CN114516918B - 一种抗体及其应用 - Google Patents
一种抗体及其应用 Download PDFInfo
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- CN114516918B CN114516918B CN202210210607.7A CN202210210607A CN114516918B CN 114516918 B CN114516918 B CN 114516918B CN 202210210607 A CN202210210607 A CN 202210210607A CN 114516918 B CN114516918 B CN 114516918B
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Abstract
本发明公开了一种抗体及其应用,所述抗体包含SEQ ID NO.1的HCDR1、SEQ ID NO.2的HCDR2和SEQ ID NO.3的HCDR3,与SEQ ID NO.9的LCDR1、SEQ ID NO.10的LCDR2和SEQ ID NO.11的LCDR3;所述抗体具有较高的亲和力。
Description
技术领域
本发明属于细胞生物技术、免疫学领域,涉及一种抗体及其应用,具体的涉及一种抗CD38的抗体及其应用。
背景技术
人CD38蛋白的编码基因定位在4号染色体,基因包含8个外显子和7个内含子,其中最大的外显子1,编码胞内和跨膜区域以及胞外近膜端33个氨基酸序列(Van de Stadt LA,de Koning MH,van de Stadt RJ,et a1.Development of the anticitrullinatedprotein antibodyrepertoire prior to the onset of rheumatoidarthritis.Arthritis Rheum.2011;63(11):3226-3233.)。启动子区域5'-UTR缺乏经典的TATA盒和CpG岛区域。一段高GC含量区可能是CD38的启动子区,调节CD38的表达。启动子区域存在与免疫相关的转录因子结合位点。如:T细胞转录因子1,白介素-6核因子。内含子5’端含有视黄酸反应元件和过氧化物酶体增殖物激活受体γ(PPARγ)。引物延伸分析试验表明,可在多位点启动CD38的转录(Nata K,Takamura T, Karasawa T,et al. Human geneencoding CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase):organization, nucleotide sequence and alternative splicing. Gene.1997;186(2):285-292.)。
CD38分子可以催化环腺苷二磷酸核糖(cADPR, cyclic ADP-ribose )的合成和降解,通过作用于ryanodine受体(RyRs)参与细胞内钙离子信号传递。它是一种具有酶催化功能、受体功能、信号传导功能等独特生物学特性的跨膜糖蛋白,广泛表达于免疫细胞及各个组织中,参与T、B淋巴细胞及NK细胞的信号传导、调节细胞生长和分化增殖、诱导细胞因子的产生,是淋巴细胞激活状态的特异标志(QuaronaV, Zaccare11oG,Chi11emiA, etal.CD38 and CD157: a Long Journey from activation markers to multifunctionalmolecules.International Clinical Cytometry Society.2013;84(4):207-217.)。基因敲除小鼠实验证明,CD38缺失将导致小鼠出现免疫系统损害、代谢紊乱等一系列生理变化。近年来研究发现CD38可能参与了多种自身免疫性疾病的发病过程(Partida-SanchezS,Rivero-Naval, Shi GSet a1.CD38: an ecto enzyme at the crossroads of innateand adapive immune responses. Adv Exp Med Biol. 2007; 590: 171-183.)。因此,研发新的抗CD38的抗体对于实现CD38阳性疾病的检测和治疗具有重要的作用。
发明内容
为了弥补现有技术的不足,本发明的目的在于提供一种抗CD38的抗体,所述抗体具有较高的结合CD38的活性。
本发明的第一方面提供了一种抗CD38的单克隆抗体,所述单克隆抗体包含:
SEQ ID NO. 1的HCDR1、SEQ ID NO. 2的HCDR2和SEQ ID NO. 3的HCDR3,与SEQ IDNO. 9的LCDR1、SEQ ID NO. 10的LCDR2和SEQ ID NO. 11的LCDR3。
进一步,所述单克隆抗体还包含具有与SEQ ID NO.4、5、6、7所示氨基酸序列至少90%序列一致性的重链可变区框架区HFR1、HFR2、HFR3和HFR4;以及具有与SEQ ID NO.12、13、14、15所示氨基酸序列至少90%序列一致性的轻链可变区框架区LFR1、LFR2、LFR3和LFR4。
进一步,所述单克隆抗体重链可变区具有与SEQ ID NO.8所示的氨基酸序列至少90%序列一致性,优选95%序列一致性的VH,所述轻链可变区具有与SEQ ID NO.16所示的氨基酸序列至少90%序列一致性,优选95%序列一致性的VL。
进一步,所述单克隆抗体的VH具有SEQ ID NO.8所示的氨基酸序列;所述单克隆抗体的VL具有SEQ ID NO.16所示的氨基酸序列。
进一步,所述单克隆抗体的重链亚型为IgG。
进一步,所述单克隆抗体的轻链亚型为κ。
进一步,所述单克隆抗体进一步包含重链恒定区和轻链恒定区。
本发明的第二方面提供了如下任一项所述的物质:
1)核酸分子,所述核酸分子编码本发明第一方面所述的单克隆抗体或其功能片段;
2)重组表达载体,所述重组表达载体包含1)中所述的核酸分子;
3)宿主细胞,所述宿主细胞包含2)中所述的重组表达载体;
4)药物偶联物,所述药物偶联物包含本发明第一方面所述的单克隆抗体或其功能片段;
5)一种检测CD38的产品,所述产品包含本发明第一方面所述的单克隆抗体或其功能片段;
6)一种组合物,所述组合物包含本发明第一方面所述的单克隆抗体或其功能片段,1)中所述的核酸分子、2)中所述的重组表达载体、3)中所述的宿主细胞。
进一步,编码HCDR1、HCDR2、HCDR3的核酸分子具有与SEQ ID NO.17、18、19所示的核苷酸序列至少90%,优选95%序列的同一性的序列;编码LCDR1、LCDR2、LCDR3的核酸分子具有与SEQ ID NO.25、26、27所示的核苷酸序列至少90%,优选95%序列的同一性的序列。
进一步,编码HCDR1、HCDR2、HCDR3的核酸分子具有SEQ ID NO. 17、18、19所示的核苷酸序列;编码LCDR1、LCDR2、LCDR3的核酸分子具有SEQ ID NO. 25、26、27所示的核苷酸序列。
进一步,编码重链可变区框架区HFR1、HFR2、HFR3和HFR4的核酸分子具有与SEQ IDNO.20、21、22、23所示的核苷酸序列至少90%,优选95%序列的同一性的序列;编码轻链可变区框架区LFR1、LFR2、LFR3和LFR4的核酸分子具有与SEQ ID NO.28、29、30、31所示的核苷酸序列至少90%,优选95%序列的同一性的序列。
进一步,编码VH的核酸分子具有与SEQ ID NO.24所示的核苷酸序列至少90%,优选95%序列同一性的序列;编码VL的核酸分子具有与SEQ ID NO.32所示的核苷酸序列至少90%,优选95%序列同一性的序列。
进一步,编码VH的核苷酸序列如SEQ ID NO.24所示,编码VL的核苷酸序列如SEQID NO.32所示。
进一步,所述重组表达载体具有与抗体可操作地连接的信号肽。
进一步,所述重组表达载体进一步包含转录调控元件。
进一步,所述的产品还包含用于执行抗原-抗体反应的试剂或用于检测反应的试剂。
进一步,用于执行抗原-抗体反应的试剂包括缓冲剂、盐等。
本发明的第三方面提供了一种药物组合物,所述药物组合物包括本发明第一方面所述的单克隆抗体或本发明第二方面所述的物质;和/或药学上可接受的载体。
本发明第四方面提供了如下任一项所述的方法:
1)一种制备本发明第一方面所述单克隆抗体的方法,所述方法包括:培养本发明第二方面中所述的宿主细胞,回收单克隆抗体;
2)一种检测样品中CD38的方法,所述方法包括:使本发明第一方面所述的抗CD38的单克隆抗体接触待测样本,确定所述待测样本中CD38的存在或水平。
进一步,1)中所述方法还包括对所述单克隆抗体进行纯化。
本发明的第四方面提供了如下任一项所述的应用:
1)本发明第一方面所述的单克隆抗体、本发明第二方面所述的物质在检测CD38中的应用;
2)本发明第一方面所述的单克隆抗体、本发明第二方面所述的物质在制备诊断CD38阳性疾病的产品中的应用;
3)本发明第一方面所述的单克隆抗体、本发明第二方面所述的物质或本发明第三方面所述的药物组合物在制备预防和/或治疗与CD38阳性疾病的药物中的应用。
进一步,所述产品包括试剂盒。
进一步,所述试剂盒包括:胶体金免疫试剂盒、化学发光试剂盒、放射免疫试剂盒、酶联免疫试剂盒(ELISA)、荧光免疫试剂盒和微流体芯片。
进一步,所述CD38阳性疾病为肿瘤或免疫性疾病。
进一步,所述免疫性疾病选自:类风湿性关节炎、牛皮癣、强直性脊柱炎、关节银屑病、皮炎、系统性硬皮病及硬化症、炎症性肠病、克罗恩氏病、溃疡性结肠炎、呼吸窘迫综合征、脑膜炎、脑炎、胃炎、葡萄膜炎、肾小球肾炎、湿疹、哮喘、动脉硬化、白细胞粘附缺陷病、Raynaud症候群、Sjogren症候群、青少年糖尿病、Reiter病、Behcet病、免疫复合物性肾炎、IgA肾病、IgM多发性神经病、免疫介导的血小板减少症状、溶血性贫血、重症肌无力、狼疮性肾炎、系统性红斑狼疮、风湿关节炎、异位性皮炎、天疱疮、Graves病、桥本氏甲状腺炎、Wegener肉芽肿、Omenn症候群、慢性肾功能衰竭、急性传染性单核细胞增多征、多发性硬化症、HIV和疱疹病毒相关的疾病、严重急性呼吸综合征和脉络视网膜炎、移植物对抗宿主疾病、以及病毒感染引起的免疫性疾病。
进一步,所述肿瘤选自: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。
进一步,所述B细胞淋巴瘤选自:成熟B细胞肿瘤、前体B细胞成淋巴细胞白血病/淋巴瘤、B细胞非霍奇金淋巴瘤、B细胞霍奇金淋巴瘤。
进一步,所述肿瘤选自:急性淋巴细胞白血病、急性成淋巴细胞白血病、急性早幼粒细胞白血病、慢性淋巴细胞白血病、急性或慢性骨髓型白血病、多发性骨髓瘤、前髓细胞肿瘤、轻链淀粉样变性、B细胞慢性淋巴细胞性白血病、小淋巴细胞性白血病、B细胞急性淋巴细胞性白血病、B细胞前淋巴细胞白血病、淋巴浆细胞样淋巴瘤、套细胞淋巴瘤、滤泡性淋巴瘤、皮肤滤泡中心淋巴瘤、边缘区B细胞淋巴瘤、毛细胞白血病、弥漫性大B细胞淋巴瘤、伯基特淋巴瘤、浆细胞瘤、浆细胞骨髓瘤、浆细胞白血病、移植后淋巴增生性疾病、Waldenstrom巨球蛋白血症、浆细胞白血病和间变性大细胞淋巴瘤、多毛细胞淋巴瘤。
附图说明
图1是ELISA检测抗体与抗原的结合能力图;
图2是流式细胞检测技术检测抗体与抗原的结合能力图,其中,2A是对照;2B是30G4抗体。
具体实施方式
定义
如本文所用,术语“抗体”包括与特定抗原结合的任何免疫球蛋白、单克隆抗体、多克隆抗体、多价抗体、二价抗体、一价抗体、多特异性抗体或双特异性抗体。天然完整抗体包含两条重(H)链和两条轻(L)链。哺乳动物重链分类为α、δ、ε、γ和μ,每条重链由可变区(VH)以及第一、第二、第三和任选存在的第四恒定区(分别为CH1、CH2、CH3、CH4)组成;哺乳动物轻链分类为λ或κ,而每条轻链由可变区(VL)和恒定区组成。抗体呈“Y”形,其中Y的茎部由通过二硫键结合在一起的两条重链的第二和第三恒定区组成。Y的每个臂包括与单一轻链的可变区和恒定区结合的单一重链的可变区和第一恒定区。轻链和重链的可变区负责抗原结合。两条链中的可变区一般含有三个高度可变的环,称为互补决定区(complementaritydetermining region;CDR)(轻链CDR包括LCDR1、LCDR2和LCDR3,重链CDR包括HCDR1、HCDR2、 HCDR3)。本文中所公开的抗体和抗原结合片段的CDR边界可通过Kabat、IMGT、Chothia或Al- Lazikani的约定来限定或鉴定三个CDR插在被称为构架区(frameworkregion;FR)(轻链FR包括LFR1、LFR2、LFR3和LFR4,重链FR包括 HFR1、HFR2、HFR3和HFR4)的侧翼链段(stretch)之间,所述侧翼链段比CDR更高度保守且形成支撑高度可变环的支架。重链和轻链的恒定区不参与抗原结合,但呈现出各种效应功能。 基于抗体重链恒定区的氨基酸序列来对抗体分类。抗体的五种主要类别或同型为大免疫球蛋白A(IgA)、IgD、IgE、IgG和IgM,其特征分别在于α、δ、ε、γ和μ重链的存在。若干主要抗体类别分为亚类,如IgG1(γ1重链)、IgG2(γ2重链)、IgG3(γ3重链)、IgG4(γ4重链)、IgA1(α 1重链)或IgA2(α2重链)。
在某些实施例中,本文提供的抗体涵盖其任何抗原结合片段。如本文所用,术语“抗原结合片段”是指由抗体的一部分形成的抗体片段,其包含一或多个CDR或与抗原结合但不包含完整天然抗体结构的任何其它抗体片段。抗原结合片段的实例包括但不限于双功能抗体、Fab、Fab '、F(ab ')2、Fv片段、二硫键稳定的Fv片段(dsFv)、(dsFv)2、双特异性dsFv (dsFv-dsFv ')、二硫键稳定的双功能抗体(ds双功能抗体)、单链抗体分子(scFv)、scFv二聚体(二价双功能抗体)、双特异性抗体、多特异性抗体、骆驼化单结构域抗体、纳米抗体、结构域抗体和二价结构域抗体。抗原结合片段能够结合至与亲本抗体所结合相同的抗原。
术语“可操作地连接”是指两个或更多个所关注的生物序列在存在或不存在间隔子或连接子的情况下的并接,使得它们处于允许它们以预期方式起作用的关系中。当关于多肽使用时,其意指多肽序列以允许连接的产物具有预期的生物学功能的方式连接。关于多核苷酸也可以使用所述术语。举例来说,当编码多肽的多核苷酸与调控序列(例如启动子、增强子、沉默子序列等)可操作地连接时,其意指所述多核苷酸序列以允许调控由多核苷酸表达多肽的方式连接。在一个实施例中,可操作地连接的核苷酸序列是相邻的(例如在信号序列的情况下)。替代地,可操作地连接的核苷酸序列可以不相邻(例如在增强子的情况下)。
针对CD38的抗体
本发明提供了针对CD38的抗体,所述抗体包含SEQ ID NO. 1的HCDR1、SEQ ID NO.2的HCDR2和SEQ ID NO. 3的HCDR3,与SEQ ID NO. 9的LCDR1、SEQ ID NO. 10的LCDR2和SEQID NO. 11的LCDR3。
在一实施方式中,所述单克隆抗体还包含具有与SEQ ID NO.4、5、6、7所示氨基酸序列至少90%序列一致性的重链可变区框架区HFR1、HFR2、HFR3和HFR4;以及具有与SEQ IDNO. 12、13、14、15所示氨基酸序列至少90%序列一致性的轻链可变区框架区LFR1、LFR2、LFR3和LFR4。
在又一实施方式中,所述单克隆抗体重链可变区具有与SEQ ID NO.8所示的氨基酸序列至少90%序列一致性,优选95%序列一致性的VH,所述轻链可变区具有与SEQ IDNO.16所示的氨基酸序列至少90%序列一致性,优选95%序列一致性的VL。
作为优选地实施方式,所述单克隆抗体的VH具有SEQ ID NO.8所示的氨基酸序列;所述单克隆抗体的VL具有SEQ ID NO.16所示的氨基酸序列。
在一些实施例中,本文提供的抗体和其抗原结合片段包含重链可变结构域的全部或一部分和/或轻链可变结构域的全部或一部分。在一个实施例中,本文提供的抗体和其抗原结合片段是由本文提供的重链可变结构域的全部或一部分组成的单结构域抗体。
在某些实施例中,本文提供的抗体和其抗原结合片段进一步包含免疫球蛋白(Ig)恒定区,其任选地进一步包含重链和/或轻链恒定区。在某些实施例中,重链恒定区包含CH1、铰链和/或CH2-CH3区(或任选地CH2-CH3-CH4区)。在某些实施例中,本文提供的抗体和其抗原结合片段包含人IgG1、IgG2、IgG3、IgG4、IgA1、IgA2或IgM的重链恒定区。在某些实施例中,本文提供的抗体和其抗原结合片段包含人IgG1的重链恒定区。在某些实施例中,本文提供的抗体和其抗原结合片段包含人IgG4的重链恒定区。在某些实施例中,轻链恒定区包含Ckappa(Cκ)或Clambda(Cλ)。本文提供的抗体和其抗原结合片段的恒定区可与野生型恒定区序列一致或相差一或多个突变。在某些实施例中,重链恒定区来自人IgG。在某些实施例中,轻链恒定区来自人κ轻链。
本文提供的抗体和其抗原结合片段也涵盖本文提供的抗体序列的各种变体。
在某些实施例中,本文提供的抗体和其抗原结合片段在CDR序列中的一或多个和/或FR序列中的一或多个中包含一或多个氨基酸残基取代。在某些实施例中,亲和力变体在CDR序列和/或FR序列中包含总共不超过20、15、10、9、8、7、6、5、4、3、2或1个取代。
在某些实施例中,本文提供的抗体和其抗原结合片段包含与本发明列出的那种(或那些)CDR序列具有至少80%(例如至少85%、88%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%)序列一致性但仍保持以类似于或甚至高于其亲本抗体的水平与CD38特异 性结合的1、2或3个CDR序列。
在某些实施例中,本文提供的抗体和其抗原结合片段包含与本发明中列出的那种(或那些)可变区序列具有至少80%(例如至少85%、88%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%)序列一致性但仍保持在类似于或甚至高于其亲本抗体对于CD38的特异性结合亲和力的水平的一或多个可变区序列。在一些实施例中,突变发生在CDR外的区域 (例如在FR中)。
重组表达载体
如本文所用,术语“载体”是指可以将编码蛋白质的多核苷酸可操作地插入其中以引起所述蛋白质表达的媒介物。载体可用于转化、转导或转染宿主细胞,以使其在宿主细胞内表达携带的遗传元件。载体的实例包括质粒;噬菌粒;粘粒和人工染色体,如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1衍生的人工染色体(PAC);噬菌体,如λ噬菌体或M13噬菌体;和动物病毒。用作载体的动物病毒的类别包括逆转录病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(例如单纯疱疹病毒)、痘病毒、杆状病毒、乳头状瘤病毒和乳多空病毒(例如SV40)。载体可以含有多种用于控制表达的元件,包含启动子序列、转录起始序列、增强子序列、选择元件和报告基因。另外,载体可以含有复制起点。术语“复制起点”是指 当在载体中存在时其起始复制的序列。复制起点可被复制起始因子或替代地被DNA解螺旋酶识别。载体还可以包括有助于其进入细胞的材料,包括但不限于病毒颗粒、脂质体或蛋白质包膜。
载体可以是重组表达载体或克隆载体。本发明提供了载体(例如表达载体),其含有编码抗CD38中和抗体的本文提供的核酸序列、至少一个与核酸序列可操作地连接的启动子和/或至少一个选择标记。载体的实例包括但不限于逆转录病毒(包括慢病毒)、腺 病毒、腺相关病毒、疱疹病毒(例如单纯疱疹病毒)、痘病毒、杆状病毒、乳头状瘤病毒、乳多空病毒(例如SV40)、λ噬菌体和M13噬菌体、质粒,如pcDNA3 .3、pMD18-T、pOptivec、pCMV、 pEGFP、pIRES、pQD-Hyg-GSeu、pALTER、pBAD、pcDNA、pCal、pL、pET、pGEMEX、pGEX、pCI、pEGFT、 pSV2、pFUSE、pVITRO、pVIVO、pMAL、pMONO、pSELECT、pUNO、pDUO、Psg5L、pBABE、pWPXL、pBI、 p15TV-L、pPro18、pTD、pRS10、pLexA、pACT2 .2、pCMV-SCRIPT .RTM .、pCDM8、pCDNA1 .1/amp、pcDNA3 .1、pRc/RSV、PCR 2 .1、pEF-1、pFB、pSG5、pXT1、pCDEF3、pSVSPORT、pEF-Bos等。
“重组表达载体”是编码基因的核酸分子,其在宿主细胞中表达且此外含有控制所述基因的表达的必需元件。通常,表达载体包含转录启动子、所关注基因和转录终止子。
在某些实施例中,重组表达载体是基于病毒的载体。在某些实施例中,重组表达载体是慢病毒载体。在某些实施例中,重组表达载体是腺相关病毒(AAV)载体。
在某些实施例中,编码本文提供的抗CD38中和抗体或其抗原结合片段的核酸序列进行了密码子优化。如本文所用,术语“密码子优化”是指通过,用在所关注的脊椎动物(例如人)的基因中较频繁或最频繁使用的密码子置换至少一个、超过一个或大量天然序列的密码子,来改变核酸序列以增强在所述脊椎动物细胞中的表达,但核酸序列的改变不改变原始翻译蛋白质的氨基酸序列。各种物种对特定氨基酸的某些密码子呈现出特定的偏好。
在某些实施例中,编码抗CD38中和抗体的核酸序列进行了密码子优化。在某些实施例中,编码抗CD38中和抗体的重链可变区的核酸序列进行了密码子优化。 在某些实施例中,编码抗CD38中和抗体的轻链可变区的核酸序列进行了密码子优化。在某些实施例中,编码抗CD38中和抗体的重链恒定区的核酸序列进行了密码子优化。在某些实施例中,编码抗CD38中和抗体的轻链恒定区的核酸序列进行了密码子优化。
宿主细胞
可将包含编码抗体的多核苷酸序列的载体引入到宿主细胞中进行克隆或基因表达。适用于克隆或表达本文载体中的DNA的宿主细胞是原核生物、酵母或更高级真核生物细胞。用于此目的的适合原核生物包括真细菌,如革兰氏阴性或革兰氏阳性生物体,例如肠内菌科(Enterobacteriaceae),如埃希氏菌属 (Escherichia),例如大肠杆菌;肠杆菌属(Enterobacter);欧文氏菌属(Erwinia);克雷伯 氏菌属(Klebsiella);变形杆菌属(Proteus);沙门氏菌属(Salmonella),例如鼠伤寒沙门氏菌(Salmonella typhimurium);沙雷氏菌属(Serratia),例如粘质沙雷氏菌(Serratia marcescans);和志贺杆菌属(Shigella),以及芽孢杆菌属(Bacilli),如枯草芽孢杆菌(B. subtilis)和地衣芽孢杆菌(B. licheniformis);假单胞菌属(Pseudomonas),如绿脓杆菌(P. aeruginosa);和链霉菌属(Streptomyces)。
除原核生物外,真核微生物,如丝状真菌或酵母,是适用于表达抗CD38中和抗体的克隆或表达宿主。酿酒酵母(Saccharomyces cerevisiae)或常见的烘焙酵母是低级真核宿主微生物中最常用的。然而,多种其它属、种和菌株通常可用且适用于本文中,如粟酒裂殖酵母(Schizosaccharomyces pombe);克鲁维酵母属(Kluyveromyces)宿主,例如乳酸克鲁维酵母(K . lactis)、脆壁克鲁维酵母(K . fragilis)(ATCC 12 ,424)、保加利亚克鲁 维酵母(K . bulgaricus)(ATCC 16 ,045)、威克克鲁维酵母(K . wickeramii)(ATCC 24 ,178)、克鲁维雄酵母(K . waltii) (ATCC 56 ,500)、果蝇克鲁维酵母(K .drosophilarum) (ATCC 36 ,906)、耐热克鲁维酵母(K . the rmotole ra ns)和马克斯克鲁维酵母(K . marxianus);耶氏酵母属(yarrowia) (EP 402 ,226);毕赤酵母(Pichiapastoris)(EP 183 ,070);假丝酵母属(Candida);瑞氏木霉(Trichoderma reesia) (EP244 ,234);粗糙脉孢菌(Neurosporacrassa);许旺酵母属(Schwanniomyces),如西方许旺酵母 (Schwanniomyces occidentalis);和丝状真菌,例如脉孢菌属(Neurospora)、青霉菌属 (Penicillium)、弯颈霉属(Tolypocladium)和曲霉属(Aspergillus)宿主,如构巢曲霉(A . nidulans)和黑曲霉(A . niger)。
适合表达本文提供的抗体或抗原片段的宿主细胞来源于多细胞生物体。无脊椎动物细胞的实例包括植物和昆虫细胞。已经鉴定出多种杆状病毒株和变体以及来自如下宿主的对应容许的昆虫宿主细胞:草地贪夜蛾(Spodoptera frugiperda)(毛虫)、埃及伊蚊(Aedes aegypti)(蚊子)、白纹伊蚊(Aedes albopictus)(蚊子)、黑腹果蝇(Drosophilamelanogaster)(果蝇)和家蚕(Bombyx mori)。多种用于转染的病毒株公开可用,例如苜蓿银纹夜蛾(Autographa californica)NPV的L-1变异体和家蚕NPV的Bm-5病毒株,并且所述病毒可以根据本发明用作本文中的病毒,特定来说用于转染草地贪夜蛾细胞。棉花、玉米、马铃薯、大豆、矮牵牛、番茄和烟草的植物细胞培养物也可以用作宿主。
然而,脊椎动物细胞也已引起极大关注,且在培养物(组织培养物)中繁殖脊椎动物细胞已变成常规方法。适用的哺乳动物宿主细胞系的实例是经SV40转化的猴肾CV1株系(COS-7,ATCC CRL 1651);人胚肾系(经亚克隆以便在悬浮培养物中生长的293或293细胞;幼小仓鼠肾细胞(BHK,ATCC CCL 10);中国仓鼠卵巢细胞/-DHFR;小鼠支持细胞(TM4);猴肾细胞(CV1 ATCC CCL 70);非洲绿猴肾细胞(VERO-76,ATCC CRL-1587);人宫颈癌细胞(HELA,ATCC CCL 2);犬科动物肾细胞(MDCK,ATCC CCL 34);布法罗大鼠(buffalo rat)肝细胞(BRL 3A,ATCC CRL 1442);人肺细胞(W138,ATCC CCL 75);人肝细胞(Hep G2, HB8065);小鼠乳腺肿瘤(MMT 060562,ATCC CCL51);TRI细胞;MRC 5细胞;FS4细胞;和人肝肿瘤系 (Hep G2)。
用上文所描述的表达或克隆载体转化宿主细胞以制造抗CD38中和抗体,且在适当时在改良的常规营养培养基中培养,以诱导启动子、选择转化体或扩增编码所需序列的基因。在另一实施例中,抗体可通过所属领域中已知的同源重组来制造。
药物组合物和给药方法
本发明进一步提供药物组合物,其包含表达本文提供的针对CD38的中和抗体或其抗原结合片段的重组表达载体和一或多种药学上可接受的载体。
术语“药学上可接受的”指示,指定载体一般在化学上和/或物理上与构成调配物的其它成分相容,且在生理上与其接受者相容。
用于本发明的组合物中的药学上可接受的载体可包括但不限于例如药学上可接受的液体、凝胶或固体载剂、水性媒剂(例如氯化钠注射液、林格氏注射液、等渗葡萄糖 注射液、无菌水注射液或林格氏葡萄糖和乳酸盐注射液)、非水性媒剂(例如植物来源的非挥发性油、棉籽油、玉米油、芝麻油或花生油)、抗微生物剂、等渗剂(如氯化钠或右旋糖)、缓冲液(如磷酸盐或柠檬酸盐缓冲液)、抗氧化剂(如硫酸氢钠)、麻醉剂(如盐酸普鲁卡因)、悬浮/分散剂(如羧甲基纤维素钠、羟丙基甲基纤维素或聚乙烯吡咯烷酮)、螯合剂(如EDTA(乙二胺四乙酸)或EGTA(乙二醇四乙酸))、乳化剂(如聚山梨醇酯80(Tween-80))、稀释剂、佐剂、赋形剂、或无毒辅助物质、所属领域中已知的其它组分,或其各种组合。适合的组分可包括例如填充剂、结合剂、崩解剂、缓冲剂、防腐剂、润滑剂、调味剂、增稠剂、着色剂或乳化剂。
“CD38阳性疾病”是存在表达CD38的细胞的疾病或病症。非限制性地,例如由表达CD38的B细胞、浆细胞、单核细胞和T细胞参与的免疫性疾病,疾病的特征之一为存在表达CD38的肿瘤细胞的肿瘤疾病,例如表达CD38的白血病、B细胞淋巴瘤、浆细胞恶性瘤、T/NK细胞淋巴瘤和骨髓瘤。本发明在一些实施方案中,所述白血病选自:急性淋巴细胞白血病、急性成淋巴细胞白血病、急性早幼粒细胞白血病、慢性淋巴细胞白血病、急性和慢性骨髓型白血病。在一些实施方案中,所述骨髓瘤选自:多发性骨髓瘤、前髓细胞肿瘤和轻链淀粉样变性。在一些实施方案中,所述淋巴瘤为非何杰金淋巴瘤或何杰金淋巴瘤。在一些实施方案中,所述肿瘤可选自B细胞淋巴瘤/白血病,包括但不限于:前体B细胞成淋巴细胞白血病/淋巴瘤、B细胞非霍奇金淋巴瘤或B细胞霍奇金淋巴瘤、成熟B细胞肿瘤。在一些实施方案中,所述肿瘤选自:B细胞慢性淋巴细胞性白血病(CLL)、小淋巴细胞性白血病(SLL)、B细胞急性淋巴细胞性白血病、B细胞前淋巴细胞白血病、淋巴浆细胞样淋巴瘤、套细胞淋巴瘤(MCL)、滤泡性淋巴瘤(包括低级、中级或高级FL)、皮肤滤泡中心淋巴瘤、边缘区B细胞淋巴瘤(包括MALT型、淋巴结MZBL型、脾MZBL型)、毛细胞白血病、弥漫性大B细胞淋巴瘤、伯基特淋巴瘤(Burkitt淋巴瘤)、浆细胞瘤、浆细胞骨髓瘤、浆细胞白血病、移植后淋巴增生性疾病、Waldenstrom巨球蛋白血症、浆细胞白血病和间变性大细胞淋巴瘤(ALCL)、多毛细胞淋巴瘤。在一些实施方案中,所述肿瘤为多发性骨髓瘤。在一些实施方案中,所述免疫性疾病选自:类风湿性关节炎、牛皮癣、强直性脊柱炎、关节银屑病、皮炎、系统性硬皮病及硬化症、炎症性肠病(IBD)、Crohn病(克罗恩氏病)、溃疡性结肠炎、呼吸窘迫综合征、脑膜炎、胃炎、脑炎、葡萄膜炎、肾小球肾炎、湿疹、哮喘、动脉硬化、白细胞粘附缺陷病、Raynaud症候群、Sjogren症候群、青少年糖尿病、Reiter病、Behcet病、免疫复合物性肾炎、IgA肾病、IgM多发性神经病、免疫介导的血小板减少症状(如急性特发性血小板减少性紫癜、慢性特发性血小板减少性紫癜)、溶血性贫血、重症肌无力、狼疮性肾炎、系统性红斑狼疮、风湿关节炎(RA)、异位性皮炎、天疱疮、Graves病、桥本氏甲状腺炎、Wegener肉芽肿、Omenn症候群、慢性肾功能衰竭、急性传染性单核细胞增多征、多发性硬化症、HIV和疱疹病毒相关的疾病、严重急性呼吸综合征、脉络视网膜炎(choreoretinitis)、移植物对抗宿主疾病、以及病毒感染引起的免疫性疾病(如伊波病毒(EBV)感染B细胞引起或介导的疾病)。在一些实施方案中,所述免疫性疾病选自类风湿性关节炎、系统性红斑性狼疮、哮喘、炎症性肠道疾病、多发性硬化、克罗恩氏病、胃炎、桥本氏甲状腺炎、强直性脊柱炎和移植物对抗宿主疾病。在一些实施方案中,其中所述免疫疾病是类风湿性关节炎。
本发明提供用于治疗或预防与目标抗原(例如CD38)阳性细胞相关疾病的药剂,所述药剂包含本发明的抗CD38抗体或其抗原结合片段作为活性成分,可以对有需要的对象给予治疗有效量或预防有效量的该药剂,以治疗或预防CD38阳性疾病。抗CD38抗体或其抗原结合片段可抑制CD38诱导的与疾病相关的活性或消除或降低CD38表达细胞的数目。
另外,本发明涉及用于免疫检测或测定目标抗原(例如CD38)的方法、用于免疫检测或测定目标抗原(例如CD38)的试剂、用于免疫检测或测定表达目标抗原(例如CD38)的细胞的方法和用于诊断与目标抗原(例如CD38)阳性细胞相关的疾病的诊断剂,其包含本发明的特异性识别目标抗原(例如人CD38)结合的抗体或抗体片段作为活性成分。
在本发明中,用于检测或测定目标抗原(例如CD38)的量的方法可以是任何已知方法。例如,它包括免疫检测或测定方法。
免疫检测或测定方法是使标记的抗原或抗体检测或测定抗体量或抗原量的方法。免疫检测或测定方法的实例包括放射性物质标记的免疫抗体方法(RIA)、酶免疫测定法(EIA或ELISA)、荧光免疫测定法(FIA)、发光免疫测定法、蛋白质免疫印迹法、物理化学方法等。
上述与CD38阳性细胞相关的疾病可以通过用本发明的抗体或抗体片段检测或测定表达CD38的细胞来诊断。
为了检测表达多肽的细胞,可以使用已知的免疫检测方法,并优选使用免疫沉淀法、荧光细胞染色法、免疫组织染色法等。此外,可以使用利用FMAT8100HTS系统(AppliedBiosystem)的荧光抗体染色法等。
在本发明中,对用于检测或测定目标抗原(例如CD38)的样品没有特别限制,只要它具有包含表达目标抗原(例如CD38)的细胞的可能性即可,例如组织细胞、血液、血浆、血清、胰液、尿液、粪便、组织液或培养液。
根据所需的诊断方法,含有本发明的单克隆抗体或其抗体片段的诊断剂还可以含有用于执行抗原-抗体反应的试剂或用于检测反应的试剂。用于执行抗原-抗体反应的试剂包括缓冲剂、盐等。用于检测的试剂包括通常用于免疫检测或测定方法的试剂,例如识别所述单克隆抗体、其抗体片段或其结合物的标记的第二抗体和与所述标记对应的底物等。
下面结合附图和实施例对本发明作进一步详细的说明。以下实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1 抗CD38抗体30G4的制备
合成表1所示的30G4抗体的序列,并克隆至真核表达载体中。
具体步骤如下:
1、酶切实验
采用表2所示的试剂和条件进行酶切反应。
2、酶切产物的胶回收
将上面酶切的载体用1%琼脂糖凝胶跑电泳,然后切取目的条带的胶块,胶块尽量切小一点,利用全式金的试剂盒回收目的DNA。
3、PCR产物扩增
进行PCR扩增的体系和条件分别如表3和表4所示。
4、PCR产物纯化
利用全式金试剂盒,具体操作见试剂盒说明书。
5、连接
根据表5中的Ligation Reaction,输入相应的值得到相应的体系,37℃水浴30min
6、连接产物转化StbⅠ3
从-80℃冰箱取出感受态细胞冰上融化,吸取50μl转移至预冷的EP管中,加入2.5ul连接产物,轻轻弹匀,冰浴30min,42℃水浴热激60s,迅速放回冰上并静置2min。向离心管中加入200μl LB液体培养基(无Amp),37℃、180rpm摇床培养1h,吸取适量转化产物加到LB(Amp)琼脂板上,均匀涂开。将平板倒置于37℃生化培养箱培养过夜。
7、colony PCR鉴定
挑取4-8个单菌落到100μl LB(Amp)液体培养基中,37℃、220rpm摇床培养1-3h,取菌液进行PCR鉴定。反应结束后琼脂糖凝胶电泳,PCR产物大小约600bp,挑选1个阳性菌落送测序。
8、质粒提取和保存
测序正确后,将菌落扩增至15ml培养基培养过夜,制作甘油菌,用无内毒素质粒提取试剂盒提取质粒,具体步骤参照无内毒素质粒中提试剂盒(天根)说明书进行,测定质粒浓度,用于抗体生产。
实施例2 单克隆抗体的ELISA检测
一、实验材料
二、实验方法
1、将未标记抗原(human CD38 Protein(ECD,His Tag))在Elisa Coating Buffer(1x)包被缓冲液(用D.L water稀释Elisa Coating Buffer(5x))稀释至0.5μg/ml,并将100μl转移到NuncTM MaxisorpTM ELISA Plates Uncoated单孔中,密封板,防止蒸发,在4℃孵化过夜。
2、将NuncTM MaxisorpTM ELISA Plates Uncoated置于常温,甩掉捕获抗体溶液,用Elisa Wash Buffer(1x)(用D.L water稀释Elisa Wash Buffer(20x))洗涤三次,每孔加入200μl封闭液(将BSA用Elisa Wash Buffer(1x)配置1%浓度)封闭非特异性结合位点,室温孵育1h。
3、用Elisa Wash Buffer(1x)洗涤三次,用干净的纸巾牢牢地擦干。
4、将标准品(标准品Purified anti-human CD38用封闭液稀释)和样品(单克隆抗体封闭液稀释)设置若干个浓度梯度并每组取一个复孔,NuncTM MaxisorpTM ELISA PlatesUncoated每孔添加100μl,室温孵化2h。
5、用Elisa Wash Buffer(1x)洗涤三次,用干净的纸巾牢牢地擦干。
6、将生物标记的检测抗体HRP Goat anti-mouse IgG在封闭液中稀释至0.4μg/ml(0.25-2μg/ml),分别以每孔100ul添加到标准孔和样品孔中,室温孵育1h。
7、用Elisa Wash Buffer(1x)洗涤三次,用干净的纸巾牢牢地擦干。
8、将2ml TMB Substrate A和2ml TMB Substrate B 混合均,将100μl转移到NuncTM MaxisorpTM ELISA Plates Uncoated单孔中,并在室温孵育10min(4-60min),孵育完成后加入100μl Stop solution终止反应。
9、用酶标仪在450nm条件下测取每个孔OD值,将读取标准孔绘制标准曲线,以此计算样品抗体的浓度。
三、结果
结果如图1所示,实验组的抗体检出度远远大于阴性对照组,说明抗体对CD38有很好的亲和力。
实施例3 单克隆抗体的流式细胞检测
一、实验材料
APC Goat anti-mouse IgG (minimal x-reactivity) Antibody(biolegend:405308), PBS(Gibco: C20012500BT),RPMI1640(Gibco: C11875500BT), 青霉素-链霉素双抗溶液(Hyclone: SV30010),特级胎牛血清(美森: CTCC-002-001-50_10),molm16细胞
二、实验方法
1、培养molm16细胞,进行细胞计数,然后取5×105个细胞置于1.5ml EP管中,1000rpm,5min离心,去上清;
2、加500μl PBS重悬细胞,然后1000rpm,5min离心,去上清;
3、将空白细胞培养上清与抗体生产上清分别重悬待测细胞,置于4℃,避光反应30min,然后1000rpm,5min离心,去上清;
4、加500μl PBS重悬细胞,然后1000rpm,5min离心,去上清;
5、加100μl二抗(APC anti-human IgG Fc Anti body,原液用PBS经过1:600稀释后使用)重悬细胞,置于4℃,避光反应30min,然后1000rpm,5min离心,去上清;
6、加500μl PBS重悬细胞,然后1000rpm,5min离心,去上清;
7、加400μl PBS重悬细胞,然后上机检测。
三、结果
结果如图2所示,相比空白细胞培养上清(2A),抗体生产上清能与molm16细胞表面的CD38结合(2B)。
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也将落入本发明权利要求的保护范围内。
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<110> 四川大学华西医院
<120> 一种抗体及其应用
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<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Asn Met Asn Trp Val Lys Gln Ser Asn Gly Lys Ser Leu Glu Trp Ile
1 5 10 15
Gly Val Ile
<210> 6
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Thr Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp
1 5 10 15
Gln Ser Ser Ser Thr Ala Tyr Met Gln Leu Asn Ser Leu Thr Ser Glu
20 25 30
Asp Ser Ala Val Tyr Tyr
35
<210> 7
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Gly Thr Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 8
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Glu Phe Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asp Tyr
20 25 30
Asn Met Asn Trp Val Lys Gln Ser Asn Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Asn Tyr Gly Thr Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Gln Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Gly Pro Ser Tyr Tyr Tyr Gly Ser Ser Tyr Trp Tyr Phe
100 105 110
Asp Val Trp Gly Thr Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 9
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Arg Ala Ser Gln Ser Ile Gly Thr Ser Ile His
1 5 10
<210> 10
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Tyr Ala Ser Glu Ser Ile Ser
1 5
<210> 11
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Cys Gln Gln Ser Asn Ser Trp Pro Leu Thr Phe
1 5 10
<210> 12
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Asp Ile Leu Leu Thr Gln Ser Pro Ala Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys
20
<210> 13
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys
1 5 10 15
<210> 14
<211> 31
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr
20 25 30
<210> 15
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Gly Ala Gly Thr Lys Leu Glu Leu Lys
1 5
<210> 16
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Asp Ile Leu Leu Thr Gln Ser Pro Ala Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Ser
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Ser Asn Ser Trp Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 17
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 17
ggttactcat tcactgacta c 21
<210> 18
<211> 18
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 18
aatcctaact atggtact 18
<210> 19
<211> 60
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 19
tgtgcaagat ggggcccttc ttattactac ggtagtagct actggtactt cgatgtctgg 60
<210> 20
<211> 75
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 20
gagttccagc tgcagcagtc tggacctgag ctggtgaagc ctggcgcttc agtgaagata 60
tcctgcaagg cttct 75
<210> 21
<211> 57
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 21
aacatgaact gggtgaagca gagcaatgga aagagccttg agtggattgg agtaatt 57
<210> 22
<211> 114
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 22
actagctaca atcagaagtt caagggcaag gccacattga ctgtagacca atcttccagc 60
acagcctaca tgcagctcaa cagcctgaca tctgaggact ctgcagtcta ttac 114
<210> 23
<211> 31
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 23
ggcacaggga ccacggtcac cgtctcctca g 31
<210> 24
<211> 376
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 24
gagttccagc tgcagcagtc tggacctgag ctggtgaagc ctggcgcttc agtgaagata 60
tcctgcaagg cttctggtta ctcattcact gactacaaca tgaactgggt gaagcagagc 120
aatggaaaga gccttgagtg gattggagta attaatccta actatggtac tactagctac 180
aatcagaagt tcaagggcaa ggccacattg actgtagacc aatcttccag cacagcctac 240
atgcagctca acagcctgac atctgaggac tctgcagtct attactgtgc aagatggggc 300
ccttcttatt actacggtag tagctactgg tacttcgatg tctggggcac agggaccacg 360
gtcaccgtct cctcag 376
<210> 25
<211> 33
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 25
agggccagtc agagcattgg cacaagcata cac 33
<210> 26
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 26
tatgcttctg agtctatctc t 21
<210> 27
<211> 33
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 27
tgtcaacaaa gtaatagctg gccgctcacg ttc 33
<210> 28
<211> 69
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 28
gacatcttgc tgactcagtc tccagccatc ctgtctgtga gtccaggaga aagagtcagt 60
ttctcctgc 69
<210> 29
<211> 45
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 29
tggtatcagc aaagaacaaa tggttctcca aggcttctca taaag 45
<210> 30
<211> 93
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 30
gggatccctt ccaggtttag tggcagtgga tcagggacag attttactct tagcatcaac 60
agtgtggagt ctgaagatat tgcagattat tac 93
<210> 31
<211> 28
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 31
ggtgctggga ccaagctgga gctgaaac 28
<210> 32
<211> 322
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 32
gacatcttgc tgactcagtc tccagccatc ctgtctgtga gtccaggaga aagagtcagt 60
ttctcctgca gggccagtca gagcattggc acaagcatac actggtatca gcaaagaaca 120
aatggttctc caaggcttct cataaagtat gcttctgagt ctatctctgg gatcccttcc 180
aggtttagtg gcagtggatc agggacagat tttactctta gcatcaacag tgtggagtct 240
gaagatattg cagattatta ctgtcaacaa agtaatagct ggccgctcac gttcggtgct 300
gggaccaagc tggagctgaa ac 322
Claims (13)
1.一种抗CD38的单克隆抗体,其特征在于,所述单克隆抗体包含:
SEQ ID NO. 1的HCDR1、SEQ ID NO. 2的HCDR2和SEQ ID NO. 3的HCDR3,与SEQ ID NO.9的LCDR1、SEQ ID NO. 10的LCDR2和SEQ ID NO. 11的LCDR3。
2.根据权利要求1所述的单克隆抗体,其特征在于,所述单克隆抗体还包含具有如SEQID NO.4、5、6、7所示氨基酸序列的重链可变区框架区HFR1、HFR2、HFR3和HFR4;以及具有如SEQ ID NO.12、13、14、15所示氨基酸序列的轻链可变区框架区LFR1、LFR2、LFR3和LFR4。
3.根据权利要求1或2所述的单克隆抗体,其特征在于,所述单克隆抗体重链可变区具有SEQ ID NO.8所示的氨基酸的VH,所述单克隆抗体轻链可变区具有SEQ ID NO.16所示的氨基酸序列的VL。
4.根据权利要求1或2所述的单克隆抗体,其特征在于,所述单克隆抗体进一步包含重链恒定区和轻链恒定区。
5.如下任一项所述的物质:
1)核酸分子,所述核酸分子编码权利要求1-4任一项所述的单克隆抗体或其功能片段;
2)重组表达载体,所述重组表达载体包含1)中所述的核酸分子;
3)宿主细胞,所述宿主细胞包含2)中所述的重组表达载体;
4)药物偶联物,所述药物偶联物包含权利要求1-4任一项所述的单克隆抗体或其功能片段;
5)一种检测CD38的产品,所述产品包含权利要求1-4任一项所述的单克隆抗体或其功能片段;
6)一种组合物,所述组合物包含权利要求1-4任一项所述的单克隆抗体或其功能片段,1)中所述的核酸分子、2)中所述的重组表达载体、3)中所述的宿主细胞。
6.根据权利要求5所述的物质,其特征在于,所述重组表达载体具有与抗体可操作地连接的信号肽。
7.根据权利要求6所述的物质,其特征在于,所述重组表达载体进一步包含转录调控元件。
8.根据权利要求5所述的物质,其特征在于,所述药物偶联物还包含选自下组的偶联部分:可检测标记物、药物、毒素、细胞因子或酶。
9.一种药物组合物,其特征在于,所述药物组合物包括权利要求1-4任一项所述的单克隆抗体或权利要求5中所述的药物偶联物;和/或药学上可接受的载体。
10.如下任一项所述的方法:
1)一种制备权利要求1所述单克隆抗体的方法,所述方法包括:培养权利要求5中所述的宿主细胞,回收单克隆抗体;
2)一种非诊断目的检测样品中CD38的方法,所述方法包括:使权利要求1所述的抗CD38的单克隆抗体接触待测样本,确定所述待测样本中CD38的存在或水平。
11.根据权利要求10所述的方法,其特征在于,1)中所述方法还包括对所述单克隆抗体进行纯化。
12.如下任一项所述的应用:
1)权利要求1-4任一项所述的单克隆抗体、权利要求5中所述的检测CD38的产品在非诊断目的检测CD38中的应用;
2)权利要求1-4任一项所述的单克隆抗体、权利要求5中所述的检测CD38的产品在制备诊断CD38阳性疾病的产品中的应用;
3)权利要求1-4任一项所述的单克隆抗体、权利要求5中所述的药物偶联物或权利要求9所述的药物组合物在制备预防和/或治疗与CD38阳性疾病的药物中的应用。
13.根据权利要求12所述的应用,其特征在于,所述疾病为肿瘤或免疫性疾病。
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