CN110396129B - 人源化cd19抗原结合单链抗体及其嵌合抗原受体、免疫细胞和应用 - Google Patents
人源化cd19抗原结合单链抗体及其嵌合抗原受体、免疫细胞和应用 Download PDFInfo
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Abstract
本发明提供了人源化CD19抗原结合单链抗体及其嵌合抗原受体、免疫细胞和应用。人源化CD19抗原结合单链抗体，以鼠抗人CD19抗原的FMC63抗体为基础，对轻链骨架区和重链骨架区进行人源化。人源化抗人CD19抗原的嵌合抗原受体，依次包括前导肽、所述人源化CD19抗原结合单链抗体、铰链区、跨膜区和胞内区。将人源化抗人CD19抗原的嵌合抗原受体序列转导给免疫细胞，制备出的免疫细胞在制备治疗人CD19阳性肿瘤性疾病的药物中的应用，所述免疫细胞具有更低的免疫原性，可在体内存活更久，更安全、更高效的特点，同时对人CD19阳性肿瘤细胞具有更强的杀伤作用。
Description
技术领域
本发明属于免疫治疗技术领域，具体地涉及人源化CD19抗原结合单链抗体及其嵌合抗原受体、免疫细胞和应用。
背景技术
免疫疗法是继手术、放疗、化疗之后，治疗肿瘤性疾病的新手段。肿瘤细胞能够采取各种策略进行免疫逃避，使人体免疫系统不能识别肿瘤细胞，同时抑制免疫系统的功能，使人体免疫细胞不能有效的杀伤肿瘤细胞。
嵌合抗原受体(CAR)是可以识别特定蛋白质(抗原)的细胞表面受体，这些蛋白质是由其他受体(嵌合体)的部分组成的。在免疫系统中，B细胞和T细胞分别有表面受体，叫做B细胞受体(BCRs)和T细胞受体(TCRs)，这些受体识别与疾病或病原体有关的特定蛋白质。这两种受体都有各自的优缺点。没有抗原递呈细胞的帮助，TCRs无法识别抗原。然而，TCR可以向它的T细胞发出信号，直接杀死它找到的细胞，也可以发出信号，招募更多的细胞。另一方面，BCRs可以在没有任何帮助的情况下识别抗原。然而，来自BCR的信号只能用于招募其他细胞，而不能直接杀死目标。CAR包含多个免疫受体的部分，目的是设计一种无需任何帮助就能识别抗原(如BCR)，然后直接杀死被识别的细胞。
CD19表达于B系细胞(不包括成熟浆细胞)及滤泡树突状细胞上，而在其它正常组织中不表达。CD19是一种重要的信号传导分子，调节B淋巴细胞的生长激活和活化，在调节B淋巴细胞抗原受体或其他表面受体的信号阈值中起重要作用，是与B淋巴细胞分化、活化、增殖及抗体产生有关的重要膜抗原，因此它成为了临床上诊断B淋巴细胞系肿瘤和鉴定B淋巴细胞的最好标志。
目前大多数靶向CD19的CAR-T技术中的抗体识别序列都来自于鼠源，尽管鼠源的抗体已经成功地应用到临床并展示了良好的效果，但因个体差异，有的病人在回输-后产生较强的免疫源性，引起人抗鼠抗体(HAMA)反应和抗抗体反应(AAR)，使得回输后的CAR-T细胞容易被自身免疫系统识别并清除，影响CAR-T的长期疗效，可能存在复发的风险。据报道，接受鼠源CAR-T回输治疗后，虽然短期(3个月)缓解率很可观，但是超过一半患者在一年内再次复发。
综上所述，本领域迫切需要开发低免疫原性和高活性的针对CD19抗原的结合单链抗体、以及相应的嵌合抗原受体(CAR)和免疫细胞。
发明内容
本发明的目的就是提供一种人源化CD19抗原结合单链抗体(scFV)、含所述人源化抗人CD19抗原的CAR及其应用。
在发明的第一方面，提供了一种人源化CD19抗原结合单链抗体，所述抗体以鼠抗人CD19抗原的FMC63抗体为基础，对轻链骨架区VL FR1、VL FR2、VL FR3、VL FR4和重链骨架区VH FR1、VH FR2、VH FR3、VH FR4进行人源化；
优选地，人源化VL FR1的氨基酸序列如SEQ ID No:1所示；
人源化VL FR2的氨基酸序列如SEQ ID No:2所示；
人源化VL FR3的氨基酸序列如SEQ ID No:3所示；
人源化VL FR4的氨基酸序列如SEQ ID No:4所示；
人源化VH FR1的氨基酸序列如SEQ ID No:5所示；
人源化VH FR2的氨基酸序列如SEQ ID No:6所示；
人源化VH FR3的氨基酸序列如SEQ ID No:7所示；和
人源化VH FR4的氨基酸序列如SEQ ID No:8所示。
在另一优选例中，所述人源化CD19抗原结合单链抗体的重链可变区包括三个互补决定区CDR：VH CDR1、VH CDR2和VH CDR3，且所述的单链抗体的轻链可变区包括以下三个互补决定区CDR：VL CDR1、VL CDR2和VL CDR3，其中，所述的6个CDR与鼠抗人CD19抗原的FMC63抗体的6个CDR相同。
在另一优选例中，所述人源化CD19抗原结合单链抗体中的6个CDR的结构如下：
VL CDR1，如SEQ ID No:9所示；
VL CDR2，如SEQ ID No:10所示；
VL CDR3，如SEQ ID No:11所示；
VH CDR1，如SEQ ID No:12所示；
VH CDR2，如SEQ ID No:13所示；和
VH CDR3，如SEQ ID No:14所示。
在另一优选例中，所述的人源化CD19抗原结合单链抗体依次包括轻链、连接区和重链，或依次包括重链、连接区和轻链；
其中，所述轻链包括3个轻链互补决定区VL CDR和4个人源化轻链骨架区VL FR；所述重链包括3个重链互补决定区VH CDR和4个人源化重链骨架区VH FR。
在另一优选例中，所述的人源化CD19抗原结合单链抗体,其轻链中各区段的连接顺序为：人源化VL FR1-VL CDR1-人源化VL FR2-VL CDR2-人源化VL FR3-VL CDR3-人源化VL FR4；
在另一优选例中，所述重链中各区段的连接顺序为：人源化VH FR1-VH CDR1-人源化VH FR2-VH CDR2-人源化VH FR3-VH CDR3-人源化VH FR4。
在另一优选例中，所述人源化CD19抗原结合单链抗体，所述的轻链可变区的序列如SEQ ID No:15位所示，而重链可变区的序列如SEQ ID No:16所示。
在另一优选例中，所述人源化CD19抗原结合单链抗体，其人源化CD19抗原结合单链抗体的氨基酸序列如SEQ ID No:19所示。
在另一优选例中，所述人源化CD19抗原结合单链抗体由核苷酸序列如SEQ ID No:20所示的单核苷酸编码。
在本发明的第二方面，提供了一种人源化抗人CD19抗原的嵌合抗原受体(CAR)，所述的CAR依次包括任选的前导肽、本发明第一方面所述的人源化CD19抗原结合单链抗体、铰链区、跨膜区和胞内区。
在另一优选例中，所述人源化抗人CD19抗原的嵌合抗原受体，其前导肽为CD8leader嵌合受体信号肽；较佳地，所述CD8 leader嵌合受体信号肽的氨基酸序列如SEQID No:21中第1-21位所示；
所述铰链区为CD28 hinge嵌合受体铰链；较佳地，所述CD28 hinge嵌合受体铰链的氨基酸序列如SEQ ID No:21中第267-311位所示；
所述跨膜区为CD28 TM跨膜区；较佳地，所述CD28 TM跨膜区的氨基酸序列如SEQID No:21中第312-335位所示；和/或
所述胞内区依次包括41-BB和CD3 zeta；
优选地，所述41-BB的氨基酸序列如SEQ ID No:21中第336-377位所示；而所述CD3zeta的氨基酸序列如SEQ ID No:21中第378-489位所示。
优选地，在另一优选例中，各元件的编码序列选自下组：
所述CD8 leader嵌合受体信号肽的核苷酸序列如SEQ ID No:22中第1-63位所示；
所述CD28 hinge嵌合受体铰链的核苷酸序列如SEQ ID No:22中第796-933位所示；
所述CD28 TM跨膜区的核苷酸序列如SEQ ID No:22中第934-1005位所示；
所述41-BB的核苷酸序列如SEQ ID No:22中第1006-1131位所示；和/或
所述CD3 zeta(ζ)的核苷酸序列如SEQ ID No:22中第1132-1467位所示。
在另一优选例中，所述嵌合抗原受体(CAR)的氨基酸序列如SEQ ID No:21所示。
本发明的第三方面提供了一种多核苷酸，所述的多核苷酸编码本发明第一方面所述人源化CD19抗原结合单链抗体或本发明第二方面所述的人源化抗人CD19抗原的嵌合抗原受体(CAR)。
在另一优选例中，所述的轻链可变区的核苷酸序列如SEQ ID No:17位所示，而重链可变区的核苷酸序列如SEQ ID No:18所示。
在另一优选例中，所述人源化CD19抗原结合单链抗体的核酸序列如SEQ ID No:20所示。
在另一优选例中，所述嵌合抗原受体(CAR)的核苷酸序列如SEQ ID No:22所示。
本发明的第四方面提供了一种表达载体，其特征在于，所述表达载体含有本发明第三方面所述的多核苷酸。
在另一优选例中,所述的表达载体选自下组：质粒、慢病毒载体、腺病毒载体、逆转录病毒载体、溶瘤病毒载体、或其组合。
在另一优选例中,所述的载体为病毒载体(如慢病毒载体)。
在另一优选例中,所述的表达载体为病毒载体。
在另一优选例中,所述的病毒载体选自下组：AAV载体、慢病毒载体、或其组合。
在本发明的第五方面，提供了一种宿主细胞，所述宿主细胞含有本发明的第四方面所述的表达载体或基因组中整合有本发明第三方面所述的多核苷酸。
在另一优选例中，所述的宿主细胞包括真核细胞。
在另一优选例中，所述的宿主细胞为免疫细胞。
在另一优选例中，所述的免疫细胞选自下组：T细胞、NK细胞、或其组合。
本发明的第六方面，提供了一种免疫细胞，所述的免疫细胞表达外源的如本发明的第一方面所述人源化CD19抗原结合单链抗体或如本发明的第二方面所述的人源化抗人CD19抗原的嵌合抗原受体。
在另一优选例中,所述免疫细胞的基因组中包含编码本发明的第一方面所述人源化CD19抗原结合单链抗体的基因序列或本发明的第二方面中任一项所述人源化抗人CD19抗原的嵌合抗原受体的基因序列。
在另一优选例中,所述免疫细胞包括T细胞或自然杀伤细胞。
本发明的第七方面，提供了本发明第一方面所述人源化CD19抗原结合单链抗体、或本发明第二方面所述人源化抗人CD19抗原的嵌合抗原受体、或本发明第六方面所述的免疫细胞的用途，它们被在制备治疗人CD19阳性肿瘤性疾病、CD19阳性的免疫性疾病或非CD19阳性的肿瘤性疾病的药物。
在另一优选例中，人CD19阳性肿瘤性疾病包括CD19阳性的急性淋巴细胞白血病、CD19阳性的急性髓细胞白血病、CD19阳性的慢性淋巴细胞白血病或CD19阳性的急性淋巴瘤。
本发明的第八方面提供了一种药物组合物，它含有：
(i)活性成分，所述活性成分选自下组：本发明第一方面所述人源化CD19抗原结合单链抗体或其抗体药物偶联物(ADC)、或第二方面所述人源化抗人CD19抗原的嵌合抗原受体、或第六方面所述的免疫细胞、或其组合；以及
(ii)药学上可接受的载体、稀释剂或赋形剂。
优选地，在另一优选例中，所述的药物组合物为液态制剂。
优选地，在另一优选例中，所述的药物组合物为注射剂。
优选地，在另一优选例中，所述药物组合物中，所述细胞的浓度为1×103-1×109个细胞/ml，较佳地1×105-1×108个细胞/ml。
优选地，在另一优选例中，所述药物组合物还含有选择性杀伤肿瘤细胞的其他药物(如核酸药物、抗体药物、靶向性药物，其他免疫细胞药物、其他CAR-T药物、化疗药物、或其组合)。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为本发明提供的人源化抗人CD19抗原的嵌合抗原受体的连接示意图，LTR为长末端重复序列；
图2为流式细胞术对人IgG的Fab'2部分特异的抗体分析细胞结果图；
图3A为不同处理组中对HeLa-CD19细胞的杀伤力的检测结果；
图3B为不同处理组中对HeLa-CD19细胞的细胞毒性检查结果；
图4为不同处理组对HeLa-CD19细胞产生INF-γ释放量结果图；
图5为不同处理组注射表达荧光素酶的Raji细胞的致瘤小鼠成像；
图6为不同处理组对致瘤小鼠处理后体重变化的影响；
图7为不同处理组对注射表达荧光素酶的Raji细胞致瘤小鼠存活期的影响；
图8为被治疗的小鼠中人源化CAR-T细胞的流式细胞术分析。
具体实施方式
本发明人经过广泛而深入的研究，经过大量筛选，首次开发了一种人源化CD19抗原结合单链抗体(single-chain variable fragment,scFv)。基于本发明人源化的新颖scFv的CAR以及相应的免疫细胞能够特异性地靶向识别人CD19抗原，有效杀灭并清除表达人CD19抗原的肿瘤细胞，同时具有更低免疫原性，在体内存活更久，更安全、更高效等优点。在此基础上完成了本发明。
具体地，本发明人以鼠抗人CD19抗原的FMC63抗体为基础，对轻链骨架区VL FR1、VL FR2、VL FR3、VL FR4和重链骨架区VH FR1、VH FR2、VH FR3、VH FR4进行人源化，并尽可能保留与抗原直接接触的抗体片段(CDR区)，用高同源人源骨架区修饰鼠源抗体scFv的骨架区，经亲和力重塑，筛选既可维持特异性和亲和力，又同时降低免疫原性和毒副作用的单链抗体。实验结果表明，当施用于人时，本发明的人源化scFv多肽对人CD19抗原具有高亲和性、低免疫原性的特点。
术语
如本文所用，术语“本发明的scFv”“本发明的单链抗体”或“本发明的人源化CD19抗原结合单链抗体”可互换使用，都指本发明第一方面中所述的单链抗体。
如本文所用，术语“给予”和“处理”是指外源性药物、治疗剂、诊断剂或组合物应用于动物、人、受试者、细胞、组织、器官或生物流体。
如本文所用，术语“治疗”指给予患者内用或外用治疗剂，包含本发明的任何一种抗CD19抗体及其组合物，所述患者具有一种或多种疾病症状，而已知所述治疗剂对这些症状具有治疗作用。通常，以有效缓解一种或多种疾病症状的治疗剂的量(治疗有效量)给予患者。
如本文所用，术语“任选”或“任选地”意味着随后所描述的事件或情况可以发生但不是必须发生。
本发明所述的“序列同一性”表示当具有适当的替换、插入或缺失等突变的情况下最佳比对和比较时，两个核酸或两个氨基酸序列之间的同一性程度。本发明中所述的序列和其具有同一性的序列之间的序列同一性可以至少为85％、90％或95％，优选至少为95％。非限制性实施例包括85％,86％,87％,88％,89％,90％,91％,92％,93％,94％,95％,96％,97％,98％,99％,100％。
抗体
如本文所用，术语“抗体”指免疫球蛋白，是由两条相同的重链和两条相同的轻链通过链间二硫键连接而成的四肽链结构。免疫球蛋白重链恒定区的氨基酸组成和排列顺序不同，故其抗原性也不同。据此，可将免疫球蛋白分为五类，或称为免疫球蛋白的同种型，即IgM、IgD、IgG、IgA和IgE，其相应的重链分别为μ链、δ链、γ链、α链、和ε链。轻链根据恒定区的不同分为κ链或λ链。不同类免疫球蛋白的亚单位结构和三维构型是本领域人员所熟知的。
在本发明中，本发明的抗体重链可进一步包含重链恒定区，所述的重链恒定区包含人源或鼠源的IgG1、IgG2、IgG3、IgG4或其变体。抗体重链和轻链靠近N端的约110个氨基酸的序列变化很大，为可变区(Fv区)；靠近C端的其余氨基酸序列相对稳定，为恒定区。可变区包括3个高变区(HVR)和4个序列相对保守的骨架区(FR)。3个高变区决定抗体的特异性，又称为互补性决定区(CDR)。每条轻链可变区(LCVR)和重链可变区(HCVR)由3个CDR区和4个FR区组成，从氨基端到竣基端依次排列的顺序序为:FR1，CDR1，FR2，CDR2，FR3，CDR3和FR4。轻链的3个CDR区指VL-CDR1、VL-CDR2和VL-CDR3；重链的3个CDR区指VH-CDR1，VH-CDR2和VH-CDR3。
术语“人源化抗体(humanized antibody)”，也称为CDR移植抗体(CDR-graftedantibody)，是指将鼠的CDR序列移植到人的抗体可变区框架，即不同类型的人种系抗体构架序列中产生的抗体。人源化抗体可以克服嵌合抗体由于携带大量鼠蛋白成分，从而诱导的异源性反应。
术语“抗体的抗原结合片段”(或简称“抗体片段”)是指抗体的保持特异性结合抗原(例如，CD19)的能力的一个或多个片段。己显示可利用全长抗体的片段来进行抗体的抗原结合功能。术语“抗体的抗原结合片段”中包含的结合片段的实例包括：
(i)Fab片段，由VL、VH、CL和CH1结构域组成的单价片段；
(ii)F(ab')2片段，包含通过较链区上的二硫桥连接的两个Fab片段的二价片段；
(iii)由VH和CH1结构域组成的Fd片段；
(iv)由抗体的单臂的VH和VL结构域组成的Fv片段。
Fv抗体(scFv)含有抗体重链可变区、轻链可变区，但没有恒定区，并具有全部抗原结合位点的最小抗体片段。一般的，Fv抗体还包含VH和VL结构域之间的多肽接头，且能够形成抗原结合所需的结构。
术语“CDR”是指抗体的可变结构域内主要促成抗原结合的6个高变区之一。所述6个CDR的最常用的定义之一由Kabat E.A等人，(1991)Sequences of proteins ofimmunological interest.NIH Publication91-3242)提供。
本发明不仅包括完整的抗体，还包括具有免疫活性的抗体的片段或抗体与其他序列形成的融合蛋白。因此，本发明还包括所述抗体的片段、衍生物和类似物。
在本发明中，本发明的抗体还包括其保守性变异体，指与本发明抗体的氨基酸序列相比，有至多5个，较佳地至多4个，更佳地至多2个，最佳地至多2个氨基酸被性质相似或相近的氨基酸所替换而形成，且结合活性基本不变的多肽。
抗CD19人源化抗体
本发明提供了一种抗CD19人源化抗体。具体地，本发明提供一种针对CD19的高特异性和高亲和力的人源化抗体，其包括重链和轻链，所述重链含有重链可变区(VH)氨基酸序列，所述轻链含有轻链可变区(VL)氨基酸序列。
具体地，本发明提供的人源化CD19抗原结合单链抗体，以鼠抗人CD19抗原的FMC63抗体为基础，对轻链骨架区VL FR1、VL FR2、VL FR3、VL FR4和重链骨架区VH FR1、VH FR2、VH FR3、VH FR4进行人源化；
人源化VL FR1的氨基酸序列如SEQ ID No:1所示；
人源化VL FR2的氨基酸序列如SEQ ID No:2所示；
人源化VL FR3的氨基酸序列如SEQ ID No:3所示；
人源化VL FR4的氨基酸序列如SEQ ID No:4所示；
人源化VH FR1的氨基酸序列如SEQ ID No:5所示；
人源化VH FR2的氨基酸序列如SEQ ID No:6所示；
人源化VH FR3的氨基酸序列如SEQ ID No:7所示；
人源化VH FR4的氨基酸序列如SEQ ID No:8所示。
所述鼠抗人CD19抗原的FMC63抗体为现有技术中报道的抗体。所述鼠抗人CD19抗原的FMC63抗体的氨基酸序列如SEQ ID No:25所示。所述单链抗体依次包括轻链、连接区和重链。
改造后的单链抗体中所述轻链包括3个轻链互补决定区VL CDR和4个人源化轻链骨架区VL FR；所述重链包括3个重链互补决定区VH CDR和4个人源化重链骨架区VH FR；所述轻链中各区段的连接顺序为人源化VL FR1-VL CDR1-人源化VL FR2-VL CDR2-人源化VLFR3-VL CDR3-人源化VL FR4。
所述VL CDR1的氨基酸序列优选如SEQ ID No:9所示。
所述VL CDR2的氨基酸序列优选如SEQ ID No:10所示。
所述VL CDR3的氨基酸序列优选如SEQ ID No:11所示。
所述重链中各区段的连接顺序为人源化VH FR1-VH CDR1-人源化VH FR2-VHCDR2-人源化VH FR3-VH CDR3-人源化VH FR4。
所述VH CDR1的氨基酸序列优选如SEQ ID No:12所示。
所述VH CDR2的氨基酸序列优选如SEQ ID No:13所示。
所述VH CDR3的氨基酸序列优选如SEQ ID No:14所示。
优选地，VL的各FR和各VL CDR的氨基酸序列和核苷酸序列如SEQ ID No:15和17中所示。
| 可变区 | FR或CDR | SEQ ID No:15中位置 | SEQ ID No:17中位置 |
| VL | FR1 | 1-23 | 1-69 |
| VL | FR2 | 35-49 | 103-147 |
| VL | FR3 | 56-88 | 166-264 |
| VL | FR4 | 97-107 | 289-321 |
| VL | CDR1 | 24-34 | 70-102 |
| VL | CDR2 | 50-55 | 148-165 |
| VL | CDR3 | 89-96 | 265-288 |
优选地，VH的各FR和各VH CDR的氨基酸序列和核苷酸序列如SEQ ID No:16和18中所示。
| 可变区 | FR或CDR | SEQ ID No:16中位置 | SEQ ID No:18中位置 |
| VH | FR1 | 1-25 | 1-75 |
| VH | FR2 | 36-49 | 106-147 |
| VH | FR3 | 65-96 | 193-288 |
| VH | FR4 | 110-120 | 328-360 |
| VH | CDR1 | 26-35 | 76-105 |
| VH | CDR2 | 50-64 | 148-192 |
| VH | CDR3 | 97-109 | 289-327 |
所述人源化CD19抗原结合单链抗体的氨基酸序列优选如SEQ ID No:19所示。
优选地，所述人源化CD19抗原结合单链抗体的核苷酸序列如SEQ ID No:20所示。
本发明提供了人源化抗人CD19抗原的嵌合抗原受体，依次包括前导肽、所述人源化CD19抗原结合单链抗体、铰链区、跨膜区和胞内区。
所述前导肽优选为CD8 leader嵌合受体信号肽；
所述铰链区优选为CD28 hinge嵌合受体铰链；
所述跨膜区优选为CD28 TM；
所述胞内区优选依次包括41-BB和CD3 zeta；
所述人源化抗人CD19抗原的嵌合抗原受体的核苷酸序列如SEQ ID No:22所示。所述人源化抗人CD19抗原的嵌合抗原受体的核苷酸序列可采用常规的人工合成方法制备。
CAR
本发明还提供了一种靶向CD19的CAR。优选地，本发明CAR的结构如下式I所示：
L1-scFv19-H1-TM1-C1-CD3ζ (I)
式中，
各“-”独立地为连接肽或肽键；
L1为任选的信号肽序列；
scFv19为本发明的靶向CD19的人源化的scFV(作为抗原结合结构域)；
H1为任选的铰链区；
TM1为跨膜结构域；
C1为共刺激信号分子；
CD3ζ为源于CD3ζ的胞浆信号传导序列。
在另一优选例中，所述的L1为选自下组的蛋白的信号肽：CD8、CD28、GM-CSF、CD4、CD137、或其组合。
在另一优选例中，所述的H1为选自下组的蛋白的铰链区：CD8、CD28、CD137、或其组合。
在另一优选例中，所述的TM1为选自下组的蛋白的跨膜区：CD28、CD3 epsilon、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、或其组合。
在另一优选例中，所述的C1为选自下组的蛋白的共刺激信号分子：OX40、CD2、CD7、CD27、CD28、CD30、CD40、CD70、CD134、4-1BB(CD137)、PD1、Dap10、CDS、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、NKG2D、GITR、TLR2、或其组合。
CAR-免疫细胞及其制法
本发明提供了一种免疫细胞，所述免疫细胞表达本发明所述的CAR构建物。本发明对所述免疫细胞没有特殊限制，代表性的免疫细胞包括(但并不限于)：T细胞或自然杀伤细胞。
在本发明中，还提供了一种制备CAR-免疫细胞的制备方法，包括：
(A)提供一待改造的免疫细胞；和
(B)将CAR表达盒导入到所述待改造的免疫细胞，其中所述CAR表达盒表达本发明的CAR构建物，从而获得工程化的免疫细胞。
优选地，所述方法包括以下步骤：合成人源化抗人CD19抗原的嵌合抗原受体(CAR)的编码序列；将得到的CAR编码序列经载体系统转染至病毒制备细胞，包装成含CAR的病毒，再通过病毒将CAR序列转导给免疫细胞或直接通过电转等方法将CAR序列转导给免疫细胞。
在本发明中，对所述转染的方法没有特殊限制，采用本领域所熟知的转染方法即可。
优选地，在本发明中，所述的制备方法还包括：对获得的工程化免疫细胞进行功能和有效性检测的步骤。
药物组合物
本发明还提供了一种组合物。在优选例中，所述的组合物是药物组合物，它含有上述的抗体或其活性片段或其ADC或相应的CAR-免疫细胞(如CAR-T细胞，或CAR-NK细胞)，以及药学上可接受的载体。通常，可将这些物质配制于无毒的、惰性的和药学上可接受的水性载体介质中，其中pH通常约为5-8，较佳地pH约为6-8，尽管pH值可随被配制物质的性质以及待治疗的病症而有所变化。配制好的药物组合物可以通过常规途径进行给药，其中包括(但并不限于)：瘤内、腹膜内、静脉内、或局部给药。
本发明所述抗体也可以是由核苷酸序列在细胞内表达用于的细胞治疗，比如，所述抗体用于嵌合抗原受体T细胞免疫疗法(CAR-T)等。
本发明的药物组合物可直接用于结合CD19蛋白分子，因而可用于预防和治疗CD19相关的疾病。此外，还可同时使用其他治疗剂。
本发明的人源化CD19抗原结合单链抗体或CAR或所述免疫细胞可用于治疗人CD19阳性肿瘤性疾病、CD19阳性的免疫性疾病。
在本发明中，CD19阳性肿瘤性疾病包括(但并不限于)：CD19阳性的急性淋巴细胞白血病、CD19阳性的急性髓细胞白血病、CD19阳性的慢性淋巴细胞白血病或CD19阳性的急性淋巴瘤。
本发明的主要优点包括：
(a)本发明提供了人源化抗人CD19抗原的嵌合抗原受体(CAR)，由前导肽、识别人CD19抗原的单链抗体、铰链区、跨膜区、胞内区依次连接组成人源化抗人CD19抗原的嵌合抗原受体序列。本发明提供的人源化CAR因其与CD19抗原具有较高的亲和力和特异性、同时免疫源性小的特点，克服了动物源CAR的各种缺陷，保证了其制备成免疫细胞具有长期疗效，避免病情的反复和药物的安全性。
(b)本发明提供了免疫细胞中包含人源化抗人CD19抗原的嵌合抗原受体(CAR)的编码序列，对人CD19阳性肿瘤性疾病具有治疗作用，由于经过了人源化修饰，上述免疫细胞产品，与未经过人源化修饰的产品相比，有更低的免疫原性，可在体内存活更久，具有更安全、更高效的特点。体内实验及体内实验表明：与原鼠源抗CD19 CAR-T相比，人源化抗CD19CAR-T能更有效的杀伤CD19阳性的靶细胞Hela-CD19，以及更高水平的细胞因子释放，且更有效地抑制小鼠体内CD19阳性的Raji肿瘤细胞的生长。
(c)本发明的人源化CD19抗体的亲和力与鼠源抗体相当。
综上，本发明的人源化抗CD19 CAR-T能更加安全、更有效地杀伤靶细胞。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring HarborLaboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
实施例1
抗人CD19抗原的scFv的人源化设计
以鼠抗人CD19抗原的FMC63抗体为母本抗体，在其scFv链的氨基酸序列的基础上，对骨架区进行人源化修饰，设计出抗人CD19抗原的人源化抗体。
首先通过分子对接模拟，确定FMC63的核心序列，确定scFv序列的重链和轻链可变区的CDR区氨基酸序列，即轻链VL的CDR1、CDR2、CDR3和重链VH的CDR1、CDR2、CDR3；然后在NCBI/lgBLAST软件中，将数据库中的人源序列与FMC63的scFv序列进行序列分析和比对，选择同源性较高的人抗体可变区序列对应的骨架区序列作为人源模板。用所选择的人源模板CDR区以外的骨架序列修饰替换FMC63的骨架序列，即将骨架区的FR序列L FR1、L FR2、LFR3、L FR4、H FR1、H FR2、H FR3和H FR4由鼠源替换为人源。将上述的各人源FR序列与CDR区进行组合可得到多个scFv序列，通过分子对接模拟，筛选出亲和力较高的序列。
与原鼠源FMC63scFv序列对比，人源化PMC288scFv序列有如下差异：
1)L FR1
原氨基酸序列：DIQMTQTTSSLSASLGDRVTISC(SEQ ID NO:23中第1-23位)
人源化序列：DIQMTQSPSSLSASVGDRVTITC(SEQ ID No:1)
2)L FR2
原氨基酸序列：WYQQKPDGTVKLLIY(SEQ ID NO:23中第35-49位)
人源化序列：WYQQKPGKAPKLLIY(SEQ ID No:2)
3)L FR3
原氨基酸序列：SGVPSRFSGSGSGTDYSLTISNLEQEDIATYFC(SEQ ID NO:23中第56-88位)
人源化序列：SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID No:3)
4)L FR4
原氨基酸序列：TFGGGTKLEI(SEQ ID NO:23中第97-107位)
人源化序列：TFGGGTKVEI(SEQ ID No:4)
5)H FR1
原氨基酸序列：EVKLQESGPGLVAPSQSLSVTCTVS(SEQ ID NO:24中第1-25位)
人源化序列：EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID No:5)
6)H FR2
原氨基酸序列：WIRQPPRKGLEWLG(SEQ ID NO:24中第36-49位)
人源化序列：WVRQAPGKGLEWVS(SEQ ID No:6)
7)H FR3
原氨基酸序列：SRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCA(SEQ ID NO:24中第65-96位)
人源化序列：SRFTISRDNSKNTLYLQMNSLRAEDTAVYYC(SEQ ID No:7)
8)H FR4
原氨基酸序列：WGQGTSVTVSS(SEQ ID NO:24第110-120位)
人源化序列：WGQGTLVTVSS(SEQ ID No:8)
9)整个scFv序列的差异如下(下划线处为CDR区)：
鼠源的scFv氨基酸序列如下：
(SEQ ID No:25)
其中，轻链的氨基酸序列如下：
DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEIK(VL，SEQ ID No:23)；
重链的氨基酸序列如下：
EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSS(VH，SEQ ID No:24)。
改造后的人源化的scFV的氨基酸序列见SEQ ID No:19，其中下划线为连接肽序列(linker)。
其中轻链的氨基酸序列如下：
DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFGGGTKVEIK(VL，SEQ ID No:15)；
其中重链的氨基酸序列如下：
EVQLVESGGGLVQPGGSLRLSCAASGVSLPDYGVSWVRQAPGKGLEWVSVIWGSETTYYNSALKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS(VH，SEQ ID No:16)。
实施例2
由人工合成抗人CD19的嵌合抗原受体(CAR)的核苷酸序列，序列如SEQ ID No:22所示，并在两端添加EcoRI和XbaI酶切位点：
用限制性内切酶EcoRI和XbaI分别对慢病毒载体和合成的DNA序列进行双酶切反应，反应完成后用T4 DNA连接酶(购自TaKaRa)将酶切后的慢病毒载体和DNA片段进行连接反应，获得表达嵌合抗原受体的慢病毒载体。具体表达嵌合抗原受体(CAR)的慢病毒载体质粒的制备方法参照QIAGEN无内毒素质粒大提试剂盒说明书操作。
所述嵌合抗原受体(CAR)的氨基酸序列如SEQ ID No:21所示。
其中，
CD8前导肽为SEQ ID No:21中第1-21位:
MALPVTALLL PLALLLHAAR P
CD8绞链区为SEQ ID No:21中第267-311位:
TTTPAPRPPT PAPTIASQPL SLRPEACRPA AGGAVHTRGL DFACD
CD8跨膜区为SEQ ID No:21中第312-335位:
IYIWAPLAGT CGVLLLSLVI TLYC
41-BB共刺激因子区为SEQ ID No:21中第336-377位:
KRGRKKLLYI FKQPFMRPVQ TTQEEDGCSC RFPEEEEGGC EL
CD3 zeta区为SEQ ID No:21中第378-489位:
RVKFSRSADA PAYKQGQNQL YNELNLGRRE EYDVLDKRRG RDPEMGGKPR RKNPQEGLYN
ELQKDKMAEA YSEIGMKGER RRGKGHDGLY QGLSTATKDT YDALHMQALP PR
实施例3
病毒的制备和纯化
使用细胞工厂扩增培养HEK293FT(ATCC)细胞进行慢病毒包装。将29mLOptiMEM、2016μL包装质粒、504μL慢病毒载体质粒DNA(1ug/uL)的混合液，与28.5mL OptiMEM、3024μL的转染试剂的混合液，混合制成转染液，转入293FT细胞工厂，在37℃、5％CO2培养箱中培养过夜。第二天更换病毒收集培养基(1L DMEM含20mL胎牛血清和60μL的0.1M丁酸钠)。在转染后的第48h和72h分别收集细胞工厂的培养液，即病毒混合液，3000rpm(2100g)10min离心澄清含病毒培养基，0.45μm滤器过滤后用核酸酶消化(37℃水浴6h)，再通过500KDa中空纤维过滤器超滤浓缩，最后4℃超离16h纯化病毒液，用适量PBS重悬后，于-80℃保存。
实施例4
CAR-T的制备方法
将新鲜外周血与PBS缓冲液按照体积比为1:1混合，将25mL血液/PBs混合液沿离心管侧管滑下加在15mL的Ficoll分离液上方，400g离心30min，用移液管吸取PBMC层至新离心管。PBS缓冲液清洗PBMC细胞并按相应比例稀释后计数，吸出5000万个PBMC细胞与1.2mL包含5000万个CD3/CD28 Dynabeads磁珠混合，混合后移入T175培养瓶培养过夜激活T细胞。第二天冰上解冻病毒液，将5×106TUs的病毒和250μL的1mg/ml DEAE-葡聚糖溶液加至T175培养瓶，第三天再加5×106TUs的病毒至培养瓶转导T细胞。第五天运用磁力架去除磁珠，将细胞悬液转入G-Rex容器放入培养箱中继续培养。细胞取样并完成相应的细胞检测。
实施例5
流式细胞术检测CAR阳性率
从培养瓶中分别吸取100μL细胞悬液至流式管中，用PBS将细胞洗一遍，并用100uL的FACS缓冲液悬浮细胞，吸取2μL山羊血清加入实施例4制备的细胞悬液中冰浴5min。吸取1μL生物素化的山羊抗人Fab'2抗体至其中一管细胞悬浮液中，并吸取1μL生物素化的山羊IgG至另一管细胞悬液中，分别标记两管冰浴30min。加入3ml预冷FACS缓冲液，300g离心5min去上清，保留80μL液体。吸取1μl PE-缀合的链霉抗生物素蛋白抗体，4μL FITC缀合的抗CD4抗体，2μL APC缀合的抗CD8抗体和5μL的7-AAD溶液至每个流式管中，冰浴30min。加入3mL预冷缓冲液，300g离心5min去上清，保留80μL液体加入200μL缓冲液将细胞混匀,上流式仪检测。运用流式软件设门分析CAR细胞比例。
通过流式细胞术对人IgG的Fab'2部分特异的抗体分析细胞。人源化CD19CAR-T细胞，对照T细胞和模拟CAR-T细胞用针对人IgG的Fab'2部分的生物素化抗体染色。用PE-缀合的链霉抗生物素蛋白检测染色的细胞，并在图中计数。该抗体与人抗体和人源化scFv结合。超过80％的T细胞与抗Fab'2抗体结合，因此是CAR-T阳性细胞。相反，未用病毒转导的T细胞和用模拟CAR编码病毒转导的T细胞则显示Fab'2抗体染色阴性(图2)。
实施例6
杀伤力的检测方法
使用稳定表达CD19的HeLa细胞通过实时细胞分析(Real-time CytotoxicityAssay(RTCA))测量CAR-T细胞杀伤力。
将HeLa-CD19靶细胞培养过夜，然后将效应细胞[鼠源CD19 CAR-T细胞，实施例4制备的人源化CD19 CAR-T细胞，模拟CAR-T细胞或对照T细胞(空载体CAR-T，制备方法同CAR-T，但是使用到的质粒及病毒载体中不含CAR序列)]：HeLa-CD19靶细胞以数量比10：1比例混合培养。在ACEA工作站进行实时细胞分析，Y轴为HeLa-CD19单层的阻抗，X轴为效应细胞添加的时间。在测定结束时(效应细胞添加后46h)的细胞毒性计算公式如式a所示；
细胞毒性＝[(X-Y)/X]*100％ 式a
其中X是没有效应细胞的靶细胞的标准化阻抗，Y是有效应细胞的靶细胞的标准化阻抗。人源化CD19 CAR-T细胞和CD19 CAR-T细胞与模拟CAR-T细胞和对照T细胞处理组之间呈极显著性差异(*p<0.0001)。
非人源化FMC63 CD19 CAR-T细胞作为阳性对照。人源化CD19 CAR-T细胞与常规CD19 CAR-T细胞一样具有细胞毒性，并且比对照T细胞和模拟CAR-T细胞显着更多细胞毒性(图3A和图3B)。
实施例7
因子释放的检测
在RTCA测定期间，评估人源化CD19 CAR-T细胞的IFN-γ分泌情况。
离心培养基以除去细胞，使用人IFN-γ的ELISA检测试剂盒，按照试剂盒说明书检测IFN-γ的分泌量。
结果见图4。由图4可知，人源化CD19 CAR-T细胞和CD19 CAR-T细胞对HeLa-CD19细胞产生高水平的INF-γ释放，而模拟CAR-T细胞或对照T细胞并不产生高水平释放。人源化CD19 CAR-T细胞和CD19 CAR-T细胞与模拟CAR-T细胞和对照T细胞处理组之间呈显著性差异(*p<0.015)。细胞因子释放水平高，表明有效性好。
实施例8
动物实验效果
在异种移植肿瘤模型中测试了人源化CD19 CAR-T细胞，其中注射了表达荧光素酶的Raji白血病细胞的NSG免疫缺陷小鼠，具体操作步骤如下：
1、准备20只NSG免疫缺陷小鼠，在第0天(D0)将小鼠随机分组为PBS注射组(即PBS)、模拟CAR-T细胞注射组(即mock CAR-T)、CD19 CAR-T细胞注射组(即CD19 CAR-T)和人源化CD19 CAR-T注射组(即huCD19 CAR-T)，每组5只小鼠，分别为每只小鼠做上标记。
2、在D0为各小鼠进行注射。所有小鼠均注射表达荧光素酶标记的Raji白血病细胞(100ul，5×106个)；另外，为PBS注射组小鼠注射PBS(100uL)，为模拟CAR-T细胞注射组注射模拟CAR-T细胞(100ul，5×106个)，为CD19 CAR-T细胞注射组注射CD19 CAR-T细胞(100uL，5×106个)，为huCD19 CAR-T细胞注射组注射huCD19CAR-T细胞(100uL，5×106个)。
3、监测小鼠体内的Raji白血病细胞：在D7、D14、D21分别给每只小鼠进行生物成像拍照，以观察Raji白血病细胞的在小鼠体内的分布和存活情况。
4、测量每只小鼠的体重：为监测各组小鼠的生存状况，在D0、D7、D14、D21、D28、D35、D42、D49、D56、D63、D70、D77、D84分别测量每只小鼠的体重。
统计生存率：从D0至D84，记录各小鼠的死亡情况，统计各组小鼠的生存率。
结果见图5。图5为注射表达荧光素酶的Raji细胞的小鼠的生物成像。由图5可知，在第1天给小鼠注射PBS、模拟CAR-T细胞、CD19 CAR-T细胞或人源化CD19 CAR-T细胞，PBS处理的小鼠在第21天前死亡。由图5可知，人源化CD19 CAR-T细胞几乎完全阻断小鼠中Raji肿瘤的生长。
人源化CD19 CAR-T细胞注射组小鼠的体重变化不大，表明CAR-T细胞的注射并不影响小鼠的日常生活和进食(图6)。
图7为注射表达荧光素酶的Raji细胞的小鼠的存活率。在第0天给小鼠注射PBS，模拟CAR-T细胞，CD19 CAR-T细胞或人源化CD19 CAR-T细胞。对于huCD19CAR-T细胞与模拟CAR-T细胞处理组，p＝0.0072(Mantel-Cox测试)。由图7可知，人源化CD19 CAR-T细胞延长了小鼠存活期；事实上，在单次治疗7周后，用人源化CD19 CAR-T细胞处理的5只小鼠中仍有3只存活。
图8为被治疗的小鼠中人源化CAR-T细胞的流式细胞术分析。CAR-T细胞处理的小鼠的外周血白细胞用针对人CD3和人Fab'2或FMC63的抗体染色。左图为表达人CD3的白细胞的百分比。右图为表达FMC63(CD19 CAR-T细胞)或人Fab'2序列(huCD19 CAR-T细胞)的人CD3+白细胞的百分比。在研究的第7天，通过流式细胞术分析被治疗的小鼠的外周血白细胞中人T细胞和CAR-T细胞的频率。用抗CD3抗体检测T细胞，用对FMC63 CD19 CAR有特异型抗体检测CD19 CAR-T细胞，用抗人Fab'2抗体检测人源化CD19 CAR-T细胞。huCD19 CAR-T细胞处理的小鼠血液中约3％的白细胞是人T细胞，并且这些T细胞中的10％是huCD19 CAR-T细胞(图8)。
该结果表明，本发明人源化CD19 CAR-T细胞的免疫原性显著降低。
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> 武汉思安医疗技术有限公司
<120> 人源化CD19抗原结合单链抗体及其嵌合抗原受体、免疫细胞和应用
<130> P2019-0983
<140> CN201910621505.2
<141> 2019-07-10
<160> 25
<170> PatentIn version 3.5
<210> 1
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys
20
<210> 2
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 3
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
1 5 10 15
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
20 25 30
Cys
<210> 4
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 5
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 6
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
1 5 10
<210> 7
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
1 5 10 15
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
20 25 30
<210> 8
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 9
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn
1 5 10
<210> 10
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
His Thr Ser Arg Leu His
1 5
<210> 11
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Gln Gln Gly Asn Thr Leu Pro Tyr
1 5
<210> 12
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Gly Val Ser Leu Pro Asp Tyr Gly Val Ser
1 5 10
<210> 13
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
1 5 10 15
<210> 14
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr
1 5 10
<210> 15
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 16
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 17
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 17
gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60
attacctgcc gcgcgagcca ggatattagc aaatatctga actggtatca gcagaaaccg 120
ggcaaagcgc cgaaactgct gatttatcat accagccgcc tgcatagcgg cgtgccgagc 180
cgctttagcg gcagcggcag cggcaccgat tttaccctga ccattagcag cctgcagccg 240
gaagattttg cgacctatta ttgccagcag ggcaacaccc tgccgtatac ctttggcggc 300
ggcaccaaag tggaaattaa a 321
<210> 18
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 18
gaagtgcagc tggtggaaag cggcggcggc ctggtgcagc cgggcggcag cctgcgcctg 60
agctgcgcgg cgagcggcgt gagcctgccg gattatggcg tgagctgggt gcgccaggcg 120
ccgggcaaag gcctggaatg ggtgagcgtg atttggggca gcgaaaccac ctattataac 180
agcgcgctga aaagccgctt taccattagc cgcgataaca gcaaaaacac cctgtatctg 240
cagatgaaca gcctgcgcgc ggaagatacc gcggtgtatt attgcgcgaa acattattat 300
tatggcggca gctatgcgat ggattattgg ggccagggca ccctggtgac cgtgagcagc 360
<210> 19
<211> 245
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Ser Thr Ser Gly
100 105 110
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser
145 150 155 160
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile
165 170 175
Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Phe
180 185 190
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn
195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys His Tyr
210 215 220
Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
225 230 235 240
Val Thr Val Ser Ser
245
<210> 20
<211> 735
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 20
gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60
attacctgcc gcgcgagcca ggatattagc aaatatctga actggtatca gcagaaaccg 120
ggcaaagcgc cgaaactgct gatttatcat accagccgcc tgcatagcgg cgtgccgagc 180
cgctttagcg gcagcggcag cggcaccgat tttaccctga ccattagcag cctgcagccg 240
gaagattttg cgacctatta ttgccagcag ggcaacaccc tgccgtatac ctttggcggc 300
ggcaccaaag tggaaattaa aggctccacc tctggatccg gcaagcccgg atctggcgag 360
ggatccacca agggcgaagt gcagctggtg gaaagcggcg gcggcctggt gcagccgggc 420
ggcagcctgc gcctgagctg cgcggcgagc ggcgtgagcc tgccggatta tggcgtgagc 480
tgggtgcgcc aggcgccggg caaaggcctg gaatgggtga gcgtgatttg gggcagcgaa 540
accacctatt ataacagcgc gctgaaaagc cgctttacca ttagccgcga taacagcaaa 600
aacaccctgt atctgcagat gaacagcctg cgcgcggaag ataccgcggt gtattattgc 660
gcgaaacatt attattatgg cggcagctat gcgatggatt attggggcca gggcaccctg 720
gtgaccgtga gcagc 735
<210> 21
<211> 489
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
20 25 30
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala
50 55 60
Pro Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
115 120 125
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
130 135 140
Lys Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
145 150 155 160
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Ser Leu Pro
165 170 175
Asp Tyr Gly Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
180 185 190
Trp Val Ser Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala
195 200 205
Leu Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
210 215 220
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
225 230 235 240
Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp
245 250 255
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro
260 265 270
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
275 280 285
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
290 295 300
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
305 310 315 320
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
325 330 335
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
340 345 350
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
355 360 365
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
370 375 380
Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu
385 390 395 400
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
405 410 415
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
420 425 430
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
435 440 445
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
450 455 460
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
465 470 475 480
Leu His Met Gln Ala Leu Pro Pro Arg
485
<210> 22
<211> 1473
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 22
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggatattc agatgaccca gagcccgagc agcctgagcg cgagcgtggg cgatcgcgtg 120
accattacct gccgcgcgag ccaggatatt agcaaatatc tgaactggta tcagcagaaa 180
ccgggcaaag cgccgaaact gctgatttat cataccagcc gcctgcatag cggcgtgccg 240
agccgcttta gcggcagcgg cagcggcacc gattttaccc tgaccattag cagcctgcag 300
ccggaagatt ttgcgaccta ttattgccag cagggcaaca ccctgccgta tacctttggc 360
ggcggcacca aagtggaaat taaaggctcc acctctggat ccggcaagcc cggatctggc 420
gagggatcca ccaagggcga agtgcagctg gtggaaagcg gcggcggcct ggtgcagccg 480
ggcggcagcc tgcgcctgag ctgcgcggcg agcggcgtga gcctgccgga ttatggcgtg 540
agctgggtgc gccaggcgcc gggcaaaggc ctggaatggg tgagcgtgat ttggggcagc 600
gaaaccacct attataacag cgcgctgaaa agccgcttta ccattagccg cgataacagc 660
aaaaacaccc tgtatctgca gatgaacagc ctgcgcgcgg aagataccgc ggtgtattat 720
tgcgcgaaac attattatta tggcggcagc tatgcgatgg attattgggg ccagggcacc 780
ctggtgaccg tgagcagcac cacgacgcca gcgccgcgac caccaacacc ggcgcccacc 840
atcgcgtcgc agcccctgtc cctgcgccca gaggcgtgcc ggccagcggc ggggggcgca 900
gtgcacacga gggggctgga cttcgcctgt gatatctaca tctgggcgcc cctggccggg 960
acttgtgggg tccttctcct gtcactggtt atcacccttt actgcaaacg gggcagaaag 1020
aaactcctgt atatattcaa acaaccattt atgagaccag tacaaactac tcaagaggaa 1080
gatggctgta gctgccgatt tccagaagaa gaagaaggag gatgtgaact gagagtgaag 1140
ttcagcagga gcgcagacgc ccccgcgtac aagcagggcc agaaccagct ctataacgag 1200
ctcaatctag gacgaagaga ggagtacgat gttttggaca agagacgtgg ccgggaccct 1260
gagatggggg gaaagccgag aaggaagaac cctcaggaag gcctgtacaa tgaactgcag 1320
aaagataaga tggcggaggc ctacagtgag attgggatga aaggcgagcg ccggaggggc 1380
aaggggcacg atggccttta ccagggtctc agtacagcca ccaaggacac ctacgacgcc 1440
cttcacatgc aggccctgcc ccctcgctaa tag 1473
<210> 23
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 23
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 24
<211> 120
<212> PRT
<213> 小鼠(Mus musculus)
<400> 24
Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 25
<211> 245
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Ser Thr Ser Gly
100 105 110
Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Lys
115 120 125
Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser
130 135 140
Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser
145 150 155 160
Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile
165 170 175
Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu
180 185 190
Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn
195 200 205
Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr
210 215 220
Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
225 230 235 240
Val Thr Val Ser Ser
245
Claims (11)
1.一种人源化CD19抗原结合单链抗体，其特征在于，以鼠抗人CD19抗原的FMC63抗体为基础，对轻链骨架区VL FR1、VL FR2、VL FR3、VL FR4和重链骨架区VH FR1、VH FR2、VH FR3、VH FR4进行人源化；其中，
人源化VL FR1的氨基酸序列如SEQ ID No:1所示；
人源化VL FR2的氨基酸序列如SEQ ID No:2所示；
人源化VL FR3的氨基酸序列如SEQ ID No:3所示；
人源化VL FR4的氨基酸序列如SEQ ID No:4所示；
人源化VH FR1的氨基酸序列如SEQ ID No:5所示；
人源化VH FR2的氨基酸序列如SEQ ID No:6所示；
人源化VH FR3的氨基酸序列如SEQ ID No:7所示；和
人源化VH FR4的氨基酸序列如SEQ ID No:8所示。
2.根据权利要求1所述人源化CD19抗原结合单链抗体，其特征在于，所述的单链抗体的重链可变区包括三个互补决定区CDR：VH CDR1、VH CDR2和VH CDR3，且所述的单链抗体的轻链可变区包括以下三个互补决定区CDR：VL CDR1、VL CDR2和VL CDR3，其中，所述单链抗体的6个CDR与鼠抗人CD19抗原的FMC63抗体的6个CDR相同。
3.如权利要求1所述的人源化CD19抗原结合单链抗体，其特征在于，所述的单链抗体中的6个CDR的结构如下：
VL CDR1，如SEQ ID No:9所示；
VL CDR2，如SEQ ID No:10所示；
VL CDR3，如SEQ ID No:11所示；
VH CDR1，如SEQ ID No:12所示；
VH CDR2，如SEQ ID No:13所示；和
VH CDR3，如SEQ ID No:14所示。
4.如权利要求1所述的人源化CD19抗原结合单链抗体，其特征在于，所述单链抗体依次包括轻链、连接区和重链，或依次包括重链、连接区和轻链；
其中，所述轻链包括3个轻链互补决定区VL CDR和4个人源化轻链骨架区VL FR；所述重链包括3个重链互补决定区VH CDR和4个人源化重链骨架区VH FR。
5.如权利要求4所述的人源化CD19抗原结合单链抗体，其特征在于，所述轻链中各区段的连接顺序为：人源化VL FR1-VL CDR1-人源化VL FR2-VL CDR2-人源化VL FR3-VL CDR3-人源化VL FR4；
所述重链中各区段的连接顺序为：人源化VH FR1-VH CDR1-人源化VH FR2-VH CDR2-人源化VH FR3-VH CDR3-人源化VH FR4。
6.根据权利要求2所述人源化CD19抗原结合单链抗体，其特征在于，所述的重链可变区的序列如SEQ ID No:16所示，而所述的轻链可变区的序列如SEQ ID No:15所示。
7.根据权利要求1所述人源化CD19抗原结合单链抗体，其特征在于，所述人源化CD19抗原结合单链抗体的氨基酸序列如SEQ ID No:19所示。
8.一种人源化抗人CD19抗原的嵌合抗原受体，其特征在于，所述的嵌合抗原受体依次包括权利要求1～7任一项所述的人源化CD19抗原结合单链抗体、铰链区、跨膜区和胞内区。
9.如权利要求8所述的嵌合抗原受体，其特征在于，所述的嵌合抗原受体依次包括前导肽、所述的人源化CD19抗原结合单链抗体、铰链区、跨膜区和胞内区。
10.一种多核苷酸，其特征在于，所述的多核苷酸编码权利要求1所述人源化CD19抗原结合单链抗体或权利要求8所述的人源化抗人CD19抗原的嵌合抗原受体。
11.一种免疫细胞，其特征在于，所述的免疫细胞表达外源的如权利要求1～7中任一项所述人源化CD19抗原结合单链抗体或如权利要求8所述的人源化抗人CD19抗原的嵌合抗原受体。
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| WO2020180551A1 (en) * | 2019-03-05 | 2020-09-10 | Promab Biotechnologies, Inc. | Car-t cells with humanized cd19 scfv |
| CN110845617B (zh) * | 2019-12-05 | 2021-07-09 | 常州费洛斯药业科技有限公司 | 针对cd19的全人源抗体或抗体片段、嵌合抗原受体及应用 |
| CN113307871B (zh) * | 2020-02-27 | 2023-05-02 | 福州拓新天成生物科技有限公司 | 新型抗cd19抗体和cd19-car-t细胞的制备及其应用 |
| CN112851814B (zh) * | 2020-03-17 | 2023-07-07 | 西安宇繁生物科技有限责任公司 | 一种靶向bcma的全人源单链抗体及其制备方法与应用 |
| CN113528449A (zh) * | 2020-04-20 | 2021-10-22 | 浙江瑞加美生物科技有限公司 | 一种制备通用型人源化car19-dnt细胞的技术及其应用 |
| CN113336847B (zh) * | 2021-02-03 | 2022-08-23 | 上海莱馥医疗科技有限公司 | 一种抗pd-1抗体 |
| CN116120451A (zh) * | 2021-06-17 | 2023-05-16 | 南京蓝盾生物科技有限公司 | 抗cd70内化的抗体、抗体偶联物及其应用 |
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