CN110396131B - 一种ErbB2单链抗体、靶向人ErbB2的嵌合抗原受体、重组载体、重组细胞和应用 - Google Patents
一种ErbB2单链抗体、靶向人ErbB2的嵌合抗原受体、重组载体、重组细胞和应用 Download PDFInfo
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Abstract
本发明提供了一种ErbB2单链抗体、靶向人ErbB2的嵌合抗原受体、重组载体、重组细胞和应用,属于肿瘤免疫生物治疗技术领域,所述ErbB2单链抗体,具有如SEQ ID No.1所示的氨基酸序列;所述靶向人ErbB2的嵌合抗原受体,具有如SEQ ID No.3所示的氨基酸序列;所述重组载体包括编码所述嵌合抗原受体的基因和初始载体;所述重组细胞,包括自然杀伤细胞和所述的重组载体。本发明所述ErbB2单链抗体能够特异性识别肿瘤抗原,避免了CAR‑NK细胞的脱靶效应,有良好的肿瘤细胞杀伤作用;所述重组细胞具有较高的连续杀伤肿瘤细胞的能力,降低了细胞因子风暴的风险。
Description
技术领域
本发明属于肿瘤免疫生物治疗技术领域,尤其涉及一种ErbB2单链抗体、靶向人ErbB2的嵌合抗原受体、重组载体、重组细胞和应用。
背景技术
传统的肿瘤治疗手段主要有手术、放射治疗、化疗,以及近年兴起的干细胞移殖等,而这些治疗手段往往是治标不治本。随着科学的发展,肿瘤的免疫治疗近年来实现了巨大的突破,其中主要包括免疫检查点抑制剂(例如anti-PD1单克隆抗体),以及嵌合抗原受体T细胞免疫疗法(Chimeric Antigen Receptor Modified T cell therapy,CAR-T)。近年来,CAR-T技术在血液性疾病治疗临床试验取得了令人鼓舞的进展,被《Science》杂志评为2013年十大科学突破之首。从2013年宾夕法尼亚大学Carl June小组报道第一例使用靶向CD19 CAR-T治疗患有急性B淋巴细胞性白血病的儿童(Emily Whitehead)得到完全缓解开始,短短几年时间CAR-T细胞免疫疗法发展迅猛。与此同时,将嵌合抗原受体表达于NK细胞,尤其是工程化的NK细胞解决了T细胞治疗难以大批量生产的问题,并且杀伤肿瘤效果好。CAR-NK细胞治疗是当前靶向性最高,一致性最佳,疗效最好的细胞免疫疗法。
CAR-NK细胞是能够经过基因工程手段在NK细胞表面表达识别特定抗原并且传递信号的一类NK细胞。一般地,CAR-NK细胞通过嵌合抗原受体CAR以抗原-抗体或配体-受体识别模式对肿瘤细胞表面的特异分子进行识别,然后通过其胞内的信号传导进行激活、增殖并发挥细胞杀伤功能。经嵌合抗原受体修饰的NK细胞,可以特异性地识别肿瘤相关抗原,使效应NK细胞的靶向性、杀伤活性和持久性均较常规应用的免疫细胞高,并可克服肿瘤局部免疫抑制微环境,打破宿主免疫耐受状态。
经修饰的NK细胞表达这样的一类嵌合抗原受体分子:胞外段一般包含CD8α或GMCSFRα信号肽,抗原识别区或抗原结合结构域,包含由抗体重链和轻链可变区组成的单链可变区;胞内段是各种信号传导分子的胞内段嵌合体,包括CD28、4-1BB、OX-40、CD3zeta等,跨膜区则来自其他分子,如PD1、CD8、CD4、CD28、CD3zeta(CD3ζ)等。目前在CAR-T领域,CD28胞内信号结构域与4-1BB胞内信号结构域联合应用的设计思路称为第三代CAR-T,可以良好的诱发杀伤肿瘤靶细胞的效应作用。在抗原识别结构域的亲和力上,如果使用ScFv形式的抗体片段,其亲和力并不是越高越好。由于天然NK细胞受体的亲和力Kd值约在10-4至10-6M级别,Drent等人发现,降低CD38靶点的CAR结构对靶蛋白的亲和力有助于提高细胞的增殖,提高杀伤的分辨率,而相对减少对正常组织的破坏(Drent E,Themeli M,Poels R,deJong-Korlaar R,Yuan H,de Bruijn J,et al.A Rational Strategy for Reducing On-Target Off-Tumor Effects of CD38-Chimeric Antigen Receptors by AffinityOptimization.Molecular therapy:thejournal of the American Society of GeneTherapy.2017;25(8):1946-58.)。另有学者发现(Liu X,Jiang S,Fang C,Yang S,OlalereD,Pequignot EC,et al.Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor TCells Exhibit an Increased Therapeutic Index against Tumors in Mice.Cancerresearch.2015;75(17):3596-607.),亲和力高于10-7M的抗体构成的CAR结构,无法带来更高水平的细胞激活。因此,调节CAR结构的亲和力将有助于提高CAR-NK细胞的杀伤潜力,增殖效率以及安全性。
ErbB2(又名ErbB2,NEU,CD340)是原癌基因erbB-2编码的185kDa的细胞膜受体,为表皮生长因子受体(epidermal growth factor receptor,EGFR)家族成员之一。ErbB2高表达肿瘤细胞中Ras-MAPK和PI3K-Akt,信号传导活性较高,细胞增殖能力较强,分化成熟和凋亡机制受到抑制,细胞恶性程度高。临床上ErbB2表达与患者预后密切相关,ErbB2高表达的患者易发生肿瘤转移,存活期短。由于ErbB2在正常细胞和肿瘤细胞中的表达水平具有显著的差异,因而已成为肿瘤免疫生物治疗的理想靶点,亦是目前肿瘤治疗研究领域的热点分子。但是,目前的CAR-NK细胞毒副作用大、杀伤肿瘤细胞的作用不持久。
发明内容
有鉴于此,本发明的目的在于提供一种ErbB2单链抗体、靶向人ErbB2的嵌合抗原受体、重组载体、重组细胞和应用;所述ErbB2单链抗体能够特异性识别肿瘤抗原,避免了CAR-NK细胞的脱靶效应,有良好的肿瘤细胞杀伤作用;所述靶向人ErbB2的嵌合抗原受体修饰的NK免疫细胞具有较高的连续杀伤能力,降低了细胞因子风暴的风险。
为了实现上述发明目的,本发明提供了以下技术方案:
本发明提供了一种ErbB2单链抗体,具有如SEQ ID No.1所示的氨基酸序列。
本发明提供了编码所述ErbB2单链抗体的基因,具有如SEQ ID No.2所示的核苷酸序列。
本发明提供了一种包括所述单链抗体的靶向人ErbB2的嵌合抗原受体,具有如SEQID No.3所示的氨基酸序列。
本发明提供了编码所述的嵌合抗原受体的基因,具有如SEQ ID No.4所示的核苷酸序列。
本发明提供了一种重组载体,包括编码所述的嵌合抗原受体的基因和初始载体。
优选的,所述初始载体为慢病毒载体。
优选的,所述慢病毒载体为pCDH-MSCV-MCS-EF1-copGFP。
本发明提供了一种重组细胞,包括自然杀伤细胞和所述的重组载体。
优选的,所述自然杀伤细胞为NK92细胞。
本发明提供了所述的重组细胞在制备治疗肿瘤的靶向药物中的应用。
本发明的有益效果:本发明提供了一种ErbB2单链抗体、靶向人ErbB2的嵌合抗原受体、重组载体、重组细胞和应用;在本发明中,所述ErbB2单链抗体是一种靶向乳腺癌细胞的单链抗体(ScFv),具有与人乳腺癌细胞结合的活性。本发明中所述靶向人ErbB2的嵌合抗原受体,顺次包括GM-CSF信号肽区、ErbB2单链抗体区、CD8跨膜区、CD28胞内区、4-1BB胞内区和CD3ζ胞内区,能够特异性的与肿瘤细胞表面抗原结合,将所述靶向人ErbB2的嵌合抗原受体转入细胞中获得重组细胞,所述靶向人ErbB2的嵌合抗原受体能够确保所述重组细胞靶向定位于肿瘤细胞,并发挥杀伤作用,避免所述重组细胞的脱靶效应,使所述重组细胞具有良好的肿瘤细胞杀伤作用。
本发明提供的所述重组细胞的亲和力与天然的自然杀伤细胞(NK细胞)相似,适度的亲和力有利于嵌合抗原受体结合触发杀伤后,NK细胞转向下个靶细胞,连续杀伤效果好,而且细胞因子释放反应更为温和。根据实施例记载,以HER2抗原靶点为例,本发明提供的靶向人ErbB2的嵌合抗原受体显示了持久的多次杀伤肿瘤细胞能力,包括所述靶向人ErbB2的嵌合抗原受体的重组NK细胞具有较高的连续杀伤能力,降低了细胞因子风暴的风险。
附图说明
图1为实施例1中筛选得到的不同单克隆抗体的EC50值;
图2为实施例1中所述的ErbB2单链抗体的抗体亚型分析图;
图3为流式细胞术分析分选后得到的CAR-NK细胞与野生型NK92细胞GFP表达量;
图4为流式细胞术分析分选后得到的CAR-NK细胞与野生型NK92细胞ErbB2蛋白结合量;
图5为19G9 CAR-NK细胞与4D5 CAR-NK细胞对表达ErbB2靶细胞的连续杀伤能力的比较;
图6为19G9 CAR-NK细胞与4D5 CAR-NK细胞对表达ErbB2靶细胞杀伤力的比较;
图7为19G9 CAR-NK细胞与4D5 CAR-NK细胞与表达ErbB2靶细胞的接触率的比较。
具体实施方式
本发明提供了一种ErbB2单链抗体,具有如SEQ ID No.1所示的氨基酸序列;如SEQID No.1所示的氨基酸序列具体如下:
LEQSGPGILQPSQTLSLICSFSGFSLSTSGMGVSWIRQPSGKGLEWLAHIYWDDDKRYNPSLKSRLTISKDTSSKQVFLKITSVDTADTATYYCALFAYYNYDGTVDYWGLGTSVTVSSGGGGSGGGGSGGGGSDIVMTQTPSSLAVSVGEKVTMSCKSSQSLLHSRTRKNYLAWYQQKLGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVEAEDLAVYYCKQSYNLYTFGGGTKLEIK。
在本发明中,所述ErbB2单链抗体包括轻链可变区、重链可变区以及连接所述轻链可变区和重链可变区的连接序列;所述轻链可变区的氨基酸序列如SEQ ID No.5所示;所述重链可变区的氨基酸序列如SEQ ID No.6所示;所述连接序列的氨基酸序列如SEQ ID No.7所示。
本发明还提供了编码所述ErbB2单链抗体的基因,具有如SEQ ID No.2所示的核苷酸序列;如SEQ ID No.2所示的核苷酸序列具体如下:
ctggagcagtcaggccctgggatattgcagccctcccagaccctcagtttgatctgttctttctctgggttttcactgagtacttctggtatgggtgtaagctggattcgccagccttcaggaaagggtctggagtggctggcacacatttactgggatgatgacaagcgctataacccatccctgaagagccggctcacaatctccaaggatacctccagcaagcaggttttcctcaagatcaccagtgttgacactgcagatactgccacatactactgtgctctcttcgcctactataactacgacgggactgtggactactggggtctaggaacctcagtcaccgtctcctcaggcggaggcggatcaggtggtggcggatctggaggtggcggaagcgacattgtgatgacacagactccatcctccctggctgtgtcagtaggagagaaggtcactatgagctgcaaatccagtcagagtctgctccacagtagaacccgaaagaactatttggcttggtatcagcagaaactagggcagtctcctaaactactgatctactgggcatccactagggaatctggggtccctgatcgcttcacaggcagtggctctgggacagatttcactctcaccatcagcagtgtggaggctgaagacctggcagtttattactgcaagcaatcttataatctgtacacgttcggaggggggaccaagctggaaataaaa。
在本发明中,编码所述ErbB2单链抗体的基因包括编码所述轻链可变区、所述重链可变区以及所述连接序列的基因;编码所述轻链可变区的基因的核苷酸序列如SEQ IDNo.8所示;编码所述重链可变区的基因的核苷酸序列如SEQ ID No.9所示;编码所述连接序列的基因的核苷酸序列如SEQ ID No.10所示。
本发明提供了一种包括所述单链抗体的靶向人ErbB2的嵌合抗原受体,具有如SEQID No.3所示的氨基酸序列;如SEQ ID No.3所示的氨基酸序列具体如下:
LLLVTSLLLCELPHPAFLLIPLEQSGPGILQPSQTLSLICSFSGFSLSTSGMGVSWIRQPSGKGLEWLAHIYWDDDKRYNPSLKSRLTISKDTSSKQVFLKITSVDTADTATYYCALFAYYNYDGTVDYWGLGTSVTVSSGGGGSGGGGSGGGGSDIVMTQTPSSLAVSVGEKVTMSCKSSQSLLHSRTRKNYLAWYQQKLGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVEAEDLAVYYCKQSYNLYTFGGGTKLEIKATTTATATTTGGGCACCACTTGCAGGGACGTGCGGCGTACTGCTTCTGTCTCTCGTGATTACTCTTTATTGTAATCATAGGAACRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR。
在本发明中,所述单链抗体的靶向人ErbB2的嵌合抗原受体顺次包括GM-CSF信号肽区、ErbB2单链抗体区、CD8跨膜区、CD28胞内区、4-1BB胞内区和CD3ζ胞内区;在本发明中,所述GM-CSF信号肽区、CD8跨膜区、CD28胞内区、4-1BB胞内区和CD3ζ胞内区的氨基酸序列依次如SEQ ID No.11~SEQ ID No.15所示。在本发明中,所述ErbB2单链抗体区能够特异性识别肿瘤细胞抗原,能够靶向肿瘤细胞;所述GM-CSF信号肽促进CAR分子蛋白合成后跨膜转移;所述CD8跨膜区提供CAR分子跨膜表达的结构;所述CD28胞内区、4-1BB胞内区和CD3ζ胞内区三者联用提供NK细胞结合靶细胞之后激活并杀伤的信号。
本发明提供了编码所述的嵌合抗原受体的基因,具有如SEQ ID No.4所示的核苷酸序列;所述如SEQ ID No.4所示的核苷酸序列具体如下:
cttctcctggtgacaagccttctgctctgtgagttaccacacccagcattcctcctgatcccactggagcagtcaggccctgggatattgcagccctcccagaccctcagtttgatctgttctttctctgggttttcactgagtacttctggtatgggtgtaagctggattcgccagccttcaggaaagggtctggagtggctggcacacatttactgggatgatgacaagcgctataacccatccctgaagagccggctcacaatctccaaggatacctccagcaagcaggttttcctcaagatcaccagtgttgacactgcagatactgccacatactactgtgctctcttcgcctactataactacgacgggactgtggactactggggtctaggaacctcagtcaccgtctcctcaggcggaggcggatcaggtggtggcggatctggaggtggcggaagcgacattgtgatgacacagactccatcctccctggctgtgtcagtaggagagaaggtcactatgagctgcaaatccagtcagagtctgctccacagtagaacccgaaagaactatttggcttggtatcagcagaaactagggcagtctcctaaactactgatctactgggcatccactagggaatctggggtccctgatcgcttcacaggcagtggctctgggacagatttcactctcaccatcagcagtgtggaggctgaagacctggcagtttattactgcaagcaatcttataatctgtacacgttcggaggggggaccaagctggaaataaaattcgtgccagtattcctgcccgcgaagcccactactactcccgcccctaggccacctacaccggcccccacaattgcatcacaaccactcagcctccggcccgaagcttgccgccccgctgctgggggcgccgtgcacactcggggcctggactttgcctgcgatatttatatttgggcaccacttgcagggacgtgcggcgtactgcttctgtctctcgtgattactctttattgtaatcataggaaccgatctaagcggtccagactgctccacagtgattacatgaacatgaccccacgcaggcctgggccaacacgaaaacactatcagccttacgcacctccccgcgactttgctgcctaccgctctagattcagcgtggtgaagcgaggaagaaaaaaactcctttatatattcaagcagcctttcatgcgacctgtccagacaactcaggaagaagacggctgttcttgtaggttcccagaagaggaagagggaggctgcgagctgcgcgtcaaattctcccgatcagcagatgcacccgcataccaacagggacagaaccagctgtacaacgaactgaatcttggaagaagggaggagtacgatgtgcttgataaaaggcgcggccgggaccccgaaatgggcggtaagcctagacgaaaaaatcctcaagagggcctgtataatgagcttcagaaagacaagatggctgaggcgtactctgaaatagggatgaaaggagaaagaaggcggggaaaaggccatgatggcctgtaccagggcctcagcaccgctaccaaggacacatacgatgcccttcatatgcaggccctccccccacgg。
在本发明中,编码所述单链抗体的靶向人ErbB2的嵌合抗原受体的基因顺次包括编码GM-CSF信号肽区的基因、编码ErbB2单链抗体区的基因、编码CD8跨膜区的基因、编码CD28胞内区的基因、编码4-1BB胞内区的基因和编码CD3ζ胞内区的基因;在本发明中,编码GM-CSF信号肽区的基因、编码CD8跨膜区的基因、编码CD28胞内区的基因、编码4-1BB胞内区的基因和编码CD3ζ胞内区的基因的核苷酸序列依次如SEQ ID No.16~SEQ ID No.20所示。
本发明还提供了一种重组载体,包括编码所述的嵌合抗原受体的基因和初始载体。在本发明中,所述初始载体优选为慢病毒载体,更优选为pCDH-MSCV-MCS-EF1-copGFP载体。在本发明中,所述pCDH-MSCV-MCS-EF1-copGFP优选为购买的市售产品。在本发明中,所述重组载体优选的通过将编码所述的嵌合抗原受体的基因进行人工合成后,亚克隆至初始载体中获得重组载体;在本发明中,所述人工合成优选的委托金唯智生物科技有限公司进行;本发明对所述亚克隆的方法没有特殊限定,采用本领域常规的方法即可,在本发明具体实施过程,所述重组载体的制备以及慢病毒载体的包装优选的委托ABM公司进行。
本发明提供了一种重组细胞,包括自然杀伤细胞和所述的重组载体。在本发明中,所述自然杀伤细胞优选为NK92细胞,本发明中,所述NK92细胞优选的购自ATCC细胞库。在本发明中,将所述重组载体感染所述NK92细胞获的所述重组细胞;在本发明中,所述感染的感染复数值优选为(90~110):1,更优选为100:1;本发明对所述感染的具体操作没有特殊要求,采用本领域常规的操作即可。
本发明还提供了所述重组细胞在制备治疗肿瘤的靶向药物中的应用。在本发明中,所述重组细胞能够特异性识别肿瘤细胞,并发挥杀伤作用,具有良好的肿瘤细胞杀伤作用,连续杀伤效果好。在本发明中,所述治疗肿瘤的靶向药物以所述重组细胞为唯一活性成分,或者以所述重组细胞和其他所述重组细胞可以接受的组分为活性成分;所述治疗肿瘤的靶向药物还可以包括所述重组细胞可以接受的辅料。
下面结合实施例对本发明提供的技术方案进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
实施例1
ErbB2单克隆抗体19G9的制备
S1,合成ErbB2-Domain4基因
ErbB2-Domain4基因的核酸序列如下:
atggagctggcggccttgtgccgctgggggctcctcctcgccctcttgccccccggagccgcgagcacctgccaccagctgtgcgcccgagggcactgctggggtccagggcccacccagtgtgtcaactgcagccagttccttcggggccaggagtgcgtggaggaatgccgagtactgcaggggctccccagggagtatgtgaatgccaggcactgtttgccgtgccaccctgagtgtcagccccagaatggctcagtgacctgttttggaccggaggctgaccagtgtgtggcctgtgcccactataaggaccctcccttctgcgtggcccgctgccccagcggtgtgaaacctgacctctcctacatgcccatctggaagtttccagatgaggagggcgcatgccagccttgccccatcaactgcacccactcctgtgtggacctggatgacaagggctgccccgccgagcagagagccagccctctgacgtccatcatctctgcggtggttggcattctgctggtcgtggtcttgggggtggtctttgggatcctcatc(SEQ ID No.21)
在合成的过程中,向所述ErbB2-Domain4基因的上下游分别加入限制性内切酶NdeI与XhoI的酶切位点获得ErbB2-Domain4基因插入片段。
S2,ErbB2-Domain4蛋白的表达和纯化
通过限制性内切酶NdeI与XhoI(Neb)各30IU分别酶切20μg载体pET-28a质粒和ErbB2-Domain4基因插入片段1h,回收酶切片段各50ng,加入T4连接酶5000单位(Neb)连接酶切后的质粒pET-28a 1h。
将连接好的重组载体热激90s转化进入大肠杆菌BL21(DE3)化学感受态(购自北京全式金生物技术(TransGen Biotech)有限公司)中。挑取克隆进行测序验证,对验证正确的菌种接种在含有50μg/ml的氨苄青霉素LB培养基中过夜培养蝴蝶种子液。将种子液1mL接入100mL的LB培养基中培养2~4h到对数中期(分光光度计测A550为0.5-1.0之间)。然后加入IPTG至终浓度为1mmol/L诱导2h后5000g离心15min收集菌体;每g菌体加入3mL STE缓冲液(购自北京索莱宝科技有限公司)重悬后,每g大肠杆菌湿菌体加入4μL 0.1mol/L的PMSF,80μl 10mg/ml的溶菌酶,搅动20min,再按照每g大肠杆菌湿菌体加入4mg脱氧胆酸,利用超声破碎仪(Sonics and Materials公司,VCX600)破碎菌体12min。超声模式为45%能量,每工作15d间隔45s。
离心后收集沉淀,用含有0.5%Triton X100的STE缓冲液震荡洗涤包涵体15min,15000g离心收集包涵体。包涵体溶解于含8M尿素与0.1mol/L的PMSF的STE缓冲液后,盐酸调节pH至8.0,利用Ni柱亲和层析纯化蛋白,收集ErbB2-Domain4蛋白作为抗原备用,ErbB2-Domain4蛋白的氨基酸序列如下:
MELAALCRWGLLLALLPPGAASTCHQLCARGHCWGPGPTQCVNCSQFLRGQECVEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARCPSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAVVGILLVVVLGVVFGILI(SEQ ID No.22)
S3,小鼠的免疫:
用纯化的ErbB2-Domain4蛋白作为抗原,对6~8周龄的雌性BALB/c小鼠3只进行三次免疫,前两次免疫间隔两周,剂量为12.5μg/只,第2次免疫后10天,尾部采血;在融合前的第3天尾静脉最后一次注射重组抗原,剂量为60μg/只,进行加强免疫一次;
S4,骨髓瘤细胞与免疫脾细胞的融合:
鼠骨髓瘤细胞SP2/0细胞(购自中国医学科学院基础医学研究所细胞资源中心)培养于含10%FBS的DMEM,每24h按照1:3的接种比例传代备用。收集免疫小鼠脾脏,研磨后通过细胞滤网获得鼠脾细胞。将鼠脾细胞和SP2/0细胞DMEM培养基洗涤3次后,调整脾细胞数与SP2/0细胞数之比为1:10,50%的PEG1500作用1~2min后,加入含有HAT的完全培养基稀释,接种于96孔培养板,37℃,5%CO2培养;
S5,阳性杂交瘤细胞筛选与克隆化:
经间接ELISA方法连续检测两次都为阳性的细胞孔,按有限稀释法进行亚克隆;如检出细胞孔有特异性抗ErbB2蛋白抗体,选择抗体效价高,呈单个克隆生长,形态良好的杂交瘤细胞孔,继续同法再克隆至少2次,克隆后阳性孔的杂交瘤细胞可移至24孔培养板,待24孔板中的杂交瘤细胞生长良好时,可冻存杂交瘤细胞;
S6,单克隆抗体的生产:
对已经建株的杂交瘤细胞以10e6/ml的密度接种至含有10%胎牛血清的DMEM培养基中放大培养,每48h离心细胞,除去上清,再以10e6/ml的密度接种到新鲜培养基中。待获得足够量的细胞后,离心除去原培养基,再以10e6/ml的密度接种到无血清的DMEM培养基中,培养72h后离心收集上清;
S7,单克隆抗体的纯化:
离心去除细胞的细胞培养上清经HiTrap protein G亲和层析进行纯化,获得治疗性的鼠抗人ErbB2单克隆抗体19G9。
ErbB2单克隆抗体19G9效价检测
对ErbB2单克隆抗体19G9,进行梯度稀释,经间接ELISA方法测定效价。间接ELISA测定单克隆抗体的效价的方法是:ErbB2-Domain4蛋白以100ng/孔包被,将ErbB2单克隆抗体19G9按1:10000、1:20000、1:40000、1:80000、1:160000、1:320000、1:640000、1:1280000、1:2560000、1:5120000、1:10240000、1:20480000稀释,通过间接ELISA法测定其A450nm值;以与免疫蛋白靶抗原发生反应的ErbB2单克隆抗体19G9的最大稀释度即为其效价,测定孔读数与阴性对照值之比大于2.1为阳性。并计算EC50值,结果如图1所示,ErbB2单克隆抗体19G9在稀释为10-7mol/L时即达到EC50值。
对ErbB2单克隆抗体19G9,采用Ig类与亚类Elisa鉴定试剂盒(义翘神州)鉴定抗人ErbB2蛋白单克隆抗体的Ig亚型,结果见图2,确定为19G9为鼠IgG1-Kappa型抗体。
ErbB2单链抗体19G9的制备
以所述ErbB2单克隆抗体19G9的重链可变区序列、轻链可变区序列以及连接所述重链可变区序列和轻链可变区序列的连接序列组成ErbB2单链抗体19G9。
所述ErbB2单链抗体19G9的制备方法如下:
通过TRIZOL试剂(Thermo Fisher),按照供应商操作说明书,提取19G9杂交瘤细胞的总RNA,具体如下:106个细胞加入TRIZOL试剂匀浆化后加入氯仿在2~8℃的条件下以12,000×g的离心力离心10min,取上清液并加入0.5mL异丙醇;12,000×g的离心力高速冷冻离心10min。用75%的乙醇洗涤RNA沉淀一次后干燥RNA沉淀,取无RNA酶的水溶解RNA。测浓度后通过Superscript III逆转录试剂盒制备1μg cDNA。通过PCR法制备轻链与重链序列。PCR体系以50μl计,包括:100ng cDNA,10nM浓度的正向与反向引物各2.5μL,25μL Taq 2XMastermix(ABM),最后加入水补足体积到50μL。按照94℃预变性3min,94℃变性30s,60℃退火0.5min,72℃延伸1min反应35个循环。送PCR产物至金唯智公司进行Sanger测序获得轻链可变区序列和重链可变区序列。
轻链与重链的PCR引物分别为:
重链反向引物:ggaagatctatagacagatgggggtgtcgttttggc(SEQ ID No.23)
重链正向引物:cttccggaattcgaggtcaagctgcagcagtcagg(SEQ ID No.24)
轻链反向引物:ggtgcatgcggatacagttggtgcagcatc(SEQ ID No.25)
轻链正向引物:gggagctcgacattgtgctgacacaatctcct(SEQ ID No.26)
将所述重链可变区序列、连接序列和轻链可变区序列顺次连接获得编码所述ErbB2单链抗体19G9的基因,具体如下(SEQ ID No.2):
ctggagcagtcaggccctgggatattgcagccctcccagaccctcagtttgatctgttctttctctgggttttcactgagtacttctggtatgggtgtaagctggattcgccagccttcaggaaagggtctggagtggctggcacacatttactgggatgatgacaagcgctataacccatccctgaagagccggctcacaatctccaaggatacctccagcaagcaggttttcctcaagatcaccagtgttgacactgcagatactgccacatactactgtgctctcttcgcctactataactacgacgggactgtggactactggggtctaggaacctcagtcaccgtctcctcaggcggaggcggatcaggtggtggcggatctggaggtggcggaagcgacattgtgatgacacagactccatcctccctggctgtgtcagtaggagagaaggtcactatgagctgcaaatccagtcagagtctgctccacagtagaacccgaaagaactatttggcttggtatcagcagaaactagggcagtctcctaaactactgatctactgggcatccactagggaatctggggtccctgatcgcttcacaggcagtggctctgggacagatttcactctcaccatcagcagtgtggaggctgaagacctggcagtttattactgcaagcaatcttataatctgtacacgttcggaggggggaccaagctggaaataaaa。
翻译获得的ErbB2单链抗体19G9的氨基酸序列如下(SEQ ID No.1):
LEQSGPGILQPSQTLSLICSFSGFSLSTSGMGVSWIRQPSGKGLEWLAHIYWDDDKRYNPSLKSRLTISKDTSSKQVFLKITSVDTADTATYYCALFAYYNYDGTVDYWGLGTSVTVSSGGGGSGGGGSGGGGSDIVMTQTPSSLAVSVGEKVTMSCKSSQSLLHSRTRKNYLAWYQQKLGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVEAEDLAVYYCKQSYNLYTFGGGTKLEIK。
实施例2
重组载体的制备
整理表达序列为GM-CSF信号肽-19G9单链抗体区-CD8跨膜区-CD28胞内区-4-1BB胞内区-CD3ζ胞内区(GM-CSF signal peptide-19G9 ScFv-CD8TM-41BBcyto-CD28cyto-CD3ζ)形式。其中各片段序列为:
GM-CSF信号肽(SEQ ID No.16)
cttctcctggtgacaagccttctgctctgtgagttaccacacccagcattcctcctgatccca
19G9单链抗体区(SEQ ID No.2)
ctggagcagtcaggccctgggatattgcagccctcccagaccctcagtttgatctgttctttctctgggttttcactgagtacttctggtatgggtgtaagctggattcgccagccttcaggaaagggtctggagtggctggcacacatttactgggatgatgacaagcgctataacccatccctgaagagccggctcacaatctccaaggatacctccagcaagcaggttttcctcaagatcaccagtgttgacactgcagatactgccacatactactgtgctctcttcgcctactataactacgacgggactgtggactactggggtctaggaacctcagtcaccgtctcctcaggcggaggcggatcaggtggtggcggatctggaggtggcggaagcgacattgtgatgacacagactccatcctccctggctgtgtcagtaggagagaaggtcactatgagctgcaaatccagtcagagtctgctccacagtagaacccgaaagaactatttggcttggtatcagcagaaactagggcagtctcctaaactactgatctactgggcatccactagggaatctggggtccctgatcgcttcacaggcagtggctctgggacagatttcactctcaccatcagcagtgtggaggctgaagacctggcagtttattactgcaagcaatcttataatctgtacacgttcggaggggggaccaagctggaaataaaa
CD8跨膜区(SEQ ID No.17)
ttcgtgccagtattcctgcccgcgaagcccactactactcccgcccctaggccacctacaccggcccccacaattgcatcacaaccactcagcctccggcccgaagcttgccgccccgctgctgggggcgccgtgcacactcggggcctggactttgcctgcgatatttatatttgggcaccacttgcagggacgtgcggcgtactgcttctgtctctcgtgattactctttattgtaatcataggaac
CD28胞内区(SEQ ID No.18)
cgatctaagcggtccagactgctccacagtgattacatgaacatgaccccacgcaggcctgggccaacacgaaaacactatcagccttacgcacctccccgcgactttgctgcctaccgctct
4-1BB胞内区(SEQ ID No.19)
agattcagcgtggtgaagcgaggaagaaaaaaactcctttatatattcaagcagcctttcatgcgacctgtccagacaactcaggaagaagacggctgttcttgtaggttcccagaagaggaagagggaggctgcgagctg
CD3zeta胞内区(SEQ ID No.20)
cgcgtcaaattctcccgatcagcagatgcacccgcataccaacagggacagaaccagctgtacaacgaactgaatcttggaagaagggaggagtacgatgtgcttgataaaaggcgcggccgggaccccgaaatgggcggtaagcctagacgaaaaaatcctcaagagggcctgtataatgagcttcagaaagacaagatggctgaggcgtactctgaaatagggatgaaaggagaaagaaggcggggaaaaggccatgatggcctgtaccagggcctcagcaccgctaccaaggacacatacgatgcccttcatatgcaggccctccccccacgg
上述序列交由金唯智进行全序列合成,亚克隆至pCDH-MSCV-MCS-EF1-copGFP慢病毒质粒,委托ABM公司进行病毒包装,获得重组载体。
实施例3
重组细胞的制备
将实施例2中包装后的病毒通过100:1的MOI(感染复数值)感染NK92细胞(购自ATCC)。感染后的NK92细胞通过LY09培养基放大培养,培养72h后,通过流式细胞术,分选copGFP报告基因(绿色荧光)阳性的细胞。此时即获得重组细胞19G9 CAR-NK。流式细胞术分析分选后得到的19G9 CAR-NK细胞与野生型NK92细胞GFP表达量结果如图3所示,19G9 CAR-NK细胞的GFP表达量较高,而野生型NK92细胞GFP表达量为零。
利用流式细胞术分析ErbB2蛋白对19G9 CAR-NK细胞的特异性结合。取1μg ErbB2-biotin(Acro)蛋白与19G9 CAR-NK细胞以及NK92细胞1000000个分别共同孵育30min后,加入Pacific Blue标记的链霉亲和素50ng,再孵育15min后,采用流式细胞术进行检测。由图4可见ErbB2蛋白对19G9 CAR-NK细胞具有高亲和力,并且与野生型的NK92细胞结合微弱。
利用流式细胞术分析19G9 CAR-NK细胞对表达ErbB2靶细胞的特异性杀伤。按100000靶细胞每孔于24孔板在含有1μg/mL hoechst33342与10%FBS的RPMI1640培养基中培养过夜,与19G9 CAR-NK细胞以及NK92细胞500000个分别共同孵育4h后,加入PI染色液(BD)10μL,再孵育15min后,采用流式细胞术进行检测。圈选带hoechst33342荧光的细胞,分析PI阳性的细胞比例,由图5可见19G9 CAR-NK细胞对靶细胞具有高杀伤力(PI阳性),野生型的NK92细胞杀伤微弱。
将质粒载体中19G9单链抗体区序列替换为4D5ScFv序列后,整理表达序列为GM-CSF信号肽-4D5单链抗体区-CD8跨膜区-CD28胞内区-4-1BB胞内区-CD3zeta胞内区(GM-CSFsignal peptide-19G9 ScFv-CD8 TM-41BBcyto-CD28cyto-CD3ζ)形式。后交由金唯智进行全序列合成,亚克隆至pCDH-MSCV-MCS-EF1-copGFP慢病毒质粒,委托ABM公司进行病毒包装。将包装后的病毒通过100:1MOI感染NK92细胞(ATCC)。感染后的NK92细胞通过LY09培养基放大培养,培养72h后,通过流式细胞术,分选copGFP报告基因(绿色荧光)阳性的细胞。此时即获得4D5 CAR-NK。
不同CAR-NK细胞(19G9 CAR-NK细胞与4D5 CAR-NK细胞)对表达ErbB2靶细胞的连续杀伤分析。按100000靶细胞每孔于24孔板在含有1μg/ml hoechst33342与10%FBS的RPMI1640培养基中培养过夜,分别与19G9 CAR-NK细胞以及4D5 CAR-NK细胞500000个共同孵育4h后,加入PI染色液(BD)10μL,再孵育15min后,采用流式细胞术进行检测。圈选带hoechst33342荧光的细胞,分析PI阳性的细胞比例(死亡率),结果如图6所示,可见19G9CAR-NK细胞对靶细胞具有高杀伤力(PI阳性),高于4D5 CAR-NK细胞的杀伤力。进一步分析GFP阳性的效应细胞PI阳性细胞的死亡比例(死亡率),可见19G9 CAR-NK细胞死亡较少,能够持续性的进行靶细胞的杀伤。
进一步分析GFP阳性的效应细胞获得的hoechst33342细胞比例(靶细胞接触率),结果如图7所示,可见19G9 CAR-NK细胞hoechst33342阳性较多,有较多细胞结合。
综上所述,本发明提供的所述ErbB2单链抗体能够特异性识别肿瘤抗原,所述靶向人ErbB2的嵌合抗原受体修饰的NK免疫细胞具有较高的连续杀伤能力,降低了细胞因子风暴的风险。
以上所述仅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,这些改进和润饰也应视为本发明的保护范围。
序列表
<110> 北京鼎成肽源生物技术有限公司
焦顺昌
<120> 一种ErbB2单链抗体、靶向人ErbB2的嵌合抗原受体、重组载体、重组细胞和应用
<141> 2019-08-16
<160> 26
<170> SIPOSequenceListing 1.0
<210> 1
<211> 246
<212> PRT
<213> Artificial Sequence
<400> 1
Leu Glu Gln Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln Thr Leu Ser
1 5 10 15
Leu Ile Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser Gly Met Gly
20 25 30
Val Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu Trp Leu Ala
35 40 45
His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys Ser
50 55 60
Arg Leu Thr Ile Ser Lys Asp Thr Ser Ser Lys Gln Val Phe Leu Lys
65 70 75 80
Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Leu
85 90 95
Phe Ala Tyr Tyr Asn Tyr Asp Gly Thr Val Asp Tyr Trp Gly Leu Gly
100 105 110
Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Ser Ser
130 135 140
Leu Ala Val Ser Val Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser
145 150 155 160
Gln Ser Leu Leu His Ser Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Leu Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser
180 185 190
Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Glu Ala Glu Asp Leu Ala
210 215 220
Val Tyr Tyr Cys Lys Gln Ser Tyr Asn Leu Tyr Thr Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Glu Ile Lys
245
<210> 2
<211> 738
<212> DNA
<213> Artificial Sequence
<400> 2
ctggagcagt caggccctgg gatattgcag ccctcccaga ccctcagttt gatctgttct 60
ttctctgggt tttcactgag tacttctggt atgggtgtaa gctggattcg ccagccttca 120
ggaaagggtc tggagtggct ggcacacatt tactgggatg atgacaagcg ctataaccca 180
tccctgaaga gccggctcac aatctccaag gatacctcca gcaagcaggt tttcctcaag 240
atcaccagtg ttgacactgc agatactgcc acatactact gtgctctctt cgcctactat 300
aactacgacg ggactgtgga ctactggggt ctaggaacct cagtcaccgt ctcctcaggc 360
ggaggcggat caggtggtgg cggatctgga ggtggcggaa gcgacattgt gatgacacag 420
actccatcct ccctggctgt gtcagtagga gagaaggtca ctatgagctg caaatccagt 480
cagagtctgc tccacagtag aacccgaaag aactatttgg cttggtatca gcagaaacta 540
gggcagtctc ctaaactact gatctactgg gcatccacta gggaatctgg ggtccctgat 600
cgcttcacag gcagtggctc tgggacagat ttcactctca ccatcagcag tgtggaggct 660
gaagacctgg cagtttatta ctgcaagcaa tcttataatc tgtacacgtt cggagggggg 720
accaagctgg aaataaaa 738
<210> 3
<211> 551
<212> PRT
<213> Artificial Sequence
<400> 3
Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro Ala
1 5 10 15
Phe Leu Leu Ile Pro Leu Glu Gln Ser Gly Pro Gly Ile Leu Gln Pro
20 25 30
Ser Gln Thr Leu Ser Leu Ile Cys Ser Phe Ser Gly Phe Ser Leu Ser
35 40 45
Thr Ser Gly Met Gly Val Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly
50 55 60
Leu Glu Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn
65 70 75 80
Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Ser Lys
85 90 95
Gln Val Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr
100 105 110
Tyr Tyr Cys Ala Leu Phe Ala Tyr Tyr Asn Tyr Asp Gly Thr Val Asp
115 120 125
Tyr Trp Gly Leu Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr
145 150 155 160
Gln Thr Pro Ser Ser Leu Ala Val Ser Val Gly Glu Lys Val Thr Met
165 170 175
Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser Arg Thr Arg Lys Asn
180 185 190
Tyr Leu Ala Trp Tyr Gln Gln Lys Leu Gly Gln Ser Pro Lys Leu Leu
195 200 205
Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Thr
210 215 220
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Glu
225 230 235 240
Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln Ser Tyr Asn Leu Tyr
245 250 255
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Ala Thr Thr Thr Ala
260 265 270
Thr Ala Thr Thr Thr Gly Gly Gly Cys Ala Cys Cys Ala Cys Thr Thr
275 280 285
Gly Cys Ala Gly Gly Gly Ala Cys Gly Thr Gly Cys Gly Gly Cys Gly
290 295 300
Thr Ala Cys Thr Gly Cys Thr Thr Cys Thr Gly Thr Cys Thr Cys Thr
305 310 315 320
Cys Gly Thr Gly Ala Thr Thr Ala Cys Thr Cys Thr Thr Thr Ala Thr
325 330 335
Thr Gly Thr Ala Ala Thr Cys Ala Thr Ala Gly Gly Ala Ala Cys Arg
340 345 350
Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro
355 360 365
Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro
370 375 380
Arg Asp Phe Ala Ala Tyr Arg Ser Arg Phe Ser Val Val Lys Arg Gly
385 390 395 400
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
405 410 415
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
420 425 430
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
435 440 445
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
450 455 460
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
465 470 475 480
Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly
485 490 495
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
500 505 510
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
515 520 525
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
530 535 540
Met Gln Ala Leu Pro Pro Arg
545 550
<210> 4
<211> 1650
<212> DNA
<213> Artificial Sequence
<400> 4
cttctcctgg tgacaagcct tctgctctgt gagttaccac acccagcatt cctcctgatc 60
ccactggagc agtcaggccc tgggatattg cagccctccc agaccctcag tttgatctgt 120
tctttctctg ggttttcact gagtacttct ggtatgggtg taagctggat tcgccagcct 180
tcaggaaagg gtctggagtg gctggcacac atttactggg atgatgacaa gcgctataac 240
ccatccctga agagccggct cacaatctcc aaggatacct ccagcaagca ggttttcctc 300
aagatcacca gtgttgacac tgcagatact gccacatact actgtgctct cttcgcctac 360
tataactacg acgggactgt ggactactgg ggtctaggaa cctcagtcac cgtctcctca 420
ggcggaggcg gatcaggtgg tggcggatct ggaggtggcg gaagcgacat tgtgatgaca 480
cagactccat cctccctggc tgtgtcagta ggagagaagg tcactatgag ctgcaaatcc 540
agtcagagtc tgctccacag tagaacccga aagaactatt tggcttggta tcagcagaaa 600
ctagggcagt ctcctaaact actgatctac tgggcatcca ctagggaatc tggggtccct 660
gatcgcttca caggcagtgg ctctgggaca gatttcactc tcaccatcag cagtgtggag 720
gctgaagacc tggcagttta ttactgcaag caatcttata atctgtacac gttcggaggg 780
gggaccaagc tggaaataaa attcgtgcca gtattcctgc ccgcgaagcc cactactact 840
cccgccccta ggccacctac accggccccc acaattgcat cacaaccact cagcctccgg 900
cccgaagctt gccgccccgc tgctgggggc gccgtgcaca ctcggggcct ggactttgcc 960
tgcgatattt atatttgggc accacttgca gggacgtgcg gcgtactgct tctgtctctc 1020
gtgattactc tttattgtaa tcataggaac cgatctaagc ggtccagact gctccacagt 1080
gattacatga acatgacccc acgcaggcct gggccaacac gaaaacacta tcagccttac 1140
gcacctcccc gcgactttgc tgcctaccgc tctagattca gcgtggtgaa gcgaggaaga 1200
aaaaaactcc tttatatatt caagcagcct ttcatgcgac ctgtccagac aactcaggaa 1260
gaagacggct gttcttgtag gttcccagaa gaggaagagg gaggctgcga gctgcgcgtc 1320
aaattctccc gatcagcaga tgcacccgca taccaacagg gacagaacca gctgtacaac 1380
gaactgaatc ttggaagaag ggaggagtac gatgtgcttg ataaaaggcg cggccgggac 1440
cccgaaatgg gcggtaagcc tagacgaaaa aatcctcaag agggcctgta taatgagctt 1500
cagaaagaca agatggctga ggcgtactct gaaataggga tgaaaggaga aagaaggcgg 1560
ggaaaaggcc atgatggcct gtaccagggc ctcagcaccg ctaccaagga cacatacgat 1620
gcccttcata tgcaggccct ccccccacgg 1650
<210> 5
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 5
Asp Ile Val Met Thr Gln Thr Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Leu Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Glu Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Tyr Asn Leu Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 6
<211> 119
<212> PRT
<213> Artificial Sequence
<400> 6
Leu Glu Gln Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln Thr Leu Ser
1 5 10 15
Leu Ile Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser Gly Met Gly
20 25 30
Val Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu Trp Leu Ala
35 40 45
His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys Ser
50 55 60
Arg Leu Thr Ile Ser Lys Asp Thr Ser Ser Lys Gln Val Phe Leu Lys
65 70 75 80
Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Leu
85 90 95
Phe Ala Tyr Tyr Asn Tyr Asp Gly Thr Val Asp Tyr Trp Gly Leu Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 7
<211> 15
<212> PRT
<213> Artificial Sequence
<400> 7
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 8
<211> 336
<212> DNA
<213> Artificial Sequence
<400> 8
gacattgtga tgacacagac tccatcctcc ctggctgtgt cagtaggaga gaaggtcact 60
atgagctgca aatccagtca gagtctgctc cacagtagaa cccgaaagaa ctatttggct 120
tggtatcagc agaaactagg gcagtctcct aaactactga tctactgggc atccactagg 180
gaatctgggg tccctgatcg cttcacaggc agtggctctg ggacagattt cactctcacc 240
atcagcagtg tggaggctga agacctggca gtttattact gcaagcaatc ttataatctg 300
tacacgttcg gaggggggac caagctggaa ataaaa 336
<210> 9
<211> 357
<212> DNA
<213> Artificial Sequence
<400> 9
ctggagcagt caggccctgg gatattgcag ccctcccaga ccctcagttt gatctgttct 60
ttctctgggt tttcactgag tacttctggt atgggtgtaa gctggattcg ccagccttca 120
ggaaagggtc tggagtggct ggcacacatt tactgggatg atgacaagcg ctataaccca 180
tccctgaaga gccggctcac aatctccaag gatacctcca gcaagcaggt tttcctcaag 240
atcaccagtg ttgacactgc agatactgcc acatactact gtgctctctt cgcctactat 300
aactacgacg ggactgtgga ctactggggt ctaggaacct cagtcaccgt ctcctca 357
<210> 10
<211> 45
<212> DNA
<213> Artificial Sequence
<400> 10
ggcggaggcg gatcaggtgg tggcggatct ggaggtggcg gaagc 45
<210> 16
<211> 20
<212> PRT
<213> Artificial Sequence
<400> 16
Gly Ser Gly Gly Met Leu Gly Val Val Thr His Arg Ala Glu Gly Leu
1 5 10 15
Ser Pro Gly Glu
20
<210> 17
<211> 82
<212> PRT
<213> Artificial Sequence
<400> 17
Val Pro Met Ile Thr Ile Lys Ser Asn His Glu Arg Gln Lys Gln Tyr
1 5 10 15
Ala Ala Arg Pro Cys Lys Trp Cys Pro Asn Ile Asn Ile Ala Gly Lys
20 25 30
Val Gln Ala Pro Ser Val His Gly Ala Pro Ser Ser Gly Ala Ala Ser
35 40 45
Phe Gly Pro Glu Ala Glu Trp Leu Cys Asn Cys Gly Gly Arg Cys Arg
50 55 60
Trp Pro Arg Gly Gly Ser Ser Ser Gly Leu Arg Gly Gln Glu Tyr Trp
65 70 75 80
His Glu
<210> 18
<211> 41
<212> PRT
<213> Artificial Sequence
<400> 18
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> 19
<211> 47
<212> PRT
<213> Artificial Sequence
<400> 19
Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
1 5 10 15
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
20 25 30
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40 45
<210> 20
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 20
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln 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> 11
<211> 63
<212> DNA
<213> Artificial Sequence
<400> 11
cttctcctgg tgacaagcct tctgctctgt gagttaccac acccagcatt cctcctgatc 60
cca 63
<210> 12
<211> 249
<212> DNA
<213> Artificial Sequence
<400> 12
ttcgtgccag tattcctgcc cgcgaagccc actactactc ccgcccctag gccacctaca 60
ccggccccca caattgcatc acaaccactc agcctccggc ccgaagcttg ccgccccgct 120
gctgggggcg ccgtgcacac tcggggcctg gactttgcct gcgatattta tatttgggca 180
ccacttgcag ggacgtgcgg cgtactgctt ctgtctctcg tgattactct ttattgtaat 240
cataggaac 249
<210> 13
<211> 123
<212> DNA
<213> Artificial Sequence
<400> 13
cgatctaagc ggtccagact gctccacagt gattacatga acatgacccc acgcaggcct 60
gggccaacac gaaaacacta tcagccttac gcacctcccc gcgactttgc tgcctaccgc 120
tct 123
<210> 14
<211> 141
<212> DNA
<213> Artificial Sequence
<400> 14
agattcagcg tggtgaagcg aggaagaaaa aaactccttt atatattcaa gcagcctttc 60
atgcgacctg tccagacaac tcaggaagaa gacggctgtt cttgtaggtt cccagaagag 120
gaagagggag gctgcgagct g 141
<210> 15
<211> 336
<212> DNA
<213> Artificial Sequence
<400> 15
cgcgtcaaat tctcccgatc agcagatgca cccgcatacc aacagggaca gaaccagctg 60
tacaacgaac tgaatcttgg aagaagggag gagtacgatg tgcttgataa aaggcgcggc 120
cgggaccccg aaatgggcgg taagcctaga cgaaaaaatc ctcaagaggg cctgtataat 180
gagcttcaga aagacaagat ggctgaggcg tactctgaaa tagggatgaa aggagaaaga 240
aggcggggaa aaggccatga tggcctgtac cagggcctca gcaccgctac caaggacaca 300
tacgatgccc ttcatatgca ggccctcccc ccacgg 336
<210> 21
<211> 564
<212> DNA
<213> Artificial Sequence
<400> 21
atggagctgg cggccttgtg ccgctggggg ctcctcctcg ccctcttgcc ccccggagcc 60
gcgagcacct gccaccagct gtgcgcccga gggcactgct ggggtccagg gcccacccag 120
tgtgtcaact gcagccagtt ccttcggggc caggagtgcg tggaggaatg ccgagtactg 180
caggggctcc ccagggagta tgtgaatgcc aggcactgtt tgccgtgcca ccctgagtgt 240
cagccccaga atggctcagt gacctgtttt ggaccggagg ctgaccagtg tgtggcctgt 300
gcccactata aggaccctcc cttctgcgtg gcccgctgcc ccagcggtgt gaaacctgac 360
ctctcctaca tgcccatctg gaagtttcca gatgaggagg gcgcatgcca gccttgcccc 420
atcaactgca cccactcctg tgtggacctg gatgacaagg gctgccccgc cgagcagaga 480
gccagccctc tgacgtccat catctctgcg gtggttggca ttctgctggt cgtggtcttg 540
ggggtggtct ttgggatcct catc 564
<210> 22
<211> 188
<212> PRT
<213> Artificial Sequence
<400> 22
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
Pro Pro Gly Ala Ala Ser Thr Cys His Gln Leu Cys Ala Arg Gly His
20 25 30
Cys Trp Gly Pro Gly Pro Thr Gln Cys Val Asn Cys Ser Gln Phe Leu
35 40 45
Arg Gly Gln Glu Cys Val Glu Glu Cys Arg Val Leu Gln Gly Leu Pro
50 55 60
Arg Glu Tyr Val Asn Ala Arg His Cys Leu Pro Cys His Pro Glu Cys
65 70 75 80
Gln Pro Gln Asn Gly Ser Val Thr Cys Phe Gly Pro Glu Ala Asp Gln
85 90 95
Cys Val Ala Cys Ala His Tyr Lys Asp Pro Pro Phe Cys Val Ala Arg
100 105 110
Cys Pro Ser Gly Val Lys Pro Asp Leu Ser Tyr Met Pro Ile Trp Lys
115 120 125
Phe Pro Asp Glu Glu Gly Ala Cys Gln Pro Cys Pro Ile Asn Cys Thr
130 135 140
His Ser Cys Val Asp Leu Asp Asp Lys Gly Cys Pro Ala Glu Gln Arg
145 150 155 160
Ala Ser Pro Leu Thr Ser Ile Ile Ser Ala Val Val Gly Ile Leu Leu
165 170 175
Val Val Val Leu Gly Val Val Phe Gly Ile Leu Ile
180 185
<210> 23
<211> 36
<212> DNA
<213> Artificial Sequence
<400> 23
ggaagatcta tagacagatg ggggtgtcgt tttggc 36
<210> 24
<211> 35
<212> DNA
<213> Artificial Sequence
<400> 24
cttccggaat tcgaggtcaa gctgcagcag tcagg 35
<210> 25
<211> 30
<212> DNA
<213> Artificial Sequence
<400> 25
ggtgcatgcg gatacagttg gtgcagcatc 30
<210> 26
<211> 32
<212> DNA
<213> Artificial Sequence
<400> 26
gggagctcga cattgtgctg acacaatctc ct 32
Claims (10)
1.一种ErbB2单链抗体,其特征在于,所述ErbB2单链抗体的氨基酸序列如SEQ ID No.1所示。
2.编码权利要求1所述ErbB2单链抗体的基因,其特征在于,所述基因的核苷酸序列如SEQ ID No.2所示。
3.一种包括权利要求1所述单链抗体的靶向人ErbB2的嵌合抗原受体,其特征在于,所述嵌合抗原受体的氨基酸序列如SEQ ID No.3所示。
4.编码权利要求3所述的嵌合抗原受体的基因,其特征在于,所述基因的核苷酸序列如SEQ ID No.4所示。
5.一种重组载体,其特征在于,包括编码权利要求3所述的嵌合抗原受体的基因和初始载体。
6.根据权利要求5所述的重组载体,其特征在于,所述初始载体为慢病毒载体。
7.根据权利要求6所述的重组载体,其特征在于,所述慢病毒载体为pCDH-MSCV-MCS-EF1-copGFP。
8.一种重组细胞,其特征在于,包含权利要求5~7任一项所述的重组载体的自然杀伤细胞。
9.根据权利要求8所述的重组细胞,其特征在于,所述自然杀伤细胞为NK92细胞。
10.权利要求8或9所述的重组细胞在制备治疗肿瘤的靶向药物中的应用。
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CN201910784230.4A CN110396131B (zh) | 2019-08-23 | 2019-08-23 | 一种ErbB2单链抗体、靶向人ErbB2的嵌合抗原受体、重组载体、重组细胞和应用 |
EP19204344.6A EP3782644A1 (en) | 2019-08-23 | 2019-10-21 | Anti-erbb2 single chain antibody, human erbb2-targeting chimeric antigen receptor, recombinant vector, recombinant cell, and application thereof |
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CN201910784230.4A CN110396131B (zh) | 2019-08-23 | 2019-08-23 | 一种ErbB2单链抗体、靶向人ErbB2的嵌合抗原受体、重组载体、重组细胞和应用 |
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CN114195896B (zh) * | 2021-12-06 | 2022-07-05 | 东莞清实生物科技有限公司 | 一种基于单域抗体的bcma嵌合抗原受体及其应用 |
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US7097840B2 (en) * | 2000-03-16 | 2006-08-29 | Genentech, Inc. | Methods of treatment using anti-ErbB antibody-maytansinoid conjugates |
US9498499B2 (en) * | 2012-04-19 | 2016-11-22 | The Board Of Trustees Of The Leland Stanford Junior University | Imaging-aided gene therapy using mesenchymal stem cells as target-delivery vehicle |
JP6353052B2 (ja) * | 2013-08-26 | 2018-07-04 | ヘルス リサーチ インコーポレイテッドHealth Research, Inc. | ErbB2陽性癌の予防及び/又は治療のための方法 |
CN107417791B (zh) * | 2017-08-17 | 2020-09-22 | 合肥瀚科迈博生物技术有限公司 | 抗人ErbB2双特异性抗体、其制备方法及用途 |
CN107488636A (zh) * | 2017-09-30 | 2017-12-19 | 山东兴瑞生物科技有限公司 | 一种携带分子开关的抗her2嵌合抗原受体修饰的免疫细胞及其应用 |
JP2021512614A (ja) * | 2018-02-09 | 2021-05-20 | ナショナル ユニヴァーシティー オブ シンガポール | ナチュラルキラー細胞免疫療法における接着受容体構築物及びその使用 |
CN109536455B (zh) * | 2018-12-11 | 2020-02-21 | 武汉波睿达生物科技有限公司 | 一种car-nk细胞及其制备方法和应用 |
CN109371062A (zh) * | 2018-12-12 | 2019-02-22 | 北京鼎成肽源生物技术有限公司 | 一种重组慢病毒表达载体、重组细胞及其在自然杀伤细胞培养中的应用 |
CN109824781B (zh) * | 2019-01-21 | 2022-07-19 | 卢英 | 抗人her 2抗原的特异性嵌合抗原受体、编码基因和表达载体以及应用 |
-
2019
- 2019-08-23 CN CN201910784230.4A patent/CN110396131B/zh active Active
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