 150 155 160
Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr
165 170 175
Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr
180 185 190
Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser
195 200 205
Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
210 215 220
Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala
225 230 235 240
Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly
245 250 255
Gly Thr Lys Leu Glu Ile Thr Arg Ala Asp Ala Ala Pro Thr Val Ser
260 265 270
Ile Phe Pro Pro Ser Ser Asn Thr Thr Thr Pro Ala Pro Arg Pro Pro
275 280 285
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
290 295 300
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
305 310 315 320
Phe Ala Cys Asp Gly Leu Val Val Ala Ile Val Leu Ile Val Leu Cys
325 330 335
Leu Ile Gly Leu Ile Val Ala Ile Leu Arg Trp Pro Pro Ser Ala Ala
340 345 350
Cys Ser Gly Lys Glu Ser Val Val Ala Ile Arg Thr Asn Ser Gln Ser
355 360 365
Asp Phe His Leu Gln Thr Tyr Gly Asp Glu Asp Leu Asn Glu Leu Asp
370 375 380
Pro His Tyr Glu Met Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
385 390 395 400
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
405 410 415
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
420 425 430
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
435 440 445
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
450 455 460
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
465 470 475 480
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
485 490
<210> 7
<211> 24
<212> DNA
<213> Artificial Sequence
<400> 7
cgacgcgtat ggccttacca gtga 24
<210> 8
<211> 64
<212> DNA
<213> Artificial Sequence
<400> 8
tgcacacgag ggggctggac ttcgcctgtg atggtctggt cgtggctata gtgctgatag 60
tatt 64
<210> 9
<211> 64
<212> DNA
<213> Artificial Sequence
<400> 9
aatactatca gcactatagc cacgaccaga ccatcacagg cgaagtccag ccccctcgtg 60
tgca 64
<210> 10
<211> 20
<212> DNA
<213> Artificial Sequence
<400> 10
ggactagttt agcgaggggg 20
Claims (32)
1.嵌合抗原受体的共刺激信号结构域，其特征在于，所述共刺激信号结构域包含RD-1胞内区。
2.根据权利要求1所述的共刺激信号结构域，其特征在于，所述共刺激信号结构域包含CD3ζ。
3.根据权利要求1所述的共刺激信号结构域，其特征在于，所述RD-1胞内区包含含有SEQ No.1的氨基酸序列或与所述SEQ No.1不低于90％同一性的氨基酸序列。
4.包含根据权利要求1-3中任一所述的共刺激信号结构域的嵌合抗原受体。
5.根据权利要求4所述的嵌合抗原受体，其特征在于，所述嵌合抗原受体包括依次连接的抗原识别域、CD8α铰链区、跨膜区、RD-1胞内区和CD3ζ。
6.根据权利要求5所述的嵌合抗原受体，其特征在于，所述跨膜区包含的氨基酸序列能够将所述嵌合抗原受体锚定在细胞膜上。
7.根据权利要求6所述的嵌合抗原受体，其特征在于，所述跨膜区包含RD-1跨膜区。
8.根据权利要求7所述的嵌合抗原受体，其特征在于，所述RD-1跨膜区包含含有SEQNo.2氨基酸序列或与所述SEQ No.2不低于90％同一性的氨基酸序列。
9.根据权利要求5所述的嵌合抗原受体，其特征在于，所述抗原识别域是HER2结合域。
10.根据权利要求9所述的嵌合抗原受体，其特征在于，所述嵌合抗原受体包含含有SEQNo.5的氨基酸序列。
11.根据权利要求5所述的嵌合抗原受体，其特征在于，所述抗原识别域是CD19结合域。
12.根据权利要求11所述的嵌合抗原受体，其特征在于，所述的嵌合抗原受体包含含有SEQ No.6的氨基酸序列。
13.权利要求4所述的嵌合抗原受体的合成方法，其特征在于，包括以下步骤：步骤(1)合成RD-1-CD3ζ基因序列；步骤(2)合成嵌合抗原受体基因序列。
14.根据权利要求13所述的合成方法，其特征在于，所述步骤(2)具体包括：先用引物F1、R1扩增抗原识别域和CD8α铰链区结合的基因序列，然后再用引物F2、R2扩增所述RD-1-CD3ζ基因序列，最后以所述抗原识别域和CD8α铰链区结合的基因序列和所述RD-1-CD3ζ基因序列为模板，以F1、R2为引物，合成所述嵌合抗原受体的基因序列。
15.根据权利要求14所述的合成方法，其特征在于，所述引物F1如SEQ No.7所示，R1如SEQ No.8所示，F2如SEQ No.9所示，R2如SEQ No.10所示。
16.根据权利要求4所述的嵌合抗原受体与表达载体构建的重组质粒载体。
17.根据权利要求16所述的重组质粒载体，其特征在于，所述表达载体为pCLK载体。
18.根据权利要求16所述的重组质粒载体的构建方法，其特征在于，包括以MluI和SpeI为酶切位点，连接所述抗原受体基因与所述表达载体，从而获得所述重组质粒载体。
19.根据权利要求4所述的嵌合抗原受体修饰的免疫细胞。
20.根据权利要求19所述的免疫细胞，其特征在于，所述免疫细胞为T淋巴细胞。
21.一种获取根据权利要求19或20所述的免疫细胞的方法，其特征在于，包括以下步骤：以Mlu I和Spe I为酶切位点，连接所述嵌合抗原受体基因与表达载体，得重组质粒载体；将所述重组质粒载体与包装质粒共同转入培养细胞中培养，获得重组病毒颗粒；再用所述重组病毒颗粒对免疫细胞进行修饰。
22.根据权利要求19所述的免疫细胞，其特征在于，所述修饰的方法包括采用病毒载体或非病毒载体系统。
23.根据权利要求22所述的免疫细胞，其特征在于，所述病毒载体系统包括逆转录病毒载体、慢病毒载体、腺病毒载体、腺相关病毒载体和仙台病毒载体中的一种或多种。
24.根据权利要求22所述的免疫细胞，其特征在于，所述非病毒载体系统包括转座子系统、CRISPR基因编辑系统、TALEN系统、脂质体转染系统和电转染系统中的一种或多种。
25.根据权利要求19或20所述的免疫细胞在制备抗肿瘤药物中的应用。
26.包含根据权利要求19或20所述的免疫细胞的抗肿瘤药物组合物。
27.根据权利要求26所述的抗肿瘤药物组合物，其特征在于，还包括化学药物。
28.根据权利要求27所述的抗肿瘤药物组合物，其特征在于，所述化学药物包括环磷酰胺和/或氟达拉滨。
29.根据权利要求19所述的免疫细胞，其特征在于，所述免疫细胞包括B淋巴细胞、K淋巴细胞和NK淋巴细胞中的一种或多种。
30.根据权利要求26所述的抗肿瘤药物组合物，其特征在于，所述抗肿瘤药物组合物为抗乳腺癌和/或抗卵巢癌药物。
31.包含根据权利要求4所述嵌合抗原受体的组合物，其特征在于，还包括与所述共刺激信号结构域结合的β-葡聚糖受体、Syk、CR3和CD11b中的一种或多种。
32.根据权利要求1所述的共刺激信号结构域，其特征在于，所述共刺激信号结构域还包含CD3,CD4,CD8,FcR,DAP10,DAP12,CD27,CD28,CD137,CD134,ICOS,OX40,CD30,CD40,PD-1,LFA-1,CD2,CD7,LIGHI,NKG2C,B7-H3,特异结合CD83的配体，CDS,ICAM-1,GITR,BAFFR,HVEM(IGHTR),SLAMF7,NKp80 KLRE1,CD160,CD19,CD83,IL-2Rβ,IL-Rγ,IL-7Rα,ITGA4,VLA1,CD49α,ITGA4,IA4,CD49D,ITGA6,LA-6,CD49f,ITGAD,CD11d,ITGAE,CD103,ITGAL,CD11α,LFA-1,ITGAM,CDIIB,ITGAX,CD11c,ITGB1,CD29,ITGB2,CD18,LFA-1.ITGB7 TAFR2,TRANCE/RANKL,DNAM1(CD226),SLAMF4(CD244,2B4),CD84,CD96(Tactile),CEACAM1 CRTAM,Ly9(CD229),D160(BY55),PSGL1,CD100(SEMA4D),CD69,SLAMF6(NTB-A,Ly108 SLAM(SLAMF1,CD150,IPO-3),BLAME(SLAME8),SELPLG(CD162),LTBR,LAT,GADS,SLP-76PAG/Cbp,NKp4,NWKp30,NKp46,NKG2D中的一种或多种。
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| CN202010090749.5A CN113248620A (zh) | 2020-02-13 | 2020-02-13 | 一种嵌合抗原受体的共刺激信号结构域及其应用 |
| JP2022548605A JP7466231B2 (ja) | 2020-02-13 | 2021-02-05 | キメラ抗原受容体及びその適用 |
| PCT/CN2021/075544 WO2021160038A1 (zh) | 2020-02-13 | 2021-02-05 | 一种嵌合抗原受体及应用 |
| CN202180000930.5A CN113166274B (zh) | 2020-02-13 | 2021-02-05 | 一种嵌合抗原受体及应用 |
| EP21753498.1A EP4105240A1 (en) | 2020-02-13 | 2021-02-05 | Chimeric antigen receptor and use thereof |
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Application publication date: 20210813 |