CN109824778B - 抗cd19全人抗体以及靶向cd19的免疫效应细胞 - Google Patents
抗cd19全人抗体以及靶向cd19的免疫效应细胞 Download PDFInfo
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Abstract
本发明涉及抗CD19全人抗体以及靶向CD19的免疫效应细胞。本发明揭示了新的特异性识别CD19的全人抗体,本发明的抗体可以被应用于制备靶向性抗肿瘤药物以及诊断肿瘤的药物。
Description
本申请为CN201510599065.7的分案申请,原申请的申请日为2015年09月18日。
技术领域
本发明属于肿瘤免疫治疗或诊断领域,更具体地,本发明涉及抗CD19全人抗体以及靶向CD19的免疫效应细胞。
背景技术
B细胞恶性肿瘤有非何杰金淋巴瘤(NHL),急性淋巴母细胞白血病(ALL)以及慢性淋巴细胞白血病(CLL)等。目前B细胞恶性肿瘤主要包括化疗、放疗、骨髓移植以及外周血干细胞移植。尽管有这些治疗手段,大多数病人仍然无法得到根治。
CD19是一个分子量为95kDa的糖蛋白,表达于从早期发育到分化成浆细胞的各个阶段的B细胞。CD19仅表达于B系细胞,而不表达于多能血液干细胞。CD19也表达于大多数的B细胞淋巴瘤,套细胞巴瘤、ALL、CLL、毛细胞性白血病以及一部分急性髓细胞性白血病。CD19除了表达于正常的B系细胞外,不表达于其他正常组织。因此,CD19是一个非常有吸引力的免疫治疗靶点。
目前一些产品如Blinatumomab采用的抗体是小鼠抗CD19抗体,那么就有可能在人体产生人抗小鼠抗体(HAMA)反应,影响其临床使用。因此本领域还有必要研究毒副作用低的抗CD19抗体。
发明内容
本发明的目的在于提供抗CD19全人抗体以及靶向CD19的免疫效应细胞。
在本发明的第一方面,提供可特异结合CD19的全人抗体,该全人抗体选自:
(a)抗体,其包含重链可变区,所述重链可变区具有包含SEQ ID NO:5所示的氨基酸序列的CDR1、包含SEQ ID NO:6所示的氨基酸序列的CDR2、包含SEQ ID NO:7所示的氨基酸序列的CDR3;
(b)抗体,其包含轻链可变区,所述轻链可变区具有包含SEQ ID NO:8所示的氨基酸序列的CDR1、包含SEQ ID NO:9所示的氨基酸序列的CDR2、包含SEQ ID NO:10所示氨基酸序列的CDR3;
(c)抗体,包含(a)所述抗体的重链可变区及(b)所述抗体的轻链可变区;
(d)抗体,包含重链可变区,所述重链可变区具有包含SEQ ID NO:11所示的氨基酸序列的CDR1、包含SEQ ID NO:12所示的氨基酸序列的CDR2、包含SEQ ID NO:13所示的氨基酸序列的CDR3;
(e)抗体,包含轻链可变区,所述轻链可变区具有包含SEQ ID NO:14所示的氨基酸序列的CDR1、包含SEQ ID NO:15所示的氨基酸序列的CDR2、包含SEQ ID NO:16所示的氨基酸序列的CDR3;
(f)抗体,包含(d)所述抗体的重链可变区及(e)所述抗体的轻链可变区;
(g)抗体,识别与(a)~(f)中任一项所述的抗体所识别的抗原决定部位相同的抗原决定部位。
在一个优选例中,该全人抗体包括重链可变区和轻链可变区,其重链可变区的氨基酸序列如SEQ ID NO:2中第1-120位所示;其轻链可变区的氨基酸序列如SEQ ID NO:2中第136-246位所示;或
该全人抗体包括重链可变区和轻链可变区,其重链可变区的氨基酸序列如SEQ IDNO:4中第1-124位所示;其轻链可变区的氨基酸序列如SEQ ID NO:4中第140-252位所示。
在另一优选例中,所述的可特异结合CD19的全人抗体可以是:单链抗体(scFV),单克隆抗体,结构域抗体,Fab片段,Fd片段,Fv片段,F(ab’)2片段和其衍生物,或其它形式的抗体;较佳地为单链抗体。
在本发明的另一方面,提供编码所述的抗体的核酸。
在本发明的另一方面,提供一种表达载体,其包含所述的核酸。
在本发明的另一方面,提供一种宿主细胞,其包含述的表达载体或基因组中整合有所述的核酸。
在本发明的另一方面,提供所述的抗体的用途,用于制备特异性靶向表达CD19的肿瘤细胞的靶向性药物,抗体药物偶联物或多功能抗体;或用于制备诊断肿瘤的试剂,该肿瘤表达CD19;或用于制备嵌合抗原受体修饰的免疫细胞。
在本发明的另一方面,提供包含所述的抗体的嵌合抗原受体,所述的嵌合抗原受体包含顺序连接的:所述的抗体,跨膜区和胞内信号区;所述的胞内信号区选自:CD3ζ,FcεRIγ,CD27,CD28,CD137,CD134,MyD88,CD40的胞内信号区序列,或其组合。
在一个优选例中,所述的跨膜区包含CD8或CD28的跨膜区。
在另一优选例中,所述的嵌合抗原受体包括如下的顺序连接的抗体,跨膜区和胞内信号区:
所述的抗体、CD8和CD3ζ;
所述的抗体、CD8、CD137和CD3ζ;
所述的抗体、CD28分子的跨膜区、CD28分子的胞内信号区和CD3ζ;或
所述的抗体、CD28分子的跨膜区、CD28分子的胞内信号区、CD137和CD3ζ。
在另一优选例中,所述的抗体是单链抗体或结构域抗体。
在另一优选例中,所述的嵌合抗原受体具有:SEQ ID NO:41所示的氨基酸序列;SEQ ID NO:42所示的氨基酸序列;SEQ ID NO:43所示的氨基酸序列;SEQ ID NO:44所示的氨基酸序列;SEQ ID NO:45所示的氨基酸序列;或SEQ ID NO:46所示的氨基酸序列。
在本发明的另一方面,提供编码所述的嵌合抗原受体的核酸。
在一个优选例中,编码所述的嵌合抗原受体的核酸具有:SEQ ID NO:35或其中第443-1417位所述的核苷酸序列;SEQ ID NO:36或其中第443-1852位所述的核苷酸序列;SEQID NO:37或其中第443-1987位所述的核苷酸序列;SEQ ID NO:38或其中第443-1435位所述的核苷酸序列;SEQ ID NO:39或其中第443-1870位所述的核苷酸序列;或SEQ ID NO:40或其中第443-2005位所述的核苷酸序列。
在本发明的另一方面,提供一种表达载体,其包含所述的核酸。
在另一优选例中,所述的表达载体来源于慢病毒质粒pRRL。
在本发明的另一方面,提供一种病毒,所述的病毒包含所述载体。
在本发明的另一方面,提供所述的嵌合抗原受体、或所述的核酸、或所述的表达载体、或所述的病毒的用途,用于制备靶向表达CD19的肿瘤细胞的基因修饰的免疫细胞。
在一个优选例中,所述的表达CD19的肿瘤包括:B细胞白血病,B细胞淋巴瘤,套细胞淋巴瘤、ALL、CLL、毛细胞性白血病或多发性骨髓瘤。
在本发明的另一方面,提供一种基因修饰的免疫细胞,其转导有所述的核酸,或所述的表达载体或所述的病毒;或其表面表达所述的嵌合抗原受体。
在一个优选例中,所述的免疫细胞还携带外源的细胞因子的编码序列;较佳地,所述的细胞因子包括:IL-12,IL-15或IL-21。
在另一优选例中,所述的免疫细胞还表达另一种嵌合抗原受体,该受体不含有CD3ζ,但含有CD28的胞内信号结构域、CD137的胞内信号结构域或者这两者的组合。
在另一优选例中,所述的免疫细胞还表达趋化因子受体;较佳地,所述的趋化因子受体包括:CCR2。
在另一优选例中,所述的免疫细胞还表达能降低PD-1表达的siRNA或者阻断PD-L1的蛋白。
在另一优选例中,所述的免疫细胞还表达安全开关;较佳地,所述的安全开关包括:iCaspase-9,Truancated EGFR或RQR8。
在另一优选例中,所述的免疫细胞包括:T淋巴细胞、NK细胞或者NKT淋巴细胞。
在本发明的另一方面,提供所述的基因修饰的免疫细胞的用途,用于制备抑制肿瘤的药物,所述的肿瘤是表达CD19的肿瘤。
在本发明的另一方面,提供一种多功能免疫辍合物,所述的多功能免疫辍合物包括:所述的抗体;以及与之连接(包括共价连接、偶联、附着、吸附)的功能性分子;所述的功能性分子选自:靶向肿瘤表面标志物的分子,抑制肿瘤的分子,靶向免疫细胞的表面标志物的分子或可检测标记物。
在一个优选例中,所述的多功能免疫辍合物中,所述的靶向肿瘤表面标志物的分子是结合肿瘤表面标志物的抗体或配体;或
所述的抑制肿瘤的分子是抗肿瘤的细胞因子或抗肿瘤的毒素;较佳地,所述的细胞因子包括(但不限于):IL-12、IL-15、IFN-beta、TNF-alpha。
在另一优选例中,所述的多功能免疫辍合物中,所述的可检测标记物包括(但不限于):荧光标记物、显色标记物。
在另一优选例中,所述的多功能免疫辍合物中,所述的靶向免疫细胞的表面标志物的分子是结合T细胞表面标志物的抗体,其与所述的抗体形成T细胞参与的双功能抗体(Bispecific T cell engager,BiTE)。
在另一优选例中,所述的多功能免疫辍合物中,所述的结合T细胞表面标志物的抗体是抗CD3抗体。
在另一优选例中,所述的抗CD3抗体是单链抗体(scFV),单克隆抗体,Fab片段,Fd片段,Fv片段,F(ab’)2片段和其衍生物,或其它形式的抗体;较佳地为单链抗体。
在另一优选例中,所述的抗CD3抗体是人源化的,嵌合的,全人源的或鼠源的。
在另一优选例中,所述的多功能免疫辍合物是融合多肽,所述的抗体以及与之连接的功能性分子之间,还包括连接肽(接头)。
在另一优选例中,所述的连接肽的序列为(GlyGlyGlyGlySer)n,其中n为1到5的整数;更佳地,n=3。
在另一优选例中,所述的多功能免疫辍合物采用多肽给药或基因给药的方式。
在本发明的另一方面,提供编码所述的多功能免疫辍合物的核酸。
在本发明的另一方面,提供权述的多功能免疫辍合物的用途,用于制备抗肿瘤药物,或用于制备诊断肿瘤的试剂,该肿瘤表达CD19;或用于制备嵌合抗原受体修饰的免疫细胞;较佳地,所述免疫细胞包括:T淋巴细胞、NK细胞或者NKT淋巴细胞。
在本发明的另一方面,提供药物组合物,其包括:
所述的抗体或编码该抗体的核酸;或
所述的免疫辍合物或编码该辍合物的核酸;或
所述的嵌合抗原受体或编码该嵌合抗原受体的核酸;或
所述的基因修饰的免疫细胞。
本发明的其它方面由于本文的公开内容,对本领域的技术人员而言是显而易见的。
附图说明
图1、两个不同的单链抗体1F1和1H11分别进行噬菌体ELISA实验,检测其对人CD19的结合情况,以BSA为对照。
图2、抗体-Fc融合蛋白scFv-1F1-Fc和scFv-1H11-Fc,聚丙烯酰氨凝胶电泳鉴定结果。
图3、抗体scFv-1F1-Fc和scFv-1H11-Fc在浓度梯度ELISA实验中获得的结合曲线。
图4、流式细胞分析抗体scFv-1F1-Fc的荧光峰在人CD19表达阳性的K562-CD19细胞上与空白对照(PBS)相比有显著的差异,在人CD19表达阴性的K562细胞上无明显差别。
图5、流式细胞分析抗体scFv-1H11-Fc的荧光峰在人CD19表达阳性的K562-CD19细胞上与空白对照(PBS)相比有显著的差异,在人CD19表达阴性的K562细胞上无明显差别。
具体实施方式
本发明人经过深入的研究筛选,获得了特异性识别CD19的全人抗体,本发明的抗体可以被应用于制备靶向性抗肿瘤药物以及诊断肿瘤的药物。
抗CD19抗体
本发明人从全人源天然抗体库中筛选获得对于CD19结合性能良好且适用于制备基因修饰的免疫效应细胞的特异性抗体,并且找到了其发挥结合性能的关键CDR区。
本发明的抗体可以是完整的免疫球蛋白分子,也可以是抗原结合片段,包括但不限于Fab片段,Fd片段,Fv片段,F(ab’)2片段、互补决定区(CDR)片段、单链抗体(scFv)、结构域抗体,二价单链抗体、单链噬菌体抗体、双特异双链抗体、三链抗体、四链抗体。
抗体的抗原结合特性可由位于重链和轻链可变区的3个特定的区域来描述,称为互补决定区(CDR),所述的CDR区将可变区间隔成4个框架区域(FR),4个FR的氨基酸序列相对比较保守,不直接参与结合反应。这些CDR形成环状结构,通过其间的FR形成的β折叠在空间结构上相互靠近,重链上的CDR和相应轻链上的CDR构成了抗体的抗原结合位点。可以通过比较同类型的抗体的氨基酸序列来确定是哪些氨基酸构成了FR或CDR区域。CDR区是免疫学感兴趣的蛋白质的序列,本发明的抗体的CDR区是全新的。所述抗体可包含本文揭示的二、三、四、五或者所有六个CDR区。
本发明的另一方面包括本文所述抗体的功能变体,如果变体能与亲代抗体竞争特异性结合CD19,且其识别肿瘤细胞表达的CD19的能力接近于本发明实施例中提供的具体的抗体。所述功能变体可以具有保守序列修饰,包括核苷酸和氨基酸取代、添加和缺失。这些修饰可以通过本领域己知的标准技术导入,例如定向诱变和随机PCR介导的诱变,并且可包含天然以及非天然核苷酸和氨基酸。较佳地,序列的修饰发生在所述抗体的CDR区以外的区域上。
本发明的抗体可以被应用于制备各种靶向性抗肿瘤药物以及诊断肿瘤的药物,特别是应用于制备靶向CD19的免疫效应细胞。
嵌合抗原受体及基因修饰的免疫细胞
本发明提供了一种表达于免疫效应细胞(免疫细胞)表面的嵌合抗原受体,所述的嵌合抗原受体包含顺序连接的:胞外结合区,跨膜区和胞内信号区,其中所述胞外结合区包含本发明的抗体。将该嵌合抗原受体表达于免疫效应细胞的表面,可使得免疫效应细胞对表CD19的肿瘤细胞具有高度特异性的细胞毒性作用。
如本文所用,所述的“免疫细胞”与“免疫效应细胞”可互换使用,其包括:T淋巴细胞,NK细胞或NKT细胞等。
作为本发明的优选方式,所述的嵌合抗原受体中,包含的抗体为单链抗体,其通过CD8铰链区与CD8或者CD28的跨膜区相连接,跨膜区后紧接胞内信号区。
本发明也包括编码所述嵌合抗原受体的核酸。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或多肽的片段、类似物和衍生物。
嵌合抗原受体的跨膜区可以选自CD8或CD28等蛋白的跨膜区。人CD8蛋白是个异二聚体,由αβ或者γδ两条链组成。在本发明的一个实施方案中,跨膜区选自CD8α或者CD28的跨膜区。此外,CD8α铰链区(hinge)是一个柔性区域,因此,CD8或CD28和跨膜区加上铰链区被用于将嵌合抗原受体CAR的靶点识别结构域scFv和胞内信号区连接起来。
胞内信号区可以选自CD3ζ,FcεRIγ,CD27,CD28,CD137,CD134,MyD88,CD4蛋白的胞内信号区,及其组合。CD3分子由五个亚单位组成,其中CD3ζ亚单位(又称CD3zeta,简称Z)含有3个ITAM基序,该基序是TCR-CD3复合体中重要的信号转导区。CD3δZ是截短的不具有ITAM基序的CD3ζ序列,在实践中一般作为阴性对照的构建。FcεRIγ主要分布在肥大细胞和嗜碱性粒细胞表面,其含有一个ITAM基序,在结构、分布及功能上与CD3ζ类似。此外如前所述,CD28,CD137,CD134是共刺激信号分子,在与各自配体结合后其胞内信号区段产生的共刺激作用引起免疫效应细胞(主要是T淋巴细胞)的持续增殖,并能够提高免疫效应细胞分泌IL-2和IFN-γ等细胞因子的水平,同时提高CAR免疫效应细胞在体内的存活周期和抗肿瘤效果。
本发明的嵌合抗原受体可以按如下方式顺序连接:
本发明的抗体、CD8和CD3ζ;
本发明的抗体、CD8、CD137和CD3ζ;
本发明的抗体、CD28分子的跨膜区、CD28分子的胞内信号区和CD3ζ;或
本发明的抗体、CD28分子的跨膜区、CD28分子的胞内信号区、CD137和CD3ζ。
及其组合,其中相关嵌合抗原受体蛋白中CD28a代表CD28分子的跨膜区,CD28b代表CD28分子的胞内信号区。上述各种嵌合抗原受体统称为scFv(CD19)-CAR。
本发明还提供了包含上述编码表达于免疫效应细胞表面的嵌合抗原受体蛋白的核酸的载体。在一个具体实施方案中,本发明使用的载体是一种慢病毒质粒载体pRRLSIN-cPPT.EF-1α-EGFP.WPRE。该质粒属于第三代自灭活慢病毒载体***,该***共有四个质粒,即编码VSV-G蛋白的包膜质粒pCMV-VSV-G、编码Rev蛋白的包装质粒pRSV-Rev、编码Gal和Pol的pMDLg/pRRE及基于空载体pRRLSIN.cPPT.PGK-GFP.WPRE的编码目的基因CAR的重组表达载体,该***可以有效降低形成可复制性慢病毒颗粒的风险。应理解,其它表达载体也是可用的。
本发明还包括包含上述载体的病毒。本发明的病毒包括包装后的具有感染力的病毒,也包括包含包装为具有感染力的病毒所必需成分的待包装的病毒。本领域内已知的其它可用于将外源基因转导入免疫效应细胞的病毒及其对应的质粒载体也可用于本发明。
本发明还提供了基因修饰的免疫效应细胞,其被转导有本发明的核酸或被转导有本发明的上述包含所述含有该核酸的重组质粒,或包含该质粒的病毒。本领域常规的核酸转导方法,包括非病毒和病毒的转导方法都可以用于本发明。基于非病毒的转导方法包括电穿孔法和转座子法。近期Amaxa公司研发的Nucleofector核转染仪能够直接将外源基因导入细胞核获得目的基因的高效转导。另外,基于睡美人转座子(Sleeping Beautysystem)或PiggyBac转座子等转座子***的转导效率较普通电穿孔有较大提高,将nucleofector转染仪与睡美人转座子***联合应用已有报道[Davies JK.,etal.Combining CD19redirection and alloanergization to generate tumor-specifichuman T cells for allogeneic cell therapy of B-cell malignancies.Cancer Res,2010,70(10):OF1-10.],该方法既具有较高的转导效率又能够实现目的基因的定点整合。在本发明的一个实施方案中,实现嵌合抗原受体基因修饰的免疫效应细胞的转导方法是基于病毒如逆转录病毒或慢病毒的转导方法。该方法具有转导效率高,外源基因能够稳定表达,且可以缩短体外培养免疫效应细胞到达临床级数量的时间等优点。在该转基因免疫效应细胞表面,转导的核酸通过转录、翻译表达在其表面。通过对各种不同的培养的肿瘤细胞进行体外细胞毒实验证明,本发明的免疫效应细胞具有高度特异性的肿瘤细胞杀伤效果(亦称细胞毒性)。因此本发明的编码嵌合抗原受体蛋白的核酸,包含该核酸的质粒,包含该质粒的病毒和转导有上述核酸,质粒或病毒的转基因免疫效应细胞可以有效地用于肿瘤的免疫治疗。
本发明所述的免疫细胞还可以携带外源的细胞因子的编码序列;所述的细胞因子包括但不限于:IL-12,IL-15或IL-21等。这些细胞因子具有免疫调节或抗肿瘤的活性,能增强效应T细胞及活化的NK细胞的功能,或直接发挥抗肿瘤作用。因此,本领域技术人员可以理解,这些细胞因子的运用有助于所述的免疫细胞更好地发挥作用。
本发明所述的免疫细胞还可以表达除了上述嵌合抗原受体以外的另一种嵌合抗原受体,该受体不含有CD3ζ,但含有CD28的胞内信号结构域、CD137的胞内信号结构域或者这两者的组合。
本发明所述的免疫细胞还可以表达趋化因子受体;所述的趋化因子受体包括但不限于CCR2。本领域技术人员可以理解,所述的CCR2趋化因子受体可以使得体内的CCR2与之竞争性结合,对于阻断肿瘤的转移是有利的。
本发明所述的免疫细胞还可以表达能降低PD-1表达的siRNA或者阻断PD-L1的蛋白。本领域技术人员可以理解,竞争性阻断PD-L1与其受体PD-1的相互作用,有利于恢复抗肿瘤T细胞反应,从而抑制肿瘤生长。
本发明所述的免疫细胞还可以表达安全开关;较佳地,所述的安全开关包括:iCaspase-9,Truancated EGFR或RQR8。
免疫辍合物
本发明还提供了多功能免疫缀合物,其包含本文所述抗体以及进一步包含至少一种其它类型的功能性分子。所述的功能性分子选自但不限于:靶向肿瘤表面标志物的分子,抑制肿瘤的分子,靶向免疫细胞的表面标志物的分子或可检测标记物。所述抗体与所述功能性分子可以通过共价连接、偶联、附着、交联等方式构成辍合物。
作为一种优选方式,所述免疫缀合物可包含:本发明的抗体以及至少一种靶向肿瘤表面标志物的分子或抑制肿瘤的分子。所述的抑制肿瘤的分子可以是抗肿瘤的细胞因子,或抗肿瘤的毒素;较佳地,所述的细胞因子包括(但不限于):IL-12、IL-15、IFN-beta、TNF-alpha。所述的靶向肿瘤表面标志物的分子例如可以与本发明的抗体协同作用,更精准地靶向肿瘤细胞。
作为一种优选方式,所述免疫缀合物可包含:本发明的抗体以及可检测标记物。所述的可检测标记物包括但不限于:荧光标记物、显色标记物;如:酶、辅基、荧光材料、发光材料,生物发光材料、放射性材料、正电子发射金属以及非放射性顺磁性金属离子。也可包含一个以上的标记物。为了检测和/或分析和/或诊断目的用于标记抗体的标记依赖于使用的特定检测/分析/诊断技术和/或方法例如免疫组织化学染色(组织)样品、流式细胞计量术等。对于本领域已知的检测/分析/诊断技术和/或方法合适的标记为本领域技术人员所熟知。
作为一种优选方式,所述免疫缀合物可包含:本发明的抗体以及靶向免疫细胞的表面标志物的分子。所述靶向免疫细胞的表面标志物的分子可识别免疫细胞,其携带本发明的抗体达到免疫细胞,同时本发明的抗体可将免疫细胞靶向于肿瘤细胞,从而引发免疫细胞特异性地杀伤肿瘤。
作为通过直接或间接(例如通过接头)缀合而化学产生免疫缀合物的一种方式,所述免疫缀合物可以作为融合蛋白而产生,所述融合蛋白包含本发明的抗体及合适的其它蛋白。融合蛋白可以通过本领域已知方法产生,例如通过构建核酸分子以及随后表达所述核酸分子而重组产生,所述核酸分子包含符合读框的编码抗体的核苷酸序列以及编码合适标记的核苷酸序列。
本发明另一方面提供了编码本发明的至少一种抗体、其功能变体或者免疫缀合物的核酸分子。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。
本发明还涉及包含上述的适当DNA序列以及适当启动子或者控制序列的载体。这些载体可以用于转化适当的宿主细胞,以使其能够表达蛋白质。宿主细胞可以是原核细胞,如细菌细胞;或是低等真核细胞,如酵母细胞;或是高等真核细胞,如哺乳动物细胞。
药物组合物
本发明的抗体、包含该抗体的免疫辍合物以及基因修饰的免疫细胞可以应用于制备药物组合物或诊断试剂。所述的组合物除了包括有效量的所述抗体、免疫辍合物或免疫细胞,还可包含药学上可接受的载体。术语“药学上可接受的”是指当分子本体和组合物适当地给予动物或人时,它们不会产生不利的、过敏的或其它不良反应。
可作为药学上可接受的载体或其组分的一些物质的具体例子是糖类,如乳糖、葡萄糖和蔗糖;淀粉,如玉米淀粉和土豆淀粉;纤维素及其衍生物,如羧甲基纤维素钠、乙基纤维素和甲基纤维素;西黄蓍胶粉末;麦芽;明胶;滑石;固体润滑剂,如硬脂酸和硬脂酸镁;硫酸钙;植物油,如花生油、棉籽油、芝麻油、橄榄油、玉米油和可可油;多元醇,如丙二醇、甘油、山梨糖醇、甘露糖醇和聚乙二醇;海藻酸;乳化剂,如润湿剂,如月桂基硫酸钠;着色剂;调味剂;压片剂、稳定剂;抗氧化剂;防腐剂;无热原水;等渗盐溶液;和磷酸盐缓冲液等。
本发明的组合物可根据需要制成各种剂型,并可由医师根据患者种类、年龄、体重和大致疾病状况、给药方式等因素确定对病人有益的剂量进行施用。给药方式例如可以采用注射或其它治疗方式。
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,通常按照常规条件如J.萨姆布鲁克等编著,分子克隆实验指南,第三版,科学出版社,2002中所述的条件,或按照制造厂商所建议的条件。
实施例1、结合人类CD19的特异性单链抗体(scFv)的制备
1.1基于噬菌体展示的人CD19特异性结合抗体的筛选
利用噬菌体展示技术,从全人源天然抗体库中筛选人CD19特异性抗体。为此目的,在400ml 2×YT/氨苄青霉素培养基接种噬菌体展示全人源单链抗体天然库的甘油菌(购自上海锐劲生物技术有限公司),使细胞密度达到OD600=0.1,在37℃和200rpm条件下振荡培养直至细胞密度达到OD600=0.5。用1012pfu的M13KO7辅助噬菌体(购自Invitrogen)感染,在30℃和50rpm条件下培养30分钟。加入50mg/l卡那霉素后在37℃和200rpm条件下振荡培养30分钟后,通过离心(15分钟,1600×g,4℃)分离沉淀,重悬于400ml 2×YT/氨苄青霉素/卡那霉素培养基,在37℃和200rpm条件下振荡培养16小时。最后细胞通过离心(20分钟,5000×g,4℃)分离沉淀并丢弃,上清用0.45μm规格滤膜过滤后,加入1/4体积20%(w/v)PEG8000、2.5M NaCl溶液并在冰浴中保温1小时沉淀噬菌体颗粒。随后离心沉淀(20分钟,8000×g,4℃),弃上清,将噬菌体重悬于25ml预冷PBS(137mM NaCl,2.7mM KCl,8mMNa2HPO4,2mM KH2PO4)中,离心(5分钟,20000×g,4℃)。向上清液加入1/4体积20%(w/v)PEG8000、2.5M NaCl溶液,并冰浴30分钟再次沉淀噬菌体颗粒。离心沉淀(30分钟,20000×g,4℃),再次将噬菌体沉淀重悬于2ml预冷PBS中,在冰上保持30分钟并离心(30分钟,17000×g,4℃)。上清液与含4%(w/v)BSA的PBS溶液以1:1混合,置于旋转混合器上,室温下保温30分钟,然后直接用于筛选。
利用上述噬菌体抗体库,针对生物素标记的人CD19重组蛋白(购自上海锐劲生物技术有限公司)实施了四轮定向筛选,筛选方案如下:该噬菌体抗体库与生物素标记的人CD19抗原,在室温下保温2小时,然后与经封闭液2%(w/v)BSA(牛血清白蛋白)封闭过的链霉亲和素磁珠MyOne M-280(购自Invitrogen)在室温下保温30分钟。随后用PBST(含0.1%吐温-20)缓冲液洗涤磁珠,除去非特异性结合或结合能力较弱的噬菌体。结合能力强的噬菌体,则用甘氨酸-盐酸(pH 2.2)从磁珠上洗脱下来,用Tris中和液(pH 9.1)中和后,用于感染处于对数生长中期的大肠杆菌ER2738,并被用于下一轮筛选。在四轮筛选中,磁珠的用量分别为50μl、20μl、10μl和10μl,生物素标记的人CD19抗原浓度分别为100nM、10nM、5nM和1nM,PBST的洗涤次数分别为10次、10次、15次和20次。
1.2人CD19特异性结合抗体的鉴定
从第三轮和第四轮筛选所得的克隆中随机挑选单克隆,并用单噬菌体ELISA(酶联免疫吸附实验)分析其与人CD19的结合能力。为此目的,每个单菌落接种300μl 2×YT/氨苄青霉素培养基(含2%葡萄糖)于96孔深孔培养板,并在37℃和250rpm下振荡培养16小时。用20μl培养物接种到500μl 2×YT/氨苄青霉素培养基(含0.1%葡萄糖),在37℃和250rpm下振荡培养1.5小时。准备辅助噬菌体溶液,取75μl的M13KO7(滴度为3×1012pfu/ml)混入到15ml 2×YT培养基中,50μl/孔加到培养板中。在37℃和150rpm条件培养30分钟,然后加入准备好的卡那霉素溶液50μl/孔(取180μl的50mg/ml卡那霉素,加入到15ml 2×YT培养基),在37℃和250rpm下振荡培养16小时。最后离心沉淀细胞(30分钟,5000×g,4℃),将上清转移到新的96孔深孔培养板。
为进行单噬菌体ELISA,在96孔MediSorp ELISA板(购自Nunc)上分别使用100ng/孔抗原人CD19以及阴性对照蛋白BSA(100μl/孔),在4℃包被过夜。每个孔用含2%BSA(w/v)的PBST封闭。随后用PBST清洗孔三次并排净。然后加入100μl/孔上面制备的每种噬菌体溶液到板上各孔中。37℃保温2小时后,用PBST洗涤三次。为了检测结合的噬菌体,将抗M13抗体过氧化物歧化酶偶联物(购自GE Healthcare)以1:5000稀释于PBST中,并取100μl加到每个孔中。37℃保温1小时后用PBST漂洗孔三次,然后用PBS漂洗三次。最后吸取50μl TMB底物加入到孔中,并在室温下显色10分钟,随后加入每孔50μl的2M H2SO4终止显色反应。用酶联免疫检测仪(Bio-Rad)在450nm测量消光值。结合测序分析,观察到两个不同的单链抗体1F1(SEQ ID NO:1(核苷酸),2(氨基酸))和1H11(SEQ ID NO:3(核苷酸),4(氨基酸)),在ELISA实验中对人CD19(huCD19)结合信号很强,对BSA无结合(图1)。
SEQ ID NO:1(核苷酸):
Caggtcaccttgaaggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctctggattcaccttcagtagttatgtcatgcactgggtccgccaggctccaggcaaggggctggagtgggtggcagttatctcaaatgatggaactaataagtatcacatagactccgtgaagggccgattctccatctccagagacaatgccaagaactcactgtatctgcaaatgaacagcctgagagccgaggacacggctgtttattactgtgcgagagaaggtcccgccagctacggtgactttgactactggggccaaggaaccctggtcaccgtctcgagtggtggaggcggttcaggcggaggtggttctggcggtggcggatcgcaatctgccctgactcagcctcgctcagtgtccgggtctcctggacagtcagtcaccatctcctgcactggaaccaacagagatgttggtggttataactttgtctcctggtaccaacaacatccaggcaaagcccccaaactcatgctttatgaagtcagtaatcggccctcaggggtttctaatcgcttgtctggctccaagtctggcaacacggcctccctgaccatctctgggctccagcctgaggacgaggctgattattactgcagctcatatacaagcagcaggactcttgtcttcggaactgggaccaaggtcaccatcctaggt
SEQ ID NO:2(氨基酸)
QVTLKESGGGVVQPGRSLRLSCAASGFTFSSYVMHWVRQAPGKGLEWVAVISNDGTNKYHIDSVKGRFSISRDNAKNSLYLQMNSLRAEDTAVYYCAREGPASYGDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSALTQPRSVSGSPGQSVTISCTGTNRDVGGYNFVSWYQQHPGKAPKLMLYEVSNRPSGVSNRLSGSKSGNTASLTISGLQPEDEADYYCSSYTSSRTLVFGTGTKVTILG
其中,重链可变区的氨基酸序列如SEQ ID NO:2中第1-120位所示;其轻链可变区的氨基酸序列如SEQ ID NO:2中第136-246位所示。
其中,重链CDR1氨基酸序列为SYVMH(SEQ ID NO:5),重链CDR2氨基酸序列为VISNDGTNKYHIDSVKG(SEQ ID NO:6),重链CDR3氨基酸序列为EGPASYGDFDY(SEQ ID NO:7);轻链CDR1氨基酸序列为TGTNRDVGGYNFVS(SEQ ID NO:8),轻链CDR2氨基酸序列为EVSNRPS(SEQ ID NO:9),轻链CDR3氨基酸序列为SSYTSSRTLV(SEQ ID NO:10)。
SEQ ID NO:3(核苷酸)
cagatgcagctggtgcagtctggggctgaggtgaagaagcctgggtcctcggtgaaggtctcctgcaaggcttctggaggcaccttcagcagctatgctatcagctgggtgcgacaggcccctggacaagggcttgagtggatgggagggatcatccctatctttggtacagcaaactacgcacagaagttccagggcagagtcacgattactgcggacgaatccacgagcacagcctacatggagctgagcagcctgagatctgaggacacggccgtgtattactgtgcgagcgagtcagcagctggtacgtccttctactactacggtatggacgtctggggcaaaggcaccctggtcaccgtctcgagtggtggaggcggttcaggcggaggtggttctggcggtggcggatcggaaattgtgctgactcagtctccactctccctgcccgtcacccctggagagccggcctccatctcctgcaggtctagtcagggcctcgtgcatggtaatggatacacctttttggattggtacctgcagaagccagggcagtctccacagctcctgatctatttgggttctaatcgggcctccggggtccctgacaggttcagtggcagtggatcaggcacagattttacactaaaaatcagccgggtggaggctgaggatgttggggtttattactgcatgcaagctctacaaactccgtacacttttggccaggggaccaaagtggatatcaaacgt
SEQ ID NO:4(氨基酸)
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCASESAAGTSFYYYGMDVWGKGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPLSLPVTPGEPASISCRSSQGLVHGNGYTFLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYTFGQGTKVDIKR
其中,重链可变区的氨基酸序列如SEQ ID NO:4中第1-124位所示;其轻链可变区的氨基酸序列如SEQ ID NO:4中第140-252位所示。
其中,重链CDR1氨基酸序列为SYAIS(SEQ ID NO:11),重链CDR2氨基酸序列为GIIPIFGTANYAQKFQG(SEQ ID NO:12),重链CDR3氨基酸序列为ESAAGTSFYYYGMDV(SEQ IDNO:13);轻链CDR1氨基酸序列为RSSQGLVHGNGYTFLD(SEQ ID NO:14),轻链CDR2氨基酸序列为LGSNRAS(SEQ ID NO:15),轻链CDR3氨基酸序列为MQALQTPYT(SEQ ID NO:16)。
实施例2、抗CD19的单链抗体的表达和纯化
2.1人CD19单链抗体的制备
使用引物对V5-1F1-F(SEQ ID NO:17)和V5-1F1-R(SEQ ID NO:18)从实施例1中所得克隆pCantab-1F1中扩增出scFv-1F1片段;使用引物对V5-1H11-F(SEQ ID NO:19)和V5-1H11-R(SEQ ID NO:20)从所得克隆pCantab-1H11中扩增出scFv-1H11片段,通过NheI/BamHI(购自NEB)双酶切,以T4DNA连接酶于同样以NheI/BamHI双酶切载体质粒pCMV-V5-Fc(该载体在多克隆位点下游融合表达人IgG1抗体的Fc片段,以下简称V5-Fc,购自上海锐劲生物技术有限公司)连接并转化于宿主菌TOP10中,挑取克隆通过PCR鉴定阳性克隆并通过测序确认,分别获得V5-scFv-1F1-Fc和V5-scFv-1H11-Fc真核表达质粒。
SEQ ID NO:17:gatgGCTAGCAcaggtcaccttgaaggagtctg;
SEQ ID NO:18:gactggatccACCTAGGATGGTGACCTTGG;
SEQ ID NO:19:gatgGCTAGCAcagatgcagctggtgcagtctggggctgaggtga;
SEQ ID NO:20:gactggatccACGTTTGATATCCACTTTGGTCC。
将上述表达质粒分别转染生长良好的HEK-293F细胞,37℃,5%CO2,125rpm摇床连续培养7天,4000rpm离心10min,去除沉淀,收集上清,并用0.45μm滤膜过滤,将处理好的样品以protein A(购自GE)亲和柱进行亲和纯化,最终获得纯化的抗体-Fc融合蛋白scFv-1F1-Fc和scFv-1H11-Fc,聚丙烯酰氨凝胶电泳鉴定结果如图2所示。
实施例3、抗人CD19的单链抗体的抗原结合活性分析
通过浓度梯度ELISA实验,测定筛选到的抗体对抗原人CD19的结合活性。为此目的,用0.1M NaHCO3(pH 9.6)包被液稀释抗原人CD19,每孔包被100ng,50μl/孔,4℃包被过夜,并用含2%(w/v)BSA和0.01%(v/v)Tween-20的PBST封闭液于室温下封闭2小时。然后用PBST漂洗平板三次并去除干净。随后,向每个孔板加入100μl含一系列浓度(起始浓度10nM,进行3倍梯度稀释,直至稀释到1:729)的各抗体蛋白的PBST溶液,每个样品的测定使用平行三孔分析。37℃保温2小时后,用PBST漂洗三次,随后加入1:20000稀释的带辣根过氧化物酶标记的羊抗人抗体(购自上海锐劲生物技术有限公司)100μl/孔,37℃反应1小时。为了检测,用PBST漂洗孔三次,然后用PBS漂洗三次,最后加入TMB显示15分钟,用每孔50μl的2MH2SO4终止显色反应,用酶联免疫检测仪(Bio-Rad)在450nm测量消光值。用GraphPad软件评估所得到的吸光强度值,计算抗体的结合强度。为此目的,每种情况下测量的消光值对相应的抗体浓度作图,并用下面的非线性回归对所得曲线进行拟合。
其中鉴定固定的抗原和抗体蛋白之间的结合/解离平衡是:
x=抗体蛋白的浓度;
y=抗原/抗体复合体的浓度(通过显色反应后的吸光值间接测量);
a=固定化抗原的总浓度;
b=解离常数(KD)。
抗体scFv-1F1-Fc和scFv-1H11-Fc在浓度梯度ELISA实验中获得的结合曲线示例性表示于图3,其中scFv-1F1-Fc的表观亲和力为475pM,scFv-1H11-Fc的表观亲和力为957pM。
实施例4、人CD19稳定表达细胞系的构建
4.1质粒载体的构建
本实施例使用的载体***属于第三代自灭活慢病毒载体***,该***共有三个质粒即编码蛋白Gag/Pol、编码Rev蛋白的包装质粒psPAX2;编码VSV-G蛋白的包膜质粒PMD2.G及基于空载体pWPT(购自Addgene公司)的编码目的基因人CD19胞外区域和跨膜区域的重组质粒pWPT-huCD19。
根据Genbank登录号NM_001178098提供的人CD19序列,使用基于PCR搭桥的基因合成方法,合成包含信号肽、人CD19胞外区域、跨膜区域、胞内区域及Flag tag的目的基因片段(SEQ ID NO:21(核苷酸),22(氨基酸)),通过引物对pWCD19F(SEQ ID NO:23,GCTTACGCGTCCTAGCGCTACCGGTCGCCACCATGCCACCTCCTCGCCTC)和pWCD19R(SEQ ID NO:24,CGAGGTCGACCTA CTTGTCGTCATCGTCTTTGTAATCCCTGGTGCTCCAGGTG)进行PCR扩增,扩增条件为预变性:94℃,4min;变性:94℃,30s;退火:58℃,30s;延伸:68℃,80s;30个循环。获得的片段理论大小为1716bp,扩增产物经琼脂糖电泳确认与理论大小一致。其中在开放阅读框的上下游引入MluI和SalI酶切位点。上述获得的目的基因由MluI和SalI双酶切,连入同样双酶切的pWPT载体中,构建成功的慢病毒载体pWPT-huCD19,经MluI和SalI酶切鉴定及序列测定正确后进行慢病毒包装。
4.2质粒转染293T细胞包装慢病毒
以6×106的密度接种培养至第6~10代的293T细胞(ATCC:CRL-11268)于10cm培养皿中,37℃,5%CO2培养过夜准备用于转染。培养基为含10%胎牛血清(Sigma公司)的DMEM(Invitrogen公司),次日,在转染前约2小时更换培养液为无血清DMEM。
转染的步骤如下:
1)将5μg目的基因质粒pWPT-huCD19,分别与7.5μg包装质粒PAX2和2.5μg包膜质粒pMD2.G,溶入500μL MillQ水中,混匀,
2)逐滴加入62μL 2.5M CaCl2(Sigma公司),以1200rpm/min vortex混匀,
3)最后逐滴加入500μL 2×HBS(280mM NaCl,10mM KCl,1.5mM Na2HPO4,12mM葡萄糖,50mM Hepes(Sigma公司),pH7.05,0.22μM过滤除菌),1200rpm/min振荡混匀10s,
4)立即逐滴加入培养皿中,轻轻摇匀,37℃,5%CO2,培养4~6h后,更换为含10%胎牛血清的DMEM。
在转染48h或72h后,离心除去细胞碎片,然后用0.45μm滤器(Millipore公司)过滤收集病毒。
4.3重组慢病毒感染白血病细胞K562
将上述收集的病毒液经浓缩滴定后,分别感染铺于6cm平皿内的细胞K562(购自ATCC)。感染三天后收集细胞,取部分混合克隆,使用细胞裂解液裂解后,取40μg细胞蛋白进行SDS-PAGE凝胶电泳,随后对凝胶电泳进行免疫印迹,并用小鼠抗Flag-tag抗体染色。PBS洗涤后,使用辣根过氧化物酶标记的羊抗小鼠抗体孵育,洗涤后使用ECL试剂显色,最后进行显影。Western blot结果显示,在感染了人CD19的K562细胞(即K562-CD19)中可检测到分子量大小约60kDa的条带,而未感染的K562细胞中未检测到相应的条带。其余的细胞扩大培养后冻存一部分,并用于下一步实验。
实施例5、流式细胞学分析各个细胞系与抗CD19单链抗体的结合情况
通过荧光激活细胞分选仪(FACS)(Guava 8HT,由Millipore公司提供)分析抗体scFv-1F1-Fc和scFv-1H11-Fc各自与细胞表面的人CD19的结合能力。
具体方法如下:
1)取对数生长期的细胞K562-CD19和K562分别接种到6cm平皿中,接种细胞密度约为90%,37℃孵箱过夜培养。
2)使用10mM的EDTA消化细胞,200g×5min离心收集细胞。以2~3×106/mL的浓度重悬于1%含小牛血清的磷酸盐缓冲液(NBS PBS)中,按100ul/管的量加入流式专用管中。
3)200g×5min离心,弃上清。
4)两个实验组分别加入待测抗体scFv-1F1-Fc和scFv-1H11-Fc,另设一个对照组为不加抗体的PBS空白对照。各抗体的终浓度均为20μg/ml,每管加入100ul。冰浴,45分钟。
5)每管加入2ml 1%NBS PBS,以200g×5min离心,共二遍。
6)弃上清,加入1:100稀释的羊抗人抗体-FITC(来自上海业力生物科技有限公司),每管加入100ul。冰浴,45分钟。
7)每管加入2ml 1%NBS PBS,以200g×5min离心,共二遍。
8)弃上清,重悬于300ul 1%NBS PBS中,流式细胞仪检测。
9)应用流式细胞仪数据分析软件Flowjo7.6分析数据。
流式细胞分析结果表明,抗体scFv-1F1-Fc和scFv-1H11-Fc的荧光峰在人CD19表达阳性的K562-CD19细胞上与空白对照(PBS)相比有显著的差异(图4A,图5A),在人CD19表达阴性的K562细胞上无明显差别(图4B,图5B),表明其都可以特异识别人CD19表达阳性的K562-CD19细胞,但是与人CD19表达阴性的K562细胞不结合。因此,抗体scFv-1F1-Fc和scFv-1H11-Fc可以特异性识别细胞表面的人CD19蛋白。
实施例6、表达本发明核酸编码的嵌合抗原受体蛋白的慢病毒质粒的构建及病毒包装
构建嵌合抗原受体,本发明示例的嵌合抗原受体(CAR)各部分的连接顺序如表1。
表1
嵌合抗原受体 | 胞外结合区-跨膜区-胞内信号区1-胞内信号区2等 | 描述 |
1F1-δZ | scFv(1F1)-CD8-CD3δzeta | 阴性对照 |
1F1-BBZ | scFv(1F1)-CD8-CD137-CD3zeta | 第二代 |
1F1-28BBZ | scFv(1F1)-CD28a-CD28b-CD137-CD3zeta | 第三代 |
1H11-δZ | scFv(1H11)-CD8-CD3δzeta | 阴性对照 |
1H11-BBZ | scFv(1H11)-CD8-CD137-CD3zeta | 第二代 |
1H11-28BBZ | scFv(1H11)-CD28a-CD28b-CD137-CD3zeta | 第三代 |
注:CD28a代表CD28分子的跨膜区,CD28b代表CD28分子的胞内信号区。
本实施例中使用的慢病毒质粒载体***属于第三代慢病毒四质粒***,该***共有四个质粒即编码VSV-G蛋白的包膜质粒pCMV-VSV-G(购自addgene)、编码Rev蛋白的包装质粒pRSV-Rev(购自addgene)、编码Gal和Pol的pMDLg/pRRE(购自addgene)及基于空载体pRRLSIN.cPPT.PGK-GFP.WPRE(购自addgene)的编码目的基因CAR的重组表达载体,该***可以有效降低形成可复制性慢病毒颗粒的风险。所有CAR的基因载体启动子均利用已经公开的专利201310164725.X中的载体上延长因子-1α(elongation factor-1α,EF-1α)。构建具体方法如下:
首先通过常规分子克隆的技术方式,对空载体pRRLSIN-cPPT.PGK-GFP.WPRE进行改造,用延长因子-1α(elongation factor-1α,简称EF-1α)的启动子替代了原载体的启动子,并在启动子和CD8αsp信号肽之间增加了MluI酶切位点。具体地,使用ClaI/SalI(购自NEB)双酶切载体pWPT-EGFP(购自Addgene),回收1.1Kb的DNA片段,用T4DNA连接酶连接于经ClaI/SalI双酶切的载体pRRLSIN-cPPT.PGK-GFP.WPRE,并转化于宿主菌TOP10中,挑取克隆通过菌落PCR鉴定阳性克隆并通过测序确认,获得重组质粒pRRLSIN-cPPT.EF-1α-EGFP.WPRE。
1、核酸片段的扩增
(1)获得信号肽片段
具体地,包含CD8αsp信号肽序列的片段F1以本实施例中构建的质粒pRRLSIN-cPPT.EF-1α-EGFP.WPRE为模板,以引物对PWXLF(SEQ ID NO:25,引物序列:gcaggggaaagaatagtagaca)和PRRL-CD8SP-R1(SEQ ID NO:26,引物序列:CGGCCTGGCGGCGTGGAG)进行PCR扩增获得。
(2)scFv序列的扩增
以前述获得的V5-scFv-1F1-Fc和V5-scFv-1H11-Fc为模板,分别采用对应的引物对1F1-F(SEQ ID NO:27,包含部分CD8signal peptide(CD8sp)的序列,引物序列为:5’-tgctccacgccgccaggccgcaggtcaccttgaaggagtctg-3’)和引物1F1-R(SEQ ID NO:28,包含部分CD8hinge的序列,引物序列为:5’-CGCGGCGCTGGCGTCGTGGTACCTA GGATGGTGACCTTGG-3’),以及引物对1H11-F(SEQ ID NO:29,5’-tgctccacgccgccaggccgcagatgcagctggtgcagtc-3’)和1H11-R(SEQ ID NO:30,5’-CGCGGCGCTGGCGTCGTGGTACGTTTGATATCCACTTTGGTCC-3’),PCR扩增获得分别包含1F1和1H11的scFv DNA片段F2-1F1和F2-1H11。
(3)嵌合抗原受体其他部分的核酸序列
包含CD8-CD3δzeta(δZ)的片段F3-δZ以申请专利201310164725.X中SEQ ID NO:26质粒为模板,采用引物对PRRL-CD8hinge(SEQ ID NO:31,引物序列:accacgacgccagcgccg)和δZ re(SEQ ID NO:32,引物序列:GATTGTCGACCTACGCGGGGGCGTCTGCGCTCCTGCTGAACTTCACTCT)通过PCR扩增获得。
包含CD8-CD137-CD3zeta(BBZ)的片段F3-BBZ和包含CD28a-CD28b-CD137-CD3zeta(28BBZ)的片段F3-28BBZ序列分别以申请专利201310164725.X中SEQ ID NO:28和SEQ IDNO:30对应的质粒为模板,采用引物对PRRL-CD8hinge(SEQ ID NO:33,引物序列:accacgacgccagcgccg)和R3R(SEQ ID NO:34,引物序列:aatccagaggttgattgtcgacctagcgagggggcagggcctgc)通过PCR扩增获得。
2、核酸片段的拼接
分别将如前述获得的F1核酸片段(包含信号肽序列),F2核酸片段(分别包含两种scFv序列)以及F3-δZ或F3-BBZ或F3-28BBZ核酸片段等摩尔比混合,进行三片段拼接PCR,拼接条件为:预变性:94℃,4min;变性:94℃,40s;退火:60℃,40s;延伸:68℃,140s,进行5个循环,然后总延伸68℃,10min,补充DNA聚合酶及正向引物PWXLF和反向引物R3R(CD8-CD3δzeta对应的反向引物为δZ re,其余的皆为R3R)后PCR扩增30个循环,扩增条件为预变性:94℃,4min;变性:94℃,40s;退火:60℃,40s;延伸:68℃,140s,进行30个循环,然后总延伸68℃,10min。本实施例构建的由F1片段、F2抗体scFv片段、以及各类F3片段所组成的片段可以简称为CAR片段,扩增获得的片段分别称为:
3、慢病毒质粒载体的构建
本实施例构建了由F1片段、F2scFv片段、以及F3片段组件构成的片段,简称为CAR。通过MluI/SalI限制性内切酶双酶切,连入同样双酶切的pRRLSIN-cPPT.EF-1α-EGFP.WPRE载体中,从而构建表达各嵌合抗原受体的慢病毒载体pRRLSIN-cPPT.EF-1α-CAR。构建成功的载体经MluI/SalI酶切鉴定及序列测定正确后,可以用于慢病毒包装。如前所述,相关CAR基因经转录翻译为一条肽链,在CD8α信号肽的引导下,抗CD19嵌合抗原受体将定位在细胞膜上。
通过以上构建,分别可获得六个CAR多肽序列,称为:
4、质粒转染293T包装慢病毒
以6×106的密度接种培养至第6~10代的HEK-293T细胞(ATCC:CRL-11268)于10cm培养皿中,37℃,5%CO2培养过夜准备用于转染。培养基为含10%胎牛血清和DMEM(均购自Life公司)。
转染的步骤如下:
A液配制:将5.2μg的各目的基因质粒pRRLSIN-cPPT.EF-1α-CAR,分别与6.2μg包装质粒pMDLg RRE和pRSV-REV、以及2.4μg包膜质粒pCMV-VSV-G,溶入800μL的无血清DMEM培养液中,混匀。
B液配制:将60μg PEI(聚乙烯亚胺1μg/μl,购自Polysciences公司)溶解于800μL的无血清DMEM培养液中,轻轻混匀,室温孵育5min。
转染复合物的形成:将A液加入B液中轻轻混合,加入后立即涡旋混合或轻轻混匀,室温下孵育20min。
将转染复合物1.6ml滴加入HEK-293T细胞中,4-5h小时后,用2%FBS的DMEM培基给转染的293T细胞换液。
在转染孵育72h后,使用0.45μm滤器(购自Millipore公司)过滤收集病毒,然后采用Beckman Optima L-100XP超速离心机28000rpm,4℃离心2小时,弃离心上清,离心所得沉淀用1/10~1/50原液体积的AIM-V培养液(购自Life公司)进行重悬,以100μL/管分装冻存于-80℃,以待病毒滴定或感染T淋巴细胞。
实施例7、重组慢病毒感染T细胞
由健康人外周血通过密度梯度离心法获得人外周血单个核细胞(上海市血液中心提供),FACS分析CD3阳性率,然后按照CD3阳性T细胞与磁珠比例为1:2加入同时包被有抗CD3和CD28抗体的磁珠(Invitrogen公司)和终浓度300U/mL的重组人IL-2(购自上海华新生物高技术有限公司)刺激培养24h。然后以MOI≈5用上述重组慢病毒感染T细胞。感染后的细胞每隔一天采用5×105/mL的密度进行传代,同时在淋巴细胞培养液中补加终浓度300U/mL的重组人IL-2。
感染的T细胞在培养第8天时通过流式细胞检测各不同嵌合抗原受体表达。首先,感染后的CAR T细胞与生物素标记的人CD19蛋白37℃孵育1h,D-PBS洗2次,然后加入PE-标记的streptavidin在37℃孵育40min。D-PBS洗3次后流式细胞仪检测阳性细胞比率。以未感染的T淋巴细胞作为阴性对照,表达不同嵌合抗原受体的病毒感染T细胞其阳性率如表2所示。该阳性率结果表明,通过慢病毒感染的方法能够获得一定阳性率的CAR T细胞。
表2
转染有下列CAR的T细胞 | T细胞转染阳性率 |
1F1-δZ | 58% |
1F1-BBZ | 85% |
1F1-28BBZ | 73% |
1H11-δZ | 68% |
1H11-BBZ | 83% |
1H11-28BBZ | 77% |
T细胞在分别感染包装有不同嵌合抗原受体的病毒后,以细胞密度为5×105/ml隔天传代培养、计数、并对传代的细胞培养液补加IL-2(终浓度为300U/ml),培养第11天约有50~200倍的扩增,表明表达不同CAR T细胞在体外能够进行一定数量的扩增,为后续体外毒性试验及体内试验提供了保证。
实施例8、表达嵌合抗原受体的T淋巴细胞的体外毒性效果实验
体外毒性实验使用的材料如下:
如表3所示的白血病细胞K562和转染了CD19的K562细胞(K562-CD19)作为靶细胞,效应细胞为前述制备的CAR T细胞,效靶比视情况分别为3:1,1:1和1:3,靶细胞数量为10000个/孔,根据不同效靶比对应效应细胞。各组均设5个复孔,取5个复孔的平均值。检测时间为第18h。
其中各实验组和各对照组如下:
各实验组:各靶细胞+表达不同嵌合抗原受体的T,
对照组1:靶细胞最大释放LDH,
对照组2:靶细胞自发释放LDH,
对照组3:效应细胞自发释放LDH。
检测方法:采用CytoTox 96非放射性细胞毒性检测试剂盒(Promega公司)进行。该方法是基于比色法的检测方法,可替代51Cr释放法。CytoTox检测定量地测量乳酸脱氢酶(LDH)。LDH是一种稳定的胞质酶,在细胞裂解时会释放出来,其释放方式与51Cr在放射性分析中的释放方式基本相同。释放出的LDH培养基上清中,可通过30分钟偶联的酶反应来检测,在酶反应中LDH可使一种四唑盐(INT)转化为红色的甲臜(formazan)。生成的红色产物的量与裂解的细胞数成正比。具体参照CytoTox 96非放射性细胞毒性检测试剂盒说明书。
细胞毒性计算公式为:
具体如表4所示,本发明的抗CD19的单链抗体(1F1,1H11)的CAR均有明显的杀伤CD19阳性的K562细胞(K562-CD19)的活性,δZ组没有明显杀伤。此外,所有CAR T细胞对K562细胞(未转CD19的K562)均没有杀伤活性。这些结果表明,本发明的抗CD19的CAR-T细胞(包括二、三代CAR T)可以选择性地针对CD19阳性的K562细胞,并进行有效的杀伤。此外,本发明的抗CD19的第二、三代CAR T对CD19阳性肿瘤细胞呈现效靶比梯度依赖性即效靶比越高细胞毒性作用越强。
表3、融合表达单链抗体的CAR T细胞的体外抗肿瘤细胞毒性
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> 上海科济制药有限公司
<120> 抗CD19全人抗体以及靶向CD19的免疫效应细胞
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Gly
<210> 7
<211> 11
<212> PRT
<213> 智人(Homo Sapiens)
<400> 7
Glu Gly Pro Ala Ser Tyr Gly Asp Phe Asp Tyr
1 5 10
<210> 8
<211> 14
<212> PRT
<213> 智人(Homo Sapiens)
<400> 8
Thr Gly Thr Asn Arg Asp Val Gly Gly Tyr Asn Phe Val Ser
1 5 10
<210> 9
<211> 7
<212> PRT
<213> 智人(Homo Sapiens)
<400> 9
Glu Val Ser Asn Arg Pro Ser
1 5
<210> 10
<211> 10
<212> PRT
<213> 智人(Homo Sapiens)
<400> 10
Ser Ser Tyr Thr Ser Ser Arg Thr Leu Val
1 5 10
<210> 11
<211> 5
<212> PRT
<213> 智人(Homo Sapiens)
<400> 11
Ser Tyr Ala Ile Ser
1 5
<210> 12
<211> 17
<212> PRT
<213> 智人(Homo Sapiens)
<400> 12
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 13
<211> 15
<212> PRT
<213> 智人(Homo Sapiens)
<400> 13
Glu Ser Ala Ala Gly Thr Ser Phe Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 14
<211> 16
<212> PRT
<213> 智人(Homo Sapiens)
<400> 14
Arg Ser Ser Gln Gly Leu Val His Gly Asn Gly Tyr Thr Phe Leu Asp
1 5 10 15
<210> 15
<211> 7
<212> PRT
<213> 智人(Homo Sapiens)
<400> 15
Leu Gly Ser Asn Arg Ala Ser
1 5
<210> 16
<211> 9
<212> PRT
<213> 智人(Homo Sapiens)
<400> 16
Met Gln Ala Leu Gln Thr Pro Tyr Thr
1 5
<210> 17
<211> 33
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> (1)..(33)
<223> 引物
<400> 17
gatggctagc acaggtcacc ttgaaggagt ctg 33
<210> 18
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 18
gactggatcc acctaggatg gtgaccttgg 30
<210> 19
<211> 45
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 19
gatggctagc acagatgcag ctggtgcagt ctggggctga ggtga 45
<210> 20
<211> 33
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 20
gactggatcc acgtttgata tccactttgg tcc 33
<210> 21
<211> 1698
<212> DNA
<213> 智人(Homo Sapiens)
<400> 21
atgccacctc ctcgcctcct cttcttcctc ctcttcctca cccccatgga agtcaggccc 60
gaggaacctc tagtggtgaa ggtggaagag ggagataacg ctgtgctgca gtgcctcaag 120
gggacctcag atggccccac tcagcagctg acctggtctc gggagtcccc gcttaaaccc 180
ttcttaaaac tcagcctggg gctgccaggc ctgggaatcc acatgaggcc cctggccatc 240
tggcttttca tcttcaacgt ctctcaacag atggggggct tctacctgtg ccagccgggg 300
cccccctctg agaaggcctg gcagcctggc tggacagtca atgtggaggg cagcggggag 360
ctgttccggt ggaatgtttc ggacctaggt ggcctgggct gtggcctgaa gaacaggtcc 420
tcagagggcc ccagctcccc ttccgggaag ctcatgagcc ccaagctgta tgtgtgggcc 480
aaagaccgcc ctgagatctg ggagggagag cctccgtgtc tcccaccgag ggacagcctg 540
aaccagagcc tcagccagga cctcaccatg gcccctggct ccacactctg gctgtcctgt 600
ggggtacccc ctgactctgt gtccaggggc cccctctcct ggacccatgt gcaccccaag 660
gggcctaagt cattgctgag cctagagctg aaggacgatc gcccggccag agatatgtgg 720
gtaatggaga cgggtctgtt gttgccccgg gccacagctc aagacgctgg aaagtattat 780
tgtcaccgtg gcaacctgac catgtcattc cacctggaga tcactgctcg gccagtacta 840
tggcactggc tgctgaggac tggtggctgg aaggtctcag ctgtgacttt ggcttatctg 900
atcttctgcc tgtgttccct tgtgggcatt cttcatcttc aaagagccct ggtcctgagg 960
aggaaaagaa agcgaatgac tgaccccacc aggagattct tcaaagtgac gcctccccca 1020
ggaagcgggc cccagaacca gtacgggaac gtgctgtctc tccccacacc cacctcaggc 1080
ctcggacgcg cccagcgttg ggccgcaggc ctggggggca ctgccccgtc ttatggaaac 1140
ccgagcagcg acgtccaggc ggatggagcc ttggggtccc ggagcccgcc gggagtgggc 1200
ccagaagaag aggaagggga gggctatgag gaacctgaca gtgaggagga ctccgagttc 1260
tatgagaacg actccaacct tgggcaggac cagctctccc aggatggcag cggctacgag 1320
aaccctgagg atgagcccct gggtcctgag gatgaagact ccttctccaa cgctgagtct 1380
tatgagaacg aggatgaaga gctgacccag ccggtcgcca ggacaatgga cttcctgagc 1440
cctcatgggt cagcctggga ccccagccgg gaagcaacct ccctggcagg gtcccagtcc 1500
tatgaggata tgagaggaat cctgtatgca gccccccagc tccgctccat tcggggccag 1560
cctggaccca atcatgagga agatgcagac tcttatgaga acatggataa tcccgatggg 1620
ccagacccag cctggggagg agggggccgc atgggcacct ggagcaccag ggattacaaa 1680
gacgatgacg acaagtag 1698
<210> 22
<211> 565
<212> PRT
<213> 智人(Homo Sapiens)
<400> 22
Met Pro Pro Pro Arg Leu Leu Phe Phe Leu Leu Phe Leu Thr Pro Met
1 5 10 15
Glu Val Arg Pro Glu Glu Pro Leu Val Val Lys Val Glu Glu Gly Asp
20 25 30
Asn Ala Val Leu Gln Cys Leu Lys Gly Thr Ser Asp Gly Pro Thr Gln
35 40 45
Gln Leu Thr Trp Ser Arg Glu Ser Pro Leu Lys Pro Phe Leu Lys Leu
50 55 60
Ser Leu Gly Leu Pro Gly Leu Gly Ile His Met Arg Pro Leu Ala Ile
65 70 75 80
Trp Leu Phe Ile Phe Asn Val Ser Gln Gln Met Gly Gly Phe Tyr Leu
85 90 95
Cys Gln Pro Gly Pro Pro Ser Glu Lys Ala Trp Gln Pro Gly Trp Thr
100 105 110
Val Asn Val Glu Gly Ser Gly Glu Leu Phe Arg Trp Asn Val Ser Asp
115 120 125
Leu Gly Gly Leu Gly Cys Gly Leu Lys Asn Arg Ser Ser Glu Gly Pro
130 135 140
Ser Ser Pro Ser Gly Lys Leu Met Ser Pro Lys Leu Tyr Val Trp Ala
145 150 155 160
Lys Asp Arg Pro Glu Ile Trp Glu Gly Glu Pro Pro Cys Leu Pro Pro
165 170 175
Arg Asp Ser Leu Asn Gln Ser Leu Ser Gln Asp Leu Thr Met Ala Pro
180 185 190
Gly Ser Thr Leu Trp Leu Ser Cys Gly Val Pro Pro Asp Ser Val Ser
195 200 205
Arg Gly Pro Leu Ser Trp Thr His Val His Pro Lys Gly Pro Lys Ser
210 215 220
Leu Leu Ser Leu Glu Leu Lys Asp Asp Arg Pro Ala Arg Asp Met Trp
225 230 235 240
Val Met Glu Thr Gly Leu Leu Leu Pro Arg Ala Thr Ala Gln Asp Ala
245 250 255
Gly Lys Tyr Tyr Cys His Arg Gly Asn Leu Thr Met Ser Phe His Leu
260 265 270
Glu Ile Thr Ala Arg Pro Val Leu Trp His Trp Leu Leu Arg Thr Gly
275 280 285
Gly Trp Lys Val Ser Ala Val Thr Leu Ala Tyr Leu Ile Phe Cys Leu
290 295 300
Cys Ser Leu Val Gly Ile Leu His Leu Gln Arg Ala Leu Val Leu Arg
305 310 315 320
Arg Lys Arg Lys Arg Met Thr Asp Pro Thr Arg Arg Phe Phe Lys Val
325 330 335
Thr Pro Pro Pro Gly Ser Gly Pro Gln Asn Gln Tyr Gly Asn Val Leu
340 345 350
Ser Leu Pro Thr Pro Thr Ser Gly Leu Gly Arg Ala Gln Arg Trp Ala
355 360 365
Ala Gly Leu Gly Gly Thr Ala Pro Ser Tyr Gly Asn Pro Ser Ser Asp
370 375 380
Val Gln Ala Asp Gly Ala Leu Gly Ser Arg Ser Pro Pro Gly Val Gly
385 390 395 400
Pro Glu Glu Glu Glu Gly Glu Gly Tyr Glu Glu Pro Asp Ser Glu Glu
405 410 415
Asp Ser Glu Phe Tyr Glu Asn Asp Ser Asn Leu Gly Gln Asp Gln Leu
420 425 430
Ser Gln Asp Gly Ser Gly Tyr Glu Asn Pro Glu Asp Glu Pro Leu Gly
435 440 445
Pro Glu Asp Glu Asp Ser Phe Ser Asn Ala Glu Ser Tyr Glu Asn Glu
450 455 460
Asp Glu Glu Leu Thr Gln Pro Val Ala Arg Thr Met Asp Phe Leu Ser
465 470 475 480
Pro His Gly Ser Ala Trp Asp Pro Ser Arg Glu Ala Thr Ser Leu Ala
485 490 495
Gly Ser Gln Ser Tyr Glu Asp Met Arg Gly Ile Leu Tyr Ala Ala Pro
500 505 510
Gln Leu Arg Ser Ile Arg Gly Gln Pro Gly Pro Asn His Glu Glu Asp
515 520 525
Ala Asp Ser Tyr Glu Asn Met Asp Asn Pro Asp Gly Pro Asp Pro Ala
530 535 540
Trp Gly Gly Gly Gly Arg Met Gly Thr Trp Ser Thr Arg Asp Tyr Lys
545 550 555 560
Asp Asp Asp Asp Lys
565
<210> 23
<211> 50
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 23
gcttacgcgt cctagcgcta ccggtcgcca ccatgccacc tcctcgcctc 50
<210> 24
<211> 53
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 24
cgaggtcgac ctacttgtcg tcatcgtctt tgtaatccct ggtgctccag gtg 53
<210> 25
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 25
gcaggggaaa gaatagtaga ca 22
<210> 26
<211> 18
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 26
cggcctggcg gcgtggag 18
<210> 27
<211> 42
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 27
tgctccacgc cgccaggccg caggtcacct tgaaggagtc tg 42
<210> 28
<211> 40
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 28
cgcggcgctg gcgtcgtggt acctaggatg gtgaccttgg 40
<210> 29
<211> 40
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 29
tgctccacgc cgccaggccg cagatgcagc tggtgcagtc 40
<210> 30
<211> 43
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 30
cgcggcgctg gcgtcgtggt acgtttgata tccactttgg tcc 43
<210> 31
<211> 18
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 31
accacgacgc cagcgccg 18
<210> 32
<211> 49
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 32
gattgtcgac ctacgcgggg gcgtctgcgc tcctgctgaa cttcactct 49
<210> 33
<211> 18
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 33
accacgacgc cagcgccg 18
<210> 34
<211> 44
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 引物
<400> 34
aatccagagg ttgattgtcg acctagcgag ggggcagggc ctgc 44
<210> 35
<211> 1427
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 1F1 scFv-δZ
<400> 35
gcaggggaaa gaatagtaga cataatagca acagacatac aaactaaaga attacaaaaa 60
caaattacaa aaattcaaaa ttttatcgat ggctccggtg cccgtcagtg ggcagagcgc 120
acatcgccca cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag 180
agaaggtggc gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc 240
gagggtgggg gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac 300
gggtttgccg ccagaacaca ggtgtcgtga cgcggatcca ggcctaagct tacgcgtcct 360
agcgctaccg gtcgccacca tggccttacc agtgaccgcc ttgctcctgc cgctggcctt 420
gctgctccac gccgccaggc cgcaggtcac cttgaaggag tctgggggag gcgtggtcca 480
gcctgggagg tccctgagac tctcctgtgc agcctctgga ttcaccttca gtagttatgt 540
catgcactgg gtccgccagg ctccaggcaa ggggctggag tgggtggcag ttatctcaaa 600
tgatggaact aataagtatc acatagactc cgtgaagggc cgattctcca tctccagaga 660
caatgccaag aactcactgt atctgcaaat gaacagcctg agagccgagg acacggctgt 720
ttattactgt gcgagagaag gtcccgccag ctacggtgac tttgactact ggggccaagg 780
aaccctggtc accgtctcga gtggtggagg cggttcaggc ggaggtggtt ctggcggtgg 840
cggatcgcaa tctgccctga ctcagcctcg ctcagtgtcc gggtctcctg gacagtcagt 900
caccatctcc tgcactggaa ccaacagaga tgttggtggt tataactttg tctcctggta 960
ccaacaacat ccaggcaaag cccccaaact catgctttat gaagtcagta atcggccctc 1020
aggggtttct aatcgcttgt ctggctccaa gtctggcaac acggcctccc tgaccatctc 1080
tgggctccag cctgaggacg aggctgatta ttactgcagc tcatatacaa gcagcaggac 1140
tcttgtcttc ggaactggga ccaaggtcac catcctaggt accacgacgc cagcgccgcg 1200
accaccaaca ccggcgccca ccatcgcgtc gcagcccctg tccctgcgcc cagaggcgtg 1260
ccggccagcg gcggggggcg cagtgcacac gagggggctg gacttcgcct gtgatatcta 1320
catctgggcg cccttggccg ggacttgtgg ggtccttctc ctgtcactgg ttatcaccag 1380
agtgaagttc agcaggagcg cagacgcccc cgcgtaggtc gacaatc 1427
<210> 36
<211> 1874
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 1F1 scFv-BBZ
<400> 36
gcaggggaaa gaatagtaga cataatagca acagacatac aaactaaaga attacaaaaa 60
caaattacaa aaattcaaaa ttttatcgat ggctccggtg cccgtcagtg ggcagagcgc 120
acatcgccca cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag 180
agaaggtggc gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc 240
gagggtgggg gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac 300
gggtttgccg ccagaacaca ggtgtcgtga cgcggatcca ggcctaagct tacgcgtcct 360
agcgctaccg gtcgccacca tggccttacc agtgaccgcc ttgctcctgc cgctggcctt 420
gctgctccac gccgccaggc cgcaggtcac cttgaaggag tctgggggag gcgtggtcca 480
gcctgggagg tccctgagac tctcctgtgc agcctctgga ttcaccttca gtagttatgt 540
catgcactgg gtccgccagg ctccaggcaa ggggctggag tgggtggcag ttatctcaaa 600
tgatggaact aataagtatc acatagactc cgtgaagggc cgattctcca tctccagaga 660
caatgccaag aactcactgt atctgcaaat gaacagcctg agagccgagg acacggctgt 720
ttattactgt gcgagagaag gtcccgccag ctacggtgac tttgactact ggggccaagg 780
aaccctggtc accgtctcga gtggtggagg cggttcaggc ggaggtggtt ctggcggtgg 840
cggatcgcaa tctgccctga ctcagcctcg ctcagtgtcc gggtctcctg gacagtcagt 900
caccatctcc tgcactggaa ccaacagaga tgttggtggt tataactttg tctcctggta 960
ccaacaacat ccaggcaaag cccccaaact catgctttat gaagtcagta atcggccctc 1020
aggggtttct aatcgcttgt ctggctccaa gtctggcaac acggcctccc tgaccatctc 1080
tgggctccag cctgaggacg aggctgatta ttactgcagc tcatatacaa gcagcaggac 1140
tcttgtcttc ggaactggga ccaaggtcac catcctaggt accacgacgc cagcgccgcg 1200
accaccaaca ccggcgccca ccatcgcgtc gcagcccctg tccctgcgcc cagaggcgtg 1260
ccggccagcg gcggggggcg cagtgcacac gagggggctg gacttcgcct gtgatatcta 1320
catctgggcg cccttggccg ggacttgtgg ggtccttctc ctgtcactgg ttatcaccct 1380
ttactgcaaa cggggcagaa agaaactcct gtatatattc aaacaaccat ttatgagacc 1440
agtacaaact actcaagagg aagatggctg tagctgccga tttccagaag aagaagaagg 1500
aggatgtgaa ctgagagtga agttcagcag gagcgcagac gcccccgcgt acaagcaggg 1560
ccagaaccag ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga 1620
caagagacgt ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga 1680
aggcctgtac aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat 1740
gaaaggcgag cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc 1800
caccaaggac acctacgacg cccttcacat gcaggccctg ccccctcgct aggtcgacaa 1860
tcaacctctg gatt 1874
<210> 37
<211> 2009
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 1F1 scFv-28BBZ
<400> 37
gcaggggaaa gaatagtaga cataatagca acagacatac aaactaaaga attacaaaaa 60
caaattacaa aaattcaaaa ttttatcgat ggctccggtg cccgtcagtg ggcagagcgc 120
acatcgccca cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag 180
agaaggtggc gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc 240
gagggtgggg gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac 300
gggtttgccg ccagaacaca ggtgtcgtga cgcggatcca ggcctaagct tacgcgtcct 360
agcgctaccg gtcgccacca tggccttacc agtgaccgcc ttgctcctgc cgctggcctt 420
gctgctccac gccgccaggc cgcaggtcac cttgaaggag tctgggggag gcgtggtcca 480
gcctgggagg tccctgagac tctcctgtgc agcctctgga ttcaccttca gtagttatgt 540
catgcactgg gtccgccagg ctccaggcaa ggggctggag tgggtggcag ttatctcaaa 600
tgatggaact aataagtatc acatagactc cgtgaagggc cgattctcca tctccagaga 660
caatgccaag aactcactgt atctgcaaat gaacagcctg agagccgagg acacggctgt 720
ttattactgt gcgagagaag gtcccgccag ctacggtgac tttgactact ggggccaagg 780
aaccctggtc accgtctcga gtggtggagg cggttcaggc ggaggtggtt ctggcggtgg 840
cggatcgcaa tctgccctga ctcagcctcg ctcagtgtcc gggtctcctg gacagtcagt 900
caccatctcc tgcactggaa ccaacagaga tgttggtggt tataactttg tctcctggta 960
ccaacaacat ccaggcaaag cccccaaact catgctttat gaagtcagta atcggccctc 1020
aggggtttct aatcgcttgt ctggctccaa gtctggcaac acggcctccc tgaccatctc 1080
tgggctccag cctgaggacg aggctgatta ttactgcagc tcatatacaa gcagcaggac 1140
tcttgtcttc ggaactggga ccaaggtcac catcctaggt accacgacgc cagcgccgcg 1200
accaccaaca ccggcgccca ccatcgcgtc gcagcccctg tccctgcgcc cagaggcgtg 1260
ccggccagcg gcggggggcg cagtgcacac gagggggctg gacttcgcct gtgatttttg 1320
ggtgctggtg gtggttggtg gagtcctggc ttgctatagc ttgctagtaa cagtggcctt 1380
tattattttc tgggtgagga gtaagaggag caggctcctg cacagtgact acatgaacat 1440
gactccccgc cgccccgggc caacccgcaa gcattaccag ccctatgccc caccacgcga 1500
cttcgcagcc tatcgctcca aacggggcag aaagaaactc ctgtatatat tcaaacaacc 1560
atttatgaga ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga 1620
agaagaagaa ggaggatgtg aactgagagt gaagttcagc aggagcgcag acgcccccgc 1680
gtaccagcag ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta 1740
cgatgttttg gacaagagac gtggccggga ccctgagatg gggggaaagc cgcagagaag 1800
gaagaaccct caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta 1860
cagtgagatt gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca 1920
gggtctcagt acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc 1980
tcgctaggtc gacaatcaac ctctggatt 2009
<210> 38
<211> 1445
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 1H11 scFv-δZ
<400> 38
gcaggggaaa gaatagtaga cataatagca acagacatac aaactaaaga attacaaaaa 60
caaattacaa aaattcaaaa ttttatcgat ggctccggtg cccgtcagtg ggcagagcgc 120
acatcgccca cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag 180
agaaggtggc gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc 240
gagggtgggg gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac 300
gggtttgccg ccagaacaca ggtgtcgtga cgcggatcca ggcctaagct tacgcgtcct 360
agcgctaccg gtcgccacca tggccttacc agtgaccgcc ttgctcctgc cgctggcctt 420
gctgctccac gccgccaggc cgcagatgca gctggtgcag tctggggctg aggtgaagaa 480
gcctgggtcc tcggtgaagg tctcctgcaa ggcttctgga ggcaccttca gcagctatgc 540
tatcagctgg gtgcgacagg cccctggaca agggcttgag tggatgggag ggatcatccc 600
tatctttggt acagcaaact acgcacagaa gttccagggc agagtcacga ttactgcgga 660
cgaatccacg agcacagcct acatggagct gagcagcctg agatctgagg acacggccgt 720
gtattactgt gcgagcgagt cagcagctgg tacgtccttc tactactacg gtatggacgt 780
ctggggcaaa ggcaccctgg tcaccgtctc gagtggtgga ggcggttcag gcggaggtgg 840
ttctggcggt ggcggatcgg aaattgtgct gactcagtct ccactctccc tgcccgtcac 900
ccctggagag ccggcctcca tctcctgcag gtctagtcag ggcctcgtgc atggtaatgg 960
atacaccttt ttggattggt acctgcagaa gccagggcag tctccacagc tcctgatcta 1020
tttgggttct aatcgggcct ccggggtccc tgacaggttc agtggcagtg gatcaggcac 1080
agattttaca ctaaaaatca gccgggtgga ggctgaggat gttggggttt attactgcat 1140
gcaagctcta caaactccgt acacttttgg ccaggggacc aaagtggata tcaaacgtac 1200
cacgacgcca gcgccgcgac caccaacacc ggcgcccacc atcgcgtcgc agcccctgtc 1260
cctgcgccca gaggcgtgcc ggccagcggc ggggggcgca gtgcacacga gggggctgga 1320
cttcgcctgt gatatctaca tctgggcgcc cttggccggg acttgtgggg tccttctcct 1380
gtcactggtt atcaccagag tgaagttcag caggagcgca gacgcccccg cgtaggtcga 1440
caatc 1445
<210> 39
<211> 1892
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 1H11 scFv-BBZ
<400> 39
gcaggggaaa gaatagtaga cataatagca acagacatac aaactaaaga attacaaaaa 60
caaattacaa aaattcaaaa ttttatcgat ggctccggtg cccgtcagtg ggcagagcgc 120
acatcgccca cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag 180
agaaggtggc gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc 240
gagggtgggg gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac 300
gggtttgccg ccagaacaca ggtgtcgtga cgcggatcca ggcctaagct tacgcgtcct 360
agcgctaccg gtcgccacca tggccttacc agtgaccgcc ttgctcctgc cgctggcctt 420
gctgctccac gccgccaggc cgcagatgca gctggtgcag tctggggctg aggtgaagaa 480
gcctgggtcc tcggtgaagg tctcctgcaa ggcttctgga ggcaccttca gcagctatgc 540
tatcagctgg gtgcgacagg cccctggaca agggcttgag tggatgggag ggatcatccc 600
tatctttggt acagcaaact acgcacagaa gttccagggc agagtcacga ttactgcgga 660
cgaatccacg agcacagcct acatggagct gagcagcctg agatctgagg acacggccgt 720
gtattactgt gcgagcgagt cagcagctgg tacgtccttc tactactacg gtatggacgt 780
ctggggcaaa ggcaccctgg tcaccgtctc gagtggtgga ggcggttcag gcggaggtgg 840
ttctggcggt ggcggatcgg aaattgtgct gactcagtct ccactctccc tgcccgtcac 900
ccctggagag ccggcctcca tctcctgcag gtctagtcag ggcctcgtgc atggtaatgg 960
atacaccttt ttggattggt acctgcagaa gccagggcag tctccacagc tcctgatcta 1020
tttgggttct aatcgggcct ccggggtccc tgacaggttc agtggcagtg gatcaggcac 1080
agattttaca ctaaaaatca gccgggtgga ggctgaggat gttggggttt attactgcat 1140
gcaagctcta caaactccgt acacttttgg ccaggggacc aaagtggata tcaaacgtac 1200
cacgacgcca gcgccgcgac caccaacacc ggcgcccacc atcgcgtcgc agcccctgtc 1260
cctgcgccca gaggcgtgcc ggccagcggc ggggggcgca gtgcacacga gggggctgga 1320
cttcgcctgt gatatctaca tctgggcgcc cttggccggg acttgtgggg tccttctcct 1380
gtcactggtt atcacccttt actgcaaacg gggcagaaag aaactcctgt atatattcaa 1440
acaaccattt atgagaccag tacaaactac tcaagaggaa gatggctgta gctgccgatt 1500
tccagaagaa gaagaaggag gatgtgaact gagagtgaag ttcagcagga gcgcagacgc 1560
ccccgcgtac aagcagggcc agaaccagct ctataacgag ctcaatctag gacgaagaga 1620
ggagtacgat gttttggaca agagacgtgg ccgggaccct gagatggggg gaaagccgag 1680
aaggaagaac cctcaggaag gcctgtacaa tgaactgcag aaagataaga tggcggaggc 1740
ctacagtgag attgggatga aaggcgagcg ccggaggggc aaggggcacg atggccttta 1800
ccagggtctc agtacagcca ccaaggacac ctacgacgcc cttcacatgc aggccctgcc 1860
ccctcgctag gtcgacaatc aacctctgga tt 1892
<210> 40
<211> 2027
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> misc_feature
<223> 1H11 scFv-28BBZ
<400> 40
gcaggggaaa gaatagtaga cataatagca acagacatac aaactaaaga attacaaaaa 60
caaattacaa aaattcaaaa ttttatcgat ggctccggtg cccgtcagtg ggcagagcgc 120
acatcgccca cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag 180
agaaggtggc gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc 240
gagggtgggg gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac 300
gggtttgccg ccagaacaca ggtgtcgtga cgcggatcca ggcctaagct tacgcgtcct 360
agcgctaccg gtcgccacca tggccttacc agtgaccgcc ttgctcctgc cgctggcctt 420
gctgctccac gccgccaggc cgcagatgca gctggtgcag tctggggctg aggtgaagaa 480
gcctgggtcc tcggtgaagg tctcctgcaa ggcttctgga ggcaccttca gcagctatgc 540
tatcagctgg gtgcgacagg cccctggaca agggcttgag tggatgggag ggatcatccc 600
tatctttggt acagcaaact acgcacagaa gttccagggc agagtcacga ttactgcgga 660
cgaatccacg agcacagcct acatggagct gagcagcctg agatctgagg acacggccgt 720
gtattactgt gcgagcgagt cagcagctgg tacgtccttc tactactacg gtatggacgt 780
ctggggcaaa ggcaccctgg tcaccgtctc gagtggtgga ggcggttcag gcggaggtgg 840
ttctggcggt ggcggatcgg aaattgtgct gactcagtct ccactctccc tgcccgtcac 900
ccctggagag ccggcctcca tctcctgcag gtctagtcag ggcctcgtgc atggtaatgg 960
atacaccttt ttggattggt acctgcagaa gccagggcag tctccacagc tcctgatcta 1020
tttgggttct aatcgggcct ccggggtccc tgacaggttc agtggcagtg gatcaggcac 1080
agattttaca ctaaaaatca gccgggtgga ggctgaggat gttggggttt attactgcat 1140
gcaagctcta caaactccgt acacttttgg ccaggggacc aaagtggata tcaaacgtac 1200
cacgacgcca gcgccgcgac caccaacacc ggcgcccacc atcgcgtcgc agcccctgtc 1260
cctgcgccca gaggcgtgcc ggccagcggc ggggggcgca gtgcacacga gggggctgga 1320
cttcgcctgt gatttttggg tgctggtggt ggttggtgga gtcctggctt gctatagctt 1380
gctagtaaca gtggccttta ttattttctg ggtgaggagt aagaggagca ggctcctgca 1440
cagtgactac atgaacatga ctccccgccg ccccgggcca acccgcaagc attaccagcc 1500
ctatgcccca ccacgcgact tcgcagccta tcgctccaaa cggggcagaa agaaactcct 1560
gtatatattc aaacaaccat ttatgagacc agtacaaact actcaagagg aagatggctg 1620
tagctgccga tttccagaag aagaagaagg aggatgtgaa ctgagagtga agttcagcag 1680
gagcgcagac gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct 1740
aggacgaaga gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg 1800
gggaaagccg cagagaagga agaaccctca ggaaggcctg tacaatgaac tgcagaaaga 1860
taagatggcg gaggcctaca gtgagattgg gatgaaaggc gagcgccgga ggggcaaggg 1920
gcacgatggc ctttaccagg gtctcagtac agccaccaag gacacctacg acgcccttca 1980
catgcaggcc ctgccccctc gctaggtcga caatcaacct ctggatt 2027
<210> 41
<211> 324
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 41
Gln Val Thr Leu Lys Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Asn Asp Gly Thr Asn Lys Tyr His Ile Asp Ser Val
50 55 60
Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Pro Ala Ser Tyr Gly Asp Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Arg Ser
130 135 140
Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr
145 150 155 160
Asn Arg Asp Val Gly Gly Tyr Asn Phe Val Ser Trp Tyr Gln Gln His
165 170 175
Pro Gly Lys Ala Pro Lys Leu Met Leu Tyr Glu Val Ser Asn Arg Pro
180 185 190
Ser Gly Val Ser Asn Arg Leu Ser Gly Ser Lys Ser Gly Asn Thr Ala
195 200 205
Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr Tyr
210 215 220
Cys Ser Ser Tyr Thr Ser Ser Arg Thr Leu Val Phe Gly Thr Gly Thr
225 230 235 240
Lys Val Thr Ile Leu Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
245 250 255
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
260 265 270
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
275 280 285
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
290 295 300
Leu Leu Leu Ser Leu Val Ile Thr Arg Val Lys Phe Ser Arg Ser Ala
305 310 315 320
Asp Ala Pro Ala
<210> 42
<211> 469
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
Gln Val Thr Leu Lys Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Asn Asp Gly Thr Asn Lys Tyr His Ile Asp Ser Val
50 55 60
Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Pro Ala Ser Tyr Gly Asp Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Arg Ser
130 135 140
Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr
145 150 155 160
Asn Arg Asp Val Gly Gly Tyr Asn Phe Val Ser Trp Tyr Gln Gln His
165 170 175
Pro Gly Lys Ala Pro Lys Leu Met Leu Tyr Glu Val Ser Asn Arg Pro
180 185 190
Ser Gly Val Ser Asn Arg Leu Ser Gly Ser Lys Ser Gly Asn Thr Ala
195 200 205
Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr Tyr
210 215 220
Cys Ser Ser Tyr Thr Ser Ser Arg Thr Leu Val Phe Gly Thr Gly Thr
225 230 235 240
Lys Val Thr Ile Leu Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
245 250 255
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
260 265 270
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
275 280 285
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
290 295 300
Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys
305 310 315 320
Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr
325 330 335
Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
340 345 350
Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro
355 360 365
Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly
370 375 380
Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro
385 390 395 400
Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr
405 410 415
Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly
420 425 430
Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln
435 440 445
Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln
450 455 460
Ala Leu Pro Pro Arg
465
<210> 43
<211> 514
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
Gln Val Thr Leu Lys Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Asn Asp Gly Thr Asn Lys Tyr His Ile Asp Ser Val
50 55 60
Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Pro Ala Ser Tyr Gly Asp Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Arg Ser
130 135 140
Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr
145 150 155 160
Asn Arg Asp Val Gly Gly Tyr Asn Phe Val Ser Trp Tyr Gln Gln His
165 170 175
Pro Gly Lys Ala Pro Lys Leu Met Leu Tyr Glu Val Ser Asn Arg Pro
180 185 190
Ser Gly Val Ser Asn Arg Leu Ser Gly Ser Lys Ser Gly Asn Thr Ala
195 200 205
Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr Tyr
210 215 220
Cys Ser Ser Tyr Thr Ser Ser Arg Thr Leu Val Phe Gly Thr Gly Thr
225 230 235 240
Lys Val Thr Ile Leu Gly Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
245 250 255
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
260 265 270
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
275 280 285
Ala Cys Asp Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys
290 295 300
Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser
305 310 315 320
Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg
325 330 335
Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg
340 345 350
Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr
355 360 365
Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu
370 375 380
Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu
385 390 395 400
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
405 410 415
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
420 425 430
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
435 440 445
Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
450 455 460
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
465 470 475 480
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
485 490 495
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
500 505 510
Pro Arg
<210> 44
<211> 330
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 44
Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Glu Ser Ala Ala Gly Thr Ser Phe Tyr Tyr Tyr Gly Met Asp
100 105 110
Val Trp Gly Lys Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr
130 135 140
Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile
145 150 155 160
Ser Cys Arg Ser Ser Gln Gly Leu Val His Gly Asn Gly Tyr Thr Phe
165 170 175
Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile
180 185 190
Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala
210 215 220
Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala Leu Gln Thr Pro Tyr
225 230 235 240
Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys Arg Thr Thr Thr Pro
245 250 255
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
260 265 270
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
275 280 285
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
290 295 300
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Arg Val
305 310 315 320
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala
325 330
<210> 45
<211> 475
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Glu Ser Ala Ala Gly Thr Ser Phe Tyr Tyr Tyr Gly Met Asp
100 105 110
Val Trp Gly Lys Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr
130 135 140
Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile
145 150 155 160
Ser Cys Arg Ser Ser Gln Gly Leu Val His Gly Asn Gly Tyr Thr Phe
165 170 175
Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile
180 185 190
Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala
210 215 220
Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala Leu Gln Thr Pro Tyr
225 230 235 240
Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys Arg Thr Thr Thr Pro
245 250 255
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
260 265 270
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
275 280 285
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
290 295 300
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
305 310 315 320
Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
325 330 335
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
340 345 350
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
355 360 365
Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr
370 375 380
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
385 390 395 400
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
405 410 415
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
420 425 430
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
435 440 445
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
450 455 460
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
465 470 475
<210> 46
<211> 520
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 46
Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Glu Ser Ala Ala Gly Thr Ser Phe Tyr Tyr Tyr Gly Met Asp
100 105 110
Val Trp Gly Lys Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr
130 135 140
Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile
145 150 155 160
Ser Cys Arg Ser Ser Gln Gly Leu Val His Gly Asn Gly Tyr Thr Phe
165 170 175
Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile
180 185 190
Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala
210 215 220
Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala Leu Gln Thr Pro Tyr
225 230 235 240
Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys Arg Thr Thr Thr Pro
245 250 255
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
260 265 270
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
275 280 285
Thr Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val
290 295 300
Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile
305 310 315 320
Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr
325 330 335
Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln
340 345 350
Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly
355 360 365
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
370 375 380
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
385 390 395 400
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
405 410 415
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
420 425 430
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
435 440 445
Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu
450 455 460
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
465 470 475 480
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
485 490 495
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
500 505 510
His Met Gln Ala Leu Pro Pro Arg
515 520
Claims (38)
1. 可特异结合CD19的全人抗体,其特征在于,该全人抗体包含:
(a)重链可变区,其具有SEQ ID NO: 5所示的氨基酸序列的CDR1、SEQ ID NO: 6所示的氨基酸序列的CDR2、SEQ ID NO: 7所示的氨基酸序列的CDR3;和
(b)轻链可变区,其具有SEQ ID NO: 8所示的氨基酸序列的CDR1、SEQ ID NO: 9所示的氨基酸序列的CDR2、SEQ ID NO: 10所示氨基酸序列的CDR3。
2. 如权利要求1所述的全人抗体,其特征在于,该全人抗体包括重链可变区和轻链可变区,其重链可变区的氨基酸序列如SEQ ID NO: 2中第1-120位所示;其轻链可变区的氨基酸序列如SEQ ID NO: 2中第136-246位所示。
3.编码权利要求1-2任一所述的抗体的核酸。
4.一种表达载体,其包含权利要求3所述的核酸。
5. 一种宿主细胞,其包含权利要求4所述的表达载体或基因组中整合有权利要求3所述的核酸。
6. 权利要求1-2任一所述的抗体的用途,用于制备特异性靶向表达CD19的肿瘤细胞的靶向性药物,抗体药物偶联物或多功能抗体;或
用于制备诊断肿瘤的试剂,该肿瘤表达CD19;或
用于制备嵌合抗原受体修饰的免疫细胞。
7.包含权利要求1-2任一所述的抗体的嵌合抗原受体,其特征在于,所述的嵌合抗原受体包含顺序连接的:权利要求1-2任一所述的抗体,跨膜区和胞内信号区;所述的胞内信号区选自:CD3ζ,FcεRIγ,CD27,CD28,CD137,CD134,MyD88,CD40的胞内信号区序列,或其组合。
8.如权利要求7所述的嵌合抗原受体,其特征在于,所述的跨膜区包含CD8或CD28的跨膜区。
9.如权利要求7所述的嵌合抗原受体,其特征在于,所述的嵌合抗原受体包括如下的顺序连接的抗体,跨膜区和胞内信号区:
权利要求1-2任一所述的抗体、CD8和CD3ζ;
权利要求1-2任一所述的抗体、CD8、CD137和CD3ζ;
权利要求1-2任一所述的抗体、CD28分子的跨膜区、CD28分子的胞内信号区和CD3ζ;或
权利要求1-2任一所述的抗体、CD28分子的跨膜区、CD28分子的胞内信号区、CD137和CD3ζ。
10.如权利要求7所述的嵌合抗原受体,其特征在于,所述的抗体是单链抗体或结构域抗体。
11.如权利要求7所述的嵌合抗原受体,其特征在于,所述的嵌合抗原受体具有:
SEQ ID NO: 41所示的氨基酸序列;
SEQ ID NO: 42所示的氨基酸序列;
SEQ ID NO: 43所示的氨基酸序列。
12.编码权利要求7-11任一所述的嵌合抗原受体的核酸。
13.一种表达载体,其特征在于,其包含权利要求12所述的核酸。
14.一种病毒,其特征在于,所述的病毒包含权利要求13所述载体。
15.权利要求7-11任一所述的嵌合抗原受体、或权利要求12所述的核酸、或权利要求13所述的表达载体、或权利要求14所述的病毒的用途,用于制备靶向表达CD19的肿瘤细胞的基因修饰的免疫细胞。
16. 如权利要求15所述的用途,其特征在于,所述的表达CD19的肿瘤包括:B细胞白血病,B细胞淋巴瘤,套细胞淋巴瘤、急性淋巴母细胞白血病、慢性淋巴细胞白血病、毛细胞性白血病或骨髓瘤。
17.一种基因修饰的免疫细胞,其特征在于,其转导有权利要求12所述的核酸,或权利要求13所述的表达载体或权利要求14所述的病毒;或
其表面表达权利要求7-11任一所述的嵌合抗原受体。
18.如权利要求17所述的免疫细胞,其特征在于,其还携带外源的细胞因子的编码序列。
19.如权利要求18所述的免疫细胞,其特征在于,所述的细胞因子包括:IL-12,IL-15或IL-21。
20.如权利要求17所述的免疫细胞,其特征在于,其还表达另一种嵌合抗原受体,该受体不含有CD3ζ,但含有CD28的胞内信号结构域、CD137的胞内信号结构域或者这两者的组合。
21.如权利要求17所述的免疫细胞,其特征在于,其还表达趋化因子受体。
22.如权利要求21所述的免疫细胞,其特征在于,所述的趋化因子受体包括:CCR2。
23.如权利要求17所述的免疫细胞,其特征在于,其还表达能降低PD-1表达的siRNA或者阻断PD-L1的蛋白。
24.如权利要求17所述的免疫细胞,其特征在于,其还表达安全开关。
25. 如权利要求24所述的免疫细胞,其特征在于,所述的安全开关包括:iCaspase-9,Truancated EGFR或RQR8。
26.如权利要求17所述的免疫细胞,其特征在于,所述的免疫细胞包括:T淋巴细胞、NK细胞或者NKT淋巴细胞。
27.权利要求17-26任一所述的基因修饰的免疫细胞的用途,其特征在于,用于制备抑制肿瘤的药物,所述的肿瘤是表达CD19的肿瘤。
28. 一种多功能免疫辍合物,其特征在于,所述的多功能免疫辍合物包括:
权利要求1-2任一所述的抗体;以及
与之连接的功能性分子;所述的功能性分子选自:靶向肿瘤表面标志物的分子,抑制肿瘤的分子,靶向免疫细胞的表面标志物的分子或可检测标记物。
29.如权利要求28所述的多功能免疫辍合物,其特征在于,所述的靶向肿瘤表面标志物的分子是结合肿瘤表面标志物的抗体或配体;或
所述的抑制肿瘤的分子是抗肿瘤的细胞因子或抗肿瘤的毒素。
30.如权利要求29所述的多功能免疫缀合物,其特征在于,所述的细胞因子包括:IL-12、IL-15、IFN-beta、TNF-alpha。
31.如权利要求28所述的多功能免疫辍合物,其特征在于,所述的可检测标记物包括:荧光标记物、显色标记物。
32.如权利要求28所述的多功能免疫辍合物,其特征在于,所述的靶向免疫细胞的表面标志物的分子是结合T细胞表面标志物的抗体,其与权利要求1-2任一所述的抗体形成T细胞参与的双功能抗体。
33.如权利要求32所述的多功能免疫辍合物,其特征在于,所述的结合T细胞表面标志物的抗体是抗CD3抗体。
34.如权利要求28所述的多功能免疫辍合物,其特征在于,其是融合多肽,权利要求1-2任一所述的抗体以及与之连接的功能性分子之间,还包括连接肽。
35. 编码权利要求28-34任一所述的多功能免疫辍合物的核酸。
36. 权利要求28-34任一所述的多功能免疫辍合物的用途,用于制备抗肿瘤药物,或
用于制备诊断肿瘤的试剂,该肿瘤表达CD19;或
用于制备嵌合抗原受体修饰的免疫细胞。
37.如权利要求36所述的用途,其特征在于,所述免疫细胞包括:T淋巴细胞、NK细胞或者NKT淋巴细胞。
38. 药物组合物,其特征在于,其包括:
权利要求1-2任一所述的抗体或编码该抗体的核酸;或
权利要求28-34任一所述的免疫辍合物或编码该辍合物的核酸;或
权利要求7-11任一所述的嵌合抗原受体或编码该嵌合抗原受体的核酸;或
权利要求17-26任一所述的基因修饰的免疫细胞。
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