CN115141806A - 靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞及其制备方法和应用 - Google Patents
靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供了一种靶向Her2并表达PD‑L1抗体的嵌合抗原受体T细胞,其特征在于,包括靶向Her2的的嵌合抗原受体CAR‑Her2和PD‑L1抗体。其中,CAR‑Her2可以专一性地靶向Her2阳性肿瘤细胞,激活T细胞发挥细胞免疫作用,实现其对Her2阳性肿瘤细胞高效且特异性的杀伤,且具有持久的细胞活力和杀伤力,与此同时,PD‑L1抗体能激活T细胞对肿瘤的免疫应答效应,降低肿瘤细胞逃逸几率,提高CAR‑T细胞治疗耐受性和有效性。
Description
技术领域
本发明涉及医学生物领域,特别涉及靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞及其制备方法和应用。
背景技术
胶质母细胞瘤(GBM)是胶质瘤中恶性程度最高的病理类型,也是原发性脑肿瘤中最常见、最具侵袭性的一种肿瘤,侵袭性强,极易复发。虽然GBM的治疗已发展为手术、放疗和化疗相结合的综合治疗模式,其预后仍很差,整体中位生存期(OS)仅为15个月,5年生存率不到10%。侵袭性恶性肿瘤细胞产生耐药性是GBM复发的根源,从而导致治疗失败。
免疫细胞治疗是现有技术中唯一有可能彻底清除癌细胞的方法,其治疗肿瘤具有特异性强、几乎无毒副作用的巨大优势弥补了传统疗法的弊端,在国内外已经用于临床治疗恶性肿瘤,嵌合抗原受体T细胞技术(CAR-T)为当前过继性细胞回输治疗技术最新的免疫细胞技术之一,因其能够在体内能激活自身免疫系统,持续性地靶向肿瘤细胞进行杀伤,最终达到清除恶性肿瘤细胞的目的而受到广泛的关注和研究。因此,亟需一种可以用于胶质瘤治疗的嵌合抗原受体T细胞。
发明内容
有鉴于此,本发明提供了一种靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞,包括靶向Her2的的嵌合抗原受体CAR-Her2和PD-L1抗体。其中,CAR-Her2可以专一性地靶向Her2阳性肿瘤细胞,激活T细胞发挥细胞免疫作用,实现其对Her2阳性肿瘤细胞高效且特异性的杀伤,且具有持久的细胞活力和杀伤力,与此同时,PD-L1抗体能激活T细胞对肿瘤的免疫应答效应,降低肿瘤细胞逃逸几率,提高CAR-T细胞治疗耐受性和有效性。
第一方面,一种靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞,包括靶向Her2的的嵌合抗原受体CAR-Her2和PD-L1抗体。
可选的,所述CAR-Her2包括从氨基端到羧基端顺次连接的靶向Her2的单链抗体、胞外铰链区、跨膜区和胞内信号区的氨基酸序列,所述靶向Her2的单链抗体的氨基酸序列包括如SEQ ID NO:1所示的氨基酸序列。
在本发明中,所述“从氨基端到羧基端顺次连接”具体为:单链抗体的氨基酸序列的羧基端与所述胞外铰链区的氨基酸序列的氨基端相连,所述胞外铰链区的氨基酸序列的羧基端与所述跨膜区的氨基酸序列的氨基端相连,所述跨膜区的氨基酸序列的羧基端与所述胞内信号区的氨基酸序列的氨基端相连。
本发明中,靶向Her2的单链抗体能特异性识别肿瘤细胞上的Her2蛋白,并与其发生特异性结合,对表达Her2的恶性肿瘤细胞具有较强的亲和活性及内化活性。
在本发明中,所述胞外铰链区用于促进所述靶向Her2的单链抗体与肿瘤上的Her2结合。
可选的,所述胞外铰链区包括CD8α铰链区、CD28铰链区、CD4铰链区、CD5铰链区、CD134铰链区、CD137铰链区、ICOS铰链区中的一种或多种的组合。进一步可选的,所述胞外铰链区包括CD8α铰链区。
在本发明中,所述跨膜区用于固定所述靶向Her2的嵌合抗原受体CAR-Her2。
可选的,所述跨膜区包括CD3跨膜区、CD4跨膜区、CD8跨膜区、CD28跨膜区中的一种或多种的组合。进一步可选的,所述跨膜区包括CD8跨膜区。
在本发明中,所述胞内信号区用于提供T细胞活化的信号,维持T细胞的生存时间和激活T细胞增殖信号通路。
可选的,所述胞内信号区包括4-1BB信号区、CD3ζ信号区、ICOS信号区、CD27信号区、OX40信号区、CD28信号区、IL1R1信号区、CD70信号区、TNFRSF19L信号区中的一种或多种的组合。可选的,所述胞内信号区包括4-1BB信号区和CD3ζ信号区。其中CD3ζ信号区为T细胞的信号传导结构域,4-1BB信号区作为T细胞的共刺激信号,在它们的共同作用下,T细胞在识别抗原后被完全活化。
可选的,所述CAR-Her2的氨基酸序列包括从氨基端到羧基端顺次连接的靶向Her2的单链抗体、CD8α铰链区、CD8跨膜区、4-1BB信号区和CD3ζ信号区的氨基酸序列。
可选的,所述CAR-Her2的氨基酸序列包括如SEQ ID NO:2所示的氨基酸序列。
在本发明中,所述靶向Her2的嵌合抗原受体CAR-Her2的编码基因包括所述靶向Her2的嵌合抗原受体CAR-Her2的氨基酸序列对应的核苷酸序列。
Her2是表皮生长因子受体2,是肿瘤相关抗原,在80%的恶性胶质瘤细胞表面均有表达,而在出生后正常的神经元和胶质细胞表面不表达,是一种特异性较高的免疫治疗靶点;因此,通过CAR-Her2可以专一性地靶向Her2阳性肿瘤细胞,实现其对Her2阳性肿瘤细胞高效且特异性的杀伤。
可选的,所述PD-L1抗体的氨基酸序列包括如SEQ ID NO:3所示的氨基酸序列。
PD-L1为程序性死亡受体-配体1,PD-L1与T细胞表面程序性死亡受体1(PD-1)结合,可以传导抑制性的信号,减低T细胞的增生,使肿瘤细胞发生免疫逃逸。PD-L1在多种实体瘤的肿瘤微环境中表达,包括在癌细胞和肿瘤浸润巨噬细胞中都有表达;因此,通过表达的PD-L1抗体激活T细胞对肿瘤的免疫应答效应,从而达到抗肿瘤的效果。
本发明第一方面提供的靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞具有靶向Her2的嵌合抗原受体,可以专一性地靶向表达Her2的肿瘤细胞,激活T细胞发挥细胞免疫作用,对Her2阳性肿瘤细胞实现高效且特异性的杀伤,具有持久的细胞活力和杀伤力;与此同时,PD-L1抗体通过与肿瘤细胞或肿瘤浸润免疫细胞上表达的PD-L1结合,激活T细胞对肿瘤的免疫应答效应,降低肿瘤细胞逃逸几率,提高CAR-T细胞治疗耐受性和有效性。
第二方面,本发明提供了一种靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞的制备方法,包括:
提供靶向Her2的嵌合抗原受体CAR-Her2的编码基因和PD-L1抗体的编码基因,将所述CAR-Her2的编码基因和所述PD-L1抗体的编码基因插入到同一基因传递载体中,得到重组基因传递载体;
将所述重组基因传递载体进行包装并转染宿主细胞,得到重组慢病毒;
将所述重组慢病毒转染CD3阳性T淋巴细胞,获得靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞。
可选的,所述CAR-Her2的编码基因包括从5’端到3’端顺次连接的信号肽的编码基因、靶向Her2的单链抗体的编码基因、胞外铰链区的编码基因、跨膜区的编码基因、胞内信号区的编码基因,其中,所述靶向Her2的单链抗体的编码基因包括如SEQ ID NO:1所示的氨基酸序列对应的核苷酸序列。
上述“从5’端到3’端顺次连接”具体为:所述信号肽的编码基因序列的3’端与单链抗体的编码基因的5’端相连,所述单链抗体的编码基因的3’端与所述胞外铰链区的编码基因的5’端相连,所述胞外铰链区的编码基因的3’端与所述跨膜区的编码基因的5’端相连,所述跨膜区的编码基因的3’端与所述胞内信号区的编码基因的5’端相连。
在本发明中,所述信号肽用于指导所述嵌合抗原受体CAR-Her2表达到细胞表面,所述信号肽在蛋白翻译成熟过程中被信号肽酶切割。
可选的,所述信号肽的氨基酸序列包括如SEQ ID NO:4所示的氨基酸序列。
所述胞外铰链区、跨膜区、胞内信号区的具体选择及相应的编码基因序列如本发明第二方面部分所述,这里不再赘述。
可选的,所述CAR-Her2的编码基因包括从5’端到3’端顺次连接的信号肽的编码基因、靶向Her2的单链抗体的编码基因、CD8α铰链区的编码基因、CD8跨膜区的编码基因、4-1BB信号区的编码基因和CD3ζ信号区的编码基因。
可选的,所述CAR-Her2的编码基因包括如SEQ ID NO:2所示的氨基酸序列对应的核苷酸序列。
可选的,所述PD-L1抗体的编码基因包括如SEQ ID NO:3所示的氨基酸序列对应的核苷酸序列。
可选的,所述PD-L1抗体的编码基因包括从5’端到3’端顺次连接的介导翻译元件。其中,所述介导翻译元件用于介导核糖体对所述PD-L1抗体的编码基因进行翻译。进一步的,所述介导翻译元件包括内部核糖体进入位点(IRES)和自剪切多肽2A中的至少一种。更进一步的,所述介导翻译元件为IRES。
可选的,所述PD-L1抗体的编码基因包括从5’端到3’端顺次连接的IRES的编码基因和如SEQ ID NO:3所示的氨基酸序列对应的核苷酸序列。IRES能招募核糖体对mRNA进行翻译,有利于PD-L1抗体的表达。更进一步的,所述IRES的编码基因包括如SEQ ID NO:5所示的核苷酸序列。
可选的,将所述CAR-Her2的编码基因和所述PD-L1抗体的编码基因插入到同一基因传递载体中,得到重组基因传递载体,包括:将所述CAR-Her2的编码基因和所述PD-L1抗体的编码基因按顺序插入到基因传递载体中。具体的,可以先将所述CAR-Her2的编码基因插入其中,再插入所述PD-L1抗体的编码基因;也可以先插入所述PD-L1抗体的编码基因,再插入所述CAR-Her2的编码基因。其中,在所述重组基因传递载体中,所述CAR-Her2的编码基因和所述PD-L1抗体的编码基因的连接顺序不限定,所述CAR-Her2的编码基因可以在所述PD-L1抗体的编码基因上游,或所述PD-L1抗体的编码基因可以在所述CAR-Her2的编码基因上游。
可选的,所述CAR-Her2的编码基因插入到pWPXLD载体中BamHⅠ和EcoRⅠ酶切位点之间,且位于pWPXLD载体的EF1α之后,以EF1α为启动子。所述CAR-Her2的编码基因插入到pWPXLD载体时,所述CAR-Her2的编码基因的5’端可加入起始密码子(如ATG)与pWPXLD载体中BamHⅠ酶切位点相连,3’端可加入终止密码子(如TAA)与pWPXLD载体中EcoRⅠ酶切位点相连。可选的,所述PD-L1抗体的编码基因插入到pWPXLD载体中SpeⅠ和NdeⅠ酶切位点之间。
可选的,将所述重组基因传递载体进行包装并转染宿主细胞,得到重组慢病毒,包括:将所述重组基因传递载体与包膜质粒和包装质粒共同转染宿主细胞,得到所述重组慢病毒。进一步的,所述包膜质粒为PMD2G,所述包装质粒为psPAX2,所述宿主细胞为HEK293T细胞。所述包膜质粒PMD2G编码水疱性口炎病毒糖蛋白衣壳,所述水疱性口炎病毒糖蛋白衣壳协助重组慢病毒向细胞膜粘附,并保持重组慢病毒的感染性。
本发明所述重组慢病毒可以进一步含有来自其它病毒的被膜蛋白。例如,作为这种蛋白质,最好是来自感染人类细胞的病毒被膜蛋白。对这种蛋白质没有特别的限定,如逆转录病毒的兼嗜性病毒手皮膜蛋白等,例如可以使用来自小鼠白血病病毒(MuMLV)4070A株的被膜蛋白。另外,也可以使用来自MuMLV10Al的被膜蛋白。另外,作为疱疹病毒科的蛋白,如单纯性疱疹病毒的gB、gD、gH、gp85蛋白,EB病毒的gp350、gp220蛋白等。作为嗜肝病毒科的蛋白,如B型肝炎病毒的S蛋白等。所述被膜蛋白还可为麻疹病毒糖蛋白与其他单链抗体融合后形成。
重组慢病毒的包装通常采用瞬时转染或采用细胞系包装。瞬时转染时可以用作包装细胞使用的人类细胞株,例如包括293细胞、293T细胞、293FT细胞、293LTV细胞、293EBNA细胞及其他的从293细胞分离的克隆;SW480细胞、u87MG细胞、HOS细胞、C8166细胞、MT-4细胞、Molt-4细胞、HeLa细胞、HT1080细胞、TE671细胞等。也可以采用来源于猴子的细胞株,例如,COS1细胞、COS7细胞、CV-1细胞、BMT10细胞等。而且,通常采用的磷酸钙和PEI转染试剂,还有一些转染试剂如Lipofectamine2000、FuGENE和S93fectin也被经常使用。
重组慢病毒的包装也采用一些慢病毒包装细胞系,如使用最普遍的Env糖蛋白、VSVG蛋白或HIV-1gag-pol蛋白所产生的稳定细胞系。
为了安全起见,大规模使用的慢病毒载体系统都是采用分割基因组的方法,即将起不同辅助功能的基因定位于不同的质粒。目前有四质粒系统(编码gag-pol基因、Rev基因、VSVG基因、SIN转移基因分别位于四个不同的质粒)、三质粒系统(去掉了编码Rev基因的质粒,在gag-pol质粒中gag-pol基因采用了在人细胞中偏爱性的密码子)和二质粒系统(慢病毒载体包装所必需的辅助基因位于同一个质粒上,这些辅助基因是单一的基因序列;另一个则是转基因质粒)。也有超过四质粒系统的慢病毒包装系统在使用。
可选的,所述CD3阳性T淋巴细胞是从人源外周血单个核细胞中分离获得。进一步的,所述人源外周血单个核细胞来源于自体静脉血、自体骨髓、脐带血和胎盘血等。进一步的,来源于癌症患者手术一个月后、放化疗一个月后采集的新鲜外周血或骨髓。
具体的,所述CD3阳性T淋巴细胞的获得过程如下:向外周血单个核细胞中按一定比例加入CD3/CD28免疫磁珠,孵育一段时间后,放入磁铁进行筛选,得到免疫磁珠包被的CD3阳性T淋巴细胞,去除磁珠后,获得CD3阳性T淋巴细胞。
第三方面,本发明提供了一种重组载体,所述重组载体包括如第一方面所述的或如第二方面所述的制备方法制得的靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞中所述CAR-Her2和所述PD-L1抗体的编码基因。
在本发明中,所述载体可以但不限于为基因传递载体。
可选的,所述载体为病毒载体和非病毒载体中的至少一种。
进一步的,所述非病毒载体包括质粒载体和噬菌体载体。具体的,所述质粒载体可以但不限于为真核质粒载体、原核质粒载体、微环DNA、转座子等。进一步的,所述病毒载体包括慢病毒载体、腺病毒载体或逆转录病毒载体。更进一步的,所述病毒载体为慢病毒载体。
本发明第三方面提供的重组载体安全高效,可以稳定地实现将CAR-Her2和PD-L1抗体的编码基因导入宿主细胞中或复制,并可以用于嵌合抗原受体T细胞的制备。
第四方面,本发明提供了一种宿主细胞,所述宿主细胞包括如第三方面所述的重组载体。
可选的,当所述重组载体为重组病毒载体时,所述宿主细胞可以用于组装所述重组病毒载体,使其具有感染性。进一步的,所述宿主细胞可以包括HEK293T细胞、293细胞、293T细胞、293FT细胞、SW480细胞、u87MG细胞、HOS细胞或COS7细胞等,但不限于此。更进一步的,所述宿主细胞为HEK293T细胞。
可选的,当所述重组质粒为重组真核质粒载体、重组原核质粒载体和重组微环DNA时,所述宿主细胞为相应的真核宿主细胞或原核宿主细胞。
本发明第四方面提供的宿主细胞可以稳定保存CAR-Her2和PD-L1抗体的编码基因,有利于靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞的制备。
第五方面,本发明提供了一种如第一方面所述的或如第二方面所述的制备方法制得的靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞、如第三方面所述的重组载体或如第四方面所述的宿主细胞在制备预防、诊断和治疗恶性肿瘤的药物中的应用。
在应用中,给药方式可以但不限于为静脉注射、肿瘤原位注射、皮下注射等。具体应用时选择的剂量、次数等根据实际需要进行选择,对此不做限定。
所述应用具体为:提供了一种试剂盒,所述试剂盒包括第一方面所述的靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞、第三方面所述的重组载体或第四方面所述的宿主细胞中的一种或多种。
在本发明中,所述恶性肿瘤包括表达Her2的肿瘤,进一步的包括高表达Her2的肿瘤。可选的,所述恶性肿瘤包括恶性脑胶质瘤、乳腺癌、卵巢癌、胃癌、食管癌、肺癌、胆管癌、膀胱癌、前列腺癌和结直肠癌中的至少一种。本发明的靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞可以高效识别并杀伤表达有Her2的癌细胞,尤其适用于恶性脑胶质瘤细胞。
附图说明
图1为本发明实施例提供的pWPXLD-CAR-Her2重组质粒的质粒图谱。
图2为本发明实施例提供的pWPXLd-CAR-Her2-PD-L1重组质粒的质粒图谱。
图3为效果实施例中杀伤效果检测结果。
具体实施方式
以下所述是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也视为本发明的保护范围。
实施例一
一种靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞的制备方法,包括:
(1)制备靶向Her2的嵌合抗原受体CAR-Her2的基因序列
提供SEQ ID NO:2所示的氨基酸序列对应的核苷酸序列(CAR-Her2的基因序列),在其5’端添加如SEQ ID NO:4所示的氨基酸序列对应的核苷酸序列(信号肽的基因序列)。
(2)制备PD-L1抗体的基因序列
提供SEQ ID NO:3所示的氨基酸序列对应的核苷酸序列,在其5’端添加如SEQ IDNO:5所示的核苷酸序列。
(3)构建pWPXLd-CAR-Her2重组质粒
将步骤(1)的核苷酸序列插入到pWPXLD载体的BamHⅠ和EcoRⅠ酶切位点之间,并在pWPXLD载体EF1α之后,以EF1α为启动子。上述核苷酸序列插入到pWPXLD载体时,在上述核苷酸序列的5’端可加入起始密码子(如ATG)与pWPXLD载体中BamHⅠ酶切位点相连,3’端可加入终止密码子(如TAA)与pWPXLD载体中EcoRⅠ酶切位点相连。然后转入大肠杆菌感受态细胞DH5α,进行阳性克隆PCR鉴定和测序鉴定。经过PCR产物凝胶电泳检测和测序鉴定符合目的片段大小和序列,成功构建pWPXLD-CAR-Her2重组质粒,如图1所示为pWPXLD-CAR-Her2重组质粒的质粒图谱。
(4)构建pWPXLd-CAR-Her2-PD-L1重组质粒
采用SpeⅠ和NdeⅠ两种限制性内切酶于37℃酶切pWPXLD-CAR-Her2重组质粒30min,电泳回收后,将步骤(2)的核苷酸序列插入到pWPXLD-CAR-Her2重组质粒SpeⅠ和NdeⅠ酶切位点之间。然后转入大肠杆菌感受态细胞DH5α,进行阳性克隆PCR鉴定和测序鉴定。经过PCR产物凝胶电泳检测和测序鉴定符合目的片段大小和序列,成功构建pWPXLd-CAR-Her2-PD-L1重组质粒,如图2所示为pWPXLd-CAR-Her2-PD-L1重组质粒的质粒图谱。
(5)重组慢病毒构建
将pWPXLd-CAR-Her2-PD-L1重组质粒、包装质粒psPAX2、包膜质粒pMD2G三者共转染入培养好的HEK293T细胞。第48h收获含病毒的上清,经0.45μm滤膜过滤,-80℃超低温冰箱中保存;第72h二次收获含病毒的上清,0.45μm滤膜过滤,与第48h收获的病毒上清合并一起加入超速离心管中,逐一放入至Beckman超速离心机内,设置离心参数为25000rpm,离心时间为2h,离心温度控制在4℃;离心结束后,弃去上清,尽量去除残留在管壁上的液体,加入病毒保存液,轻轻反复吹打重悬;经充分溶解后,高速离心10000rpm,离心5min后,取上清荧光法测定滴度,病毒按照100μl,2×108个/mL分装,保存于-80℃超低温冰箱,得到重组慢病毒。
(6)靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞的制备
a)PBMC(外周血单个核细胞)的分离
PBMC来源于自体静脉血、自体骨髓、脐带血和胎盘血等。最好是来源于癌症患者手术一个月后、放化疗一个月后采集的新鲜外周血或骨髓。
抽取病人血液,送样至血液分离室;采集外周血单个核细胞,Ficoll离心分离后取中间层细胞;经PBS洗涤后,得到PBMC。
b)免疫磁珠法分离抗原特异性T淋巴细胞
取上述PBMC,加入不含血清的基础培养基,配成细胞悬液;按磁珠与细胞的比例为3:1,加入CD3/CD28免疫磁珠,室温孵1-2h;采用磁铁对孵育好磁珠的细胞进行筛选;PBS洗涤,去除免疫磁珠后,得到CD3阳性T淋巴细胞。
c)病毒转染法制备抗原特异性T淋巴细胞
取上述经过免疫磁珠分离法得到的CD3阳性T淋巴细胞,加入与CD3阳性细胞数相应的病毒滴度的重组慢病毒进行共同培养。
培养的第3天,进行细胞计数和换液,调整细胞浓度为1×106个/mL,接种,培养;培养的第5天,观察细胞状态,如果细胞密度增大,则稀释细胞浓度为1×106个/mL,检测细胞活性,继续培养。扩增培养到第9-11天,收集细胞,制得靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞,将其保存在回输专用的细胞冻存液中。
效果实施例
为了评估本发明所描述的上述方法制备的靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞,进行如下效果实施例。
将经过本发明方法制得的靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞(实验组)与靶向Her2嵌合抗原受体T细胞(对照组)、T淋巴细胞(阴性对照组)的体外肿瘤杀伤效果进行比较,U373细胞作为空白对照组,具体的:在体外将效应细胞(靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞/靶向Her2嵌合抗原受体T细胞/T淋巴细胞)与靶细胞(U373细胞)数量比为2:1的比例,在37℃,5%CO2的细胞板中共培养;在培养后的15h-18h,收集细胞,进行流式染色,检测细胞杀伤情况。细胞杀伤效果检测结果如图3所示,靶向Her2嵌合抗原受体T细胞的细胞肿瘤杀伤率为53%,本发明制备的靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞的细胞肿瘤杀伤率为80%,高于靶向Her2嵌合抗原受体T细胞的细胞肿瘤杀伤率,且远远高于阴性对照组。本发明提供的靶向Her2并表达PD-L1抗体避免了肿瘤抑制,激活T细胞杀伤功能,提高了细胞杀伤效率,该靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞在制备预防、诊断和治疗恶性肿瘤的药物中具有非常可观的应用前景。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
序列表
<110> 深圳宾德生物技术有限公司
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Claims (10)
1.一种靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞,其特征在于,包括靶向Her2的的嵌合抗原受体CAR-Her2和PD-L1抗体。
2.如权利要求1所述的靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞,其特征在于,所述CAR-Her2包括从氨基端到羧基端顺次连接的靶向Her2的单链抗体、胞外铰链区、跨膜区和胞内信号区的氨基酸序列,所述靶向Her2的单链抗体的氨基酸序列包括如SEQ ID NO:1所示的氨基酸序列。
3.如权利要求1所述的靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞,其特征在于,所述CAR-Her2的氨基酸序列包括如SEQ ID NO:2所示的氨基酸序列。
4.如权利要求1所述的靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞,其特征在于,所述PD-L1抗体的氨基酸序列包括如SEQ ID NO:3所示的氨基酸序列。
5.一种靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞的制备方法,其特征在于,包括:
提供靶向Her2的嵌合抗原受体CAR-Her2的编码基因和PD-L1抗体的编码基因,将所述CAR-Her2的编码基因和所述PD-L1抗体的编码基因插入到同一基因传递载体中,得到重组基因传递载体;
将所述重组基因传递载体进行包装并转染宿主细胞,得到重组慢病毒;
将所述重组慢病毒转染CD3阳性T淋巴细胞,获得靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞。
6.如权利要求5所述的制备方法,其特征在于,所述CAR-Her2的编码基因包括从5’端到3’端顺次连接的信号肽的编码基因、靶向Her2的单链抗体的编码基因、胞外铰链区的编码基因、跨膜区的编码基因、胞内信号区的编码基因,其中,所述靶向Her2的单链抗体的编码基因包括如SEQ ID NO:1所示的氨基酸序列对应的核苷酸序列。
7.如权利要求5所述的制备方法,其特征在于,所述PD-L1抗体的编码基因包括如SEQID NO:3所示的氨基酸序列对应的核苷酸序列。
8.一种重组载体,其特征在于,包括如权利要求1-4任一项所述的或如权利要求5-7任一项所述的制备方法制得的靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞中所述CAR-Her2和所述PD-L1抗体的编码基因。
9.一种宿主细胞,其特征在于,包括如权利要求8所述的重组载体。
10.一种如权利要求1-4任一项所述或如权利要求5-7任一项所述的制备方法制得的靶向Her2并表达PD-L1抗体的嵌合抗原受体T细胞、如权利要求8所述的重组载体或如权利要求9所述的宿主细胞在制备预防、诊断和治疗恶性肿瘤的药物中的应用。
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CN116514998A (zh) * | 2023-05-12 | 2023-08-01 | 再少年(北京)生物科技有限公司 | 一种嵌合抗原受体、嵌合抗原受体-自然杀伤细胞及其在制备抗肿瘤药物中的应用 |
CN116514998B (zh) * | 2023-05-12 | 2023-09-15 | 再少年(北京)生物科技有限公司 | 一种嵌合抗原受体、嵌合抗原受体-自然杀伤细胞及其在制备抗肿瘤药物中的应用 |
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