CN117229397A - 抗cd40抗体及其用途 - Google Patents
抗cd40抗体及其用途 Download PDFInfo
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- CN117229397A CN117229397A CN202210639198.2A CN202210639198A CN117229397A CN 117229397 A CN117229397 A CN 117229397A CN 202210639198 A CN202210639198 A CN 202210639198A CN 117229397 A CN117229397 A CN 117229397A
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Abstract
本发明提供了一种抗CD40抗体及其用途,其可通过与Fc受体交联激活CD40蛋白,从而实现CD40在Fc受体高表达的肿瘤微环境中的特异性激活,降低由于CD40分子广泛表达引起的外周毒副作用,提高CD40激动剂的安全性。
Description
技术领域
本发明涉及一种识别CD40蛋白的抗体及其应用。
背景技术
癌症免疫治疗已成为第三代癌症治疗中最活跃的研究领域。过去几十年的许多临床研究表明,靶向肿瘤微环境(TME)并刺激抗肿瘤免疫反应可产生强健而持久的抗肿瘤作用。这导致了以PD-1等一系列靶点的免疫检查点抑制(ICI)疗法的应用。ICI治疗的主要目的是维持先前建立的抗肿瘤活性,相比之下,刺激性免疫靶点如CD40则用激动剂来激活免疫,主要集中在免疫反应的早期阶段。
CD40是大小为48kda的I型跨膜糖蛋白,属于肿瘤坏死因子(TNF)和神经生长因子(NGF)受体超家族成员,是连接固有免疫和适应性免疫的重要免疫细胞通讯介质。广泛存在于血小板、B细胞和髓系细胞,但也存在于非造血细胞,如内皮细胞、成纤维细胞、平滑肌细胞甚至某些类型的肿瘤细胞,如B细胞淋巴瘤和大约70%的实体瘤。CD40L(CD154/TNFSF5)是CD40的配体,属于II型跨膜糖蛋白,分子量为39kda,也属于肿瘤坏死因子(TNF)受体超家族成员,是很重要的激活APC的共刺激分子。CD40L的表达通常可诱导并局限于造血***的细胞,如血小板、粒细胞、活化T细胞、活化B细胞和活化自然杀伤细胞(NK)细胞,但内皮细胞和平滑肌细胞也有弱表达。CD40L常以可溶性三聚体形式与CD40结合,引起一定的生物学功能。CD40-CD40L的相互作用是体液免疫和细胞免疫中很重要的信号传导通路,在一些炎症以及某些自身免疫性疾病等方面也起到重要作用。已有证据表明CD40的激活已被证实可以逆转对肿瘤特异性抗原的耐受性,引起特异性抗肿瘤免疫。
不同类型的Fc受体在免疫***中发挥着不同的作用。例如,在NK细胞和巨噬细胞上表达的FcyRIII受体,与附着在感染细胞或入侵病原体上的抗体结合,引发抗体介导的吞噬作用(ADCP)或抗体依赖的细胞毒作用(ADCC),从而导致感染细胞或入侵病原体被消灭。另一方面,在B细胞和树突状细胞上表达的FcyRIIB受体与IgG抗体结合后,可以下调免疫细胞的活性。激活免疫细胞的治疗方法是消除病变细胞(如癌细胞)的有效方法。然而,这类治疗方法往往会引发安全问题。例如,过度激活的免疫细胞将导致非预期细胞毒性作用,造成组织损伤。因此,开发有效和安全的新的免疫疗法是目前亟待解决的问题。
发明内容
本发明的目的为提供一种结合CD40蛋白的高亲和力抗体,其可通过与Fc受体交联激活CD40蛋白,从而实现CD40在Fc受体高表达的肿瘤微环境中的特异性激活,降低由于CD40分子广泛表达引起的外周毒副作用,提高CD40激动剂的安全性。
为了实现目的,本发明提供以下技术方案:
本发明的一方面,提供一种结合CD40蛋白的抗体或其抗原结合部分,所述抗体或其抗原结合部分包含选自氨基酸序列SEQ ID NO:1-3、11、12或其任何变体的重链CDR,和/或选自氨基酸序列SEQ ID NO:6-8、16-18或其任何变体的轻链CDR,以及重链恒定区;所述重链恒定区包含如SEQ ID NO:25或其任何变体所示的氨基酸序列。
在一实施方案中,所述抗体或其抗原结合部分依赖于与Fc受体的结合激活CD40,从而激活DC细胞,产生抗肿瘤功效。
在一优选的实施方式中,所述Fc受体为FcγRIIB,与外周血液、脾脏和***中的免疫细胞相比,FcγRIIB在肿瘤微环境中的DC和单核细胞/巨噬细胞中高表达。
本发明中,所述抗体依赖于FcγRIIB介导的交联反应激活CD40,该抗体可以实现在肿瘤微环境中富集,通过FcγRIIB可以实现CD40在肿瘤微环境中的特异性激活,产生抗肿瘤效果,从而降低CD40激动剂抗体的毒副反应,提高其安全使用剂量。
在一实施方案中,所述抗体或其抗原结合部分包含选自氨基酸序列SEQ ID NO:1、11或其任何变体的重链CDR1,选自氨基酸序列SEQ ID NO:2、12或其任何变体的重链CDR2,选自氨基酸序列SEQ ID NO:3或其任何变体的重链CDR3;和/或选自氨基酸序列SEQ ID NO:6、16或其任何变体的轻链CDR1,选自氨基酸序列SEQ ID NO:7、17或其任何变体的轻链CDR2,选自氨基酸序列SEQ ID NO:8、18或其任何变体的轻链CDR3。
在一实施方案中,所述抗体或其抗原结合部分包含选自氨基酸序列SEQ ID NO:4、14或其任何变体的重链可变区,和/或选自氨基酸序列SEQ ID NO:9、19或其任何变体的轻链可变区。
在一实施方案中,所述抗体或其抗原结合部分包含选自下列的重链和轻链的CDR组合:
(1)分别包含SEQ ID NO:1-3的重链CDR1、CDR2及CDR3序列,和/或分别包含EQ IDNO:6-8的轻链CDR1、CDR2及CDR3序列;
(2)分别包含SEQ ID NO:1-3的重链CDR1、CDR2及CDR3序列,和/或分别包含EQ IDNO:16-18的轻链CDR1、CDR2及CDR3序列;
(3)分别包含SEQ ID NO:11、12、3的重链CDR1、CDR2及CDR3序列,和/或分别包含EQID NO:6-8的轻链CDR1、CDR2及CDR3序列;
(4)分别包含SEQ ID NO:11、12、3的重链CDR1、CDR2及CDR3序列,和/或分别包含EQID NO:16-18的轻链CDR1、CDR2及CDR3序列。
在一实施方案中,所述抗体或其抗原结合部分是人源化的。
在一实施方案中,所述抗体或其抗原结合部分包含氨基酸序列SEQ ID NO:13或其任何变体所示的轻链恒定区。
在一实施方式中,所述重链恒定区为人lgG2亚型。
在一实施方式中,所述重链恒定区为lgG2亚型重链恒定区JAC3,其具有hIgG2(S267E/L328F)突变。
在一实施方案中,所述抗体或其抗原结合部分包含氨基酸序列SEQ ID NO:5、15或其任何变体所示的重链氨基酸序列,和/或SEQ ID NO:10、20或其任何变体所示的轻链氨基酸序列。
在一实施方案中,所述抗体或其抗原结合部分能阻断CD40与其配体的结合。
本发明的另一方面,提供一种抗原受体,其包括:特异性识别CD40蛋白的抗原结合结构域,所述抗原结合结构域为上述抗体或其抗原结合部分。
本发明的另一方面,提供编码上述抗体或其抗原结合部分或抗原受体的核酸分子,或与其具有至少大于60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或更高的序列同一性的核酸分子。
本发明的另一方面,提供包含上述核酸分子的载体。
本发明的另一方面,提供包含上述载体的细胞或试剂盒。
本发明的另一方面,提供包含上述抗受体、核酸分子、载体和/或细胞或试剂盒的药物组合物。
本发明的另一方面,提供包含上述抗体或其抗原结合部分、抗原受体、核酸分子、载体、细胞或试剂盒和/或药物组合物在制备用于治疗与CD40相关的疾病的药物或试剂盒中的用途。
在一实施方案中,所述与CD40相关的疾病包括肿瘤和感染。
在一实施方案中,所述肿瘤包括实体肿瘤和血液肿瘤。
在一实施方案中,所述与CD40相关的疾病包括结直肠癌、结肠癌、膀胱癌、乳腺癌、子宫/***、卵巢癌、***癌、睾丸癌、食管癌、胃肠癌、胰腺癌、肾癌、头颈癌、肺癌、胃癌、生殖细胞癌、骨癌、肝癌、甲状腺癌、皮肤癌、中枢神经***的肿瘤、淋巴瘤、白血病、骨髓瘤、肉瘤和黑色素瘤。
在一实施方案中,所述感染包括病毒感染、细菌感染、真菌感染和寄生虫感染。
在一实施方案中,所述血液肿瘤包括白血病、淋巴瘤和骨髓瘤。
附图说明
图1A示出了实施例1中不存在Fc介导的交联情况下,本公开的CD40激动剂抗体激活CD40的能力。
图1B示出了实施例1中存在Fc介导的交联情况下,本公开的CD40激动剂抗体激活CD40的能力。
图2示出了本公开实施例2中的抗体结合CD40蛋白的能力,A为结合人CD40蛋白的能力,B为结合过表达人CD40蛋白的CHOK1细胞的能力,C为结合过表达猴CD40蛋白的CHOK1细胞的能力。
图3示出了本公开实施例2中的抗体结合TNF家族蛋白(OX40、CD137、HVEM、LTBR、CD120b、DR5)的特异性结合能力。
图4示出了本公开实施例3中的抗体激活CD40的能力,A为在无CHOK1-hFcγRIIB细胞交联条件下抗体的激活活性,B为在有CHOK1-hFcγRIIB细胞交联条件下抗体的激活活性。
图5示出了本公开实施例4中抗体激活Mo-DC(CD80、CD86、CD83、MHCII)的能力。
图6示出了本公开实施例4中抗体激活Mo-DC(IL-12p40、IL-8、IL-6、TNF)的能力。
图7示出了本公开实施例5中抗体对T淋巴细胞增殖的影响,A为抗CD40抗体介导DC细胞对T细胞增殖的影响,B为对CD8+T淋巴细胞增殖情况的影响,C为对IFN-γ的释放水平的影响。
图8示出了了本公开实施例6中各组小鼠的肿瘤生长曲线。
图9示出了本公开实施例6中各组小鼠的相对体重变化。
具体实施方式
I.定义
在本公开中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的蛋白质和核酸化学、分子生物学、细胞和组织培养、免疫学相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。同时,为了更好地理解本公开,下面提供相关术语的定义和解释。
如本文中使用的,术语“CD40”指来自任何脊椎动物来源,包括哺乳动物,诸如灵长动物(例如人),非人灵长动物(例如食蟹猴)和啮齿动物(例如小鼠和大鼠)的任何天然CD40。如本文使用的和除非另作说明,术语“约”或“大约”是指在给定值或范围的加或减10%之内。在需要整数的情况下,该术语是指在给定值或范围的加或减10%之内、向上或向下舍入到最接近的整数。
就抗体链多肽序列而言,短语“基本相同”可理解为表现出与参照多肽序列至少60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或更多的序列同一性的抗体链。就核酸序列而言,该术语可理解为表现出与参照核酸序列至少大于60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或更高的序列同一性的核苷酸序列。
序列“相同性”或“同一性”具有本领域公认的含义,并且可以利用公开的技术计算两个核酸或多肽分子或区域之间序列相同性的百分比。可以沿着多核苷酸或多肽的全长或者沿着该分子的区域测量序列相同性。(参见,例如:Computational Molecular Biology,Lesk,A.M.,ed.,Oxford University Press,New York,1988;Biocomputing:Informaticsand Genome Projects,Smith,D.W.,ed.,Academic Press,New York,1993;ComputerAnalysis of Sequence Data,Part I,Griffin,A.M.,and Griffin,H.G.,eds.,HumanaPress,New Jersey,1994;Sequence Analysis in Molecular Biology,von Heinje,G.,Academic Press,1987;and Sequence Analysis Primer,Gribskov,M.and Devereux,J.,eds.,M Stockton Press,New York,1991)。虽然存在许多测量两个多核苷酸或多肽之间的相同性的方法,但是术语“相同性”是技术人员公知的(Carrillo,H.&Lipman,D.,SIAMJApplied Math48:1073(1988))。
就抗体的可变结构域而言,术语“可变”系指抗体之间有广泛序列差异的相关分子的某些部分,且被用于针对其特异靶的特定抗体的特异识别和结合。但是,可变性在抗体的整个可变结构域内不是均匀分布的。可变性集中在被称为互补决定区域(CDRs;即CDR1、CDR2和CDR3)或超变区的三个区段,它们均位于轻链和重链的可变结构域内。可变结构域内保守程度更高的部分被称为构架(FR)区或构架序列。天然重链和轻链的每个可变结构域均包括四个FR区,其主要采用β-折叠构型,它们籍三个CDRs连接起来,CDRs形成环,所述环连接β-折叠结构并在某些情形下形成部分的β-折叠结构。每条链的CDRs通常被FR区在邻近连接起来,并且借助于来自其它链的CDR,有助于抗体靶结合位点(表位或决定簇)的形成。正如本文所使用,免疫球蛋白氨基酸残基的编号是依据Kabat等人的免疫球蛋白氨基酸残基编号***而进行的,除非另有说明。一个CDR可具有特异结合关联表位的能力。
如本文所用,抗体的“抗体片段”或“抗原结合片段”指全长抗体的任何部分,其少于全长,但是至少包含结合抗原的所述抗体的部分可变区(例如一个或多个CDR和/或一个或多个抗体结合位点),并且因此保留结合特异性以及所述全长抗体的至少部分特异性结合能力。因此,抗原结合片段指包含与衍生抗体片段的抗体结合相同抗原的抗原结合部分的抗体片段。抗体片段包括通过酶促处理全长抗体所产生的抗体衍生物,以及合成产生的衍生物,例如重组产生的衍生物。抗体包括抗体片段。抗体片段的实例包括但不限于Fab、Fab′、F(ab′)2、单链Fv(scFv)、Fv、dsFv、双抗体、Fd和Fd′片段以及其他片段,包括修饰的片段。所述片段可以包括连接在一起的多条链,例如通过二硫键和/或通过肽接头。抗体片段一般包含至少或约50个氨基酸,并且典型至少或约200个氨基酸。抗原结合片段包括任何抗体片段,其在被***抗体框架(例如通过置换相应区域)时获得免疫特异性地结合(即表现出至少或至少约107-108M-1的Ka)抗原的抗体。“功能片段”或“抗GPC3抗体的类似物”是可防止或实质降低所述受体结合配体或启动信号转导的能力的片段或类似物。正如本文所使用,功能片段一般与“抗体片段″含义相同,且就抗体而论,可指能防止或实质降低所述受体结合配体或启动信号转导的能力的片段,例如Fv、Fab、F(ab′)2等等。“Fv”片段由一条重链的可变结构域和一条轻链的可变结构域籍非共价结合方式而形成的二聚体(VH-VL二聚体)组成。在该构型中,每个可变结构域的三个CDRs相互作用,以确定VH-VL二聚体表面上的靶结合位点,与完整抗体的情况一样。所述六个CDRs共同赋予完整抗体的靶结合特异性。但是,即使是单个可变结构域(或仅包括3个靶特异的CDRs的Fv的一半),仍可具有识别和结合靶的能力;“Fab”是由VL区、VH区、CL区和CH1区组成的抗体的单价抗原结合片段,该片段比Fv片段稍大。例如,Fab片段包括重链和轻链的可变区以及所有或部分第一恒定区。因此,Fab片段还包括例如重链和轻链的约110至约220个氨基酸残基。
如本文中所用,术语“抗CD40抗体”、“识别CD40蛋白的抗体”和“结合CD40蛋白的抗体”指能够以足够亲和力结合CD40,使得该抗体作为诊断剂和/或治疗剂在靶向CD40中有用的抗体。在一个实施方案中,抗CD40抗体对无关非CD40蛋白的结合程度小于该抗体对CD40的结合的约10%,如通过例如放射免疫测定法(RIA)测量的。在某些实施方案中,结合CD40的抗体具有≤1μM,≤100nM,≤10nM,≤1nM,≤0.1nM,≤0.01nM,或≤0.001nM(例如10-8M或更低,例如10-8M至10-13M,例如10-9M至10-13M)的解离常数(Kd)。在某些实施方案中,抗CD40抗体结合在来自不同物种的CD40间保守的CD40表位。
如本文所用,术语“抗原受体”,是基于抗体的针对期望的抗原(例如,肿瘤抗原)的特异性与T细胞受体-激活细胞内结构域结合以产生展示特异性抗肿瘤细胞免疫活性的嵌合抗原受体(CAR)或嵌合蛋白的分子。
利用上述能够特异性识别CD40的抗体或其抗原结合部分可以制备嵌合抗原受体或免疫细胞。
如本文所用,术语“Fc区”或“Fc”是指包含IgG分子的CH2-CH3结构域的多肽,并且在一些情况下,包括铰链。在人IgG1的EU编号中,所述CH2-CH3结构域包含氨基酸231至氨基酸447,并且所述铰链是氨基酸216至氨基酸230。因此,“Fc区”的定义包括氨基酸231-447(CH2-CH3)或216-447(铰链-CH2-CH3)、或其片段。在此上下文中的“Fc片段”可含有来自N-末端和C-末端中的一者或两者的更少的氨基酸,但仍然保留了与另一Fc区形成二聚体的能力,所述能力是如使用标准方法(通常基于尺寸)可检测的(例如,非变性色谱、尺寸排阻色谱)。人IgG Fc区在本披露中具有特定的用途,并且可以是来自人IgG1或IgG2的Fc区。
如本文所用,术语“CDR”指互补决定区(complementarity-determining region),已知抗体分子的每个重链和轻链各具有3个CDR。CDR也称作高变区,且存在于抗体的每个重链和轻链的可变区中,在CDR的一级结构中具有非常高的变异性位点。本说明书中,重链的CDR由来自重链的氨基端序列的氨基端的CDRH1、CDRH2、CDRH3或重链CDR1、重链CDR2、重链CDR3表示,轻链的CDR由来自轻链的氨基端序列的氨基端的CDRL1、CDRL2、CDRL3或轻链CDR1、轻链CDR2、轻链CDR3表示。这些位点在三级结构中彼此临近,并决定抗体所结合的抗原的特异性。
如本文所用,术语“人源化”抗体是指非人(例如小鼠)抗体形式,其是嵌合的免疫球蛋白、免疫球蛋白链或者其片段(如Fv、Fab、Fab′、F(ab′)2或者抗体的其它抗原结合亚序列),含有源自非人免疫球蛋白的最小序列。优选地,人源化抗体是人免疫球蛋白(接受者抗体),其中接受者抗体的互补决定区(CDR)的残基由来自具有希望的特异性、亲和性和能力的非人物种(供体抗体)如小鼠、大鼠或者兔的CDR残基置换。如本文所用,术语“核酸分子”指包含至少两个连接的核苷酸或核苷酸衍生物的寡聚体或聚合物,包括通常通过磷酸二酯键连接在一起的脱氧核糖核酸(DNA)和核糖核酸(RNA)。如本文所使用,术语“核酸分子”意欲包括DNA分子及RNA分子。核酸分子可为单链或双链,且可为cDNA。
如本文所用,“表达”指通过多核苷酸的转录和翻译产生多肽的过程。多肽的表达水平可以利用本领域已知的任何方法来评价,包括例如测定从宿主细胞产生的多肽的量的方法。这类方法可以包括但不限于通过ELISA定量细胞裂解物中的多肽,凝胶电泳之后考马斯蓝染色,Lowry蛋白测定以及Bradford蛋白测定。
如本文所用,“载体”是可复制的核酸,当载体转化入适当的宿主细胞时,可以从该载体表达一种或多种异源蛋白。关于载体包括那些通常通过限制酶切消化和连接可以将编码多肽或其片段的核酸引入其中的载体。关于载体还包括那些包含编码多肽的核酸的载体。载体用来将编码多肽的核酸引入宿主细胞,用于扩增核酸或者用于表达/展示核酸所编码的多肽。载体通常保持游离,但是可以设计为使基因或其部分整合入基因组的染色体。还考虑人工染色体的载体,例如酵母人工载体和哺乳动物人工染色体。这类媒介物的选择和用途是本领域技术人员公知的。
如本文所用,术语“与CD40相关的疾病”或相似表达意指根据本发明,CD40在患病组织或器官的细胞中表达。
本发明所使用的术语“药物组合物”系指多种制备物的制剂。含有治疗有效量的多价抗体的制剂为无菌液体溶液、液体悬浮剂或冻干形式,任选地包含稳定剂或赋形剂。应当理解,根据所述实施方案的治疗剂将与合适的药学上可接受的载体、赋形剂、以及其它被掺入制剂中以提供改善的转移、递送、耐受性等的试剂一同施用。大量适当的制剂可见于所有药物化学工作者已知的药典中:Remington′s Pharmaceutical Sciences(第15版,MackPublishing Company,Easton,Pa.(1975)),特别是其中Blaug、Seymour的第87章。这些制剂包括例如粉末、糊剂、膏剂、凝胶剂、蜡、油、脂质、含脂质(阳离子或阴离子)载体(例如LipofectinTM)、DNA缀合物、无水吸浆、水包油和油包水乳液、乳液聚乙二醇(各种分子量的聚乙二醇)、半固态凝胶以及含有聚乙二醇的半固态混合物。任何前述混合物均可适用于根据本发明的治疗或疗法,条件是制剂中的活性成分不被制剂灭活并且制剂在生理学上是相容的并耐受给药途径。
II.具体实施方式
本发明的一方面,提供一种结合人CD40蛋白的抗体或其抗原结合部分,所述抗CD40蛋白的抗体或其抗原结合部分包含选自氨基酸序列SEQ ID NO:1-3、11、12或其任何变体的重链CDR,和/或选自氨基酸序列SEQ ID NO:6-8、16-18或其任何变体的轻链CDR,以及重链恒定区;所述重链恒定区包含如SEQ ID NO:25或其任何变体所示的氨基酸序列。
在一实施方案中,所述抗体或其抗原结合部分依赖于与Fc受体的结合激活CD40,从而激活DC细胞,产生抗肿瘤功效。
在一优选的实施方式中,所述Fc受体为FcγRIIB,与外周血液、脾脏和***中的免疫细胞相比,FcγRIIB在肿瘤微环境中的DC和单核细胞、巨噬细胞中高表达。
本发明中,所述抗体依赖于FcγRIIB介导的交联反应激活CD40,该抗体可以实现在肿瘤微环境中富集,通过FcγRIIB可以实现CD40在肿瘤微环境中的特异性激活,产生抗肿瘤效果,从而降低CD40激动剂抗体的毒副反应,提高其安全使用剂量。
在一实施方案中,所述抗体或其抗原结合部分包含选自氨基酸序列SEQ ID NO:1、11或其任何变体的重链CDR1,选自氨基酸序列SEQ ID NO:2、12或其任何变体的重链CDR2,选自氨基酸序列SEQ ID NO:3或其任何变体的重链CDR3;和/或选自氨基酸序列SEQ ID NO:6、16或其任何变体的轻链CDR1,选自氨基酸序列SEQ ID NO:7、17或其任何变体的轻链CDR2,选自氨基酸序列SEQ ID NO:8、18或其任何变体的轻链CDR3。
在一实施方案中,所述抗体或其抗原结合部分包含选自氨基酸序列SEQ ID NO:4、14或其任何变体的重链可变区,和/或选自氨基酸序列SEQ ID NO:9、19或其任何变体的轻链可变区。
在一实施方案中,所述抗体或其抗原结合部分包含选自氨基酸序列SEQ ID NO:4或其任何变体的重链可变区,和/或选自氨基酸序列SEQ ID NO:9或其任何变体的轻链可变区。
在一实施方案中,所述抗体或其抗原结合部分包含选自氨基酸序列SEQ ID NO:4或其任何变体的重链可变区,和/或选自氨基酸序列SEQ ID NO:19或其任何变体的轻链可变区。
在一实施方案中,所述抗体或其抗原结合部分包含选自氨基酸序列SEQ ID NO:14或其任何变体的重链可变区,和/或选自氨基酸序列SEQ ID NO:9或其任何变体的轻链可变区。
在一实施方案中,所述抗体或其抗原结合部分包含选自氨基酸序列SEQ ID NO:14或其任何变体的重链可变区,和/或选自氨基酸序列SEQ ID NO:19或其任何变体的轻链可变区。
在一实施方案中,所述抗体或其抗原结合部分包含选自下列的重链和轻链的CDR组合:
(1)分别包含SEQ ID NO:1-3的重链CDR1、CDR2及CDR3序列,和/或分别包含EQ IDNO:6-8的轻链CDR1、CDR2及CDR3序列;
(2)分别包含SEQ ID NO:1-3的重链CDR1、CDR2及CDR3序列,和/或分别包含EQ IDNO:16-18的轻链CDR1、CDR2及CDR3序列;
(3)分别包含SEQ ID NO:11、12、3的重链CDR1、CDR2及CDR3序列,和/或分别包含EQID NO:6-8的轻链CDR1、CDR2及CDR3序列;
(4)分别包含SEQ ID NO:11、12、3的重链CDR1、CDR2及CDR3序列,和/或分别包含EQID NO:16-18的轻链CDR1、CDR2及CDR3序列。
在一实施方案中,所述抗体或其抗原结合部分包含氨基酸序列SEQ ID NO:13或其任何变体所示的轻链恒定区。
在一实施方式中,所述重链恒定区为人lgG2亚型。
在一实施方案中,所述抗体或其抗原结合部分包含氨基酸序列SEQ ID NO:5、15或其任何变体所示的重链氨基酸序列,和/或SEQ ID NO:10、20或其任何变体所示的轻链氨基酸序列。
在一实施方案中,所述抗体或其抗原结合部分,其与前述任一方面的抗体或其抗原结合部分具有至少大于60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或更高的序列同一性。
在一实施方案中,所述抗体或其抗原结合部分能阻断CD40与其配体的结合。本发明的另一方面,提供一种抗原受体,其包括:特异性识别CD40蛋白的抗原结合结构域,所述抗原结合结构域为上述抗体或其抗原结合部分。
本发明的另一方面,提供编码上述抗体或其抗原结合部分或抗原受体的核酸分子,或与其具有至少大于60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或更高的序列同一性的核酸分子。
本发明的另一方面,提供含有如前述任一方面的核酸的载体。
本发明的另一方面,提供含有如前述任一方面的载体的细胞。
本发明的另一方面,提供包含上述载体的细胞或试剂盒。
本发明的另一方面,提供包含上述抗体或其抗原结合部分、抗原受体、核酸分子、载体、细胞和/或试剂盒的药物组合物。
可将本文所述抗体和其衍生物、片段、类似物和同系物掺入适于施用的药物组合物中。制备此类组合物所涉及的原理和考虑事项以及选择组分的指南在本领域中是熟知的。此类组合物通常包含抗体和药学上可接受的载体。当使用抗体片段时,与靶蛋白结合结构域特异性结合的最小抑制片段可为优选的。例如,基于抗体的可变区序列,可以设计保留结合靶蛋白质序列能力的肽分子。此类肽可化学合成和/或通过重组DNA技术产生(参见例如Marasco等人,Proc.Natl.Acad.Sci.USA,90:7889-7893(1993))。
如本文所用,术语“药学上可接受的载体”旨在包括与药物给药相容的任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延缓剂等。合适的药学上可接受的载体描述于最新版的Remington′s Pharmaceutical Sciences中,这是本领域的标准参考书目,其以引用方式并入本文。此类载体或稀释剂的优选示例包括但不限于水、盐水、林格氏溶液、葡萄糖溶液和5%的人血清白蛋白。也可以使用脂质体和非水性载体,例如固定化油。将此类介质和试剂用于药物活性物质是本领域熟知的。除去任何常规的介质或试剂与抗体不相容之外,设想其在组合物中的用途。
将所述实施方案的药物组合物配制成与其预期施用途径相容。给药途径的示例包括肠胃外,例如静脉内、皮内、皮下、经口(例如吸入)、经皮(即局部的)、经粘膜和直肠给药。用于肠胃外、皮内或皮下施用的溶液或悬浮液可包括以下组分:注射用无菌稀释剂例如水、盐溶液、固定油、聚乙二醇类、甘油、丙二醇或其它合成溶剂;抗细菌剂,例如苄醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸(EDTA);缓冲剂,例如乙酸盐、柠檬酸盐或磷酸盐、以及调节渗透压的试剂,例如氯化钠或右旋糖。pH可用酸或碱进行调节,例如盐酸或氢氧化钠。可将肠胃外制剂包装在安瓿、一次性注射器或玻璃或塑料制多剂量小瓶内。
适于注射用途的药物组合物包括无菌水性溶液(在此是水溶性的)或分散体以及用于即时制备无菌注射液或分散体的无菌粉末。对于静脉内施用,合适的药学上可接受的载体包括生理盐水、抑菌水、Cremophor ELTM(BASF,Parsippany,N.J.)或磷酸盐缓冲盐水(PBS)。在所有情况下,组合物必须是无菌的并且应当为流动性达到易于注射的程度。其在制造和储存条件下必须是稳定的并且必须能防止微生物例如细菌和真菌的污染作用。载体可以是含有例如水、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇等)的溶剂或分散介质,及其适宜的混合物。例如通过利用涂层例如卵磷脂,在分散体情况下维持所需颗粒尺寸,以及利用表面活性剂,可以保持适宜的流动性。对微生物作用的防止可以通过各种抗细菌剂和抗真菌剂例如对羟基苯甲酸酯、氯代丁醇、苯酚、抗坏血酸、硫柳汞等来实现。在许多情况下,将优选在组合物中包含等渗剂,例如糖、多元醇(诸如甘露糖醇、山梨醇)、氯化钠。注射用组合物的延长吸收可通过在所述组合物中包含延缓吸收的试剂例如单硬脂酸铝和明胶来达到。
根据需要,可以通过将抗体以所需量掺入具有上文所列成分中的一种或组合(按需要)的合适溶剂中来制备无菌注射溶液,然后过滤消毒。一般来讲,通过将抗体掺入含有碱性分散介质和上文所列那些中的所需其它成分的无菌载体中来制备分散体。就用于制备无菌注射溶液的无菌粉末而言,制备方法是获得粉末的真空干燥和冷冻干燥,该粉末包含活性成分和任何另外的期望成分,它们来自前述的这些成分的无菌过滤溶液。
对于吸入给药,从包含合适推进剂如二氧化碳等气体的加压容器或分配器或者喷雾器以气溶胶喷雾形式递送化合物。
还可以通过经粘膜或透皮方式全身给药。对于经粘膜或透皮给药,在制剂中使用适于渗透屏障的渗透剂。此类渗透剂通常在本领域是通常所知的,并且包括如用于经粘膜给药的去污剂、胆盐和夫西地酸衍生物。经粘膜给药可以通过使用喷鼻剂或栓剂来实现。对于透皮给药,可将一种或多种所述抗体配制成如本领域通常所知的膏剂、软膏、凝胶、或霜膏。
还可将化合物以栓剂(例如,具有常规栓剂基质,如可可脂或其它甘油酯)或滞留性灌肠剂形式进行制备以用于经直肠递送。
在一个实施方案中,所述抗体可用防止其不被身体迅速消除的载体制备,例如缓释/控释制剂,包括植入体和微胶囊化递送体系。可使用可生物降解、可生物相容的聚合物,例如乙烯-乙酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。用于制备此类制剂的方法对于本领域技术人员而言是显而易见的。
尤其有利的是以剂量单位形式配制肠胃外组合物以易于施用和剂量的一致性。如本文所用,剂量单位形式是指用于待治疗的受试者,适合作为单位剂量的物理上可分离的单位;每个单位含有经计算与所需药物载体结合产生期望治疗效果的预定量的一种或多种所述抗体。所述实施方案的剂量单位形式的规格由以下指示并直接取决于:抗体的独特特征和待实现的具体治疗效果,和用于治疗个体的此类抗体的调配领域中固有的局限性。
所述药物组合物可与给药说明书一起放于容器、包装、或分配器中。
本文所述制剂还可根据要治疗的具体情况而包含多于一种所述抗体,优选具有互补活性但对彼此无负面影响的那些。另选地或除此之外,组合物可例如包含增强其功能的试剂,诸如细胞毒素试剂、细胞因子、化学治疗剂、或生长抑制剂。此类分子以对预期目的有效的量适当地联合存在。例如,可以在试剂盒中联合存在,也可以在使用中联合存在。
在一个实施方案中,一种或多种所述抗体可在联合治疗中施用,即与其它试剂例如治疗剂(其可用于治疗病理学病症或障碍,例如各种形式的癌症、自身免疫性障碍和炎性疾病)联合。术语“联合”在本文中是指将试剂基本上同步地,同时地或顺次地给予。如果顺次给予,则在开始施用第二种化合物时,两种化合物中的第一种仍优选在治疗位点处以有效浓度被检测到。在一种情况下,“联合”也可以是在试剂盒中同时包含本发明的抗体和其他治疗剂。
例如,联合治疗可包含本文所述一种或多种抗体与一种或多种附加治疗剂(例如一种或多种细胞因子和生长因子抑制剂、免疫抑制剂、抗炎剂、代谢抑制剂、酶抑制剂、和/或细胞毒素或细胞生长抑制剂,如下更详述的)共同配制和/或共同施用。此类联合治疗可有利地利用较低剂量的施用的治疗剂,因而避免了与各种单一疗法相关的可能毒性或并发症。
治疗癌症的方法,其包括下述步骤:向所述哺乳动物施用治疗有效量的前述任一方面的抗体或其抗原结合片段或核酸分子或载体或细胞或药物组合物。
本发明的另一方面,提供包含上述抗体或其抗原结合部分、抗原受体、核酸分子、载体、细胞或试剂盒和/或药物组合物在制备用于治疗与CD40相关的疾病的药物或试剂盒中的用途。
例如所述试剂盒包括本公开的抗体、其片段、同源物、其衍生物等,例如带标记或具有细胞毒性的缀合物,以及抗体使用说明书、杀死特定类型细胞的缀合物等等。该说明书可包括在体外、体内或离体使用抗体、缀合物等的指导。抗体可以是液体形式或固体,通常是冻干的。该试剂盒可包含其它适宜的试剂,如缓冲液、重构溶液以及为了预定用途的其它必要成分。考虑了以预定量包装好的试剂组合与用于其用途的说明书,所述用途例如用于治疗用途或用于进行诊断测定。当抗体是带标记的时,例如用酶标记的,那么该试剂盒可包括底物和酶所需的辅因子(例如提供可检测生色团或荧光团的底物前体)。此外,其它添加剂,如稳定剂、缓冲液(例如封闭缓冲液或裂解缓冲液)等也可包括在内。多种试剂的相对量可以改变而提供试剂溶液的浓缩物,这就提供了用户灵活性、节省空间、节省试剂等。这些试剂也可以干粉形式提供,通常是冻干形式,包括赋形剂,它在溶解时可提供具有适当浓度的试剂溶液。
在一实施方案中,所述与CD40相关的疾病包括肿瘤和感染。
III.实施例
实施例1:CD40抗体的制备
酵母抗体展示文库(Adimab)按照现有的方法进行文库扩增并进行磁珠细胞分选,得到一系列特异性结合人CD40的抗体可变区序列。为了提高抗体与人CD40结合的亲和力,通过随机突变的方式在CDR中引入突变构建突变文库,经过磁珠细胞分选后得到亲和力成熟的抗体分子。通过点突变的方式突变抗体可变区中出现的互作蛋白修饰(PTMs)位点得到性质相似的氨基酸,通过抗原结合实验确定突变后的序列是否改变了其结合抗原的能力。
将筛选得到的抗体可变区SEQ ID NO:4、9和SEQ ID NO:14、19分别克隆至含有抗体IgG2-S267E/L328F恒定区(下称IgG2Fc)的pcDNA3.1载体中构建出表达载体。该IgG2-S267E/L328F突变恒定区来自专利CN107474136A(参见SEQ 13),该突变体IgG2 Fc增强了与人FcγIIB的结合亲和力,实现依赖FcγIIB介导的交联。IgG2 Fc抗体重链恒定区序列如SEQ ID NO:25所示,抗体轻链恒定区序列如SEQ ID NO:13所示。而后将构建的表达载体分别转染入HEK293细胞(人胚肾细胞293)中。转染的HEK293细胞在37℃,8%CO2条件下培养7天。收集细胞液,13000rpm离心20分钟。取上清液,Protein A纯化上清液,分别得到抗体A和抗体B,SEC检测抗体纯度,同时控制内毒素含量。表达纯化的抗体经过蛋白水平的ELISA实验,细胞水平的FACS实验,通过报告基因NFκB-Luc2P/CD40 U2OS分析所有的抗体分子,在体外通过protein G磁珠介导的交联反应验证其依赖Fc交联激活CD40的能力(图1A和图1B),最终得到特异性识别人CD40,并且以依赖Fc交联的方式激活CD40的抗体A和抗体B。结果显示在存在Fc交联条件下,抗体A和抗体B均可以显著的激活CD40。
分析中使用的参考抗体来自同类抗体的专利信息,参考抗体-01(重链和轻链序列分别来自US7338660,参见SEQ46、SEQ48),参考抗体-02(抗体可变区序列来自US 2014/0348836A1,参见SEQ 25,SEQ 37,其重链IgG1亚型恒定区包括SEQ ID NO:24所示的氨基酸序列(对应US 2014/0348836A1中SEQ 62),按照专利恒定区融合表达IgG1-Fc)。
抗体氨基酸序列如下所示:
表1抗体的氨基酸序列
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参考抗体-02重链IgG1亚型恒定区氨基酸序列、重链IgG2亚型恒定区氨基酸序列(IgG2-S267E/L328F)、抗体A和抗体B轻链恒定区氨基酸序列如下:
参考抗体-02重链IgG1亚型恒定区氨基酸序列
重链IgG2亚型恒定区氨基酸序列
抗体A和抗体B轻链恒定区氨基酸序列
抗体A和抗体B的可变区序列如下:
抗体A
重链VH可变区的氨基酸序列如SEQ ID NO:4所示,其CDRH1、CDRH2和CDRH3分别如SEQ ID NO:1、2、3所示,其重链氨基酸序列如SEQ ID NO:5所示。
抗体A重链氨基酸序列
轻链VL可变区的氨基酸序列如SEQ ID NO:9所示,其CDRH1、CDRH2和CDRH3分别如SEQ ID NO:6、7、8所示,其轻链氨基酸序列如SEQ ID NO:10所示。
抗体A轻链氨基酸序列
抗体B
重链VH可变区的氨基酸序列如SEQ ID NO:14所示,其CDRH1、CDRH2和CDRH3分别如SEQ ID NO:11、12、3所示,其重链氨基酸序列如SEQ ID NO:15所示。
抗体B重链氨基酸序列
轻链VL可变区的氨基酸序列如SEQ ID NO:19所示,其CDRH1、CDRH2和CDRH3分别如SEQ ID NO:16、17、18所示,其轻链氨基酸序列如SEQ ID NO:20所示。
抗体B轻链氨基酸序列
实施例2:CD40抗体特性表征
通过体外的ELISA的结合实验检测抗体A和抗体B特异性结合人CD40蛋白(SEQ IDNO:21)的能力(图2A),通过FACS结合实验检测抗体A和抗体B特异性结合过表达人CD40蛋白和猴CD40蛋白(SEQ ID NO:22)的CHOK1细胞(图2B和图2C)、TNF同家族蛋白(OX40、CD137、HVEM、LTBR、CD120b、DR5)的能力(图3),该些实验所用同型对照抗体均为Anti-MOPC21antibody,FACS结合实验检测抗体结合TNF同家族蛋白能力实验(图3)使用的阳性对照抗体分别为OX40:Mouse Anti-Human CD134,BD,Cat#563664;CD137:Mouse Anti-Human CD137,BD,Cat#564091;HVEM:Hu HVEM(CD270)BV421 CW10,BD,Cat#565517;LTBR:BV421 MouseAnti-Human LTβR,BD,Cat#744854;CD120b:Alexa647 Rat Anti-Human CD120b,BD,Cat#562909;DR5:Hu TRAIL-R2(CD262)BV421 YM366,BD,Cat#743835。结果显示抗体A和抗体B均能特异性结合人CD40分子,交叉结合猴CD40分子。
通过ForteBio Octet***测定了抗体结合抗原的动力学常数,并且确定了抗体A和抗体B均可阻断CD40蛋白和CD40配体(SEQ ID NO:23)的结合(表2)。
表2 ForteBio Octet检测CD40抗体结合人/猴CD40蛋白的动力学常数
人CD40蛋白、猴CD40蛋白、人CD40配体的氨基酸序列如下:
人CD40蛋白氨基酸序列
猴CD40蛋白氨基酸序列
人CD40配体氨基酸序列
实施例3:体外验证CD40抗体激活报告基因能力
为了探索CD40激动剂抗体的体外激活活性,使用NFκB-Luc2P/CD40 U2OS人骨肉瘤细胞系,通过Bio-Glo荧光报告***检测抗体在CHOK1-FcγRIIB细胞交联下的体外激活能力。首先,体外培养扩增NFκB-Luc2P/CD40 U2OS报告基因细胞系,胰酶消化重悬后,按照2×104/100μL/孔的细胞密度接种至96孔板中,37℃培养过夜。第二天,小心吸弃细胞上清,换成含1%FBS的新鲜细胞培养基(根据实验设置添加或者不添加CHO-K1-hFcγRIIB细胞(2x104/64μL/孔)),进行抗体交联,并加入梯度稀释好的各抗体,放置于37℃恒温培养箱继续培养4h。加入Bio-Glo试剂,检测不同处理条件下的化学发光强度。通过倍数变化来显示抗体激活报告基因的能力,计算方法为实验组(抗体A/抗体B)Emax/同型对照抗体Emax。
结果如图4所示,在无CHOK1-hFcγRIIB细胞交联条件下,参考抗体-01表现出激活活性,而抗体A和抗体B未检测到激活活性(图4A)。在CHOK1-hFcγRIIB细胞交联条件下,抗体A和抗体B均表现出较强的激活活性,抗体A激活能力与参考抗体-01相当,抗体B的激活能力稍强于参考抗体-01(图4B)。可见,抗体A和抗体B的激活能力依赖于FcγRIIB的介导。
实施例4:体外验证CD40抗体激活Mo-DC的能力
探索CD40激动剂抗体对外周血单核树突状细胞(Mo-DC细胞)的激活活性,首先从人外周血单个核细胞(PBMC)中分选单核细胞,然后利用刺激因子人GM-CSF和IL-4刺激单核细胞向DC分化,将梯度稀释的CD40抗体与分化的DC细胞共孵育48h,最后评价DC表面活化分子CD80、CD83、CD86、MHCII的上调,以及培养上清中细胞因子IL-6、IL-8、TNF、IL-12p40的释放,进而分析抗体A对DC细胞的激活活性。
结果表明,CD80、CD86、CD83、MHCII的表达明显上调(图5),并释放大量的IL-6、IL-8、TNF、IL-12p40(图6),可见,抗体A在DC细胞中Fc受体的介导下能激活DC细胞,并分泌相应的细胞因子。
实施例5:MLR实验验证CD40激动剂能力
通过MLR实验来探索CD40激动剂抗体对T淋巴细胞增殖的影响,首先从人PBMC中分选CD14+单核细胞,利用刺激因子人GM-CSF和IL-4刺激单核细胞向DC分化,将梯度稀释的CD40抗体与分化的DC细胞共孵育48h,然后将CFSE荧光染料标记的CD8+T淋巴细胞与DC细胞共孵育5天,通过流式细胞术分析CD8+T淋巴细胞的增殖情况,并用流式CBA法检测培养上清中细胞因子IFN-γ的释放水平。
结果显示,CD40激动剂抗体呈剂量依赖性的促进T淋巴细胞的增殖,高浓度条件下,T淋巴细胞最大增殖比例在20%-30%左右,并且能检测到较高水平的IFN-γ分泌(图7)。
实施例6:小鼠模型验证CD40激动剂抗体抑制肿瘤细胞能力
评价CD40激动型抗体在Raji人淋巴瘤模型中的体内药效,将Raji细胞与PBMC混合皮下接种NCG小鼠,建立小鼠肿瘤细胞异源移植肿瘤模型(cell line derived xenografttumor model,CDX)。在此模型上,进行CD40激动型抗体的体内抗肿瘤药效研究。
实验设计:小鼠肿瘤接种1h后开始腹腔注射给药,随机分为9组,每组5只小鼠,分别为:
G1:空白组;
G2:对照组(同型对照抗体,1mpk(同mg/kg))每周1次,腹腔注射给药,给药20天;
G3:抗体A治疗组(0.1mpk),每周1次,腹腔注射给药,给药20天;
G4:抗体A治疗组(0.3mg/kg),每周1次,腹腔注射给药,给药20天;
G5:抗体A治疗组(1mpk),每周1次,腹腔注射给药,给药20天;
G6:参考抗体-01治疗组(1mpk),每周1次,腹腔注射给药,给药20天;
G7:参考抗体-02治疗组(1mpk),每周1次,腹腔注射给药,给药20天;
小鼠腹腔注射给药体积为10mL/kg。每天用电子天平对动物进行称重,每周用游标卡尺测量肿瘤体积3次,动物给药方案见表3。
表3 Raji+PBMC药效模型治疗药物的给药方案
组别 | 治疗药物 | 动物数 | 给药途径 | 剂量(mg/kg) | 给药频率 | 给药周期(天) |
G1 | NA | 8 | NA | NA | NA | 20 |
G2 | 同型对照抗体 | 8 | i.p. | 1 | qw | 20 |
G3 | 抗体A | 8 | i.p. | 0.1 | qw | 20 |
G4 | 抗体A | 8 | i.p. | 0.3 | qw | 20 |
G5 | 抗体A | 8 | i.p. | 1 | qw | 20 |
G6 | 参考抗体-01 | 8 | i.p. | 1 | qw | 20 |
G7 | 参考抗体-02 | 8 | i.p. | 1 | qw | 20 |
皮下肿瘤(Tumor volume,TV)体积计算公式:
TV=(L×W2)/2,
其中,L为肿瘤的长径,W为肿瘤的宽径。
相对肿瘤体积(Relative tumor volume,RTV)计算公式:
RTV=Vt/V0,
其中,V0为分笼给药时测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。
瘤重抑制率(Tumor weight inhibition,TWI)的计算公式:
TWI=(1-TWtreatment/TWcontrol)×100%,
其中,TWcontrol为对照组平均肿瘤重量(g),TWtreatment为治疗组平均肿瘤重量(g)。
相对体重变化(relative change ofbody weight,RCBW)计算公式:
RCBW(%)=(BWi-BW0)/BW0×100%,
其中,BWi是动物在特定天的体重,BW0是该动物在开始给药天的体重。
各组Raji+PBMC荷瘤鼠的肿瘤生长结果如图8所示,对应的各个给药组的TWI(%)见表4。统计分析表明,与同型对照组相比,抗体A0.1mpk,0.3mpk和1mpk每周1次腹腔注射连续给药20天,能够显著性抑制Raji肿瘤生长,抑制作用呈剂量依赖性。抗体A1mpk对肿瘤的抑制作用与参考抗体-01 1mpk对肿瘤的抑制作用相当,优于参考抗体-02 1mpk治疗组的肿瘤抑制效果。
各治疗组每只荷瘤鼠的相对体重变化见图9。抗体A0.1mpk、0.3mpk、1mpk治疗组和参考抗体-01 1mpk治疗组,参考抗体-02 1mpk治疗组每周1次腹腔注射连续给药20天对动物体重未见明显影响。
表4治疗药物对Raji+PBMC荷瘤鼠肿瘤体积的影响
注:**p<0.01,***p<0.001,****p<0.0001;单向方差分析,Dunnett′s法方差分析,分别与G2对照组比较。
前述对本发明的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本发明限定为所公开的精确形式,并且很显然,根据上述教导,可以进行很多改变和变化。对示例性实施例进行选择和描述的目的在于解释本发明的特定原理及其实际应用,从而使得本领域的技术人员能够实现并利用本发明的各种不同的示例性实施方案以及各种不同的选择和改变。本发明的范围意在由权利要求书及其等同形式所限定。
序列表
<110> 劲方医药科技(上海)有限公司
<120> 抗CD40抗体及其用途
<130> MTI220090
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Phe Thr Phe Ser Ser Tyr Gly Met His
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<213> 人工序列(Artificial Sequence)
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Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
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Gly
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Ala Arg Asp Thr Ser Arg Gly His Asp Ile
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
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Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
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Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
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Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Asp Thr Ser Arg Gly His Asp Ile Trp Gly Gln Gly Thr Met
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Val Thr Val Ser Ser
115
<210> 5
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<223> 合成多肽
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
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Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
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Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Asp Thr Ser Arg Gly His Asp Ile Trp Gly Gln Gly Thr Met
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Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
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Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
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Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
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Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
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Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
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Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
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Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
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Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
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Cys Val Val Val Asp Val Glu His Glu Asp Pro Glu Val Gln Phe Asn
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Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
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Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
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Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
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Asn Lys Gly Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
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Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
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Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
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Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
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Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
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Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
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Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
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<210> 6
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
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<223> 合成多肽
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Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala
1 5 10
<210> 7
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 7
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 8
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 8
Gln Gln Tyr Ala Asp Tyr Pro Pro Phe Thr
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<210> 9
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 9
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
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Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
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Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
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Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
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Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ala Asp Tyr Pro
85 90 95
Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 10
<211> 216
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 10
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ala Asp Tyr Pro
85 90 95
Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
115 120 125
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
130 135 140
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
145 150 155 160
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
165 170 175
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
180 185 190
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
195 200 205
Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 11
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 11
Phe Thr Phe Glu Lys Tyr Gly Met His
1 5
<210> 12
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 12
Val Ile Ser Tyr Glu Gly Thr Lys Lys Tyr Tyr Ala Glu Ser Val Lys
1 5 10 15
Gly
<210> 13
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
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Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
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Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
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Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
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Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
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Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
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Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
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Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 14
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
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Gln Val Gln Leu Val 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 Glu Lys Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Glu Gly Thr Lys Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 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 Asp Thr Ser Arg Gly His Asp Ile Trp Gly Gln Gly Thr Met
100 105 110
Val Thr Val Ser Ser
115
<210> 15
<211> 443
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 15
Gln Val Gln Leu Val 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 Glu Lys Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Glu Gly Thr Lys Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 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 Asp Thr Ser Arg Gly His Asp Ile Trp Gly Gln Gly Thr Met
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
180 185 190
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
210 215 220
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Glu His Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
290 295 300
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 16
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 16
Arg Ala Ser Gln Ser Val Ser Tyr Ser Tyr Leu Ala
1 5 10
<210> 17
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 17
Gly Ala Ser Ser Leu Ala Thr
1 5
<210> 18
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 18
Gln Gln Tyr Ser Asp Tyr Pro Pro Phe Thr
1 5 10
<210> 19
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 19
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Tyr Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Leu Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asp Tyr Pro
85 90 95
Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 20
<211> 216
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 20
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Tyr Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Leu Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asp Tyr Pro
85 90 95
Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
115 120 125
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
130 135 140
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
145 150 155 160
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
165 170 175
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
180 185 190
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
195 200 205
Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 21
<211> 277
<212> PRT
<213> Homo sapiens
<400> 21
Met Val Arg Leu Pro Leu Gln Cys Val Leu Trp Gly Cys Leu Leu Thr
1 5 10 15
Ala Val His Pro Glu Pro Pro Thr Ala Cys Arg Glu Lys Gln Tyr Leu
20 25 30
Ile Asn Ser Gln Cys Cys Ser Leu Cys Gln Pro Gly Gln Lys Leu Val
35 40 45
Ser Asp Cys Thr Glu Phe Thr Glu Thr Glu Cys Leu Pro Cys Gly Glu
50 55 60
Ser Glu Phe Leu Asp Thr Trp Asn Arg Glu Thr His Cys His Gln His
65 70 75 80
Lys Tyr Cys Asp Pro Asn Leu Gly Leu Arg Val Gln Gln Lys Gly Thr
85 90 95
Ser Glu Thr Asp Thr Ile Cys Thr Cys Glu Glu Gly Trp His Cys Thr
100 105 110
Ser Glu Ala Cys Glu Ser Cys Val Leu His Arg Ser Cys Ser Pro Gly
115 120 125
Phe Gly Val Lys Gln Ile Ala Thr Gly Val Ser Asp Thr Ile Cys Glu
130 135 140
Pro Cys Pro Val Gly Phe Phe Ser Asn Val Ser Ser Ala Phe Glu Lys
145 150 155 160
Cys His Pro Trp Thr Ser Cys Glu Thr Lys Asp Leu Val Val Gln Gln
165 170 175
Ala Gly Thr Asn Lys Thr Asp Val Val Cys Gly Pro Gln Asp Arg Leu
180 185 190
Arg Ala Leu Val Val Ile Pro Ile Ile Phe Gly Ile Leu Phe Ala Ile
195 200 205
Leu Leu Val Leu Val Phe Ile Lys Lys Val Ala Lys Lys Pro Thr Asn
210 215 220
Lys Ala Pro His Pro Lys Gln Glu Pro Gln Glu Ile Asn Phe Pro Asp
225 230 235 240
Asp Leu Pro Gly Ser Asn Thr Ala Ala Pro Val Gln Glu Thr Leu His
245 250 255
Gly Cys Gln Pro Val Thr Gln Glu Asp Gly Lys Glu Ser Arg Ile Ser
260 265 270
Val Gln Glu Arg Gln
275
<210> 22
<211> 239
<212> PRT
<213> Macaca fascicularis
<400> 22
Met Val Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu
1 5 10 15
Val Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly
20 25 30
Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile
35 40 45
Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr
50 55 60
Leu Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His Met Lys
65 70 75 80
Lys His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln Glu
85 90 95
Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu
100 105 110
Val Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly
115 120 125
Ile Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr
130 135 140
Asn Tyr Asn Ser His Asn Val Tyr Ile Met Ala Asp Lys Gln Lys Asn
145 150 155 160
Gly Ile Lys Ala Asn Phe Lys Val Arg His Asn Ile Glu Asp Gly Ser
165 170 175
Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly Asp Gly
180 185 190
Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser Ala Leu
195 200 205
Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu Glu Phe
210 215 220
Val Thr Ala Ala Gly Ile Thr Leu Gly Met Asp Glu Leu Tyr Lys
225 230 235
<210> 23
<211> 261
<212> PRT
<213> Homo sapiens
<400> 23
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 24
<211> 329
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 24
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 25
<211> 326
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成多肽
<400> 25
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Glu His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Phe Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly Lys
325
Claims (20)
1.结合CD40蛋白的抗体或其抗原结合部分,所述抗体或其抗原结合部分包含选自氨基酸序列SEQ ID NO:1-3、11、12或其任何变体的重链CDR,和/或选自氨基酸序列SEQ ID NO:6-8、16-18或其任何变体的轻链CDR,以及重链恒定区;所述重链恒定区包含如SEQ ID NO:25或其任何变体所示的氨基酸序列。
2.根据权利要求1所述的抗体或其抗原结合部分,所述抗体或其抗原结合部分依赖于与Fc受体的结合激活CD40,从而激活DC细胞;优选地,所述Fc受体为FcγRIIB。
3.根据权利要求1或2所述的抗体或其抗原结合部分,所述抗体或其抗原结合部分包含选自氨基酸序列SEQ ID NO:1、11或其任何变体的重链CDR1,选自氨基酸序列SEQ ID NO:2、12或其任何变体的重链CDR2,选自氨基酸序列SEQ ID NO:3或其任何变体的重链CDR3;和/或选自氨基酸序列SEQ ID NO:6、16或其任何变体的轻链CDR1,选自氨基酸序列SEQ ID NO:7、17或其任何变体的轻链CDR2,选自氨基酸序列SEQ ID NO:8、18或其任何变体的轻链CDR3。
4.根据权利要求1-3任一项所述的抗体或其抗原结合部分,所述抗体或其抗原结合部分包含选自氨基酸序列SEQ ID NO:4、14或其任何变体的重链可变区,和/或选自氨基酸序列SEQ ID NO:9、19或其任何变体的轻链可变区。
5.根据权利要求1-4任一项所述的抗体或其抗原结合部分,所述抗体或其抗原结合部分包含选自下列的重链和轻链的CDR组合:
(1)分别包含SEQ ID NO:1-3的重链CDR1、CDR2及CDR3序列,和/或分别包含EQ ID NO:6-8的轻链CDR1、CDR2及CDR3序列;
(2)分别包含SEQ ID NO:1-3的重链CDR1、CDR2及CDR3序列,和/或分别包含EQ ID NO:16-18的轻链CDR1、CDR2及CDR3序列;
(3)分别包含SEQ ID NO:11、12、3的重链CDR1、CDR2及CDR3序列,和/或分别包含EQ IDNO:6-8的轻链CDR1、CDR2及CDR3序列;
(4)分别包含SEQ ID NO:11、12、3的重链CDR1、CDR2及CDR3序列,和/或分别包含EQ IDNO:16-18的轻链CDR1、CDR2及CDR3序列。
6.根据权利要求1-5任一项所述的抗体或其抗原结合部分,所述抗体或其抗原结合部分是人源化的。
7.根据权利要求1-6任一项所述的抗体或其抗原结合部分,所述抗体或其抗原结合部分包含氨基酸序列SEQ ID NO:13或其任何变体所示的轻链恒定区。
8.根据权利要求1-7任一项所述的抗体或其抗原结合部分,所述重链恒定区为人lgG2亚型。
9.根据权利要求1-8任一项所述的抗体或其抗原结合部分,其包含氨基酸序列SEQ IDNO:5、15或其任何变体所示的重链氨基酸序列,和/或SEQ ID NO:10、20或其任何变体所示的轻链氨基酸序列。
10.根据权利要求1-9任一项所述的抗体或其抗原结合部分,所述抗体或其抗原结合部分能阻断CD40与其配体的结合。
11.一种抗原受体,其特征在于,包括:特异性识别CD40蛋白的抗原结合结构域,所述抗原结合结构域为权利要求1-10任一项所述的抗体或其抗原结合部分。
12.编码权利要求1-10任一项所述的抗体或其抗原结合部分或权利要求11所述的抗原受体的核酸分子,或与其具有至少大于60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或更高的序列同一性的核酸分子。
13.含有权利要求12所述核酸分子的载体。
14.含有权利要求13所述的载体的细胞或试剂盒。
15.含有权利要求1-10任一项所述的抗体或其抗原结合部分、权利要求11所述的抗原受体、权利要求12所述的核酸分子、权利要求13所述的载体或权利要求14所述的细胞或试剂盒的药物组合物。
16.权利要求1-10任一项所述的抗体或其抗原结合部分、权利要求11所述的抗原受体、权利要求12所述的核酸分子、权利要求13所述的载体、权利要求14所述的细胞或试剂盒或权利要求15所述的药物组合物在制备用于治疗与CD40相关的疾病的药物或试剂盒中的用途;优选地,所述与CD40相关的疾病包括肿瘤和感染。
17.根据权利要求16所述的用途,所述肿瘤包括实体肿瘤和血液肿瘤。
18.根据权利要求17所述的用途,所述血液肿瘤包括白血病、淋巴瘤和骨髓瘤。
19.根据权利要求16所述的用途,所述与CD40相关疾病包括结直肠癌、结肠癌、膀胱癌、乳腺癌、子宫/***、卵巢癌、***癌、睾丸癌、食管癌、胃肠癌、胰腺癌、肾癌、头颈癌、肺癌、胃癌、生殖细胞癌、骨癌、肝癌、甲状腺癌、皮肤癌、中枢神经***的肿瘤、淋巴瘤、白血病、骨髓瘤、肉瘤和黑色素瘤。
20.根据权利要求16所述的用途,所述感染包括病毒感染、细菌感染、真菌感染和寄生虫感染。
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