CN114075285B - 抗人cd38人源化单克隆抗体及其应用 - Google Patents
抗人cd38人源化单克隆抗体及其应用 Download PDFInfo
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- CN114075285B CN114075285B CN202010841602.5A CN202010841602A CN114075285B CN 114075285 B CN114075285 B CN 114075285B CN 202010841602 A CN202010841602 A CN 202010841602A CN 114075285 B CN114075285 B CN 114075285B
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Abstract
本发明提供了一种结合CD38抗原的单克隆抗体及其应用。本发明提供的人源化单克隆抗体能够特异性地识别CD38抗原，具有较好的亲和力，同时具有抗体依赖的细胞介导的细胞毒性(ADCC)活性及补体依赖的细胞毒性(CDC)活性，从而杀死CD38+细胞。本申请还提供了所述单克隆抗体或变体在预防和/或治疗肿瘤中的应用。
Description
技术领域
本发明属于生物医药领域，具体涉及一种结合人CD38蛋白的人源化单克隆抗体及其应用。
背景技术
多发性骨髓瘤(multiple myeloma，MM)是一种浆细胞异常增生的恶性血液肿瘤，可影响骨髓中白细胞、红细胞、干细胞的生成，造成贫血；破坏骨质，损伤骨骼和软组织；引起反复感染、肾功能不全等症状。其发病率逐年升高，2019年全球多发性骨髓瘤发病率占所有肿瘤的1.8％，占血液肿瘤的10％-15％，排在血液肿瘤的第2位。随着人们对多发性骨髓瘤认知不断加深，研发力度不断加大，新的药物、诊断、治疗手段越来越丰富，尤其是免疫调节剂(如沙利度胺、来那度胺)、蛋白酶体抑制剂(如硼替佐米、卡非佐米)、自体造血干细胞移植(ASCT)、单克隆抗体(如达雷木单抗(Daratumumab))等药物的临床应用，MM患者的总生存期(overallsurvival，OS)在过去二十年中有了显著改善，依从性也显著提高；但由于患者体内骨髓瘤干细胞和微小残留病灶的存在，目前多发性骨髓瘤还不能完全治愈，几乎所有患者最终都会复发。然而目前针对复发/难治性骨髓瘤(relapsed/refractory multiplemyeloma，RRMM)的治疗方案有限，患者生存结局较差；因此，RRMM的治疗已成为国内外研究者关注的热点。
现有技术表明，浆细胞的免疫表型包括：CD138+、CD38+、CD19+、CD56-。通常情况下，CD38由造血细胞和实体组织表达，大多数髓质胸腺细胞为CD38+，静止和循环的T和B细胞为CD38-，活化的细胞为CD38+。CD38蛋白是恶性浆细胞上表达的抗原之一，在各种恶性血液病细胞中表达，包括但不限于多发性骨髓瘤细胞，B细胞慢性淋巴细胞性白血病细胞，B细胞急性淋巴细胞性白血病细胞。
CD38作为单链跨膜糖蛋白，长度45kDa，包括一个短的氨基端胞内区，一个跨膜区和一个长的羧基端胞外区，其除了作为细胞分化的表型标记物，还具有酶活、受体及黏附功能。CD38作为一种胞外酶，能催化烟酰胺腺嘌呤二核苷酸(NAD+)转化为腺苷二磷酸核糖(ADPR)和烟酸腺嘌呤二核苷酸磷酸(NAADP)，这个过程参与了细胞内钙离子的动员。作为受体，CD38在免疫过程中发挥作用，它介导了细胞因子的生成，T淋巴细胞的增殖和保护成熟B淋巴细胞和树突细胞免于凋亡。CD38还参与了细胞与细胞间的黏附，这使得CD38表达水平不同的细胞迁移到组织的模式不同。此外，CD38的黏附功能和受体功能紧密相联，CD31是CD38的天然配体，人类T淋巴细胞通过CD38-CD31相互作用黏附于内皮细胞。CD38主要在T细胞、树突细胞、自然杀伤(NK)细胞和造血干细胞中表达，此外，在胰脏细胞和眼角膜细胞等也有表达。最重要的是，CD38在骨髓瘤细胞中存在高表达，这使得CD38成为一个极具吸引力的MM治疗靶点。
抗CD38抗体已有文献报道，例如Lande R，et al.，Cell Immunol.220(1)，30-8(2002)、Ausiello CM，et al.，Tissue Antigens.56(6)，539-47(2000)，和Cotner T，etal.，lnt J Immunopharmacol.3(3)，255-68(1981)。专利CN110144008A公开了一种能与CD38蛋白结合的抗体，具有较好的亲和力，能够通过抗体依赖的细胞介导的细胞毒性ADCC、补体依赖的细胞毒性CDC和/或细胞凋亡杀死CD38+细胞。专利WO2020/052546A1也公开了一系列包含抗CD38抗体CDR区的鼠源抗体、嵌合抗体或人源化抗体，以及包含抗CD38抗体或其抗原结合片段的药物组合物及其作为药物的用途。
虽然近几年，针对多发性骨髓瘤的CAR-T和ADC产品在疗效上表现出一定的好的结果，但其缺点也不容忽视。例如CAR-T产品的脱靶效应、过度激活T细胞、诱发细胞因子释放综合征及神经毒性；ADC产品的生产工艺复杂，分子体内稳定性较差，小分子的脱靶毒性；BCMA靶点的成熟度不如CD38靶点高。结合达雷木单抗的临床治疗效果及Sarclisa和MOR202的临床研究数据，针对多发性骨髓瘤和复发/难治性骨髓瘤的治疗，CD38靶点的单克隆抗体仍是非常好的选择。
因此，针对CD38靶点继续研究开发具有高选择性、高亲和力、高药性的单克隆抗体仍是目前亟需解决的问题。
发明内容
本发明提供了一种结合CD38蛋白的人源化单克隆抗体及其应用。本发明提供的结合CD38蛋白的人源化单克隆抗体具有较高的亲和力，能够通过抗体依赖的细胞介导的细胞毒性ADCC和补体依赖的细胞毒性CDC功能，杀伤肿瘤细胞，抑制肿瘤生长，从而达到肿瘤预防和治疗的目的。
一方面，本发明提供了一系列结合CD38蛋白的单克隆抗体。
具体地，所述的结合CD38蛋白的单克隆抗体包含：
(1)含有序列分别如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的重链HCDR1、HCDR2和HCDR3中的任意一个或多个的重链互补决定区，或者与SEQ ID NO:1、SEQ ID NO:2或SEQ ID NO:3所示的重链HCDR1、HCDR2或HCDR3分别具有3、2或1个氨基酸差异的HCDR变体；
和/或(2)含有序列分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的轻链LCDR1、LCDR2和LCDR3中的任意一个或多个的轻链互补决定区，或者与SEQ ID NO:4、SEQ IDNO:5或SEQ ID NO:6所示的轻链LCDR1、LCDR2或LCDR3分别具有3、2或1个氨基酸差异的LCDR变体。
进一步具体地，所述的结合CD38蛋白的单克隆抗体包含：
(1)含有如SEQ ID NO:7或SEQ ID NO:8所示的重链可变区，或者与SEQ ID NO:7和SEQ ID NO:8所示的重链可变区具有3、2或1个氨基酸差异的重链可变区变体；
和/或(2)含有如SEQ ID NO:9或SEQ ID NO:10所示的轻链可变区，或者与SEQ IDNO:9和SEQ ID NO:10所示的轻链可变区具有3、2或1个氨基酸差异的轻链可变区变体。
进一步具体地，所述的结合CD38蛋白的单克隆抗体包含：
(1)序列如SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13或SEQ ID NO:14所示的重链；
和/或(2)序列如SEQ ID NO:15或SEQ ID NO:16所示的轻链。
进一步具体地，所述的结合CD38蛋白的单克隆抗体包含：
(1)序列如SEQ ID NO:11所示的重链和序列如SEQ ID NO:15所示的轻链；
或(2)序列如SEQ ID NO:12所示的重链和序列如SEQ ID NO:15所示的轻链；
或(3)序列如SEQ ID NO:13所示的重链和序列如SEQ ID NO:16所示的轻链；
或(4)序列如SEQ ID NO:14所示的重链和序列如SEQ ID NO:16所示的轻链。
另一方面，本发明提供了一系列编码所述结合CD38蛋白的单克隆抗体的核酸分子。
具体地，所述的核酸分子包含一种或多种经密码子优化的核酸分子。
另一方面，本发明提供了一系列载体，所述的载体包含本申请所述的一个或多个核酸分子。
具体地，所述的载体包括但不限于质粒、病毒、噬菌体。
另一方面，本发明提供了一系列包含或生产所述结合CD38蛋白的单克隆抗体的宿主细胞。
另一方面，本发明提供了制备所述单克隆抗体或其变体的方法，所述方法包括在使得所述单克隆抗体或其变体表达的条件下，培养本申请所述的宿主细胞。
具体地，所述的宿主细胞包括但不限于微生物、植物或动物细胞，可通过本领域技术人员已知的方法将本发明所述的载体引入所述宿主细胞中，例如电穿孔、lipofectine转染、lipofectamin转染等方法。
另一方面，本发明提供了一种药物组合物，所述的药物组合物包含本发明所述的单克隆抗体或其变体、所述的核酸分子、所述的载体和/或所述的细胞，以及任选的药学上可接受的佐剂。
具体地，所述的药学上可接受的佐剂包括但不限于：稀释剂、赋形剂、填充剂、润湿剂、崩解剂、矫味剂和粘合剂。
另一方面，本发明提供了所述的单克隆抗体或其变体、所述的核酸分子、所述的载体和/或所述的细胞在制备用于预防和/或治疗CD38阳性疾病或病症的药物、试剂盒和/或装置中的用途。
具体地，所述的CD38阳性疾病或病症包括免疫性疾病或者血液肿瘤。
进一步具体地，所述的免疫性疾病包括类风湿性关节炎、系统性红斑狼疮、免疫介导的血小板减少症状、溶血性贫血、强直性脊柱炎、多发性硬化症、牛皮癣、克罗恩氏病、肾小球肾炎、哮喘等疾病。
进一步具体地，所述的血液肿瘤包括白血病、B细胞淋巴瘤、T细胞淋巴瘤、NK细胞淋巴瘤、浆细胞恶性瘤和骨髓瘤。
优选地，所述的血液肿瘤为多发性骨髓瘤。
另一方面，本发明提供了一种预防和/或治疗肿瘤的方法，所述的方法包括向需要的受试者施用本发明所述的单克隆抗体或其变体、所述的核酸分子、所述的载体、所述的宿主细胞和/或所述的药物组合物、试剂盒和/或装置。
与现有技术相比，本发明的积极和有益效果在于：
(1)本发明提供了一系列结合CD38抗原的单克隆抗体，所述的单克隆抗体为人源化单克隆抗体。
(2)本发明提供的单克隆抗体为高表达序列，表达量高且杂质少，易纯化收集得到，降低纯化收集成本，有利于大规模生产及应用。
(3)本发明提供的单克隆抗体热稳定性及溶液稳定性较好，便于保存。
(4)本发明提供的单克隆抗体可特异性识别人的CD38抗原，且亲和力高。
(5)本发明提供的单克隆抗体具有较好的结合CD38抗原的能力，具有有效的抗体依赖性细胞介导的细胞毒性(ADCC)活性及补体依赖的细胞毒素作用(CDC)活性。
(6)本发明提供的单克隆抗体在体内具有较好的抗肿瘤活性。
附图说明
图1为单克隆抗体RB0021-S1、RB0021-S2、RB0021-S3、RB0021-S4的SDS-PAGE 4-12％梯度胶电泳图。
图2为单克隆抗体RB0021-S1的SEC-HPLC色谱图。
图3为单克隆抗体RB0021-S2的SEC-HPLC色谱图。
图4为单克隆抗体RB0021-S3的SEC-HPLC色谱图。
图5为单克隆抗体RB0021-S4的SEC-HPLC色谱图。
图6为单克隆抗体RB0021-S1、RB0021-S2、RB0021-S3、RB0021-S4与细胞表面抗原的结合能力检测结果图。
图7为单克隆抗体RB0021-S1、RB0021-S2、RB0021-S3、RB0021-S4ADCC活性检测结果图。
图8为单克隆抗体RB0021-S1、RB0021-S2、RB0021-S3、RB0021-S4CDC活性检测结果图。
图9为单克隆抗体体内活性实验小鼠平均肿瘤体积结果统计图。
图10为单克隆抗体体内活性实验小鼠平均肿瘤重量结果统计图。
图11为单克隆抗体体内活性实验小鼠的肿瘤示意图。
具体实施方式
下面结合具体实施例，对本发明作进一步详细的阐述，下述实施例不用于限制本发明，仅用于说明本发明。以下实施例中所使用的实验方法如无特殊说明，实施例中未注明具体条件的实验方法，通常按照常规条件，下述实施例中所使用的材料、试剂等，如无特殊说明，均可从商业途径得到。
术语
为了更容易理解本发明，以下具体定义了某些技术和科学用语。除非在本文中另有明确定义，本文使用的所有的其他技术和科学术语都具有本公开所属领域的一般技术人员通常理解的含义。
本发明所用氨基酸三字母代码和单字母代码如J.biol.chem,243,p3558(1968)中所述。
本发明所述的“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链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、IgE，其相应的重链分别为μ链、δ链、γ链、α链、ε链。同一类Ig根据其铰链区氨基酸组成和重链二硫键的数目和位置的差别，又可分为不同的亚类，如IgG可以分为IgG1、IgG2、IgG3、IgG4。轻链通过恒定区的不同分为κ链或λ链。五类Ig中每类Ig都可以有κ链或λ链。
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，又称为互补决定区(CDR)。每条轻链可变区(VL或LCVR)和重链可变区(VH或HCVR)由3个CDR区和4个FR区组成，从氨基端到羧基端依次排列的顺序为：FR1，CDR1，FR2，CDR2，FR3，CDR3，FR4。轻链的3个CDR区指LCDR1、LCDR2和LCDR3，重链的3个CDR区指HCDR1、HCDR2和HCDR3。
术语“互补决定区”(CDR)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。通常每个重链可变区中存在三个CDR(HCDR1、HCDR2、HCDR3)，每个轻链可变区中存在三个CDR(LCDR1、LCDR2、LCDR3)。本发明中使用“Kabat编号规则”(参见Kabat等(1991))确定CDR的氨基酸序列边界。
术语“单克隆抗体”是指从基本上均质抗体的群里获得的抗体，即除可能的变体抗体外，构成所述群体的个别抗体相同和/或结合相同的表位。与通常包含针对不同决定簇的不同抗体的多克隆抗体制备物不同，单克隆抗体制备物的每个单克隆抗体是针对抗原上的单一决定簇的。因此。“单克隆”是指从基本上均质抗体群体获得的抗体的特性，且不应解释为需要通过任何特定方法来制造抗体。本发明所述的单克隆抗体可通过各种本领域技术人员已知的技术制备，所述技术包括但不限于杂交瘤方法、重组DNA方法、噬菌体展示方法及转基因方法等。
本发明公开的单克隆抗体为人源化单克隆抗体。
术语“鼠源单克隆抗体”在本发明中为根据本领域知识和技能制备抗人CD38的单克隆抗体。制备时用CD38抗原注射试验对象，然后分离表达具有所需序列或功能特性的抗体的杂交瘤。在本发明一个优选的实施方案中，所述的鼠源CD38抗体或其抗原结合片段，可进一步包含鼠源κ、λ链或其变体的轻链恒定区，或进一步包含鼠源IgG1、IgG2、IgG3或其变体的重链恒定区。
术语“人源化单克隆抗体”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框架序列中产生的抗体，可以克服由于嵌合抗体携带大量鼠蛋白成分，从而诱导的异源性反应。为避免免疫原性下降的同时，引起的活性下降，可对所述的人抗体可变区框架序列进行最少反向突变(或回复突变)，以保持活性。
本发明所述的结合CD38蛋白的单克隆抗体包括下表1所述的重链及轻链的组合。
表1结合CD38蛋白的单克隆抗体的序列特征
术语“特异性结合”、“选择性结合”是指抗体对预先确定的抗原上的表位的结合。通常，抗体以大约小于10-8M，例如大约小于10-9M、10-10M、10-11M或更小的亲和力(KD)结合。其中，“KD”指特定抗体-抗原相互作用的解离平衡常数。
术语“ADCC”是抗体依赖性细胞介导的细胞毒性(anti bodydependent cell-mediated cytotoxicity，ADCC)，通常是指具有杀伤活性的细胞通过其表面表达的Fc受体(FcR)识别包被于靶抗原上的Fc段，由此免疫系统的效应细胞主动溶解其膜表面抗原已被特异性抗体结合的靶细胞。
术语“CDC”是补体依赖型细胞毒性(complement dependent cytotoxicity，CDC)，通常是指补体参与的细胞毒作用，即通过特异性抗体与细胞膜表面相应抗原结合，形成复合物而激活补体经典途径，所形成的攻膜复合物对靶细胞发挥裂解效应。
术语“Daudi细胞”通常是指来源于Burkitt淋巴瘤的细胞系。尽管Daudi细胞存在胞内I类重链，但其表面无I类人类白血球抗原(human leukocyte antigen，HLA)分子表达，这是因为其编码β2-微球蛋白(β2m)的基因存在缺陷，导致该蛋白质缺乏可翻译的mRNA。
术语“Jurkat-Lucia NFAT-CD16细胞”由人源T淋巴细胞Jurkat细胞系进行基因工程改造而得。细胞系在最小启动子和6个NFAT反应原件的控制下稳定表达Lucia荧光素酶报告基因，以及细胞表面Fc受体CD16a(FcγRIIIA；V158高亲和力同种异体)。Jurkat细胞天然表达NFAT功能性信号通路。
术语“NCI-H929细胞”指建立于骨髓瘤患者的恶性积液的细胞系，是一种人骨髓瘤细胞，其细胞表面可表达CD38抗原。
术语“NOD/SCID小鼠”即非肥胖糖尿病/重症联合免疫缺陷小鼠是在SCID(重症联合免疫缺陷)小鼠的基础上与非肥胖性糖尿病小鼠(NOD/Lt)品系(TL，BL，NK细胞缺陷)回交的免疫缺陷鼠。NOD/SCID小鼠既有先天免疫缺陷，又有T和B淋巴细胞缺乏，各种肿瘤细胞可以植入，且较少发生排斥反应及移植物抗宿主病(GVHD)，所以NOD/SCID小鼠逐渐成为血液学实验研究的有用工具。
实施例1单克隆抗体制备
RB0021-S1重链的DNA核苷酸序列为：
CAAGTGACACTGAAAGAGAGCGGCCCTACACTGGTGAAGCCCACCCAGACACTGACACTGACATGCACCACCAGCGGCTACACATTCACCTCCCACGGCATCAACTGGGTGAGACAGCCCCCCGGCAAGGCCCTCGAGTGGATCGGCTACATCTACATCGGCAACGGCTACACCGAGTACAACGAGAAGTTCAAGGGAAGAGCTACACTGACCAGCGACACCAGCAAGAATCAAGCCGTGCTGACCATGACCAACATGGACCCCGTGGATACCGCCACCTACTTCTGCGCTAGATCCCACTACGACAGCTCCAGCTGGTTTGCTTACTGGGGCCAAGGCACACTGGTGACCGTGAGCTCCGCCAGCACCAAGGGACCTAGCGTGTTTCCTCTGGCCCCTTCTAGCAAGAGCACAAGCGGAGGAACAGCCGCTCTGGGCTGTCTGGTGAAAGACTACTTTCCCGAGCCCGTGACCGTGTCTTGGAATTCAGGAGCCCTGACCAGCGGAGTGCACACATTTCCAGCCGTGCTGCAGAGCAGCGGACTGTATAGCCTGAGCAGCGTGGTGACCGTGCCTTCTTCTTCTCTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGTCTTGCGACAAGACCCACACTTGCCCCCCTTGTCCAGCTCCAGAACTCCTGGGAGGACCTAGCGTGTTCCTGTTCCCTCCCAAGCCTAAGGACACCCTGATGATCAGCCGGACCCCAGAAGTGACTTGCGTGGTGGTGGACGTGTCCCACGAAGACCCCGAGGTCAAGTTCAATTGGTACGTGGACGGAGTGGAGGTGCACAACGCTAAGACCAAGCCCAGGGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACAGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCAGCCCCTATCGAGAAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCTCAGGTGTACACCCTGCCCCCTAGCAGAGACGAGCTGACCAAGAACCAGGTGTCCCTGACTTGCCTCGTGAAGGGCTTCTACCCCAGCGATATCGCCGTGGAGTGGGAATCTAACGGTCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAAAGCCGCTGGCAGCAGGGCAACGTGTTCTCTTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGAGCCCAGGAAAG
RB0021-S2重链的DNA核苷酸序列为：
CAAGTGACACTGAAAGAGAGCGGCCCTACACTGGTGAAGCCCACCCAGACACTGACACTGACATGCACCACCAGCGGCTACACATTCACCTCCCACGGCATCAACTGGGTGAGACAGCCCCCCGGCAAGGCCCTCGAGTGGATCGGCTACATCTACATCGGCAACGGCTACACCGAGTACAACGAGAAGTTCAAGGGAAGAGCTACACTGACCAGCGACACCAGCAAGAATCAAGCCGTGCTGACCATGACCAACATGGACCCCGTGGATACCGCCACCTACTTCTGCGCTAGATCCCACTACGACAGCTCCAGCTGGTTTGCTTACTGGGGCCAAGGCACACTGGTGACCGTGAGCTCCGCCAGCACCAAGGGACCTAGCGTGTTTCCTCTGGCCCCTTCTAGCAAGAGCACAAGCGGAGGAACAGCCGCTCTGGGCTGTCTGGTGAAAGACTACTTTCCCGAGCCCGTGACCGTGTCTTGGAATTCAGGAGCCCTGACCAGCGGAGTGCACACATTTCCAGCCGTGCTGCAGAGCAGCGGACTGTATAGCCTGAGCAGCGTGGTGACCGTGCCTTCTTCTTCTCTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGTCTTGCGACAAGACCCACACTTGCCCCCCTTGTCCAGCTCCAGAACTCCTGGGAGGACCTAGCGTGTTCCTGTTCCCTCCCAAGCCTAAGGACACCCTGATGATCAGCCGGACCCCAGAAGTGACTTGCGTGGTGGTGGACGTGTCCCACGAAGACCCCGAGGTCAAGTTCAATTGGTACGTGGACGGAGTGGAGGTGCACAACGCTAAGACCAAGCCCAGGGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACAGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCAGCCCCTATCGAGAAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAAAGCCTCAGGTGTACACCCTGCCCCCTAGCAGAGACGAGCTGACCAAGAACCAGGTGTCCCTGACTTGCCTCGTGAAGGGCTTCTACCCCAGCGATATCGCCGTGGAGTGGGAATCTAACGGTCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAAAGCCGCTGGCAGCAGGGCAACGTGTTCTCTTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGAGCCCAGGAAAG
RB0021-S3重链的DNA核苷酸序列为：
CAAGTGCAGCTGGTGCAGAGCGGCGCTGAGGTGAAGAAACCCGGCAGCAGCGTGAAGGTGAGCTGCAAGACCAGCGGCTACACCTTCACCAGCCACGGCATCAACTGGGTGAGACAAGCCCCCGGCCAAGGACTGGAGTGGATCGGCTACATCTACATCGGCAACGGCTACACCGAGTACAACGAGAAGTTCAAGGGAAGAGCCACACTGACCTCCGACACAAGCACCAGCACCGCCTACATGGAGCTGAGCTCTCTGAGGAGCGAGGACACCGCCGTGTATTTCTGCGCTAGAAGCCACTACGACAGCAGCAGCTGGTTCGCTTACTGGGGACAAGGCACACTGGTGACCGTGTCCAGCGCCAGCACCAAGGGACCTAGCGTGTTTCCTCTGGCCCCTTCTAGCAAGAGCACAAGCGGAGGAACAGCCGCTCTGGGCTGTCTGGTGAAAGACTACTTTCCCGAGCCCGTGACCGTGTCTTGGAATTCAGGAGCCCTGACCAGCGGAGTGCACACATTTCCAGCCGTGCTGCAGAGCAGCGGACTGTATAGCCTGAGCAGCGTGGTGACCGTGCCTTCTTCTTCTCTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGTCTTGCGACAAGACCCACACTTGCCCCCCTTGTCCAGCTCCAGAACTCCTGGGAGGACCTAGCGTGTTCCTGTTCCCTCCCAAGCCTAAGGACACCCTGATGATCAGCCGGACCCCAGAAGTGACTTGCGTGGTGGTGGACGTGTCCCACGAAGACCCCGAGGTCAAGTTCAATTGGTACGTGGACGGAGTGGAGGTGCACAACGCTAAGACCAAGCCCAGGGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACAGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCAGCCCCTATCGAGAAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCTCAGGTGTACACCCTGCCCCCTAGCAGAGACGAGCTGACCAAGAACCAGGTGTCCCTGACTTGCCTCGTGAAGGGCTTCTACCCCAGCGATATCGCCGTGGAGTGGGAATCTAACGGTCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAAAGCCGCTGGCAGCAGGGCAACGTGTTCTCTTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGAGCCCAGGAAAG
RB0021-S4重链的DNA核苷酸序列为：
CAAGTGCAGCTGGTGCAGAGCGGCGCTGAGGTGAAGAAACCCGGCAGCAGCGTGAAGGTGAGCTGCAAGACCAGCGGCTACACCTTCACCAGCCACGGCATCAACTGGGTGAGACAAGCCCCCGGCCAAGGACTGGAGTGGATCGGCTACATCTACATCGGCAACGGCTACACCGAGTACAACGAGAAGTTCAAGGGAAGAGCCACACTGACCTCCGACACAAGCACCAGCACCGCCTACATGGAGCTGAGCTCTCTGAGGAGCGAGGACACCGCCGTGTATTTCTGCGCTAGAAGCCACTACGACAGCAGCAGCTGGTTCGCTTACTGGGGACAAGGCACACTGGTGACCGTGTCCAGCGCCAGCACCAAGGGACCTAGCGTGTTTCCTCTGGCCCCTTCTAGCAAGAGCACAAGCGGAGGAACAGCCGCTCTGGGCTGTCTGGTGAAAGACTACTTTCCCGAGCCCGTGACCGTGTCTTGGAATTCAGGAGCCCTGACCAGCGGAGTGCACACATTTCCAGCCGTGCTGCAGAGCAGCGGACTGTATAGCCTGAGCAGCGTGGTGACCGTGCCTTCTTCTTCTCTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGTCTTGCGACAAGACCCACACTTGCCCCCCTTGTCCAGCTCCAGAACTCCTGGGAGGACCTAGCGTGTTCCTGTTCCCTCCCAAGCCTAAGGACACCCTGATGATCAGCCGGACCCCAGAAGTGACTTGCGTGGTGGTGGACGTGTCCCACGAAGACCCCGAGGTCAAGTTCAATTGGTACGTGGACGGAGTGGAGGTGCACAACGCTAAGACCAAGCCCAGGGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACAGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCAGCCCCTATCGAGAAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAAAGCCTCAGGTGTACACCCTGCCCCCTAGCAGAGACGAGCTGACCAAGAACCAGGTGTCCCTGACTTGCCTCGTGAAGGGCTTCTACCCCAGCGATATCGCCGTGGAGTGGGAATCTAACGGTCAGCCAGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAAAGCCGCTGGCAGCAGGGCAACGTGTTCTCTTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGAGCCCAGGAAAG
RB0021-S1和RB0021-S2轻链DNA的核苷酸序列为：
GATGTGGTGATGACCCAGAGCCCCGACTCTCTGGCCGTGTCTCTGGGAGAGAGAGCCACCATCAACTGCAGATCCAGCCAGAGCCCCGAGCACAGCAACGGCAACACCTATCTGCACTGGTATCAGCAGAAGCCCGGCCAGCCTCCCAAGCTGCTGATCTACAAGGTGTCCAATAGATTCAGCGGCGTGCCCGACAGATTCAGCGGATCCGGCAGCGGCACCGATTTCACACTGACCATCAGCTCTCTGCAAGCCGAAGACGTGGCCGTGTACTTCTGCAGCCAAGGCACACACTTCCCTTTCACCTTCGGCCAAGGCACCAAGGTGGAGATTAAGAGAACCGTGGCCGCTCCTAGCGTGTTCATCTTCCCTCCCAGCGACGAGCAGCTGAAAAGCGGAACAGCCAGCGTCGTCTGCCTGCTGAATAACTTCTACCCCCGGGAGGCCAAAGTCCAGTGGAAAGTGGACAACGCCCTGCAGAGCGGAAACTCTCAGGAGAGCGTGACCGAGCAGGACAGCAAGGACAGCACCTACAGCCTGAGCAGCACACTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCTTGCGAGGTCACACACCAGGGACTGTCTAGCCCAGTGACCAAGAGCTTCAACCGCGGCGAGTGTTGA
RB0021-S3和RB0021-S4轻链DNA的核苷酸序列为：
GACGTGCAGATGACCCAGTCCCCTAGCAGCGTGAGCGCTTCCGTGGGAGACAGAGTGACCATCACATGCAGAAGCAGCCAGAGCCCCGAGCATAGCAACGGCAACACCTATCTGCACTGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTCATCTACAAGGTGTCCAATAGATTCAGCGGCGTGCCCTCCAGATTCAGCGGATCCGGCAGCGGCACCGATTTCACACTGACCATCAGCTCTCTGCAGCCCGAGGACTTCGCCACCTACTTTTGCTCCCAAGGCACCCACTTCCCCTTCACCTTCGGCCAAGGCACCAAGGTGGAGATCAAGAGAACCGTGGCCGCTCCTAGCGTGTTCATCTTCCCTCCCAGCGACGAGCAGCTGAAAAGCGGAACAGCCAGCGTCGTCTGCCTGCTGAATAACTTCTACCCCCGGGAGGCCAAAGTCCAGTGGAAAGTGGACAACGCCCTGCAGAGCGGAAACTCTCAGGAGAGCGTGACCGAGCAGGACAGCAAGGACAGCACCTACAGCCTGAGCAGCACACTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCTTGCGAGGTCACACACCAGGGACTGTCTAGCCCAGTGACCAAGAGCTTCAACCGCGGCGAGTGTTGA
将不同的抗体核苷酸序列分别克隆到pcDNA3.1表达载体，用控内毒质粒大抽试剂盒大抽质粒，OPM-293 CD05 medium培养293F细胞准备转染。转染前一天细胞计数，密度2.59*106/mL，活率98.1％，用新鲜培养基稀释细胞至1.5*106/mL，继续培养。转染当天细胞计数，密度3.01*106/mL，活率98.8％，用新鲜培养基稀释细胞至2.78*106/mL。取1/10转染体积的OPM-293 CD05 medium(奥浦迈，货号81075-001)，先1:1加入重链和轻链质粒，至1.5μg/mL转染体积，再加入3倍质粒量的PEI，室温孵育15min。向上述处理好的细胞中加入孵育混合物，边加边混匀。放入摇床培养，培养条件37℃，90rpm，8％CO2。转染后第一天和第四天分别加入OPM-CHO PFF05补料(奥浦迈，货号FB1279-001)，转染后第6天收集上清。
实施例2单克隆抗体的纯化及检测
1.亲和层析
用0.5M NaOH冲洗系统，0.1M NaOH冲洗填料Mabselect Sure，各处理1小时控内毒素，用20mM PB，150mM NaCl(PH7.2)平衡填料。将RB0021 PC(Daratumumab)、RB0021-S1、RB0021-S2、RB0021-S3、RB0021-S4瞬转表达上清过滤后上样，控制流速1mL/min，上样结束后先用20mM PB，150mM NaCl洗至UV280峰变水平，再用20mM PB，1M NaCl(PH6.5)洗至峰变水平，最后用20mM Cit-Na3Cit(PH3.5)洗脱，用1M Tris(PH9.0)中和。
2.阳离子层析
用0.5M NaOH冲洗系统，0.1M NaOH冲洗填料SP-HP，各处理2小时控内毒素，用20mMPB(pH6.0)平衡填料。将亲和层析得的RB0021 PC(Daratumumab)、RB0021-S1、RB0021-S2、RB0021-S3、RB0021-S4样品调节pH至6.0并稀释调整电导＜3μS/cm进行上样，控制流速1mL/min，上样结束后先用20mM PB(pH6.0)缓冲液冲洗至UV280基线，再用20mM PB，1M NaCl(pH.6.0)进行线性梯度洗脱(0-30％B，20CV)，按峰收集洗脱样品。下表2为最终得到的单克隆抗体的数据统计表。
表2单克隆抗体数据统计表
由表2可知，本发明在瞬染表达量较低的情况下，即可获得与对照组相比单体质量较高、酸碱变体类似的单克隆抗体，且本发明得到的单克隆抗体的变性温度即TM值与对照组相比较高，具有较好的热稳定性；同时本发明所述单克隆抗体等电点较高，有利于其在缓冲液中的稳定保存。
3.检测及分析
SDS-PAGE 4-12％梯度胶及SEC-HPLC分析蛋白纯度。
其中，图1为单克隆抗体RB0021-S1、RB0021-S2、RB0021-S3、RB0021-S4 SDS-PAGE4-12％梯度胶电泳图，图2、图3、图4、图5分别为RB0021-S1、RB0021-S2、RB0021-S3、RB0021-S4 SEC-HPLC色谱图。由图1-5可知，RB0021-S1、RB0021-S2、RB0021-S3、RB0021-S4电泳图均为单条带，且均为单峰，表明利用本发明得到的单克隆抗体表达量较高，杂质少。
下表3为SEC检测得到的单克隆抗体的分散指数。
表3单克隆抗体的分散指数
由表3可知，本发明所述单克隆抗体与对照相比，在大、中、小三个不同的浓度下，具有较好的分散指数，表明其具有较好的溶液稳定性。
实施例3单克隆抗体亲和力测定
用GE 8K进行Biacore亲和力测定，HBS-EP+为实验缓冲液进行，在25℃条件下进行，将配体稀释到5μg/mL，以流速10μL/min固定20s至Protein A芯片上。将分析物CD38梯度稀释至0，0.111，0.333，1，3，9(×3)，27，81nM流速30μL/min，结合300s，解离300s，用10mMGlycine-HCl(pH 1.5)再生流速100μL/min，时间30s，重复一次。测定亲和力数据如下表4所示：
表4亲和力数据
| 抗体 | affinity(human) |
| RB0021 PC(Daratumumab) | 8.86E-08 |
| RB0021-S1 | 1.17E-09 |
| RB0021-S2 | 1.17E-09 |
| RB0021-S3 | 1.04E-09 |
| RB0021-S4 | 1.04E-09 |
由上表4可知，本发明所述单克隆抗体可特异性识别人的CD38蛋白，且对CD38蛋白的亲和力优于对照组单克隆抗体。
实施例4与细胞表面抗原的结合
将培养在RPMI1640+10％FBS培养基中的Daudi细胞加入96孔板中，弃上清，加入100μL/每孔梯度稀释的抗体重悬细胞沉淀(以RB0021 PC为阳性对照，以Isotype control为阴性对照)，2-8℃孵育1小时，弃上清，加入100μL/每孔预先稀释的二抗(FITC)重悬细胞，2-8℃孵育0.5小时后于流式细胞仪上检测。
表5与细胞表面抗原的结合数据
由表5可知，本发明所述单克隆抗体具有较好的与细胞表面CD38抗原结合的能力。
实施例5抗体依赖性细胞介导的细胞毒性(ADCC)活性
将1*105NCI-H929细胞加入96孔板中，加入40μL梯度稀释的抗体(以RB0021 PC为阳性对照，以Isotype control为阴性对照)，37℃，5％CO2孵育1小时；再将2*105Jurkat-Lucia-NFAT-CD16细胞加入96孔板中。37℃，5％CO2培养6小时后，加入50μL Quanti-LUC，室温反应5分钟后读取荧光信号。
表6 ADCC活性检测数据
| Sample ID | EC50(μg/mL) | Top MFI |
| RB0021 PC(Daratumumab) | 0.017 | 57161 |
| RB0021-S1 | 0.018 | 65759 |
| RB0021-S2 | 0.011 | 45150 |
| RB0021-S3 | 0.011 | 47332 |
| RB0021-S4 | 0.014 | 56729 |
| Istype Control | 0.375 | 2118 |
由表6可知，本发明所述的单克隆抗体RB0021-S2，RB0021-S3，RB0021-S4 EC50值明显低于对照组，RB0021-S1 EC50值与对照组相比基本相同，表明本发明单克隆抗体RB0021-S2，RB0021-S3，RB0021-S4 EC50的ADCC活性优于对照组，RB0021-S1的ADCC活性与对照组相似。因此，本发明所述的单克隆抗体具有有效的ADCC活性。
实施例6补体依赖的细胞毒素作用(CDC)活性
将培养在RPMI1640+10％FBS培养基中的Daudi细胞加入96孔板中，加入40μL梯度稀释的抗体，再加入40μL预先稀释的补体，37℃，5％CO2培养6小时。以RB0021 PC(Daratumumab)为阳性对照，以Isotype control为阴性对照，用Cell Titer-GloTM Reagent检测细胞杀伤情况。
表7 CDC活性检测数据
由表7可知，本发明所述的单克隆抗体RB0021-S2和RB0021-S4对于Daudi细胞的补体依赖的细胞毒素作用(CDC)活性，明显优于对照组。
实施例7体内活性实验
将1*107个/mL NCI-H929细胞，等体积混合基质胶后，以0.2mL/只接种于5-6周NOD/SCID小鼠右侧腋窝皮下。待平均肿瘤体积为150mm3左右时，挑选肿瘤生长旺盛且无溃破、健康情况良好的荷瘤动物进行分组并开始给药。将小鼠分成11组(N＝13)，使得所有组的平均肿瘤尺寸相似，并且通过尾静脉注射开始给药(第0天)，每周给药两次。组1(图11G1-22、G1-32、G1-47、G1-48、G1-73、G1-93)接受45mg/kg的阴性对照抗体处理，每周两次；组2(图11G2-9、G2-10、G2-39、G2-74、G2-88、G2-92)接受5mg/kg的阳性对照抗体(Daratumumab)，每周两次；组3(图11G3-36、G3-38、G3-76、G3-77、G3-85、G3-86)接受45mg/kg的阳性对照抗体(Daratumumab)，每周两次。组4(图11G4-1、G4-17、G4-43、G4-64、G4-66、G4-82)接受5mg/kg的RB0021-S1抗体，每周两次；组5(图11G5-3、G5-4、G5-19、G5-30、G5-44、G5-91)接受45mg/kg的RB0021-S1抗体，每周两次。组6(图11G6-5、G6-50、G6-51、G6-60、G6-80、G6-100)接受5mg/kg的RB0021-S2抗体，每周给药两次；组7(图11G7-6、G7-18、G7-23、G7-28、G7-67、G7-75)接受45mg/kg的RB0021-S2抗体，每周两次。组8(图11G8-27、G8-40、G8-54、G8-55、G8-57、G8-78)接受5mg/kg的RB0021-S3抗体，每周两次；组9(图11G9-21、G9-24、G9-37、G9-83、G9-84、G9-90)接受45mg/kg的RB0021-S3抗体，每周给药两次。组10(图11G10-16、G10-42、G10-61、G10-63、G10-69、G10-79)接受5mg/kg的RB0021-S4抗体，每周两次；组11(图11G11-7、G11-12、G11-13、G11-26、G11-70、G11-81)接受45mg/kg的RB0021-S4抗体，每周给药两次。采用下式确定不同时间点的肿瘤体积：肿瘤体积(mm3)＝1/2×长径×短径2，根据肿瘤生长情况来判断抗肿瘤功效。每周检测体重两次以监测毒性，全部处理均良好耐受。
不同处理对肿瘤生长的抑制作用不同，图9为小鼠的平均肿瘤体积统计结果，图10为小鼠的平均肿瘤重量统计结果，由图9和图10可知，本发明所述抗CD38单克隆抗体在体内都显示出有力的抗肿瘤功效，均优于对照组单克隆抗体功效，其中，给45mg/kg的RB0021-S1抗体和给45mg/kg的RB0021-S4抗体组可显著抑制肿瘤的生长(P<0.05)。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
序列表
<110> 瑞阳(苏州)生物科技有限公司
<120> 抗人CD38人源化单克隆抗体及其应用
<130> 20200813
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Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Lys Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 15
<211> 219
<212> PRT
<213> 人工序列(artificial sequence)
<400> 15
Asp Val Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Pro Glu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Pro
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Ser Gln Gly
85 90 95
Thr His Phe Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 16
<211> 219
<212> PRT
<213> 人工序列(artificial sequence)
<400> 16
Asp Val Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Pro Glu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys Ser Gln Gly
85 90 95
Thr His Phe Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
Claims (8)
1.一种结合CD38蛋白的单克隆抗体，其特征在于，所述的结合CD38蛋白的单克隆抗体包含：
（1）含有序列分别如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的重链HCDR1、HCDR2和HCDR3的重链可变区；
和（2）含有序列分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的轻链LCDR1、LCDR2和LCDR3的轻链可变区。
2.根据权利要求1所述的单克隆抗体，其特征在于，所述的单克隆抗体包含：
（1）含有如SEQ ID NO:7或SEQ ID NO:8所示的重链可变区，或者与SEQ ID NO:7和SEQID NO:8所示的重链可变区在非CDR区具有3、2或1个氨基酸差异的重链可变区变体；
和（2）含有如SEQ ID NO:9或SEQ ID NO:10所示的轻链可变区，或者与SEQ ID NO:9和SEQ ID NO:10所示的轻链可变区在非CDR区具有3、2或1个氨基酸差异的轻链可变区变体。
3.根据权利要求1或2所述的单克隆抗体，其特征在于，所述的单克隆抗体包含：
（1）序列如SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13或SEQ ID NO:14所示的重链；
和（2）序列如SEQ ID NO:15或SEQ ID NO:16所示的轻链。
4.根据权利要求3所述的单克隆抗体，其特征在于，所述的单克隆抗体包含：
（1）序列如SEQ ID NO:11所示的重链和序列如SEQ ID NO:15所示的轻链；
或（2）序列如SEQ ID NO:12所示的重链和序列如SEQ ID NO:15所示的轻链；
或（3）序列如SEQ ID NO:13所示的重链和序列如SEQ ID NO:16所示的轻链；
或（4）序列如SEQ ID NO:14所示的重链和序列如SEQ ID NO:16所示的轻链。
5.编码权利要求1-4任一项所述的单克隆抗体的核酸分子。
6.包含权利要求5所述的核酸分子的载体。
7.包含或生产权利要求1-4任一项所述的单克隆抗体的细胞。
8.权利要求1-4任一项所述的单克隆抗体、权利要求5所述的核酸分子、权利要求6所述的载体和权利要求7所述的细胞在制备用于治疗多发性骨髓瘤的药物或试剂盒中的用途。
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Citations (3)
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|---|---|---|---|---|
| CN103492583A (zh) * | 2010-11-02 | 2014-01-01 | Abbvie公司 | 双重可变结构域免疫球蛋白及其用途 |
| WO2019154421A1 (zh) * | 2018-02-12 | 2019-08-15 | 杭州尚健生物技术有限公司 | Cd38蛋白抗体及其应用 |
| CN110139674A (zh) * | 2016-10-05 | 2019-08-16 | 豪夫迈·罗氏有限公司 | 制备抗体药物缀合物的方法 |
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| CN103492583A (zh) * | 2010-11-02 | 2014-01-01 | Abbvie公司 | 双重可变结构域免疫球蛋白及其用途 |
| CN110139674A (zh) * | 2016-10-05 | 2019-08-16 | 豪夫迈·罗氏有限公司 | 制备抗体药物缀合物的方法 |
| WO2019154421A1 (zh) * | 2018-02-12 | 2019-08-15 | 杭州尚健生物技术有限公司 | Cd38蛋白抗体及其应用 |
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