CN117229396A - 抗cd40抗体及其用途 - Google Patents
抗cd40抗体及其用途 Download PDFInfo
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- CN117229396A CN117229396A CN202210629717.7A CN202210629717A CN117229396A CN 117229396 A CN117229396 A CN 117229396A CN 202210629717 A CN202210629717 A CN 202210629717A CN 117229396 A CN117229396 A CN 117229396A
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Abstract
本发明涉及特异性结合CD40的抗体或其抗原结合片段以及含有所述抗体或其抗原结合片段的组合物。此外,此发明涉及编码所述抗体或其抗原结合片段的核酸及包含其的宿主细胞,以及相关用途。此外,此发明涉及这些抗体或其抗原结合片段的治疗和检测用途。
Description
技术领域
本发明涉及特异性结合CD40的抗体或其抗原结合片段以及含有所述抗体或其抗原结合片段的组合物。此外,此发明涉及编码所述抗体或其抗原结合片段的核酸及包含其的宿主细胞,以及相关用途。此外,此发明涉及这些抗体或其抗原结合片段的治疗和检测用途。
背景技术
CD40,也称为TNFRSF5,是TNF受体超家族蛋白成员,在多种细胞类型上均有表达,包括免疫B细胞、抗原呈递细胞(APC)及一些肿瘤细胞。CD40前体含有297aa,为I型跨膜糖蛋白,由N端信号肽(20aa)、胞膜外区(193aa)、跨膜区(22aa)和胞浆区(62aa)组成。胞膜外区包含4个CDR,共有22个半胱氨酸。CD40的糖基化程度较高,根据氨基酸序列推算的分子量为28kD,但糖基化后的分子量是40-50kD。
CD40的同源配体是CD154(TNFSF5/CD40L),其为一种39kDa的II型跨膜蛋白。CD40L的表达通常可诱导并局限于造血系统的细胞,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。
大量研究证实CD40-CD40L在免疫反应中对CD8细胞毒性T淋巴细胞(CTL)功能起着至关重要的作用,是适应性免疫应答所必需的。
CD40在单核细胞及其成熟子代DC细胞和巨噬细胞以及B细胞上的广泛表达,对于免疫细胞的功能发挥起着重要的作用。单核细胞是固有免疫前体细胞,具有很高的可塑性。它们具有分化为多种细胞类型的能力,如髓源性抑制细胞(MDSC)、巨噬细胞和DC细胞。CD40信号是单核细胞成熟过程的重要触发因素,主要驱动分化为M1谱系的巨噬细胞和DC细胞。CD40与DC细胞表面的结合促进了细胞因子和趋化因子的产生,诱导共刺激分子的表达,并促进抗原的交叉呈递。CD40L的主要功能之一是通过激活DC细胞来增强抗原对T细胞的提呈。这一步称为“许可”,通过上调表面蛋白如CD54和CD86,增加DC与T细胞的相互作用,从而激活后者。
B细胞也是CD40L活性的靶点。B细胞与活化的表达CD40L的T细胞的相互作用增加了MHC-II和CD80或CD86等共刺激分子的表达,并诱导B细胞中的Ig类别转换。活化的B细胞迁移到淋巴器官,在那里向T细胞呈递抗原,CD40激活的DC和B细胞通过释放免疫刺激性细胞因子和趋化因子如IL-12p70、CXCL10和TNFα来支持免疫应答。此外,CD40活化的B细胞能够通过促进TNFα和IFNγ等细胞因子的分泌来诱导抗原特异性CD8+T细胞。一些研究证明,体外活化的表达CD40的B细胞是完全功能性抗原提呈的B细胞,随后用这些细胞进行过继细胞转移(ACT)治疗可提高抗肿瘤的疗效。
由于CD40在抗肿瘤免疫反应中发挥关键作用,诱导CD40信号的各种策略已经被广泛地研究探索。目前针对CD40的药物研发可以分为激活(激动剂)或抑制(拮抗剂),以分别应对需要增强免疫活性的癌症环境及需要抑制免疫系统的自身免疫疾病环境。然而作为单剂治疗法,CD40抗体仅显示出适度的活性,肿瘤客观反应率低于20%,在免疫反应不足的“冷肿瘤”或在免疫细胞尚未高度浸润的肿瘤中尤为如此,许多CD40单抗项目因此陷入停滞。
鉴于CD40在肿瘤免疫反应中的重要作用,CD40被认为是一个极具吸引力的肿瘤免疫治疗靶点。因此,本领域存在开发新的CD40抗体需求,尤其是开发出不同表位的CD40抗体,阻断和非阻断配体CD40L的结合,在肿瘤免疫和自身性免疫疾病中都存在着不同的应用潜力,结合考虑临床上的组合疗法,用于疾病治疗,尤其是癌症治疗。
发明内容
本申请的发明人经过大量的研究,筛选获得了系列抗CD40的全人源抗体,其与CD40的结合亲和力高,具备与人、食蟹猴CD40的交叉反应活性,可阻断或者非阻断人CD40与其配体CD40L结合。基于此,本申请还提供了含有所述抗体或其抗原结合片段的组合物,编码所述抗体或其抗原结合片段的核酸及包含其的宿主细胞,以及相关用途。
抗体或其抗原结合片段
因此,在一方面,本申请提供了能够特异性结合CD40的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含:
(1)下述3个重链可变区(VH)互补决定区(CDR):
(a)VH CDR1,其具有选自以下的结构:
FTFX1X2YX3MH(SEQ ID NO:76),GSISSYYWS(SEQ ID NO:6);
(b)VH CDR2,其具有选自以下的结构:
VIX4YX5X6X7X8KYYAX9SVKG(SEQ ID NO:77),GISWSSX10SIX11YADSVKG(SEQ ID NO:78),SIYYSGSTNYNPSLKS(SEQ ID NO:22);
(c)VH CDR3,其具有选自以下的结构:
ARDTSRGHDI(SEQ ID NO:23),AKDPTATTGARGYFDL(SEQ ID NO:24),ARDANYYKWHPY(SEQ ID NO:25);
和/或,
(2)下述3个轻链可变区(VL)CDR:
(d)VL CDR1,其具有选自以下的结构:
X12ASQSVSX13X14YLA(SEQ ID NO:79),X15ASX16X17ISSWLA(SEQ ID NO:7);
(e)VL CDR2,其具有选自以下的结构:
GASX18X19X20X21(SEQ ID NO:8),AASX22LX23S(SEQ ID NO:9);
(f)VL CDR3,其具有选自以下的结构:
X24X25YX26DYPPFT(SEQ ID NO:10),QQX27X28SX29PPT(SEQ ID NO:11);
其中,
X1选自(i)氨基酸残基S,E,G,D和(ii)相对于(i)是保守置换的氨基酸残基;
X2选自(i)氨基酸残基S,K,D,T和(ii)相对于(i)是保守置换的氨基酸残基;
X3选自(i)氨基酸残基G,A和(ii)相对于(i)是保守置换的氨基酸残基;
X4选自(i)氨基酸残基S,H和(ii)相对于(i)是保守置换的氨基酸残基;
X5选自(i)氨基酸残基E,H和(ii)相对于(i)是保守置换的氨基酸残基;
X6选自(i)氨基酸残基G,A和(ii)相对于(i)是保守置换的氨基酸残基;
X7选自(i)氨基酸残基S,E,T,V和(ii)相对于(i)是保守置换的氨基酸残基;
X8选自(i)氨基酸残基N,S,I,K和(ii)相对于(i)是保守置换的氨基酸残基;
X9选自(i)氨基酸残基D,E和(ii)相对于(i)是保守置换的氨基酸残基;
X10选自(i)氨基酸残基G,D和(ii)相对于(i)是保守置换的氨基酸残基;
X11选自(i)氨基酸残基G,H和(ii)相对于(i)是保守置换的氨基酸残基;
X12选自(i)氨基酸残基R,Q和(ii)相对于(i)是保守置换的氨基酸残基;
X13选自(i)氨基酸残基Y,S和(ii)相对于(i)是保守置换的氨基酸残基;
X14选自(i)氨基酸残基S,D,N和(ii)相对于(i)是保守置换的氨基酸残基;
X15选自(i)氨基酸残基R,E和(ii)相对于(i)是保守置换的氨基酸残基;
X16选自(i)氨基酸残基Q,K和(ii)相对于(i)是保守置换的氨基酸残基;
X17选自(i)氨基酸残基G,V和(ii)相对于(i)是保守置换的氨基酸残基;
X18选自(i)氨基酸残基S,T,A和(ii)相对于(i)是保守置换的氨基酸残基;
X19选自(i)氨基酸残基R,L和(ii)相对于(i)是保守置换的氨基酸残基;
X20选自(i)氨基酸残基N,A和(ii)相对于(i)是保守置换的氨基酸残基;
X21选自(i)氨基酸残基T,N和(ii)相对于(i)是保守置换的氨基酸残基;
X22选自(i)氨基酸残基S,Y和(ii)相对于(i)是保守置换的氨基酸残基;
X23选自(i)氨基酸残基E,Q和(ii)相对于(i)是保守置换的氨基酸残基;
X24选自(i)氨基酸残基S,G,Q和(ii)相对于(i)是保守置换的氨基酸残基;
X25选自(i)氨基酸残基E,Q,D和(ii)相对于(i)是保守置换的氨基酸残基;
X26选自(i)氨基酸残基A,S和(ii)相对于(i)是保守置换的氨基酸残基;
X27选自(i)氨基酸残基R,H,V和(ii)相对于(i)是保守置换的氨基酸残基;
X28选自(i)氨基酸残基S,L,A和(ii)相对于(i)是保守置换的氨基酸残基;
X29选自(i)氨基酸残基F,Y和(ii)相对于(i)是保守置换的氨基酸残基。
(ADI-47754族)
在某些实施方案中,所述抗体或其抗原结合片段包含:
(1)下述3个重链可变区(VH)互补决定区(CDR):
(a)VH CDR1,其具有如FTFX1X2YX3MH(SEQ ID NO:76)所示的结构;
(b)VH CDR2,其具有如VIX4YX5X6X7X8KYYAX9SVKG(SEQ ID NO:77)所示的结构;
(c)VH CDR3,其具有如ARDTSRGHDI(SEQ ID NO:23)所示的结构;
和/或,
(2)下述3个轻链可变区(VL)CDR:
(d)VL CDR1,其具有如X12ASQSVSX13X14YLA(SEQ ID NO:79)所示的结构;
(e)VL CDR2,其具有如GASX18X19X20X21(SEQ ID NO:8)所示的结构;
(f)VL CDR3,其具有如X24X25YX26DYPPFT(SEQ ID NO:10)所示的结构;
其中,
X1选自(i)氨基酸残基S,E,G和(ii)相对于(i)是保守置换的氨基酸残基;
X2选自(i)氨基酸残基S,K和(ii)相对于(i)是保守置换的氨基酸残基;
X3选自(i)氨基酸残基G和(ii)相对于(i)是保守置换的氨基酸残基;
X4选自(i)氨基酸残基S,H和(ii)相对于(i)是保守置换的氨基酸残基;
X5选自(i)氨基酸残基E,H和(ii)相对于(i)是保守置换的氨基酸残基;
X6选自(i)氨基酸残基G,A和(ii)相对于(i)是保守置换的氨基酸残基;
X7选自(i)氨基酸残基S,E,T,V和(ii)相对于(i)是保守置换的氨基酸残基;
X8选自(i)氨基酸残基N,S,I,K和(ii)相对于(i)是保守置换的氨基酸残基;
X9选自(i)氨基酸残基D,E和(ii)相对于(i)是保守置换的氨基酸残基;
X12选自(i)氨基酸残基R,Q和(ii)相对于(i)是保守置换的氨基酸残基;
X13选自(i)氨基酸残基Y,S和(ii)相对于(i)是保守置换的氨基酸残基;
X14选自(i)氨基酸残基S,D,N和(ii)相对于(i)是保守置换的氨基酸残基;
X18选自(i)氨基酸残基S,T,A和(ii)相对于(i)是保守置换的氨基酸残基;
X19选自(i)氨基酸残基R,L和(ii)相对于(i)是保守置换的氨基酸残基;
X20选自(i)氨基酸残基N,A和(ii)相对于(i)是保守置换的氨基酸残基;
X21选自(i)氨基酸残基T,N和(ii)相对于(i)是保守置换的氨基酸残基;
X24选自(i)氨基酸残基S,G,Q和(ii)相对于(i)是保守置换的氨基酸残基;
X25选自(i)氨基酸残基E,Q,D和(ii)相对于(i)是保守置换的氨基酸残基;
X26选自(i)氨基酸残基A,S和(ii)相对于(i)是保守置换的氨基酸残基。
在某些实施方案中,X1选自氨基酸残基S,E,G;X2选自氨基酸残基S,K;X3为氨基酸残基G;X4选自氨基酸残基S,H;X5选自氨基酸残基E,H;X6选自氨基酸残基G,A;X7选自氨基酸残基S,E,T,V;X8选自氨基酸残基N,S,I,K;X9选自氨基酸残基D,E;X12选自氨基酸残基R,Q;X13选自氨基酸残基Y,S;X14选自氨基酸残基S,D,N;X18选自氨基酸残基S,T,A;X19选自氨基酸残基R,L;X20选自氨基酸残基N,A;X21选自氨基酸残基T,N;X24选自氨基酸残基S,G,Q;X25选自氨基酸残基E,Q,D;X26选自氨基酸残基A,S。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NOs:1-3任一项所示的VH CDR1;如SEQ ID NOs:12-18、82任一项所示的VH CDR2;以及,如SEQ ID NO:23所示的VH CDR3;如SEQ ID NOs:37-40任一项所示的VL CDR1;如SEQ ID NOs:45-50任一项所示的VL CDR2;以及,如SEQ ID NOs:54-57任一项所示的VL CDR3。
在某些实施方案中,所述抗体或其抗原结合片段包含:
(1)如SEQ ID NO:1所示的VH CDR1;如SEQ ID NO:12所示的VH CDR2;以及,如SEQID NO:23所示的VH CDR3;如SEQ ID NO:37所示的VL CDR1;如SEQ ID NO:45所示的VLCDR2;以及,如SEQ ID NO:54所示的VL CDR3;
(2)如SEQ ID NO:1所示的VH CDR1;如SEQ ID NO:13所示的VH CDR2;以及,如SEQID NO:23所示的VH CDR3;如SEQ ID NO:37所示的VL CDR1;如SEQ ID NO:45所示的VLCDR2;以及,如SEQ ID NO:54所示的VL CDR3;
(3)如SEQ ID NO:2所示的VH CDR1;如SEQ ID NO:14所示的VH CDR2;以及,如SEQID NO:23所示的VH CDR3;如SEQ ID NO:38所示的VL CDR1;如SEQ ID NO:46所示的VLCDR2;以及,如SEQ ID NO:55所示的VL CDR3;
(4)如SEQ ID NO:2所示的VH CDR1;如SEQ ID NO:15所示的VH CDR2;以及,如SEQID NO:23所示的VH CDR3;如SEQ ID NO:39所示的VL CDR1;如SEQ ID NO:47所示的VLCDR2;以及,如SEQ ID NO:56所示的VL CDR3;
(5)如SEQ ID NO:2所示的VH CDR1;如SEQ ID NO:16所示的VH CDR2;以及,如SEQID NO:23所示的VH CDR3;如SEQ ID NO:39所示的VL CDR1;如SEQ ID NO:48所示的VLCDR2;以及,如SEQ ID NO:57所示的VL CDR3;
(6)如SEQ ID NO:2所示的VH CDR1;如SEQ ID NO:17所示的VH CDR2;以及,如SEQID NO:23所示的VH CDR3;如SEQ ID NO:40所示的VL CDR1;如SEQ ID NO:49所示的VLCDR2;以及,如SEQ ID NO:57所示的VL CDR3;
(7)如SEQ ID NO:3所示的VH CDR1;如SEQ ID NO:18所示的VH CDR2;以及,如SEQID NO:23所示的VH CDR3;如SEQ ID NO:38所示的VL CDR1;如SEQ ID NO:50所示的VLCDR2;以及,如SEQ ID NO:54所示的VL CDR3;
或者,
(8)如SEQ ID NO:2所示的VH CDR1;如SEQ ID NO:82所示的VH CDR2;以及,如SEQID NO:23所示的VH CDR3;如SEQ ID NO:39所示的VL CDR1;如SEQ ID NO:48所示的VLCDR2;以及,如SEQ ID NO:57所示的VL CDR3。
在某些实施方案中,所述抗体或其抗原结合片段进一步包含人免疫球蛋白的框架区。例如,所述抗体或其抗原结合片段包含人胚系抗体基因所编码的氨基酸序列中所包含的框架区;例如,所述抗体或其抗原结合片段包含:人重链胚系基因所编码的氨基酸序列中所包含的重链框架区,和/或人轻链胚系基因所编码的氨基酸序列中所包含的轻链框架区。
在某些实施方案中,所述抗体或其抗原结合片段包含:
(1)重链可变区(VH),其包含选自下列的氨基酸序列:
(i)如SEQ ID NOs:26-32、83任一项所示的序列;
(ii)与SEQ ID NOs:26-32、83任一项所示的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加)的序列;或
(iii)与SEQ ID NOs:26-32、83任一项所示的序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列;
和/或,
(2)轻链可变区(VL),其包含选自下列的氨基酸序列:
(i)如SEQ ID NOs:61-66任一项所示的序列;
(ii)与SEQ ID NOs:61-66任一项所示的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加)的序列;或
(iii)与SEQ ID NOs:61-66任一项所示的序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NOs:26-32、83任一项所示的序列或其变体的VH,和,包含如SEQ ID NOs:61-66任一项所示的序列或其变体的VL;
其中,所述变体与其所源自的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加),或具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列。在某些实施方案中,所述的置换是保守置换。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NO:26所示的序列或其变体的VH,和,如SEQ ID NO:61所示的序列或其变体的VL。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NO:27所示的序列或其变体的VH,和,如SEQ ID NO:61所示的序列或其变体的VL。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NO:28所示的序列或其变体的VH,和,如SEQ ID NO:62所示的序列或其变体的VL。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NO:29所示的序列或其变体的VH,和,如SEQ ID NO:63所示的序列或其变体的VL。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NO:30所示的序列或其变体的VH,和,如SEQ ID NO:64所示的序列或其变体的VL。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NO:31所示的序列或其变体的VH,和,如SEQ ID NO:65所示的序列或其变体的VL。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NO:32所示的序列或其变体的VH,和,如SEQ ID NO:66所示的序列或其变体的VL。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NO:83所示的序列或其变体的VH,和,如SEQ ID NO:64所示的序列或其变体的VL。
其中,所述变体与其所源自的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加),或具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列。在某些实施方案中,所述的置换是保守置换。
在某些实施方案中,所述抗体或其抗原结合片段能够阻断人CD40与其配体CD40L的结合。
(ADI-47720族)
在某些实施方案中,所述抗体或其抗原结合片段包含:
(1)下述3个重链可变区(VH)互补决定区(CDR):
(a)VH CDR1,其具有如FTFX1X2YX3MH(SEQ ID NO:76)所示的结构;
(b)VH CDR2,其具有如GISWSSX10SIX11YADSVKG(SEQ ID NO:78)所示的结构;
(c)VH CDR3,其具有如AKDPTATTGARGYFDL(SEQ ID NO:24)所示的结构;
和/或,
(2)下述3个轻链可变区(VL)CDR:
(d)VL CDR1,其具有如X15ASX16X17ISSWLA(SEQ ID NO:7)所示的结构;
(e)VL CDR2,其具有如AASX22LX23S(SEQ ID NO:9)所示的结构;
(f)VL CDR3,其具有如QQX27X28SX29PPT(SEQ ID NO:11)所示的结构;
其中,
X1选自(i)氨基酸残基D和(ii)相对于(i)是保守置换的氨基酸残基;
X2选自(i)氨基酸残基D,T和(ii)相对于(i)是保守置换的氨基酸残基;
X3选自(i)氨基酸残基A和(ii)相对于(i)是保守置换的氨基酸残基;
X10选自(i)氨基酸残基G,D和(ii)相对于(i)是保守置换的氨基酸残基;
X11选自(i)氨基酸残基G,H和(ii)相对于(i)是保守置换的氨基酸残基;
X15选自(i)氨基酸残基R,E和(ii)相对于(i)是保守置换的氨基酸残基;
X16选自(i)氨基酸残基Q,K和(ii)相对于(i)是保守置换的氨基酸残基;
X17选自(i)氨基酸残基G,V和(ii)相对于(i)是保守置换的氨基酸残基;
X22选自(i)氨基酸残基S,Y和(ii)相对于(i)是保守置换的氨基酸残基;
X23选自(i)氨基酸残基E,Q和(ii)相对于(i)是保守置换的氨基酸残基;
X27选自(i)氨基酸残基R,H和(ii)相对于(i)是保守置换的氨基酸残基;
X28选自(i)氨基酸残基S,A和(ii)相对于(i)是保守置换的氨基酸残基;
X29选自(i)氨基酸残基F和(ii)相对于(i)是保守置换的氨基酸残基。
在某些实施方案中,X1为氨基酸残基D;X2选自氨基酸残基D,T;X3为氨基酸残基A;X10选自氨基酸残基G,D;X11选自氨基酸残基G,H;X15选自氨基酸残基R,E;X16选自氨基酸残基Q,K;X17选自氨基酸残基G,V;X22选自氨基酸残基S,Y;X23选自氨基酸残基E,Q;X27选自氨基酸残基R,H;X28选自氨基酸残基S,A;X29为氨基酸残基F。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NOs:4或5所示的VH CDR1;如SEQ ID NOs:19-21任一项所示的VH CDR2;以及,如SEQ ID NO:24所示的VHCDR3;如SEQ ID NOs:41-43任一项所示的VL CDR1;如SEQ ID NOs:51-53任一项所示的VLCDR2;以及,如SEQ ID NOs:58或59所示的VL CDR3。
在某些实施方案中,所述抗体或其抗原结合片段包含:
(1)如SEQ ID NO:4所示的VH CDR1;如SEQ ID NO:19所示的VH CDR2;以及,如SEQID NO:24所示的VH CDR3;如SEQ ID NO:41所示的VL CDR1;如SEQ ID NO:51所示的VLCDR2;以及,如SEQ ID NO:58所示的VL CDR3;
(2)如SEQ ID NO:4所示的VH CDR1;如SEQ ID NO:20所示的VH CDR2;以及,如SEQID NO:24所示的VH CDR3;如SEQ ID NO:42所示的VL CDR1;如SEQ ID NO:52所示的VLCDR2;以及,如SEQ ID NO:59所示的VL CDR3;
或者,
(3)如SEQ ID NO:5所示的VH CDR1;如SEQ ID NO:21所示的VH CDR2;以及,如SEQID NO:24所示的VH CDR3;如SEQ ID NO:43所示的VL CDR1;如SEQ ID NO:53所示的VLCDR2;以及,如SEQ ID NO:59所示的VL CDR3。
在某些实施方案中,所述抗体或其抗原结合片段进一步包含人免疫球蛋白的框架区。例如,所述抗体或其抗原结合片段包含人胚系抗体基因所编码的氨基酸序列中所包含的框架区;例如,所述抗体或其抗原结合片段包含:人重链胚系基因所编码的氨基酸序列中所包含的重链框架区,和/或人轻链胚系基因所编码的氨基酸序列中所包含的轻链框架区。
在某些实施方案中,所述抗体或其抗原结合片段包含:
(1)重链可变区(VH),其包含选自下列的氨基酸序列:
(i)如SEQ ID NOs:33-35任一项所示的序列;
(ii)与SEQ ID NOs:33-35任一项所示的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加)的序列;或
(iii)与SEQ ID NOs:33-35任一项所示的序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列;
和/或,
(2)轻链可变区(VL),其包含选自下列的氨基酸序列:
(i)如SEQ ID NOs:67-69任一项所示的序列;
(ii)与SEQ ID NOs:67-69任一项所示的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加)的序列;或
(iii)与SEQ ID NOs:67-69任一项所示的序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NOs:33-35任一项所示的序列或其变体的VH,和,包含如SEQ ID NOs:67-69任一项所示的序列或其变体的VL;
其中,所述变体与其所源自的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加),或具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列。在某些实施方案中,所述的置换是保守置换。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NO:33所示的序列或其变体的VH,和,如SEQ ID NO:67所示的序列或其变体的VL。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NO:34所示的序列或其变体的VH,和,如SEQ ID NO:68所示的序列或其变体的VL。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NO:35所示的序列或其变体的VH,和,如SEQ ID NO:69所示的序列或其变体的VL。
其中,所述变体与其所源自的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加),或具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列。在某些实施方案中,所述的置换是保守置换。
在某些实施方案中,所述抗体或其抗原结合片段非阻断人CD40与其配体CD40L的结合。
(ADI-47741族)
在某些实施方案中,所述抗体或其抗原结合片段包含:
(1)下述3个重链可变区(VH)互补决定区(CDR):
(a)VH CDR1,其具有如GSISSYYWS(SEQ ID NO:6)所示的结构;
(b)VH CDR2,其具有如SIYYSGSTNYNPSLKS(SEQ ID NO:22)所示的结构;
(c)VH CDR3,其具有如ARDANYYKWHPY(SEQ ID NO:25)所示的结构;
和/或,
(2)下述3个轻链可变区(VL)CDR:
(d)VL CDR1,其具有如X12ASQSVSX13X14YLA(SEQ ID NO:79)所示的结构;
(e)VL CDR2,其具有如GASX18X19X20X21(SEQ ID NO:8)所示的结构;
(f)VL CDR3,其具有如QQX27X28SX29PPT(SEQ ID NO:11)所示的结构;
其中,
X12选自(i)氨基酸残基R和(ii)相对于(i)是保守置换的氨基酸残基;
X13选自(i)氨基酸残基S和(ii)相对于(i)是保守置换的氨基酸残基;
X14选自(i)氨基酸残基D和(ii)相对于(i)是保守置换的氨基酸残基;
X18选自(i)氨基酸残基S和(ii)相对于(i)是保守置换的氨基酸残基;
X19选自(i)氨基酸残基R和(ii)相对于(i)是保守置换的氨基酸残基;
X20选自(i)氨基酸残基A和(ii)相对于(i)是保守置换的氨基酸残基;
X21选自(i)氨基酸残基T和(ii)相对于(i)是保守置换的氨基酸残基;
X27选自(i)氨基酸残基V和(ii)相对于(i)是保守置换的氨基酸残基;
X28选自(i)氨基酸残基L和(ii)相对于(i)是保守置换的氨基酸残基;
X29选自(i)氨基酸残基Y和(ii)相对于(i)是保守置换的氨基酸残基。
在某些实施方案中,X12为氨基酸残基R;X13为氨基酸残基S;X14为氨基酸残基D;X18为氨基酸残基S;X19为氨基酸残基R;X20为氨基酸残基A;X21为氨基酸残基T;X27为氨基酸残基V;X28为氨基酸残基L;X29为氨基酸残基Y。
在某些实施方案中,所述抗体或其抗原结合片段包含如SEQ ID NO:6所示的VHCDR1;如SEQ ID NO:22所示的VH CDR2;以及,如SEQ ID NO:25所示的VH CDR3;如SEQ IDNO:44所示的VL CDR1;如SEQ ID NO:45所示的VL CDR2;以及,如SEQ ID NO:60所示的VLCDR3。
在某些实施方案中,所述抗体或其抗原结合片段进一步包含人免疫球蛋白的框架区。例如,所述抗体或其抗原结合片段包含人胚系抗体基因所编码的氨基酸序列中所包含的框架区;例如,所述抗体或其抗原结合片段包含:人重链胚系基因所编码的氨基酸序列中所包含的重链框架区,和/或人轻链胚系基因所编码的氨基酸序列中所包含的轻链框架区。
在某些实施方案中,所述抗体或其抗原结合片段包含:
(1)重链可变区(VH),其包含选自下列的氨基酸序列:
(i)如SEQ ID NO:36所示的序列;
(ii)与SEQ ID NO:36所示的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加)的序列;或
(iii)与SEQ ID NO:36所示的序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列;
和/或,
(2)轻链可变区(VL),其包含选自下列的氨基酸序列:
(i)如SEQ ID NO:70任一项所示的序列;
(ii)与SEQ ID NO:70所示的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加)的序列;或
(iii)与SEQ ID NO:70所示的序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列。
在某些实施方案中,所述抗体或其抗原结合片段包含
如SEQ ID NO:36所示的序列或其变体的VH,和,包含如SEQ ID NO:70所示的序列或其变体的VL;
其中,所述变体与其所源自的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加),或具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列。在某些实施方案中,所述的置换是保守置换。
在某些实施方案中,所述抗体或其抗原结合片段能够阻断人CD40与其配体CD40L的结合。
在某些实施方案中,所述抗体或其抗原结合片段进一步包含来源于人免疫球蛋白的恒定区。
在某些实施方案中,所述抗体或其抗原结合片段的重链包含人免疫球蛋白的重链恒定区(CH)或其变体,所述变体与其所源自的序列相比具有一个或多个氨基酸的置换、缺失或添加(例如,至多20个、至多15个、至多10个、或至多5个氨基酸的置换、缺失或添加;例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加);和/或,
所述抗体或其抗原结合片段的轻链包含人免疫球蛋白的轻链恒定区(CL)或其变体,所述变体与其所源自的序列相比具有至多20个氨基酸的保守置换(例如至多15个、至多10个、或至多5个氨基酸的保守置换;例如1个,2个,3个,4个或5个氨基酸的保守置换)。
在一些实施方案中,所述重链恒定区(CH)的变体与其所源自的序列相比可以具有一个或多个氨基酸的保守置换。在此类实施方案中,所述重链恒定区(CH)的变体与其所源自的野生型序列相比可以具有相同或基本相同的效应子功能。
在另一些实施方案中,所述重链恒定区(CH)的变体可以包含一个或多个氨基酸突变或化学修饰以改变本发明抗体的下列中的一个或更多个特性:Fc受体结合、抗体糖基化、半胱氨酸残基的数目、效应细胞功能或补体功能等。可以通过将抗体恒定区中的至少一个氨基酸残基替换为不同残基或化学修饰,产生功能改变,例如,改变抗体对效应子配体(如FcR或补体C1q)的亲和力,从而改变效应子功能(例如降低或增强)。抗体的Fc区介导几种重要的效应子功能,例如ADCC、吞噬作用、CDC等。
在某些实施方案中,所述抗体或其抗原结合片段具备ADCC活性。在某些实施方案中,所述抗体或其抗原结合片段包含突变的(例如氨基酸置换)或化学修饰的Fc区,其中所述突变的或化学修饰的Fc区与野生型Fc区相比提供增加的ADCC活性。在某些实施方案中,所述抗体或其抗原结合片段通过在具有低或无岩藻糖基化活性的宿主细胞中表达来生产,所产生的抗体具有低岩藻糖基化或无岩藻糖基化,进而增加其ADCC活性。此类宿主细胞可以是缺乏表达编码岩藻糖基转移酶(例如FUT8)基因的哺乳动物细胞,例如CHO细胞。
在某些实施方案中,所述抗体或其抗原结合片段的重链包含来源于人免疫球蛋白(例如IgG1、IgG2、IgG3或IgG4)的重链恒定区。
在某些示例性实施方案中,所述抗体或其抗原结合片段的重链包含如SEQ ID NO:155所示的重链恒定区。
在某些实施方案中,所述抗体或其抗原结合片段的轻链包含来源于人免疫球蛋白(例如κ或λ)的轻链恒定区。
在某些示例性实施方案中,所述抗体或其抗原结合片段的轻链包含如SEQ ID NO:156所示的轻链恒定区。
在某些实施方案中,所述抗体或其抗原结合片段中,所述抗原结合片段选自Fab、Fab’、(Fab’)2、Fv、二硫键连接的Fv、scFv、双抗体(diabody)和单域抗体(sdAb);和/或,所述抗体为嵌合抗体、双特异性抗体或多特异性抗体。
在某些实施方案中,所述抗体或其抗原结合片段具备与人、食蟹猴CD40的交叉反应活性。
本发明的抗体可以本领域已知的各种方法来制备,例如通过基因工程重组技术来获得。例如,通过化学合成或PCR扩增获得编码本发明抗体的重链和轻链基因的DNA分子。将所得DNA分子插入表达载体内,然后转染宿主细胞。然后,在特定条件下培养转染后的宿主细胞,并表达本发明的抗体。
本发明的抗原结合片段可以通过水解完整的抗体分子获得(参见Morimoto etal.,J.Biochem.Biophys.Methods 24:107-117(1992)and Brennan et al.,Science 229:81(1985))。另外,这些抗原结合片段也可以直接由重组宿主细胞产生(reviewed inHudson,Curr.Opin.Immunol.11:548-557(1999);Little et al.,Immunol.Today,21:364-370(2000))。比如,Fab’片段可以直接从宿主细胞中获得;可以将Fab’片段化学偶联形成F(ab’)2片段(Carter et al.,Bio/Technology,10:163-167(1992))。另外,Fv、Fab或F(ab’)2片段也可以直接从重组宿主细胞培养液中直接分离得到。本领域的普通技术人员完全知晓制备这些抗原结合片段的其它技术。
分离的核酸分子
在另一方面,本申请还提供了分离的核酸分子,其编码如上所述的抗体或其抗原结合片段,或其重链可变区和/或轻链可变区。
在某些实施方案中,所述分离的核酸分子包含编码本发明的抗体或其抗原结合片段的重链或重链可变区的第一核苷酸序列和编码所述抗体或其抗原结合片段的轻链或轻链可变区的第二核苷酸序列,其中所述第一核苷酸序列和所述第二核苷酸序列存在于相同或不同的分离的核酸分子上。当所述第一核苷酸序列和所述第二核苷酸序列存在于不同的分离的核酸分子上时,本发明所述的分离的核酸分子包含含有所述第一核苷酸序列的第一核酸分子以及含有所述第二核苷酸序列的第二核酸分子。
载体
在另一方面,本申请还提供了载体,其包含如上所述的核酸分子。在某些实施方案中,所述载体为克隆载体或表达载体。
在某些实施方案中,所述载体包含编码本发明的抗体或其抗原结合片段的重链或重链可变区的第一核苷酸序列和编码所述抗体或其抗原结合片段的轻链或轻链可变区的第二核苷酸序列,其中所述第一核苷酸序列和所述第二核苷酸序列存在于相同或不同的载体上。当所述第一核苷酸序列和所述第二核苷酸序列存在于不同的载体上时,本发明所述的载体包含含有所述第一核苷酸序列的第一载体以及含有所述第二核苷酸序列的第二载体。
宿主细胞
在另一方面,本申请还提供了宿主细胞,其包含如上所述的核酸分子或载体。此类宿主细胞包括但不限于,原核细胞例如细菌细胞(如大肠杆菌细胞),以及真核细胞例如真菌细胞(例如酵母细胞),昆虫细胞,植物细胞和动物细胞(如哺乳动物细胞,例如小鼠细胞、人细胞等)。
制备方法
在另一方面,本申请还提供了制备如上所述的抗体或其抗原结合片段的方法,其包括,在允许所述抗体或其抗原结合片段表达的条件下,培养如上所述的宿主细胞,和从培养的宿主细胞培养物中回收所述抗体或其抗原结合片段。
治疗用途
在另一方面,本申请还提供了药物组合物,其包含如上所述的抗体或其抗原结合片段,以及药学上可接受的载体和/或赋形剂。
在某些示例性实施方案中,所述药学上可接受的载体和/或赋形剂包含无菌可注射液体(如水性或非水性悬浮液或溶液)。在某些示例性实施方案中,此类无菌可注射液体选自注射用水(WFI)、抑菌性注射用水(BWFI)、氯化钠溶液(例如0.9%(w/v)NaCl)、葡萄糖溶液(例如5%葡萄糖)、含有表面活性剂的溶液(例如0.01%聚山梨醇20)、pH缓冲溶液(例如磷酸盐缓冲溶液)、Ringer氏溶液及其任意组合。
在另一方面,本申请还提供了如上所述的抗体或其抗原结合片段、分离的核酸分子、载体或宿主细胞用于制备药物的用途,所述药物用于在受试者中激活CD40,提高免疫细胞活性,增强免疫应答,和/或预防和/或治疗肿瘤或者感染。
在某些实施方案中,所述免疫细胞是T细胞,B细胞,DC细胞,巨噬细胞,和/或,NK细胞。
在某些实施方案中,所述免疫应答是CD40介导的免疫应答。
在某些实施方案中,所述肿瘤选自实体肿瘤或血液肿瘤(例如,白血病、淋巴瘤、骨髓瘤)。在某些实施方案中,所述肿瘤选自实体肿瘤或淋巴瘤。
在某些实施方案中,所述肿瘤选自结直肠癌、结肠癌、膀胱癌、乳腺癌、子宫/宫颈癌、卵巢癌、前列腺癌、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、中枢神经系统的肿瘤、淋巴瘤、白血病、骨髓瘤、肉瘤、黑色素瘤。
在某些实施方案中,所述感染选自病毒感染、细菌感染、真菌感染和寄生虫感染。
在某些实施方案中,所述受试者为哺乳动物,例如人。
在某些实施方案中,所述抗体或其抗原结合片段单独使用,或与另外的药学活性剂联合使用。
在另一方面,本申请还提供了一种在受试者中增强免疫应答,和/或,预防和/或治疗肿瘤或感染的方法;所述方法包括:给有此需要的受试者施用有效量的如上所述的抗体或其抗原结合片段或药物组合物。
在某些实施方案中,所述免疫应答是CD40介导的免疫应答。
在某些实施方案中,所述肿瘤选自实体肿瘤或血液肿瘤(例如,白血病、淋巴瘤、骨髓瘤)。在某些实施方案中,所述肿瘤选自实体肿瘤或淋巴瘤。
在某些实施方案中,所述肿瘤选自结直肠癌、结肠癌、膀胱癌、乳腺癌、子宫/宫颈癌、卵巢癌、前列腺癌、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、中枢神经系统的肿瘤、淋巴瘤、白血病、骨髓瘤、肉瘤、黑色素瘤。
在某些实施方案中,所述感染选自病毒感染、细菌感染、真菌感染和寄生虫感染。
在某些实施方案中,所述受试者为哺乳动物,例如人。
本申请的抗体或其抗原结合片段或药物组合物可以配制成医学领域已知的任何剂型,例如,片剂、丸剂、混悬剂、乳剂、溶液、凝胶剂、胶囊剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、吸入剂、喷雾剂等。优选剂型取决于预期的给药方式和治疗用途。本发明的抗体或其抗原结合片段或药物组合物应当是无菌的并在生产和储存条件下稳定。一种优选的剂型是注射剂。此类注射剂可以是无菌注射溶液。例如,可通过下述方法来制备无菌注射溶液:在适当的溶剂中掺入必需剂量的本发明的抗体或其抗原结合片段,以及任选地,同时掺入其他期望的成分(包括但不限于,pH调节剂,表面活性剂,佐剂,离子强度增强剂,等渗剂、防腐剂、稀释剂,或其任何组合),随后过滤除菌。此外,可以将无菌注射溶液制备为无菌冻干粉剂(例如,通过真空干燥或冷冻干燥)以便于储存和使用。此类无菌冻干粉剂可在使用前分散于合适的载体中,例如注射用水(WFI)、抑菌性注射用水(BWFI)、氯化钠溶液(例如0.9%(w/v)NaCl)、葡萄糖溶液(例如5%葡萄糖)、含有表面活性剂的溶液(例如0.01%聚山梨醇20)、pH缓冲溶液(例如磷酸盐缓冲溶液)、Ringer氏溶液及其任意组合。
本申请的抗体或其抗原结合片段、或本发明的药物组合物可以通过本领域已知的任何合适的方法来施用,包括但不限于,口服、口腔、舌下、眼球、局部、肠胃外、直肠、叶鞘内、内胞浆网槽内、腹股沟、膀胱内、局部(如,粉剂、药膏或滴剂),或鼻腔途径。但是,对于许多治疗用途而言,优选的给药途径/方式是胃肠外给药(例如静脉注射或推注,皮下注射,腹膜内注射,肌内注射)。技术人员应理解,给药途径和/或方式将根据预期目的而发生变化。在某些实施方案中,本发明的抗体或其抗原结合片段或药物组合物通过静脉注射或推注给予。
检测用途
在另一方面,本申请还提供了缀合物,其包含如上所述的抗体或其抗原结合片段,以及与所述抗体或其抗原结合片段连接的可检测的标记。
在某些实施方案中,所述可检测的标记选自酶(例如辣根过氧化物酶或碱性磷酸酶)、化学发光试剂(例如吖啶酯类化合物、鲁米诺及其衍生物、或钌衍生物)、荧光染料(例如荧光素或荧光蛋白)、放射性核素或生物素。
在另一方面,本申请还提供了试剂盒,其包括如上所述的抗体或其抗原结合片段或缀合物。
在某些实施方案中,所述试剂盒包含如上所述的缀合物。
在某些实施方案中,所述试剂盒包含如上所述的抗体或其抗原结合片段,以及特异性识别所述抗体或其抗原结合片段的第二抗体。在某些实施方案中,所述第二抗体还包括可检测的标记,例如酶(例如辣根过氧化物酶或碱性磷酸酶)、化学发光试剂(例如吖啶酯类化合物、鲁米诺及其衍生物、或钌衍生物)、荧光染料(例如荧光素或荧光蛋白)、放射性核素或生物素。
在另一方面,本申请还提供了用于检测CD40在样品中的存在或其水平的方法,其包括使用如上所述的抗体或其抗原结合片段或缀合物。在某些实施方案中,所述方法用于治疗目的,诊断目的,或者非治疗非诊断目的。
在某些实施方案中,所述方法是免疫学检测,例如免疫印迹法、酶免疫测定法(例如ELISA)、化学发光免疫分析法、荧光免疫分析法或放射免疫测定法。
在某些实施方案中,所述方法包括使用如上所述的缀合物。
在某些实施方案中,所述方法包括使用如上所述的抗体或其抗原结合片段,并且所述方法还包括使用携带可检测的标记(例如酶(例如辣根过氧化物酶或碱性磷酸酶)、化学发光试剂(例如吖啶酯类化合物、鲁米诺及其衍生物、或钌衍生物)、荧光染料(例如荧光素或荧光蛋白)、放射性核素或生物素)的第二抗体来检测所述抗体或其抗原结合片段。
在某些实施方案中,所述方法包括:(1)将所述样品与本发明的抗体或其抗原结合片段接触;(2)检测抗原-抗体免疫复合物的形成或检测所述免疫复合物的量。所述免疫复合物的形成表明存在CD40或表达CD40的细胞。
在另一方面,本申请提供了如上所述的抗体或其抗原结合片段或缀合物在制备检测试剂中的用途,所述检测试剂用于检测CD40在样品中的存在或其水平。
在某些实施方案中,所述检测试剂通过如上所述的用于检测CD40在样品中的存在或其水平的方法来检测CD40在样品中的存在或其水平。
在某些实施方案中,所述样品为来自受试者(例如哺乳动物,优选人或食蟹猴)的细胞样品(例如,免疫细胞)。
术语定义
在本发明中,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,本文中所用的病毒学、生物化学、免疫学实验室操作步骤均为相应领域内广泛使用的常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
当本文使用术语“例如”、“如”、“诸如”、“包括”、“包含”或其变体时,这些术语将不被认为是限制性术语,而将被解释为表示“但不限于”或“不限于”。
除非本文另外指明或根据上下文明显矛盾,否则术语“一个”和“一种”以及“该”和类似指称物在描述本发明的上下文中(尤其在以下权利要求的上下文中)应被解释成覆盖单数和复数。
本文所用的术语“抗体”是指能够特异性结合靶抗原的源自免疫球蛋白的分子,所述源自免疫球蛋白的分子通过位于其可变区中的至少一个抗原结合位点来结合所述靶抗原。当提及术语“抗体”时,除非上下文明确指出,其不仅包括完整抗体,而且包括能够特异性结合靶抗原的抗原结合片段。“完整抗体”典型地由两对多肽链(每对具有一条轻链(LC)和一条重链(HC))组成。抗体轻链可分类为κ(kappa)和λ(lambda)轻链。重链可分类为μ、δ、γ、α或ε,并且分别将抗体的同种型定义为IgM、IgD、IgG、IgA和IgE。在轻链和重链内,可变区和恒定区通过大约12或更多个氨基酸的“J”区连接,重链还包含大约3个或更多个氨基酸的“D”区。各重链由重链可变区(VH)和重链恒定区(CH)组成。重链恒定区由3个结构域(CH1、CH2和CH3)组成。各轻链由轻链可变区(VL)和轻链恒定区(CL)组成。轻链恒定区由一个结构域CL组成。恒定结构域不直接参与抗体与抗原的结合,但展现出多种效应子功能,如可介导免疫球蛋白与宿主组织或因子,包括免疫系统的各种细胞(例如,效应细胞)和经典补体系统的第一组分(C1q)的结合。VH和VL区还可被细分为具有高变性的区域(称为互补决定区(CDR)),其间散布有较保守的称为构架区(FR)的区域。各VH和VL由按下列顺序:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4从氨基末端至羧基末端排列的3个CDR和4个FR组成。各重链/轻链对的可变区(VH和VL)分别形成抗原结合部位。氨基酸在各区域或结构域的分配可遵循Kabat,Sequences of Proteins of Immunological Interest(National Institutes ofHealth,Bethesda,Md.(1987and 1991)),或Chothia&Lesk(1987)J.Mol.Biol.196:901-917;Chothia等人(1989)Nature 342:878-883的定义。
如本文中所使用的,术语“互补决定区”或“CDR”是指抗体可变区中负责抗原结合的氨基酸残基。在重链和轻链的可变区中各含有三个CDR,命名为CDR1、CDR2和CDR3。这些CDR的精确边界可根据本领域已知的各种编号系统进行定义,例如可按照Kabat编号系统(Kabat et al.,Sequences of Proteins of Immunological Interest,5th Ed.PublicHealth Service,National Institutes of Health,Bethesda,Md.,1991)、Chothia编号系统(Chothia&Lesk(1987)J.Mol.Biol.196:901-917;Chothia等人(1989)Nature 342:878-883)或IMGT编号系统(Lefranc et al.,Dev.Comparat.Immunol.27:55-77,2003)中的定义。对于给定的抗体,本领域技术人员将容易地鉴别各编号系统所定义的CDR。并且,不同编号系统之间的对应关系是本领域技术人员熟知的(例如,可参见Lefranc et al.,Dev.Comparat.Immunol.27:55-77,2003)。
在本发明中,本发明的抗体或其抗原结合片段含有的CDR可根据本领域已知的各种编号系统确定。在某些实施方案中,本发明的抗体或其抗原结合片段含有的CDR通过Kabat、Chothia或IMGT编号系统确定。在某些实施方案中,本发明的抗体或其抗原结合片段含有的CDR通过如Lu X,Nobrega RP,Lynaugh H,et al.Deamidation and isomerizationliability analysis of 131clinical-stage antibodies.MAbs.2019Jan;11(1):45-57.doi:10.1080/19420862.2018.1548233.第11页“Sequence analysis”部分所述的编号方法确定,其全部内容通过引用并入本文。
如本文中所使用的,术语“构架区”或“FR”残基是指,抗体可变区中除了如上定义的CDR残基以外的那些氨基酸残基。
术语“抗体”不受任何特定的产生抗体的方法限制。例如,其包括,重组抗体、单克隆抗体和多克隆抗体。抗体可以是不同同种型的抗体,例如,IgG(例如,IgG1,IgG2,IgG3或IgG4亚型),IgA1,IgA2,IgD,IgE或IgM抗体。
如本文中所使用的,术语抗体的“抗原结合片段”是指包含全长抗体的片段的多肽,其保持特异性结合全长抗体所结合的相同抗原的能力,和/或与全长抗体竞争对抗原的特异性结合,其也被称为“抗原结合部分”。通常参见,Fundamental Immunology,Ch.7(Paul,W.,ed.,第2版,Raven Press,N.Y.(1989),其以其全文通过引用合并入本文,用于所有目的。可通过重组DNA技术或通过完整抗体的酶促或化学断裂产生抗体的抗原结合片段。抗原结合片段的非限制性实例包括Fab、Fab’、F(ab’)2、Fd、Fv、互补决定区(CDR)片段、scFv、双抗体(diabody)、单域抗体(single domain antibody)、嵌合抗体、线性抗体(linear antibody)、纳米抗体(技术来自Domantis)、、probody和这样的多肽,其包含足以赋予多肽特异性抗原结合能力的抗体的至少一部分。工程改造的抗体变体综述于Holliger等,2005;Nat Biotechnol,23:1126-1136中。
如本文中所使用的,术语“全长抗体”意指,由两条“全长重链”和两条“全长轻链”组成的抗体。其中,“全长重链”是指这样的多肽链,其在N端到C端的方向上由重链可变区(VH)、重链恒定区CH1结构域、铰链区(HR)、重链恒定区CH2结构域、重链恒定区CH3结构域组成;并且,当所述全长抗体为IgE同种型时,任选地还包括重链恒定区CH4结构域。优选地,“全长重链”是在N端到C端方向上由VH、CH1、HR、CH2和CH3组成的多肽链。“全长轻链”是在N端到C端方向上由轻链可变区(VL)和轻链恒定区(CL)组成的多肽链。两对全长抗体链通过在CL和CH1之间的二硫键和两条全长重链的HR之间的二硫键连接在一起。本发明的全长抗体可以来自单一物种,例如人;也可以是嵌合抗体或人源化抗体。本发明的全长抗体包含分别由VH和VL对形成的两个抗原结合部位,这两个抗原结合部位特异性识别/结合相同的抗原。
如本文中所使用的,术语“Fd”意指由VH和CH1结构域组成的抗体片段;术语“dAb片段”意指由VH结构域组成的抗体片段(Ward等人,Nature 341:544 546(1989));术语“Fab片段”意指由VL、VH、CL和CH1结构域组成的抗体片段;术语“F(ab’)2片段”意指包含通过铰链区上的二硫桥连接的两个Fab片段的抗体片段;术语“Fab’片段”意指还原连接F(ab’)2片段中两个重链片段的二硫键后所获片段,由一条完整的轻链和重链的Fd片段(由VH和CH1结构域组成)组成。
如本文中所使用的,术语“Fv”意指由抗体的单臂的VL和VH结构域组成的抗体片段。Fv片段通常被认为是,能形成完整的抗原结合位点的最小抗体片段。一般认为,六个CDR赋予抗体的抗原结合特异性。然而,即便是一个可变区(例如Fd片段,其仅仅含有三个对抗原特异的CDR)也能够识别并结合抗原,尽管其亲和力可能低于完整的结合位点。
如本文中所使用的,术语“Fc”意指,由抗体的第一重链的第二、第三恒定区与第二重链的第二、第三恒定区经二硫键结合而形成的抗体片段。抗体的Fc片段具有多种不同的功能,但不参与抗原的结合。
如本文中所使用的,术语“scFv”是指,包含VL和VH结构域的单个多肽链,其中所述VL和VH通过接头(linker)相连(参见,例如,Bird等人,Science 242:423-426(1988);Huston等人,Proc.Natl.Acad.Sci.USA85:5879-5883(1988);和Pluckthun,ThePharmacology of Monoclonal Antibodies,第113卷,Roseburg和Moore编,Springer-Verlag,纽约,第269-315页(1994))。此类scFv分子可具有一般结构:NH2-VL-接头-VH-COOH或NH2-VH-接头-VL-COOH。合适的现有技术接头由重复的GGGGS氨基酸序列或其变体组成。例如,可使用具有氨基酸序列(GGGGS)4的接头,但也可使用其变体(Holliger等人(1993),Proc.Natl.Acad.Sci.USA 90:6444-6448)。可用于本发明的其他接头由Alfthan等人(1995),Protein Eng.8:725-731,Choi等人(2001),Eur.J.Immunol.31:94-106,Hu等人(1996),Cancer Res.56:3055-3061,Kipriyanov等人(1999),J.Mol.Biol.293:41-56和Roovers等人(2001),Cancer Immunol.描述。在一些情况下,scFv的VH与VL之间还可以存在二硫键。在本发明的某些实施方案中,scFv可形成di-scFv,其指的是两个或两个以上单个scFv串联而形成抗体。在本发明的某些实施方案中,scFv可形成(scFv)2,其指的是两个或两个以上单个scFv并联而形成抗体。
如本文中所使用的,术语“双抗体”意指,其VH和VL结构域在单个多肽链上表达,但使用太短的连接体以致不允许在相同链的两个结构域之间配对,从而迫使结构域与另一条链的互补结构域配对并且产生两个抗原结合部位(参见,例如,Holliger P.等人,Proc.Natl.Acad.Sci.USA 90:6444-6448(1993),和Poljak R.J.等人,Structure 2:1121-1123(1994))。
如本文中所使用的,术语“单域抗体(single-domain antibody,sdAb)”具有本领域技术人员通常理解的含义,其是指由单个单体可变抗体结构域(例如单个重链可变区)所组成的抗体片段,其保持特异性结合全长抗体所结合的相同抗原的能力。单域抗体也称为纳米抗体(nanobody)。
上述各个抗体片段均保持了特异性结合全长抗体所结合的相同抗原的能力,和/或与全长抗体竞争对抗原的特异性结合。
可使用本领域技术人员已知的常规技术(例如,重组DNA技术或酶促或化学断裂法)从给定的抗体(例如本发明提供的抗体)获得抗体的抗原结合片段(例如,上述抗体片段),并且以与用于完整抗体的方式相同的方式就特异性筛选抗体的抗原结合片段。
如本文中所使用的,术语“嵌合抗体(Chimeric antibody)”是指,这样的抗体,其轻链或/和重链的一部分源自一个抗体(其可以源自某一特定物种或属于某一特定抗体类或亚类),且轻链或/和重链的另一部分源自另一个抗体(其可以源自相同或不同的物种或属于相同或不同的抗体类或亚类),但无论如何,其仍保留对目标抗原的结合活性(U.S.P4,816,567to Cabilly et al.;Morrison et al.,Proc.Natl.Acad.Sci.USA,81:68516855(1984))。在某些实施方案中,术语“嵌合抗体”可包括这样的抗体,其中抗体的重链和轻链可变区来自第一抗体,而抗体的重链和轻链恒定区来自第二抗体。
如本文中所使用的,术语“同一性”用于指两个多肽之间或两个核酸之间序列的匹配情况。为了测定两个氨基酸序列或两个核酸序列的百分比同一性,为了最佳比较目的将序列进行比对(例如,可在第一氨基酸序列或核酸序列中引入缺口以与第二氨基酸或核酸序列最佳比对)。然后比较对应氨基酸位置或核苷酸位置处的氨基酸残基或核苷酸。当第一序列中的位置被与第二序列中的对应位置相同的氨基酸残基或核苷酸占据时,则分子在该位置上是同一的。两个序列之间的百分比同一性是由序列所共享的同一性位置的数目的函数(即,百分比同一性=同一重叠位置的数目/位置的总数×100%)。在某些实施方案中,两个序列长度相同。
两个序列之间的百分比同一性的测定还可使用数学算法来实现。用于两个序列的比较的数学算法的一个非限制性实例是Karlin和Altschul的算法,1990,Proc.Natl.Acad.Sci.U.S.A.87:2264-2268,如同Karlin和Altschul,1993,Proc.Natl.Acad.Sci.U.S.A.90:5873-5877中改进的。将这样的算法整合至Altschul等人,1990,J.Mol.Biol.215:403的NBLAST和XBLAST程序中。
如本文中所使用的,术语“变体”,在多肽的情境中(包括多肽)也指包含已通过引入氨基酸残基置换、缺失或添加改变的氨基酸序列的多肽或肽。在某些情况下,术语“变体”还指已被修饰(即,通过将任何类型的分子共价连接至多肽或肽)的多肽或肽。例如,但非限制性地,多肽可以被修饰,例如通过糖基化、乙酰化、聚乙二醇化、磷酸化、酰胺化、通过已知保护/封闭基团进行的衍生化、蛋白水解切割、连接至细胞配体或其它蛋白质等。衍生多肽或肽可使用本领域技术人员已知的技术通过化学修饰来产生,所述技术包括但不限于特异性化学切割、乙酰化、甲酰化、衣霉素的代谢合成等。此外,变体具有与其所源自的多肽或肽相似、相同或改善的功能。
如本文中所使用的,术语“特异性结合”是指,两分子间的非随机的结合反应,如抗体和其所针对的抗原之间的反应。特异性结合相互作用的强度或亲和力可以该相互作用的平衡解离常数(KD)表示。在本发明中,术语“KD”是指特定抗体-抗原相互作用的解离平衡常数,其用于描述抗体与抗原之间的结合亲和力。平衡解离常数越小,抗体-抗原结合越紧密,抗体与抗原之间的亲和力越高。
两分子间的特异性结合性质可使用本领域公知的方法进行测定。一种方法涉及测量抗原结合位点/抗原复合物形成和解离的速度。“结合速率常数”(ka或kon)和“解离速率常数”(kdis或koff)两者都可通过浓度及缔合和解离的实际速率而计算得出(参见Malmqvist M,Nature,1993,361:186-187)。kdis/kon的比率等于解离常数KD(参见Davies等人,Annual Rev Biochem,1990;59:439-473)。可用任何有效的方法测量KD、kon和kdis值。在某些实施方案中,可以使用表面等离子体共振术(SPR)在Biacore中来测量解离常数。除此以外还可用生物发光干涉测量法或Kinexa来测量解离常数。
如本文中所使用的,本发明所述的可检测的标记可以是可通过荧光、光谱、光化学、生物化学、免疫学、电学、光学或化学手段检测的任何物质。这类标记是本领域熟知的,其实例包括但不限于,酶(例如,辣根过氧化物酶、碱性磷酸酶、β-半乳糖苷酶、脲酶、葡萄糖氧化酶,等)、放射性核素(例如,3H、125I、35S、14C或32P)、荧光染料(例如,异硫氰酸荧光素(FITC)、荧光素、异硫氰酸四甲基罗丹明(TRITC)、藻红蛋白(PE)、德克萨斯红、罗丹明、量子点或花菁染料衍生物(例如Cy7、Alexa 750))、发光物质(例如化学发光物质,如吖啶酯类化合物、鲁米诺及其衍生物、钌衍生物如三联吡啶钌)、磁珠(例如,)、测热标记物例如胶体金或有色玻璃或塑料(例如,聚苯乙烯、聚丙烯、乳胶,等)珠、以及用于结合上述标记物修饰的亲和素(例如,链霉亲和素)的生物素。
如本文中所使用的,术语“载体(vector)”是指,可将多聚核苷酸插入其中的一种核酸运载工具。当载体能使插入的多核苷酸编码的蛋白获得表达时,载体称为表达载体。载体可以通过转化,转导或者转染导入宿主细胞,使其携带的遗传物质元件在宿主细胞中获得表达。载体是本领域技术人员公知的,包括但不限于:质粒;噬菌粒;柯斯质粒;人工染色体,例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。可用作载体的动物病毒包括但不限于,逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。一种载体可以含有多种控制表达的元件,包括但不限于,启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外,载体还可含有复制起始位点。
如本文中所使用的,术语“宿主细胞”是指,可用于导入载体的细胞,其包括但不限于,如大肠杆菌或枯草菌等的原核细胞,如酵母细胞或曲霉菌等的真菌细胞,如S2果蝇细胞或Sf9等的昆虫细胞,或者如纤维原细胞,CHO细胞,COS细胞,NSO细胞,HeLa细胞,BHK细胞,HEK 293细胞或人细胞等的动物细胞。
如本文中所使用的,术语“保守置换”意指不会不利地影响或改变包含氨基酸序列的蛋白/多肽的预期性质的氨基酸置换。例如,可通过本领域内已知的标准技术例如定点诱变和PCR介导的诱变引入保守置换。保守氨基酸置换包括用具有相似侧链的氨基酸残基替代氨基酸残基的置换,例如用在物理学上或功能上与相应的氨基酸残基相似(例如具有相似大小、形状、电荷、化学性质,包括形成共价键或氢键的能力等)的残基进行的置换。已在本领域内定义了具有相似侧链的氨基酸残基的家族。这些家族包括具有碱性侧链(例如,赖氨酸、精氨酸和组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β分支侧链(例如,苏氨酸、缬氨酸、异亮氨酸)和芳香族侧链(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。因此,优选用来自相同侧链家族的另一个氨基酸残基替代相应的氨基酸残基。鉴定氨基酸保守置换的方法在本领域内是熟知的(参见,例如,Brummell等人,Biochem.32:1180-1187(1993);Kobayashi等人Protein Eng.12(10):879-884(1999);和Burks等人Proc.NatlAcad.Set USA94:412-417(1997),其通过引用并入本文)。
本文涉及的二十个常规氨基酸的编写遵循常规用法。参见例如,Immunology-ASynthesis(2nd Edition,E.S.Golub and D.R.Gren,Eds.,Sinauer Associates,Sunderland,Mass.(1991)),其以引用的方式并入本文中。在本发明中,术语“多肽”和“蛋白质”具有相同的含义且可互换使用。并且在本发明中,氨基酸通常用本领域公知的单字母和三字母缩写来表示。例如,丙氨酸可用A或Ala表示。
如本文中所使用的,术语“药学上可接受的载体和/或赋形剂”是指在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂,其是本领域公知的(参见例如Remington's Pharmaceutical Sciences.Edited by Gennaro AR,19thed.Pennsylvania:Mack Publishing Company,1995),并且包括但不限于:pH调节剂,表面活性剂,佐剂,离子强度增强剂,稀释剂,维持渗透压的试剂,延迟吸收的试剂,防腐剂。例如,pH调节剂包括但不限于磷酸盐缓冲液。表面活性剂包括但不限于阳离子,阴离子或者非离子型表面活性剂,例如Tween-80。离子强度增强剂包括但不限于氯化钠。防腐剂包括但不限于各种抗细菌试剂和抗真菌试剂,例如对羟苯甲酸酯,三氯叔丁醇,苯酚,山梨酸等。维持渗透压的试剂包括但不限于糖、NaCl及其类似物。延迟吸收的试剂包括但不限于单硬脂酸盐和明胶。稀释剂包括但不限于水,水性缓冲液(如缓冲盐水),醇和多元醇(如甘油)等。防腐剂包括但不限于各种抗细菌试剂和抗真菌试剂,例如硫柳汞,2-苯氧乙醇,对羟苯甲酸酯,三氯叔丁醇,苯酚,山梨酸等。稳定剂具有本领域技术人员通常理解的含义,其能够稳定药物中的活性成分的期望活性,包括但不限于谷氨酸钠,明胶,SPGA,糖类(如山梨醇,甘露醇,淀粉,蔗糖,乳糖,葡聚糖,或葡萄糖),氨基酸(如谷氨酸,甘氨酸),蛋白质(如干燥乳清,白蛋白或酪蛋白)或其降解产物(如乳白蛋白水解物)等。在某些示例性实施方案中,所述药学上可接受的载体或赋形剂包括无菌可注射液体(如水性或非水性悬浮液或溶液)。在某些示例性实施方案中,此类无菌可注射液体选自注射用水(WFI)、抑菌性注射用水(BWFI)、氯化钠溶液(例如0.9%(w/v)NaCl)、葡萄糖溶液(例如5%葡萄糖)、含有表面活性剂的溶液(例如0.01%聚山梨醇20)、pH缓冲溶液(例如磷酸盐缓冲溶液)、Ringer氏溶液及其任意组合。
如本文中所使用的,术语“预防”是指,为了阻止或延迟疾病或病症或症状在受试者体内的发生而实施的方法。如本文中所使用的,术语“治疗”是指,为了获得有益或所需临床结果而实施的方法。为了本发明的目的,有益或所需的临床结果包括(但不限于)减轻症状、缩小疾病的范围、稳定(即,不再恶化)疾病的状态,延迟或减缓疾病的发展、改善或减轻疾病的状态、和缓解症状(无论部分或全部),无论是可检测或是不可检测的。此外,“治疗”还可以指,与期望的存活期相比(如果未接受治疗),延长存活期。
如本文中所使用的,术语“受试者”是指哺乳动物,例如人。在某些实施方案中,所述受试者(例如人)患有肿瘤、感染或自身免疫性疾病,或者,具有患有上述疾病的风险。
如本文中所使用的,术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如,预防疾病(例如,肿瘤、感染或自身免疫性疾病)有效量是指,足以预防,阻止,或延迟所述疾病的发生的量;治疗疾病有效量是指,足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如,对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄,体重和性别,药物的施用方式,以及同时施用的其他治疗等等。
发明的有益效果
本发明提供了抗CD40的全人源抗体,其与CD40的结合亲和力高,具备与人、食蟹猴CD40的交叉反应活性,可阻断或者非阻断CD40与其配体CD40L结合。
附图说明
图1显示了母本抗CD40候选分子与人CD40-CHO细胞的结合活性。
图2显示了母本抗CD40候选分子在无beads交联情况下激活CD40报告基因活性。
图3显示了母本抗CD40候选分子在有beads交联情况下激活CD40报告基因活性。
图4显示了子代抗CD40候选分子与人CD40 CHO细胞的结合活性。
图5显示了子代抗CD40候选分子与猴CD40 CHO细胞的结合活性。
图6显示了子代抗CD40候选分子在有抗Fc交联情况下激活CD40报告基因活性。
图7显示了子代抗CD40候选分子在无抗Fc交联情况下激活CD40报告基因活性。
下面将结合附图和实施例对本发明的实施方案进行详细描述,但是本领域技术人员将理解,下列附图和实施例仅用于说明本发明,而不是对本发明的范围的限定。根据附图和优选实施方案的下列详细描述,本发明的各种目的和有利方面对于本领域技术人员来说将变得显然。
序列信息
本申请涉及的序列的描述提供于下表中。
表1:序列信息
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具体实施方式
现参照下列意在举例说明本发明(而非限定本发明)的实施例来描述本发明。
除非特别指明,本发明中所使用的分子生物学实验方法和免疫检测法,基本上参照J.Sambrook等人,分子克隆:实验室手册,第2版,冷泉港实验室出版社,1989,以及F.M.Ausubel等人,精编分子生物学实验指南,第3版,John Wiley&Sons,Inc.,1995中所述的方法进行;限制性内切酶的使用依照产品制造商推荐的条件。本领域技术人员知晓,实施例以举例方式描述本发明,且不意欲限制本发明所要求保护的范围。
实施例1:抗体的制备
1.1酵母展示技术筛选抗CD40全人源抗体
基于酵母抗体展示文库(Adimab),按照现有的方法(WO2009036379;WO2010105256;WO2012009568)对8个天然合成文库进行扩增,其中每个库的多样性达到1x109。简言之,前两轮的筛选使用Miltenyi公司的MACS系统进行磁珠细胞分选。首先,将文库中酵母细胞(~1x1010细胞/文库)分别在FACS洗涤缓冲液(含有0.1%BSA的磷酸盐缓冲液)室温孵育15分钟,缓冲液含有10nM生物素标记的人CD40-Fc融合蛋白抗原(购自ACRO,货号:CD0-H5253,其中,人CD40的氨基酸序列如SEQ ID NO:71所示)。使用50mL预冷的FACS洗涤缓冲液洗一次,再用40mL缓冲液重悬细胞,并加入500μL链霉亲和素磁珠(Miltenyi LS),室温孵育15分钟。1000rpm离心5分钟弃去上清后,用5mL FACS洗涤缓冲液重悬细胞,将细胞悬液加到Miltenyi LS柱中。加样完成后,用FACS洗涤缓冲液洗柱3次,每次3mL。从磁性区域取下Miltenyi LS柱,用5mL生长培养基洗脱,收集洗脱的酵母细胞并在37℃过夜生长。
使用流式细胞仪进行下一轮的分选:将经过MACS系统筛选获得的大约1x108的酵母细胞用FACS缓冲液洗三次,于含有100nM生物素标记的CD40单体蛋白(购自Acro,货号:CD0-H5228,其中,所述CD40的氨基酸序列如SEQ ID NO:71所示)或者10nM的CD40-Fc融合蛋白中室温下培养。弃去培养液,细胞用FACS洗涤缓冲液洗两次之后,将细胞与LC-FITC(FITC标记的抗人免疫球蛋白kappa轻链抗体,购自Southern Biotech)(1:100稀释)混合,并与SA-633(链霉亲和素-633,Molecular Probes)(1:500稀释)或SA-PE(链霉亲和素-PE,Sigma)(1:50稀释)混合,4℃下培养15分钟。用预冷的FACS洗涤缓冲液洗脱两次,并重悬于0.4mL缓冲液中,将细胞转移到带滤器的分离管中。使用FACS ARIA(BD Biosciences)分选细胞。
将通过筛选获得的表达抗CD40抗体的酵母细胞在30℃下震荡诱导48小时以分泌表达抗CD40的抗体(全长抗体)。诱导结束之后,1300rpm离心10分钟去除酵母细胞,收获上清液。使用Protein A对上清液中的抗CD40抗体进行纯化,pH2.0醋酸溶液洗脱,收获抗CD40抗体。本次筛选获得抗CD40抗体ADI-47754,ADI-47720ADI-47741。
1.2抗人CD40抗体的亲和力优化
为了获得更高亲和力的抗人CD40抗体,我们通过但不限于以下方法对抗体ADI-47754,ADI-47720进行了优化。
1.3 CDRH1/CDRH2筛选
将母代分子的CDRH3基因构建入1x108多样性的CDRH1/CDRH2基因库中,并对其进行四轮筛选。前两轮使用MACS方法,三四轮使用FACS方法,对抗体抗原结合物进行亲和力加压,筛选出高亲和力的抗体。
将筛选获得表达抗CD40抗体的酵母细胞在30℃震荡培养48小时以产生CD40抗体。在诱导表达完成后,1300rpm离心10分钟去除酵母细胞,收获上清液。使用Protein A对上清液中的抗CD40抗体进行纯化,pH2.0醋酸溶液洗脱,收获抗CD40抗体。使用木瓜蛋白酶并用KappaSelect(GE生命医疗集团)进行纯化获得相应fab片段。
1.4 VHmut筛选
该方法是通过常规的错配PCR方法向重链区域引入突变。PCR过程中,通过使用1μM高突变的碱基类似物dPTP和8-oxo-dGTP,从而将碱基错配概率提高到约0.01bp。
通过错配PCR获得的产物通过同源重组的方法构建入含有重链恒定区的载体中。通过这种方法,在包括CD40抗原滴度,未标记抗原竞争,以及使用母本抗体竞争的筛选压力下,获得库容为1x107的次级库,通过FACS方法进行三轮筛选,酵母表达对应抗体。
经亲和力成熟后各抗体子代与母本抗体关系如表2所示。
表2.本发明抗CD40分子子代与母本关系表
1.5抗体的表达与纯化
本申请涉及的各个抗人CD40抗体序列及标号见表3,表3中包含表2未提及的母本抗体ADI-47741。
由HEK293细胞表达并纯化实施例中使用的抗体。具体操作如下:使用化学转染的方法将带有抗体重链和轻链的pcDNA3.1载体转入HEK293细胞中(其中,所述载体编码的抗体重链恒定区氨基酸序列如SEQ ID NO:72所示,轻链恒定区氨基酸序列如SEQ ID NO:73所示),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,SEC检测抗体纯度,同时控制内毒素含量。
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实施例2:抗体亲和力检测
采用生物膜层光学干涉技术(ForteBio)测定本发明涉及抗体结合人、食蟹猴CD40的结合解离常数(KD),以及其是否阻断人CD40与其配体(人CD40L)的结合,其中,人CD40的氨基酸序列如SEQ ID NO:71所示,食蟹猴CD40的氨基酸序列如SEQ ID NO:74所示,人CD40L的氨基酸序列如SEQ ID NO:75所示。Fortebio亲和力测定按照现有方法(Este,P等人Highthroughput solution-based measurement of antibody-antigen affinity andepitope binning.Mabs,2013.5(2):p.270-8)进行。
测量候选抗体fab片段与人、食蟹猴CD40-Fc蛋白的单价亲和力:传感器在分析缓冲液中线下平衡20分钟,然后线上检测120s建立基线,加载CD40-Fc抗原至AHQ传感器至厚度1nm进行亲和力检测。将已加载抗原的传感器于100Nm fab液中作用至平台期,然后将传感器转移到分析缓冲液中至少2分钟用于解离速率测量。使用1:1结合模型进行动力学分析。
测量完整抗体与人、食蟹猴CD40-Fc蛋白的双价亲和力:传感器在分析缓冲液中线下平衡20分钟,然后线上检测120s建立基线,加载完整的CD40抗体至AHQ传感器至厚度1nm进行亲和力检测。将已加载抗体的传感器于高浓度无关完整抗体液中继续加载10分钟,饱和封闭AHQ传感器上Fc结合位点,将封闭完成的传感器于100Nm CD40-Fc抗原中作用至平台期,然后将传感器转移到分析缓冲液中至少2分钟用于解离速率测量。使用1:1结合模型进行动力学分析。
在如上测定方法中,各母本抗体分子及其变体分子的KD值如表4所示:
由以上图表结果可见:(1)经亲和力成熟后,各子代分子与母本分子相比与人CD40蛋白的单价亲和力均有显著提升。(2)经亲和力成熟后,各子代分子与母本分子相比与食蟹猴CD40蛋白的单价亲和力均有显著提升。
表4.各母本抗体分子及其变体分子的KD值
注:P.F.=Poor Fit(拟合较差),N.B.=Non-Binder under the conditions ofthis assay(此次试验未检出结合),N.A.=Not Available(没有检测)
实施例3:母本抗CD40抗体与过表达人CD40 CHO细胞结合
基于流式细胞术检测法检测抗CD40抗体母本克隆抗体与过表达在CHO细胞上的人CD40的结合活性。其中,对照抗体CP870893-IgG2的轻重链氨基酸序列分别如SEQ ID NOs:80和81所示。
具体地,通过转染克隆到MCS的人CD40 cDNA pCHO1.0载体(Invitrogen)加压筛选产生过表达人CD40的CHO-S细胞(CHO-huCD40细胞)。将扩大培养的过表达细胞调整至合适细胞密度加入96孔流式板,离心后加入梯度稀释的待测样品,4℃孵育30分钟。PBS清洗两次,加入对应稀释至合适浓度的荧光二抗,4℃孵育30分钟,PBS清洗两次。加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。结果如图1所示。
由试验结果可以得出如下结论:母本抗CD40抗体ADI-47754、ADI-47720和ADI-47741均可以与过表达人CD40的CHO细胞有良好的单点结合活性。
实施例4:母本抗CD40抗体激活人CD40信号通路活性
基于报告基因法检测抗CD40抗体母本克隆抗体在Protein G Magnetic Beads交联与否的条件下,激活CD40下游信号通路NFkB-Luc2P报告基因的活性。
具体地,通过转染克隆到NFkB-Luc2P载体(Promega,货号:11501ES03)加压筛选产生过表达人CD40的U2OS细胞。将母本克隆抗体按照终浓度10μg/ml,1μg/ml,0.1μg/ml,0.01μg/ml,0.001μg/ml与0.25μL/孔的PierceTMProtein G Magnetic Beads(ThermoScientific,货号:88847)加入NFkB-Luc2P-U2OS细胞,在细胞培养箱孵育4小时,考察beads交联引起CD40下游信号活性。另外只加入相应浓度抗体至NFkB-Luc2P-U2OS细胞在细胞培养箱孵育4小时,考察无beads交联,单独抗体诱导CD40下游信号通路活性。
由试验结果可以得出如下结论:母本克隆ADI-47754、ADI-47720和ADI-47741在无Fc交联的情况下,不能激活CD40下游信号通路;在beads交联的情况下,均能激活CD40下游信号通路;并且所有抗体在beads交联情况下,信号活性均得到加强。而阳性对照抗体CP-870893-G2-WT能不依赖抗Fc交联激活CD40信号下游信号通路。详细结果见表4,图2和图3。
表5.母本抗CD40抗体激活CD40信号通路活性表
实施例5:子代抗CD40抗体与过表达人/猴CD40 CHO细胞结合
根据实施例4的结果,我们将依赖于beads交联激活CD40报告基因活性的ADI-47720、ADI-47741、ADI-47754进行亲和力优化,产生表2中的所示抗体。
选取ADI-47720、ADI-47741、ADI-47754及其子代抗体ADI-55136、ADI-55140、ADI-55142、ADI-55144-2、ADI-55145、ADI-55147、ADI-55164、ADI-55168,进行人/猴CD40过表达细胞结合活性研究。
具体地,通过转染克隆到MCS的人/猴CD40 cDNA pCHO1.0载体(Invitrogen)加压筛选产生过表达人/猴CD40的CHO-S细胞(CHO-huCD40细胞)。将扩大培养的过表达细胞调整至合适细胞密度加入96孔流式板,离心后加入梯度稀释的待测样品,4℃孵育30分钟。PBS清洗两次,加入对应稀释至合适浓度的荧光二抗,4℃孵育30分钟,PBS清洗两次。加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。
由试验结果可以得出如下结论:相比于母本抗体,子代抗CD40抗体与人/猴CD40过表达细胞的结合活性都有了一定的提高,结果如图4和图5所示。
实施例6:子代抗CD40抗体激活人CD40信号通路活性
基于报告基因法检测抗CD40抗体的母本及子代抗体在F(ab)2片段山羊抗人IgG-Fc(Jackson,货号:109-036-098)交联与否的条件下,激活CD40下游信号通路NFkB-Luc2P报告基因的活性。
具体地,通过转染克隆到NFkB-Luc2P载体(Promega,货号:11501ES03)加压筛选产生过表达过表达人CD40的Jurkat细胞。母本及子代克隆抗体按照终浓度200nM,3倍稀释,11个浓度与F(ab)2片段山羊抗人IgG-Fc(Thermo Scientific,货号:88847)按照1:2摩尔比加入CD40-NFkB-Jurkat细胞,在细胞培养箱孵育6小时,考察抗Fc片段交联引起CD40下游信号活性。另外只加入相应浓度抗体至CD40-NFkB-Jurkat在细胞培养箱孵育6小时,考察无抗Fc片段交联,单独抗体诱导CD40下游信号通路活性。
试验结果如图6和图7所示,由试验结果可知,母本抗体ADI-47720、ADI-47741、ADI-47754及子代抗体ADI-55142、ADI-55144-2、ADI-55147、ADI-55164、ADI-55168在无抗Fc交联的情况下,都不能激活CD40下游信号通路,而在抗Fc交联的情况下,都能不同程度地激活CD40下游信号通路;而阳性对照抗体CP-870893-G2-WT能不依赖抗Fc交联激活CD40信号下游信号通路,此外,对照抗体CP-870893-G2-WT作为非交联依赖的CD40激动剂,在临床上已报道过严重的肝毒性,目前临床试验已暂停。
尽管本发明的具体实施方式已经得到详细的描述,但本领域技术人员将理解:根据已经公布的所有教导,可以对细节进行各种修改和变动,并且这些改变均在本发明的保护范围之内。本发明的全部分为由所附权利要求及其任何等同物给出。
SEQUENCE LISTING
<110> 普米斯生物技术(珠海)有限公司
<120> 抗CD40抗体及其用途
<130> IDC210446
<160> 83
<170> PatentIn version 3.5
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Phe Thr Phe Ser Ser Tyr Gly Met His
1 5
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<212> PRT
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<223> VH CDR1
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Phe Thr Phe Glu Lys Tyr Gly Met His
1 5
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<211> 9
<212> PRT
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<223> VH CDR1
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Phe Thr Phe Gly Ser Tyr Gly Met His
1 5
<210> 4
<211> 9
<212> PRT
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<223> VH CDR1
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Phe Thr Phe Asp Asp Tyr Ala Met His
1 5
<210> 5
<211> 9
<212> PRT
<213> Artificial Sequence
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<223> VH CDR1
<400> 5
Phe Thr Phe Asp Thr Tyr Ala Met His
1 5
<210> 6
<211> 9
<212> PRT
<213> Artificial Sequence
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<223> VH CDR1
<400> 6
Gly Ser Ile Ser Ser Tyr Tyr Trp Ser
1 5
<210> 7
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR1
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa选自(i)氨基酸残基Arg,Glu和(ii)相对于(i)是保守置换的氨基酸残
基
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa选自(i)氨基酸残基Gln,Lys和(ii)相对于(i)是保守置换的氨基酸残
基
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa选自(i)氨基酸残基Gly,Val和(ii)相对于(i)是保守置换的氨基酸残
基
<400> 7
Xaa Ala Ser Xaa Xaa Ile Ser Ser Trp Leu Ala
1 5 10
<210> 8
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR2
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa选自(i)氨基酸残基Ser,Thr,Ala和(ii)相对于(i)是保守置换的氨基酸
残基
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa选自(i)氨基酸残基Arg,Leu和(ii)相对于(i)是保守置换的氨基酸残
基
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa选自(i)氨基酸残基Asn,Ala和(ii)相对于(i)是保守置换的氨基酸残
基
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa选自(i)氨基酸残基Thr,Asn和(ii)相对于(i)是保守置换的氨基酸残
基
<400> 8
Gly Ala Ser Xaa Xaa Xaa Xaa
1 5
<210> 9
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR2
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa选自(i)氨基酸残基Ser,Tyr和(ii)相对于(i)是保守置换的氨基酸残
基
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa选自(i)氨基酸残基Glu,Gln和(ii)相对于(i)是保守置换的氨基酸残
基
<400> 9
Ala Ala Ser Xaa Leu Xaa Ser
1 5
<210> 10
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR3
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa选自(i)氨基酸残基Ser,Gly,Gln和(ii)相对于(i)是保守置换的氨基酸
残基
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa选自(i)氨基酸残基Glu,Gln,Asp和(ii)相对于(i)是保守置换的氨基酸
残基
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa选自(i)氨基酸残基Ala,Ser和(ii)相对于(i)是保守置换的氨基酸残
基
<400> 10
Xaa Xaa Tyr Xaa Asp Tyr Pro Pro Phe Thr
1 5 10
<210> 11
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR3
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa选自(i)氨基酸残基Arg,His,Val和(ii)相对于(i)是保守置换的氨基酸
残基
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa选自(i)氨基酸残基Ser,Leu,Ala和(ii)相对于(i)是保守置换的氨基酸
残基
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa选自(i)氨基酸残基Phe,Tyr和(ii)相对于(i)是保守置换的氨基酸残
基
<400> 11
Gln Gln Xaa Xaa Ser Xaa Pro Pro Thr
1 5
<210> 12
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<400> 12
Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 13
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<400> 13
Val Ile Ser Tyr His Ala Ser Ser Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 14
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<400> 14
Val Ile His Tyr Glu Gly Ser Ile Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 15
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<400> 15
Val Ile Ser Tyr Glu Gly Glu Lys Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 16
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<400> 16
Val Ile Ser Tyr Glu Gly Thr Lys Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 17
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<400> 17
Val Ile Ser Tyr Glu Gly Thr Ser Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 18
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<400> 18
Val Ile Ser Tyr Glu Gly Val Lys Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 19
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<400> 19
Gly Ile Ser Trp Ser Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 20
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<400> 20
Gly Ile Ser Trp Ser Ser Asp Ser Ile His Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 21
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<400> 21
Gly Ile Ser Trp Ser Ser Gly Ser Ile His Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 22
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<400> 22
Ser Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 23
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR3
<400> 23
Ala Arg Asp Thr Ser Arg Gly His Asp Ile
1 5 10
<210> 24
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR3
<400> 24
Ala Lys Asp Pro Thr Ala Thr Thr Gly Ala Arg Gly Tyr Phe Asp Leu
1 5 10 15
<210> 25
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR3
<400> 25
Ala Arg Asp Ala Asn Tyr Tyr Lys Trp His Pro Tyr
1 5 10
<210> 26
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> VH
<400> 26
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 Ser Ser 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 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
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> 27
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> VH
<400> 27
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 Ser Ser 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 His Ala Ser Ser 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
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> 28
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> VH
<400> 28
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 His Tyr Glu Gly Ser Ile 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
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> 29
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> VH
<400> 29
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 Glu Lys 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
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> 30
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> VH
<400> 30
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 Asp 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> 31
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> VH
<400> 31
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 Ser 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
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> 32
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> VH
<400> 32
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 Gly Ser 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 Val Lys 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
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> 33
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> VH
<400> 33
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Ser Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Pro Thr Ala Thr Thr Gly Ala Arg Gly Tyr Phe Asp Leu
100 105 110
Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 34
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> VH
<400> 34
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Ser Ser Asp Ser Ile His Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Pro Thr Ala Thr Thr Gly Ala Arg Gly Tyr Phe Asp Leu
100 105 110
Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 35
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> VH
<400> 35
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Thr Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Ser Ser Gly Ser Ile His Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Pro Thr Ala Thr Thr Gly Ala Arg Gly Tyr Phe Asp Leu
100 105 110
Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 36
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> VH
<400> 36
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Ala Asn Tyr Tyr Lys Trp His Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 37
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR1
<400> 37
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala
1 5 10
<210> 38
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR1
<400> 38
Arg Ala Ser Gln Ser Val Ser Tyr Asp Tyr Leu Ala
1 5 10
<210> 39
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR1
<400> 39
Arg Ala Ser Gln Ser Val Ser Tyr Ser Tyr Leu Ala
1 5 10
<210> 40
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR1
<400> 40
Gln Ala Ser Gln Ser Val Ser Tyr Asn Tyr Leu Ala
1 5 10
<210> 41
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR1
<400> 41
Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
1 5 10
<210> 42
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR1
<400> 42
Arg Ala Ser Lys Val Ile Ser Ser Trp Leu Ala
1 5 10
<210> 43
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR1
<400> 43
Glu Ala Ser Gln Val Ile Ser Ser Trp Leu Ala
1 5 10
<210> 44
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR1
<400> 44
Arg Ala Ser Gln Ser Val Ser Ser Asp Tyr Leu Ala
1 5 10
<210> 45
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR2
<400> 45
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 46
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR2
<400> 46
Gly Ala Ser Thr Arg Ala Asn
1 5
<210> 47
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR2
<400> 47
Gly Ala Ser Ser Arg Ala Asn
1 5
<210> 48
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR2
<400> 48
Gly Ala Ser Ser Leu Ala Thr
1 5
<210> 49
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR2
<400> 49
Gly Ala Ser Ser Arg Asn Asn
1 5
<210> 50
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR2
<400> 50
Gly Ala Ser Ala Arg Ala Asn
1 5
<210> 51
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR2
<400> 51
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 52
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR2
<400> 52
Ala Ala Ser Tyr Leu Glu Ser
1 5
<210> 53
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR2
<400> 53
Ala Ala Ser Tyr Leu Gln Ser
1 5
<210> 54
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR3
<400> 54
Gln Gln Tyr Ala Asp Tyr Pro Pro Phe Thr
1 5 10
<210> 55
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR3
<400> 55
Gly Glu Tyr Ala Asp Tyr Pro Pro Phe Thr
1 5 10
<210> 56
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR3
<400> 56
Ser Asp Tyr Ala Asp Tyr Pro Pro Phe Thr
1 5 10
<210> 57
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR3
<400> 57
Gln Gln Tyr Ser Asp Tyr Pro Pro Phe Thr
1 5 10
<210> 58
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR3
<400> 58
Gln Gln Arg Ala Ser Phe Pro Pro Thr
1 5
<210> 59
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR3
<400> 59
Gln Gln His Ser Ser Phe Pro Pro Thr
1 5
<210> 60
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR3
<400> 60
Gln Gln Val Leu Ser Tyr Pro Pro Thr
1 5
<210> 61
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> VL
<400> 61
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
100 105
<210> 62
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> VL
<400> 62
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 Asp
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 Thr Arg Ala Asn 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 Gly Glu Tyr Ala Asp Tyr Pro
85 90 95
Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 63
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> VL
<400> 63
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 Arg Ala Asn 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 Ser Asp Tyr Ala Asp Tyr Pro
85 90 95
Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 64
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> VL
<400> 64
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> 65
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> VL
<400> 65
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 Gln Ala Ser Gln Ser Val Ser Tyr Asn
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 Asn Asn 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> 66
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> VL
<400> 66
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 Asp
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 Ala Arg Ala Asn 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
100 105
<210> 67
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> VL
<400> 67
Asp Ile 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 Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln 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 Arg Ala Ser Phe Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 68
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> VL
<400> 68
Asp Ile 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 Ala Ser Lys Val Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Tyr Leu Glu 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 His Ser Ser Phe Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 69
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> VL
<400> 69
Asp Ile 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 Glu Ala Ser Gln Val Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Tyr Leu Gln 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 His Ser Ser Phe Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 70
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> VL
<400> 70
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 Asp
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 Val Leu Ser Tyr Pro
85 90 95
Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 71
<211> 277
<212> PRT
<213> Artificial Sequence
<220>
<223> 人CD40氨基酸序列
<400> 71
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> 72
<211> 329
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗体重链恒定区氨基酸序列
<400> 72
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> 73
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗体轻链恒定区氨基酸序列
<400> 73
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 74
<211> 239
<212> PRT
<213> Artificial Sequence
<220>
<223> 食蟹猴CD40氨基酸序列
<400> 74
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> 75
<211> 261
<212> PRT
<213> Artificial Sequence
<220>
<223> 人CD40L氨基酸序列
<400> 75
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> 76
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR1
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa选自(i)氨基酸残基Ser,Glu,Gly,Asp和(ii)相对于(i)是保守置换的氨
基酸残基
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa选自(i)氨基酸残基Ser,Lys,Asp,Thr和(ii)相对于(i)是保守置换的氨
基酸残基
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa选自(i)氨基酸残基Gly,Ala和(ii)相对于(i)是保守置换的氨基酸残
基
<400> 76
Phe Thr Phe Xaa Xaa Tyr Xaa Met His
1 5
<210> 77
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa选自(i)氨基酸残基Ser,His和(ii)相对于(i)是保守置换的氨基酸残
基
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa选自(i)氨基酸残基Glu,His和(ii)相对于(i)是保守置换的氨基酸残
基
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa选自(i)氨基酸残基Gly,Ala和(ii)相对于(i)是保守置换的氨基酸残
基
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa选自(i)氨基酸残基Ser,Glu,Thr,Val和(ii)相对于(i)是保守置换的氨
基酸残基
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa选自(i)氨基酸残基Asn,Ser,Ile,Lys和(ii)相对于(i)是保守置换的氨
基酸残基
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa选自(i)氨基酸残基Asp,Glu和(ii)相对于(i)是保守置换的氨基酸残
基
<400> 77
Val Ile Xaa Tyr Xaa Xaa Xaa Xaa Lys Tyr Tyr Ala Xaa Ser Val Lys
1 5 10 15
Gly
<210> 78
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa选自(i)氨基酸残基Gly,Asp和(ii)相对于(i)是保守置换的氨基酸残
基
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa选自(i)氨基酸残基Gly,His和(ii)相对于(i)是保守置换的氨基酸残
基
<400> 78
Gly Ile Ser Trp Ser Ser Xaa Ser Ile Xaa Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 79
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> VL CDR1
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa选自(i)氨基酸残基Arg,Gln和(ii)相对于(i)是保守置换的氨基酸残
基
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa选自(i)氨基酸残基Tyr,Ser和(ii)相对于(i)是保守置换的氨基酸残
基
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa选自(i)氨基酸残基Ser,Asp,Asn和(ii)相对于(i)是保守置换的氨基酸
残基
<400> 79
Xaa Ala Ser Gln Ser Val Ser Xaa Xaa Tyr Leu Ala
1 5 10
<210> 80
<211> 234
<212> PRT
<213> Artificial Sequence
<220>
<223> CP870893-IgG2轻链氨基酸序列
<400> 80
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Phe Pro
1 5 10 15
Gly Ser Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
35 40 45
Ile Tyr Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
50 55 60
Asn Leu Leu Ile Tyr Thr Ala Ser Thr Leu Gln Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn
100 105 110
Ile Phe Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 81
<211> 471
<212> PRT
<213> Artificial Sequence
<220>
<223> CP870893-IgG2重链氨基酸序列
<400> 81
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Asn Pro Asp Ser Gly Gly Thr Asn Tyr Ala
65 70 75 80
Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
85 90 95
Thr Ala Tyr Met Glu Leu Asn Arg Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Asp Gln Pro Leu Gly Tyr Cys Thr Asn Gly Val
115 120 125
Cys Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
130 135 140
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
145 150 155 160
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
165 170 175
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
180 185 190
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
195 200 205
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln
210 215 220
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
225 230 235 240
Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala
245 250 255
Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
275 280 285
Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
290 295 300
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
305 310 315 320
Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
325 330 335
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg
355 360 365
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
370 375 380
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
385 390 395 400
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
405 410 415
Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
420 425 430
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 82
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH CDR2
<400> 82
Val Ile Ser Tyr Glu Gly Thr Lys Lys Tyr Tyr Ala Glu Ser Val Lys
1 5 10 15
Gly
<210> 83
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> VH
<400> 83
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
Claims (21)
1.能够特异性结合CD40的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含:
(1)下述3个重链可变区(VH)互补决定区(CDR):
(a)VH CDR1,其具有选自以下的结构:
FTFX1X2YX3MH(SEQ ID NO:76),GSISSYYWS(SEQ ID NO:6);
(b)VH CDR2,其具有选自以下的结构:
VIX4YX5X6X7X8KYYAX9SVKG(SEQ ID NO:77),GISWSSX10SIX11YADSVKG(SEQ ID NO:78),SIYYSGSTNYNPSLKS(SEQ ID NO:22);
(c)VH CDR3,其具有选自以下的结构:
ARDTSRGHDI(SEQ ID NO:23),AKDPTATTGARGYFDL(SEQ ID NO:24),ARDANYYKWHPY(SEQID NO:25);
和/或,
(2)下述3个轻链可变区(VL)CDR:
(d)VL CDR1,其具有选自以下的结构:
X12ASQSVSX13X14YLA(SEQ ID NO:79),X15ASX16X17ISSWLA(SEQ ID NO:7);
(e)VL CDR2,其具有选自以下的结构:
GASX18X19X20X21(SEQ ID NO:8),AASX22LX23S(SEQ ID NO:9);
(f)VL CDR3,其具有选自以下的结构:
X24X25YX26DYPPFT(SEQ ID NO:10),QQX27X28SX29PPT(SEQ ID NO:11);
其中,
X1选自(i)氨基酸残基S,E,G,D和(ii)相对于(i)是保守置换的氨基酸残基;
X2选自(i)氨基酸残基S,K,D,T和(ii)相对于(i)是保守置换的氨基酸残基;
X3选自(i)氨基酸残基G,A和(ii)相对于(i)是保守置换的氨基酸残基;
X4选自(i)氨基酸残基S,H和(ii)相对于(i)是保守置换的氨基酸残基;
X5选自(i)氨基酸残基E,H和(ii)相对于(i)是保守置换的氨基酸残基;
X6选自(i)氨基酸残基G,A和(ii)相对于(i)是保守置换的氨基酸残基;
X7选自(i)氨基酸残基S,E,T,V和(ii)相对于(i)是保守置换的氨基酸残基;
X8选自(i)氨基酸残基N,S,I,K和(ii)相对于(i)是保守置换的氨基酸残基;
X9选自(i)氨基酸残基D,E和(ii)相对于(i)是保守置换的氨基酸残基;
X10选自(i)氨基酸残基G,D和(ii)相对于(i)是保守置换的氨基酸残基;
X11选自(i)氨基酸残基G,H和(ii)相对于(i)是保守置换的氨基酸残基;
X12选自(i)氨基酸残基R,Q和(ii)相对于(i)是保守置换的氨基酸残基;
X13选自(i)氨基酸残基Y,S和(ii)相对于(i)是保守置换的氨基酸残基;
X14选自(i)氨基酸残基S,D,N和(ii)相对于(i)是保守置换的氨基酸残基;
X15选自(i)氨基酸残基R,E和(ii)相对于(i)是保守置换的氨基酸残基;
X16选自(i)氨基酸残基Q,K和(ii)相对于(i)是保守置换的氨基酸残基;
X17选自(i)氨基酸残基G,V和(ii)相对于(i)是保守置换的氨基酸残基;
X18选自(i)氨基酸残基S,T,A和(ii)相对于(i)是保守置换的氨基酸残基;
X19选自(i)氨基酸残基R,L和(ii)相对于(i)是保守置换的氨基酸残基;
X20选自(i)氨基酸残基N,A和(ii)相对于(i)是保守置换的氨基酸残基;
X21选自(i)氨基酸残基T,N和(ii)相对于(i)是保守置换的氨基酸残基;
X22选自(i)氨基酸残基S,Y和(ii)相对于(i)是保守置换的氨基酸残基;
X23选自(i)氨基酸残基E,Q和(ii)相对于(i)是保守置换的氨基酸残基;
X24选自(i)氨基酸残基S,G,Q和(ii)相对于(i)是保守置换的氨基酸残基;
X25选自(i)氨基酸残基E,Q,D和(ii)相对于(i)是保守置换的氨基酸残基;
X26选自(i)氨基酸残基A,S和(ii)相对于(i)是保守置换的氨基酸残基;
X27选自(i)氨基酸残基R,H,V和(ii)相对于(i)是保守置换的氨基酸残基;
X28选自(i)氨基酸残基S,L,A和(ii)相对于(i)是保守置换的氨基酸残基;
X29选自(i)氨基酸残基F,Y和(ii)相对于(i)是保守置换的氨基酸残基。
2.权利要求1的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含:
(1)下述3个重链可变区(VH)互补决定区(CDR):
(a)VH CDR1,其具有如FTFX1X2YX3MH(SEQ ID NO:76)所示的结构;
(b)VH CDR2,其具有如VIX4YX5X6X7X8KYYAX9SVKG(SEQ ID NO:77)所示的结构;
(c)VH CDR3,其具有如ARDTSRGHDI(SEQ ID NO:23)所示的结构;
和/或,
(2)下述3个轻链可变区(VL)CDR:
(d)VL CDR1,其具有如X12ASQSVSX13X14YLA(SEQ ID NO:79)所示的结构;
(e)VL CDR2,其具有如GASX18X19X20X21(SEQ ID NO:8)所示的结构;
(f)VL CDR3,其具有如X24X25YX26DYPPFT(SEQ ID NO:10)所示的结构;
其中,
X1选自(i)氨基酸残基S,E,G和(ii)相对于(i)是保守置换的氨基酸残基;
X2选自(i)氨基酸残基S,K和(ii)相对于(i)是保守置换的氨基酸残基;
X3选自(i)氨基酸残基G和(ii)相对于(i)是保守置换的氨基酸残基;
X4选自(i)氨基酸残基S,H和(ii)相对于(i)是保守置换的氨基酸残基;
X5选自(i)氨基酸残基E,H和(ii)相对于(i)是保守置换的氨基酸残基;
X6选自(i)氨基酸残基G,A和(ii)相对于(i)是保守置换的氨基酸残基;
X7选自(i)氨基酸残基S,E,T,V和(ii)相对于(i)是保守置换的氨基酸残基;
X8选自(i)氨基酸残基N,S,I,K和(ii)相对于(i)是保守置换的氨基酸残基;
X9选自(i)氨基酸残基D,E和(ii)相对于(i)是保守置换的氨基酸残基;
X12选自(i)氨基酸残基R,Q和(ii)相对于(i)是保守置换的氨基酸残基;
X13选自(i)氨基酸残基Y,S和(ii)相对于(i)是保守置换的氨基酸残基;
X14选自(i)氨基酸残基S,D,N和(ii)相对于(i)是保守置换的氨基酸残基;
X18选自(i)氨基酸残基S,T,A和(ii)相对于(i)是保守置换的氨基酸残基;
X19选自(i)氨基酸残基R,L和(ii)相对于(i)是保守置换的氨基酸残基;
X20选自(i)氨基酸残基N,A和(ii)相对于(i)是保守置换的氨基酸残基;
X21选自(i)氨基酸残基T,N和(ii)相对于(i)是保守置换的氨基酸残基;
X24选自(i)氨基酸残基S,G,Q和(ii)相对于(i)是保守置换的氨基酸残基;
X25选自(i)氨基酸残基E,Q,D和(ii)相对于(i)是保守置换的氨基酸残基;
X26选自(i)氨基酸残基A,S和(ii)相对于(i)是保守置换的氨基酸残基;
优选地,X1选自氨基酸残基S,E,G;X2选自氨基酸残基S,K;X3为氨基酸残基G;X4选自氨基酸残基S,H;X5选自氨基酸残基E,H;X6选自氨基酸残基G,A;X7选自氨基酸残基S,E,T,V;X8选自氨基酸残基N,S,I,K;X9选自氨基酸残基D,E;X12选自氨基酸残基R,Q;X13选自氨基酸残基Y,S;X14选自氨基酸残基S,D,N;X18选自氨基酸残基S,T,A;X19选自氨基酸残基R,L;X20选自氨基酸残基N,A;X21选自氨基酸残基T,N;X24选自氨基酸残基S,G,Q;X25选自氨基酸残基E,Q,D;X26选自氨基酸残基A,S。
3.权利要求2的抗体或其抗原结合片段,其包含:
如SEQ ID NOs:1-3任一项所示的VH CDR1;如SEQ ID NOs:12-18、82任一项所示的VHCDR2;以及,如SEQ ID NO:23所示的VH CDR3;如SEQ ID NOs:37-40任一项所示的VL CDR1;如SEQ ID NOs:45-50任一项所示的VL CDR2;以及,如SEQ ID NOs:54-57任一项所示的VLCDR3;
优选地,所述抗体或其抗原结合片段包含:
(1)如SEQ ID NO:1所示的VH CDR1;如SEQ ID NO:12所示的VH CDR2;以及,如SEQ IDNO:23所示的VH CDR3;如SEQ ID NO:37所示的VL CDR1;如SEQ ID NO:45所示的VL CDR2;以及,如SEQ ID NO:54所示的VL CDR3;
(2)如SEQ ID NO:1所示的VH CDR1;如SEQ ID NO:13所示的VH CDR2;以及,如SEQ IDNO:23所示的VH CDR3;如SEQ ID NO:37所示的VL CDR1;如SEQ ID NO:45所示的VL CDR2;以及,如SEQ ID NO:54所示的VL CDR3;
(3)如SEQ ID NO:2所示的VH CDR1;如SEQ ID NO:14所示的VH CDR2;以及,如SEQ IDNO:23所示的VH CDR3;如SEQ ID NO:38所示的VL CDR1;如SEQ ID NO:46所示的VL CDR2;以及,如SEQ ID NO:55所示的VL CDR3;
(4)如SEQ ID NO:2所示的VH CDR1;如SEQ ID NO:15所示的VH CDR2;以及,如SEQ IDNO:23所示的VH CDR3;如SEQ ID NO:39所示的VL CDR1;如SEQ ID NO:47所示的VL CDR2;以及,如SEQ ID NO:56所示的VL CDR3;
(5)如SEQ ID NO:2所示的VH CDR1;如SEQ ID NO:16所示的VH CDR2;以及,如SEQ IDNO:23所示的VH CDR3;如SEQ ID NO:39所示的VL CDR1;如SEQ ID NO:48所示的VL CDR2;以及,如SEQ ID NO:57所示的VL CDR3;
(6)如SEQ ID NO:2所示的VH CDR1;如SEQ ID NO:17所示的VH CDR2;以及,如SEQ IDNO:23所示的VH CDR3;如SEQ ID NO:40所示的VL CDR1;如SEQ ID NO:49所示的VL CDR2;以及,如SEQ ID NO:57所示的VL CDR3;
(7)如SEQ ID NO:3所示的VH CDR1;如SEQ ID NO:18所示的VH CDR2;以及,如SEQ IDNO:23所示的VH CDR3;如SEQ ID NO:38所示的VL CDR1;如SEQ ID NO:50所示的VL CDR2;以及,如SEQ ID NO:54所示的VL CDR3;或
(8)如SEQ ID NO:2所示的VH CDR1;如SEQ ID NO:82所示的VH CDR2;以及,如SEQ IDNO:23所示的VH CDR3;如SEQ ID NO:39所示的VL CDR1;如SEQ ID NO:48所示的VL CDR2;以及,如SEQ ID NO:57所示的VL CDR3。
4.权利要求1的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含:
(1)下述3个重链可变区(VH)互补决定区(CDR):
(a)VH CDR1,其具有如FTFX1X2YX3MH(SEQ ID NO:76)所示的结构;
(b)VH CDR2,其具有如GISWSSX10SIX11YADSVKG(SEQ ID NO:78)所示的结构;
(c)VH CDR3,其具有如AKDPTATTGARGYFDL(SEQ ID NO:24)所示的结构;
和/或,
(2)下述3个轻链可变区(VL)CDR:
(d)VL CDR1,其具有如X15ASX16X17ISSWLA(SEQ ID NO:7)所示的结构;
(e)VL CDR2,其具有如AASX22LX23S(SEQ ID NO:9)所示的结构;
(f)VL CDR3,其具有如QQX27X28SX29PPT(SEQ ID NO:11)所示的结构;
其中,
X1选自(i)氨基酸残基D和(ii)相对于(i)是保守置换的氨基酸残基;
X2选自(i)氨基酸残基D,T和(ii)相对于(i)是保守置换的氨基酸残基;
X3选自(i)氨基酸残基A和(ii)相对于(i)是保守置换的氨基酸残基;
X10选自(i)氨基酸残基G,D和(ii)相对于(i)是保守置换的氨基酸残基;
X11选自(i)氨基酸残基G,H和(ii)相对于(i)是保守置换的氨基酸残基;
X15选自(i)氨基酸残基R,E和(ii)相对于(i)是保守置换的氨基酸残基;
X16选自(i)氨基酸残基Q,K和(ii)相对于(i)是保守置换的氨基酸残基;
X17选自(i)氨基酸残基G,V和(ii)相对于(i)是保守置换的氨基酸残基;
X22选自(i)氨基酸残基S,Y和(ii)相对于(i)是保守置换的氨基酸残基;
X23选自(i)氨基酸残基E,Q和(ii)相对于(i)是保守置换的氨基酸残基;
X27选自(i)氨基酸残基R,H和(ii)相对于(i)是保守置换的氨基酸残基;
X28选自(i)氨基酸残基S,A和(ii)相对于(i)是保守置换的氨基酸残基;
X29选自(i)氨基酸残基F和(ii)相对于(i)是保守置换的氨基酸残基;
优选地,X1为氨基酸残基D;X2选自氨基酸残基D,T;X3为氨基酸残基A;X10选自氨基酸残基G,D;X11选自氨基酸残基G,H;X15选自氨基酸残基R,E;X16选自氨基酸残基Q,K;X17选自氨基酸残基G,V;X22选自氨基酸残基S,Y;X23选自氨基酸残基E,Q;X27选自氨基酸残基R,H;X28选自氨基酸残基S,A;X29为氨基酸残基F。
5.权利要求4的抗体或其抗原结合片段,其包含:
如SEQ ID NOs:4或5所示的VH CDR1;如SEQ ID NOs:19-21任一项所示的VH CDR2;以及,如SEQ ID NO:24所示的VH CDR3;如SEQ ID NOs:41-43任一项所示的VL CDR1;如SEQ IDNOs:51-53任一项所示的VL CDR2;以及,如SEQ ID NOs:58或59所示的VL CDR3;
优选地,所述抗体或其抗原结合片段包含:
(1)如SEQ ID NO:4所示的VH CDR1;如SEQ ID NO:19所示的VH CDR2;以及,如SEQ IDNO:24所示的VH CDR3;如SEQ ID NO:41所示的VL CDR1;如SEQ ID NO:51所示的VL CDR2;以及,如SEQ ID NO:58所示的VL CDR3;
(2)如SEQ ID NO:4所示的VH CDR1;如SEQ ID NO:20所示的VH CDR2;以及,如SEQ IDNO:24所示的VH CDR3;如SEQ ID NO:42所示的VL CDR1;如SEQ ID NO:52所示的VL CDR2;以及,如SEQ ID NO:59所示的VL CDR3;或
(3)如SEQ ID NO:5所示的VH CDR1;如SEQ ID NO:21所示的VH CDR2;以及,如SEQ IDNO:24所示的VH CDR3;如SEQ ID NO:43所示的VL CDR1;如SEQ ID NO:53所示的VL CDR2;以及,如SEQ ID NO:59所示的VL CDR3。
6.权利要求1的抗体或其抗原结合片段,其包含:
如SEQ ID NO:6所示的VH CDR1;如SEQ ID NO:22所示的VH CDR2;以及,如SEQ ID NO:25所示的VH CDR3;如SEQ ID NO:44所示的VL CDR1;如SEQ ID NO:45所示的VL CDR2;以及,如SEQ ID NO:60所示的VL CDR3。
7.权利要求1-6任一项的抗体或其抗原结合片段,所述抗体或其抗原结合片段进一步包含人免疫球蛋白的框架区;
例如,所述抗体或其抗原结合片段包含人胚系抗体基因所编码的氨基酸序列中所包含的框架区;例如,所述抗体或其抗原结合片段包含:人重链胚系基因所编码的氨基酸序列中所包含的重链框架区,和/或人轻链胚系基因所编码的氨基酸序列中所包含的轻链框架区。
8.权利要求1-7任一项的抗体或其抗原结合片段,其包含:
(1)重链可变区(VH),其包含选自下列的氨基酸序列:
(i)如SEQ ID NOs:26-36、83任一项所示的序列;
(ii)与SEQ ID NOs:26-36、83任一项所示的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加)的序列;或
(iii)与SEQ ID NOs:26-36、83任一项所示的序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列;
和/或,
(2)轻链可变区(VL),其包含选自下列的氨基酸序列:
(i)如SEQ ID NOs:61-70任一项所示的序列;
(ii)与SEQ ID NOs:61-70任一项所示的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加)的序列;或
(iii)与SEQ ID NOs:61-70任一项所示的序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列;
优选地,所述抗体或其抗原结合片段包含:
(a)包含如SEQ ID NOs:26-32、83任一项所示的序列或其变体的VH,和,包含如SEQ IDNOs:61-66任一项所示的序列或其变体的VL;
或,
(b)包含如SEQ ID NOs:33-35任一项所示的序列或其变体的VH,和,包含如SEQ IDNOs:67-69任一项所示的序列或其变体的VL;
其中,所述变体与其所源自的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加),或具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列;优选地,所述的置换是保守置换;
例如,所述抗体或其抗原结合片段包含如SEQ ID NO:26所示的序列或其变体的VH,和,如SEQ ID NO:61所示的序列或其变体的VL;
例如,所述抗体或其抗原结合片段包含如SEQ ID NO:27所示的序列或其变体的VH,和,如SEQ ID NO:61所示的序列或其变体的VL;
例如,所述抗体或其抗原结合片段包含如SEQ ID NO:28所示的序列或其变体的VH,和,如SEQ ID NO:62所示的序列或其变体的VL;
例如,所述抗体或其抗原结合片段包含如SEQ ID NO:29所示的序列或其变体的VH,和,如SEQ ID NO:63所示的序列或其变体的VL;
例如,所述抗体或其抗原结合片段包含如SEQ ID NO:30所示的序列或其变体的VH,和,如SEQ ID NO:64所示的序列或其变体的VL;
例如,所述抗体或其抗原结合片段包含如SEQ ID NO:31所示的序列或其变体的VH,和,如SEQ ID NO:65所示的序列或其变体的VL;
例如,所述抗体或其抗原结合片段包含如SEQ ID NO:32所示的序列或其变体的VH,和,如SEQ ID NO:66所示的序列或其变体的VL;
例如,所述抗体或其抗原结合片段包含如SEQ ID NO:33所示的序列或其变体的VH,和,如SEQ ID NO:67所示的序列或其变体的VL;
例如,所述抗体或其抗原结合片段包含如SEQ ID NO:34所示的序列或其变体的VH,和,如SEQ ID NO:68所示的序列或其变体的VL;
例如,所述抗体或其抗原结合片段包含如SEQ ID NO:35所示的序列或其变体的VH,和,如SEQ ID NO:69所示的序列或其变体的VL;
例如,所述抗体或其抗原结合片段包含如SEQ ID NO:36所示的序列或其变体的VH,和,如SEQ ID NO:70所示的序列或其变体的VL;
例如,所述抗体或其抗原结合片段包含如SEQ ID NO:83所示的序列或其变体的VH,和,如SEQ ID NO:64所示的序列或其变体的VL;
其中,所述变体与其所源自的序列相比具有一个或几个氨基酸的置换、缺失或添加(例如1个,2个,3个,4个或5个氨基酸的置换、缺失或添加),或具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的序列;优选地,所述的置换是保守置换。
9.权利要求1-8任一项所述的抗体或其抗原结合片段,其进一步包含来源于人免疫球蛋白的恒定区;
优选地,所述抗体或其抗原结合片段的重链包含来源于人免疫球蛋白(例如IgG1、IgG2、IgG3或IgG4)的重链恒定区;
优选地,所述抗体或其抗原结合片段的轻链包含来源于人免疫球蛋白(例如κ或λ)的轻链恒定区。
10.权利要求1-9任一项所述的抗体或其抗原结合片段,其中,所述抗原结合片段选自Fab、Fab’、(Fab’)2、Fv、二硫键连接的Fv、scFv、双抗体(diabody)和单域抗体(sdAb);和/或,所述抗体为嵌合抗体、双特异性抗体或多特异性抗体。
11.分离的核酸分子,其编码权利要求1-10任一项所述的抗体或其抗原结合片段,或其重链可变区和/或轻链可变区。
12.载体,其包含权利要求11所述的核酸分子;优选地,所述载体为克隆载体或表达载体。
13.宿主细胞,其包含权利要求11所述的核酸分子或权利要求12所述的载体。
14.制备权利要求1-10任一项所述的抗体或其抗原结合片段的方法,其包括,在允许所述抗体或其抗原结合片段表达的条件下,培养权利要求13所述的宿主细胞,和从培养的宿主细胞培养物中回收所述抗体或其抗原结合片段。
15.药物组合物,其包含权利要求1-10任一项所述的抗体或其抗原结合片段,以及药学上可接受的载体和/或赋形剂。
16.权利要求1-10任一项所述的抗体或其抗原结合片段、权利要求11所述的分离的核酸分子、权利要求12所述的载体或权利要求13所述的宿主细胞用于制备药物的用途,所述药物用于在受试者中激活CD40,提高免疫细胞活性,增强免疫应答,和/或预防和/或治疗肿瘤或者感染;
优选地,所述免疫细胞是T细胞,B细胞,DC细胞,巨噬细胞,和/或,NK细胞;
优选地,所述免疫应答是CD40介导的免疫应答;
优选地,所述受试者为哺乳动物,例如人;
优选地,所述抗体或其抗原结合片段单独使用,或与另外的药学活性剂联合使用。
17.一种用于在受试者中增强免疫应答,和/或,预防和/或治疗肿瘤或感染的方法;所述方法包括:给有此需要的受试者施用有效量的权利要求1-10任一项所述的抗体或其抗原结合片段或权利要求15所述的药物组合物;
优选地,所述免疫应答是CD40介导的免疫应答;
优选地,所述受试者为哺乳动物,例如人。
18.缀合物,其包含权利要求1-10任一项所述的抗体或其抗原结合片段,以及与所述抗体或其抗原结合片段连接的可检测的标记;
优选地,所述可检测的标记选自酶(例如辣根过氧化物酶或碱性磷酸酶)、化学发光试剂(例如吖啶酯类化合物、鲁米诺及其衍生物、或钌衍生物)、荧光染料(例如荧光素或荧光蛋白)、放射性核素或生物素。
19.试剂盒,其包括权利要求1-10任一项所述的抗体或其抗原结合片段或权利要求18所述的缀合物;
优选地,所述试剂盒包含权利要求18所述的缀合物;
优选地,所述试剂盒包含权利要求1-10任一项所述的抗体或其抗原结合片段,以及特异性识别所述抗体或其抗原结合片段的第二抗体;任选地,所述第二抗体还包括可检测的标记,例如酶(例如辣根过氧化物酶或碱性磷酸酶)、化学发光试剂(例如吖啶酯类化合物、鲁米诺及其衍生物、或钌衍生物)、荧光染料(例如荧光素或荧光蛋白)、放射性核素或生物素。
20.用于检测CD40在样品中的存在或其水平的方法,其包括使用权利要求1-10任一项所述的抗体或其抗原结合片段或权利要求18所述的缀合物;
优选地,所述方法是免疫学检测,例如免疫印迹法、酶免疫测定法(例如ELISA)、化学发光免疫分析法、荧光免疫分析法或放射免疫测定法;
优选地,所述方法包括使用权利要求18所述的缀合物;
优选地,所述方法包括使用权利要求1-10任一项所述的抗体或其抗原结合片段,并且所述方法还包括使用携带可检测的标记(例如酶(例如辣根过氧化物酶或碱性磷酸酶)、化学发光试剂(例如吖啶酯类化合物、鲁米诺及其衍生物、或钌衍生物)、荧光染料(例如荧光素或荧光蛋白)、放射性核素或生物素)的第二抗体来检测所述抗体或其抗原结合片段。
21.权利要求1-10任一项所述的抗体或其抗原结合片段或权利要求18所述的缀合物在制备检测试剂中的用途,所述检测试剂用于检测CD40在样品中的存在或其水平;
优选地,所述检测试剂通过权利要求20所述的方法来检测CD40在样品中的存在或其水平;
优选地,所述样品为来自受试者(例如哺乳动物,优选人或食蟹猴)的细胞样品(例如,免疫细胞)。
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