CN114127118B - 一种分离的抗原结合蛋白及其应用 - Google Patents
一种分离的抗原结合蛋白及其应用 Download PDFInfo
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Abstract
一种分离的抗原结合蛋白,其具有下述性质中的一种或多种:1)能够以7x10‑12或更低的KD值结合源自人和猴的GITR蛋白,其中所述KD值通过BLI法测定;2)能够刺激免疫细胞增殖;3)能够刺激免疫细胞分泌IFN‑γ,所述分泌在T细胞活性测定中测得;4)能够抑制肿瘤生长和/或肿瘤细胞增殖;5)能够激活GITR信号通路;6)能够抑制GITR与GITRL结合。
Description
技术领域
本申请涉及生物医药领域,具体的涉及一种分离的抗原结合蛋白及其应用。
背景技术
GITR是TNF受体家族的一个成员,GITR是分子量大小约为26kDa的I型跨膜蛋白,和TNF受体家族其它分子有14-28%的同源性(Gurney AL,et al,1999)。GITR组成型在Treg上高表达,在未活化的CD4+T细胞、CD8+T细胞、NK和NKT细胞上低表达。当T细胞活化后,GITR在CD4+T、CD8+T和NK细胞高表达升高(S.Ronchetti,et al.,2004)。GITR天然配体GITRL在APC上表达,GITRL结合GITR后,提供共刺激信号,调节抗原特异性T细胞应答,加强细胞免疫和体液免疫(Selvakumar Sukumar,et al.,2017)。
发明内容
本申请提供了一种分离的抗原结合蛋白,其具有下述性质中的一种或多种:1)能够以7x10-12M或更低的KD值结合源自人和猴的GITR蛋白,其中所述KD值通过BLI法测定;2)能够刺激免疫细胞增殖;3)能够刺激免疫细胞分泌IFN-γ,所述分泌在T细胞活性测定中测得;4)能够抑制肿瘤生长和/或肿瘤细胞增殖;5)能够激活GITR信号通路;6)能够抑制GITR与GITRL结合。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包含氨基酸序列如SEQ IDNO:23所示的VH中的至少一个CDR。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包含氨基酸序列如SEQ IDNO:23所示的VH中的HCDR3。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包含氨基酸序列如SEQ IDNO:23所示的VH中的HCDR2。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包含氨基酸序列如SEQ IDNO:23所示的VH中的HCDR1。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包含氨基酸序列如SEQ IDNO:24所示的VL中的至少一个CDR。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包含氨基酸序列如SEQ IDNO:24所示的VL中的LCDR1。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包含氨基酸序列如SEQ IDNO:24所示的VL中的LCDR2。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包含氨基酸序列如SEQ IDNO:24所示的VL中的LCDR3。
在某些实施方式中,所述HCDR3包含SEQ ID NO:4所示的氨基酸序列。
在某些实施方式中,所述HCDR1包含SEQ ID NO:2所示的氨基酸序列。
在某些实施方式中,所述HCDR2包含SEQ ID NO:3所示的氨基酸序列。
在某些实施方式中,所述LCDR1包含SEQ ID NO:10所示的氨基酸序列。
在某些实施方式中,所述LCDR2包含SEQ ID NO:11所示的氨基酸序列。
在某些实施方式中,所述LCDR3包含SEQ ID NO:12所示的氨基酸序列。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包括抗体或其抗原结合片段。
在某些实施方式中,所述抗原结合片段包括Fab,Fab’,F(ab)2、Fv片段、F(ab’)2,scFv,di-scFv和/或dAb。
在某些实施方式中,所述抗体为人源化抗体。
在某些实施方式中,本申请所述的分离的抗原结合蛋白与参比抗体竞争结合GITR蛋白,其中所述参比抗体包含氨基酸序列如SEQ ID NO:23所示的VH中的HCDR1-3以及氨基酸序列如SEQ ID NO:24所示的VL中的LCDR1-3。
在某些实施方式中,所述参比抗体的HCDR1-3分别包含SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的氨基酸序列,且所述参比抗体的LCDR1-3分别包含SEQ ID NO:10、SEQID NO:11和SEQ ID NO:12所示的氨基酸序列。
在某些实施方式中,所述参比抗体的轻链可变区包含SEQ ID NO:24所示的氨基酸序列;且所述参比抗体的重链可变区包含SEQ ID NO:23所示的氨基酸序列。
在某些实施方式中,所述参比抗体的轻链包含SEQ ID NO:64、46-48中任一项所示的氨基酸序列;且所述参比抗体的重链包含SEQ ID NO:63、43-45中任一项所示的氨基酸序列。
在某些实施方式中,所述VL包括框架区L-FR1,L-FR2,L-FR3,和L-FR4。
在某些实施方式中,所述L-FR1的C末端与所述LCDR1的N末端直接或间接相连,且所述L-FR1包含SEQ ID NO:39所示的氨基酸序列。
在某些实施方式中,所述L-FR1包含SEQ ID NO:13、30、34中任一项所示的氨基酸序列。
在某些实施方式中,所述L-FR2位于所述LCDR1与所述LCDR2之间,且所述L-FR2包含SEQ ID NO:40所示的氨基酸序列。
在某些实施方式中,所述L-FR2包含SEQ ID NO:14、31中任一项所示的氨基酸序列。
在某些实施方式中,所述L-FR3位于所述LCDR2与所述LCDR3之间,且所述L-FR3包含SEQ ID NO:41所示的氨基酸序列。
在某些实施方式中,所述L-FR3包含SEQ ID NO:15、32中任一项所示的氨基酸序列。
在某些实施方式中,所述L-FR4的N末端与所述LCDR3的C末端相连,且所述L-FR4包含SEQ ID NO:42所示的氨基酸序列。
在某些实施方式中,所述L-FR4包含SEQ ID NO:16、33中任一项所示的氨基酸序列。
在某些实施方式中,所述VL包含SEQ ID NO:24所示的氨基酸序列。
在某些实施方式中,所述VL包含SEQ ID NO:9、20-22中任一项所示的氨基酸序列。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包括抗体轻链恒定区,且所述抗体轻链恒定区包括人Igκ恒定区。
在某些实施方式中,所述抗体轻链恒定区包含SEQ ID NO:55所示的氨基酸序列。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包含抗体轻链LC,且所述LC包含SEQ ID NO:64、46-48中任一项所示的氨基酸序列。
在某些实施方式中,所述VH包括框架区H-FR1,H-FR2,H-FR3,和H-FR4。
在某些实施方式中,所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连,且所述H-FR1包含SEQ ID NO:35所示的氨基酸序列。
在某些实施方式中,所述H-FR1包含SEQ ID NO:5、25、29中任一项所示的氨基酸序列。
在某些实施方式中,所述H-FR2位于所述HCDR1与所述HCDR2之间,且所述H-FR2包含SEQ ID NO:36所示的氨基酸序列。
在某些实施方式中,所述H-FR2包含SEQ ID NO:6、26中任一项所示的氨基酸序列。
在某些实施方式中,所述H-FR3位于所述HCDR2与所述HCDR3之间,且所述H-FR3包含SEQ ID NO:37所示的氨基酸序列。
在某些实施方式中,所述H-FR3包含SEQ ID NO:7、27中任一项所示的氨基酸序列。
在某些实施方式中,所述H-FR4的N末端与所述HCDR3的C末端相连,且所述H-FR4包含SEQ ID NO:38所示的氨基酸序列。
在某些实施方式中,所述H-FR4包含SEQ ID NO:8、28中任一项所示的氨基酸序列。
在某些实施方式中,所述VH包含SEQ ID NO:23所示的氨基酸序列。
在某些实施方式中,所述VH包含SEQ ID NO:1、17-19中任一项所示的氨基酸序列。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包括抗体重链恒定区,且所述抗体重链恒定区源自人IgG重链恒定区。
在某些实施方式中,所述抗体重链恒定区源自人IgG1重链恒定区。
在某些实施方式中,所述抗体重链恒定区包含SEQ ID NO:53所示的氨基酸序列。
在某些实施方式中,本申请所述的分离的抗原结合蛋白,其包含抗体重链HC,且所述HC包含SEQ ID NO:63、43-45中任一项所示的氨基酸序列。
另一方面,本申请还提供了分离的一种或多种核酸分子,其编码本申请所述的分离的抗原结合蛋白。
另一方面,本申请还提供了载体,其包含本申请所述的核酸分子。
另一方面,本申请还提供了细胞,其包含本申请所述的核酸分子或本申请所述的载体。
另一方面,本申请还提供了制备本申请所述的分离的抗原结合蛋白的方法,所述方法包括在使得本申请所述的分离的抗原结合蛋白表达的条件下,培养本申请所述的细胞。
另一方面,本申请还提供了药物组合物,其包含本申请所述的分离的抗原结合蛋白、本申请所述的核酸分子、本申请所述的载体和/或本申请所述的细胞,以及任选地药学上可接受的佐剂。
另一方面,本申请还提供了本申请所述的分离的抗原结合蛋白、本申请所述的核酸分子、本申请所述的载体、本申请所述的细胞和/或本申请所述的药物组合物在制备药物中的用途,所述药物用于预防、缓解和/或治疗肿瘤。
另一方面,本申请还提供了抑制GITR与GITR配体GITRL结合的方法,所述方法包括施用本申请所述的分离的抗原结合蛋白。
另一方面,本申请还提供了预防、缓解或治疗肿瘤的方法,所述方法包括向有需要的受试者施用本申请所述的分离的抗原结合蛋白。
另一方面,本申请还提供了激活GITR的方法,所述方法包括施用本申请所述的分离的抗原结合蛋白。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的,本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地,本申请的附图和说明书中的描述仅仅是示例性的,而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明书如下:
图1A-1D显示的是本申请所述的分离的抗原结合蛋白与细胞表面GITR结合能力检测结果;
图2显示的是本申请所述的分离的抗原结合蛋白的激活活性检测结果;
图3显示的是本申请所述的分离的抗原结合蛋白刺激T细胞增殖情况;
图4显示的是本申请所述的分离的抗原结合蛋白刺激免疫细胞分泌IFN-γ的结果;
图5显示的是本申请所述的分离的抗原结合蛋白与人GITR蛋白结合能力检测结果;
图6显示的是本申请所述的分离的抗原结合蛋白与人GITR蛋白结合能力检测结果;
图7显示的是本申请所述的分离的抗原结合蛋白与猴GITR蛋白结合能力检测结果;
图8显示的是本申请所述的分离的抗原结合蛋白与猴GITR蛋白结合能力检测结果;
图9显示的是本申请所述的分离的抗原结合蛋白激活下游信号通路的结果;
图10显示的是本申请所述的分离的抗原结合蛋白刺激T细胞增殖情况;
图11显示的是本申请所述的分离的抗原结合蛋白刺激免疫细胞分泌IFN-γ的结果;
图12显示的是本申请所述的分离的抗原结合蛋白3E2 1-3的稳定性检测结果;
图13显示的是本申请所述的分离的抗原结合蛋白3E2 1-4的稳定性检测结果;
图14显示的是本申请所述的分离的抗原结合蛋白3E2 2-3的稳定性检测结果;
图15显示的是本申请所述的分离的抗原结合蛋白3E2 1-3的聚丙烯酰胺凝胶电泳(SDS-PAGE)检测结果;
图16显示的是本申请所述的分离的抗原结合蛋白3E2 1-4的聚丙烯酰胺凝胶电泳(SDS-PAGE)检测结果;
图17显示的是本申请所述的分离的抗原结合蛋白3E2 2-3的聚丙烯酰胺凝胶电泳(SDS-PAGE)检测结果;
图18显示的是本申请所述的分离的抗原结合蛋白3E2 1-3的尺寸排阻色谱-高效液相色谱(SEC-HPLC)分析结果;
图19显示的是本申请所述的分离的抗原结合蛋白3E2 1-4的尺寸排阻色谱-高效液相色谱(SEC-HPLC)分析结果;
图20显示的是本申请所述的分离的抗原结合蛋白3E2 2-3的尺寸排阻色谱-高效液相色谱(SEC-HPLC)分析结果。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式,熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
以下对本申请做进一步描述: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,本文中所用的蛋白质和核酸化学、分子生物学、细胞和组织培养、微生物学、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,为了更好地理解本发明,下面提供相关术语的定义和解释。
在本申请中,术语“分离的”通常指从天然状态下经人工手段获得的。如果自然界中出现某一种“分离”的物质或成分,那么可能是其所处的天然环境发生了改变,或从天然环境下分离出该物质,或二者情况均有发生。例如,某一活体动物体内天然存在某种未被分离的多聚核苷酸或多肽,而从这种天然状态下分离出来的高纯度的相同的多聚核苷酸或多肽即称之为分离的。术语“分离的”不排除混有人工或合成的物质,也不排除存在不影响物质活性的其它不纯物质。
在本申请中,术语“分离的抗原结合蛋白”通常指从天然状态下经人工手段获得的具有抗原结合能力的蛋白。该“分离的抗原结合蛋白”可以包含结合抗原的部分和任选地,允许抗原结合部分采用促进所述抗原结合部分结合抗原的构象的支架或构架部分。抗原结合蛋白可以包含例如抗体来源的蛋白支架或具有移植的CDR或CDR衍生物的备选蛋白支架或人工支架。此类支架包括,但不限于包含被引入例如以稳定抗原结合蛋白的三维结构的突变的抗体来源的支架以及包含例如生物相容性聚合物的完全合成的支架。参见例如Korndorfer等,2003,Proteins:Structure,Function,andBioinformatics,53(1):121-129(2003);Roque等,Biotechnol.Prog.20:639-654(2004)。此外,肽抗体模拟物("PAMs")以及利用纤连蛋白组分基于抗体模拟物的支架可以用作支架。例如,本申请所述的分离的抗原结合蛋白能够以7x10-12或更低的KD值结合源自人和猴的GITR蛋白,其中所述KD值通过BLI法测定。
在本申请中,术语“KD”(同样地,“Kd”或“KD”)通常指“平衡解离常数”,并指在滴定测量中在平衡时、或者通过将解离速率常数(koff)除以结合速率常数(kon)所获得的值。使用结合速率常数(kon)、解离速率常数(koff)和平衡解离常数(KD)表示结合蛋白(例如本申请所述的分离的抗原结合蛋白)对抗原的结合亲和力。确定结合和解离速率常数的方法为本领域熟知。使用基于荧光的技术提供了高灵敏度以及在生理缓冲液中在平衡时检查样品的能力。可以使用其他实验途径和仪器例如BIAcore(生物分子相互作用分析)测定(例如,可以从BIAcoreInternationalAB,aGEHealthcarecompany,Uppsala,瑞典获得的仪器)。另外,也可以使用可以从SapidyneInstruments(Boise,Idaho)获得的KinExA(动态排阻测定(KineticExclusionAssay))测定。例如,本申请所述的分离的抗原结合蛋白的结合源自人和猴的GITR蛋白的KD值可以通过BLI(即,生物膜层光学干涉技术,Bio-LayerInterferometry)法测定。
在本申请中,术语“免疫细胞”通常指具有造血的起源并在免疫应答中起作用的细胞。例如,所述免疫细胞可以选自下组一种或多种:淋巴细胞、天然杀伤细胞和髓样细胞。所述淋巴细胞可以为B细胞和/或T细胞。所述髓样细胞可以选自下组一种或多种:单核细胞、巨噬细胞、嗜酸性粒细胞、肥大细胞和嗜碱性粒细胞。
在本申请中,术语“IFN-γ”通常指γ-干扰素(Interferon-γ,IFN-γ),是水溶性二聚体细胞因子。例如,本申请所述的分离的抗原结合蛋白能够刺激免疫细胞分泌IFN-γ,所述分泌可以在T细胞活性测定中测得。
在本申请中,术语“GITR”通常指“糖皮质激素诱导的TNF相关基因”,在本领域中也称为TNF受体超家族18(TNFRSF18)。人和鼠形式的GITR的氨基酸和核酸序列描述于WO98/06842中,其以引用的方式并入本文。也参见GenBank寄存号Q9Y5U5(人氨基酸序列)和AF109216(鼠核酸和氨基酸序列)。成熟的人GITR多肽的一个特定实例的氨基酸序列陈述于SEQ ID NO:49中。来自食蟹猴的示例性成熟GITR蛋白具有如SEQ ID NO:51所示的氨基酸序列。此外,术语“GITR”也包括天然存在的等位基因。
在本申请中,术语“GITRL”通常指整个GITR配体、可溶性GITR配体和GITR配体的功能活性部分。GITRL的定义内还包括GITRL的天然存在的等位基因变体、与天然存在的GI TR配体分子在氨基酸序列上不同的GITR配体变体、以及这样的变体的组合,其中这些变体保留特异性地结合GITR受体的能力。
在本申请中,术语“激活”通常指使目标分子由非活化状态转变为活化状态,或者由低活性状态转变为高活性状态。例如,在本申请中,本申请所述的分离的抗原结合蛋白能够激活GITR信号通路,使GITR由非活化状态转变为活化状态,或者由低活性状态转变为高活性状态。
在本申请中,术语“抑制”通常指降低分子和其特异性结合配偶体之间(比如配体及其特异性受体之间)的结合活性。例如,本申请所述的分离的抗原结合蛋白,其能够抑制GITR与GITR配体GITRL结合,即阻断GITRL及其受体GITR之间的相互作用,将T细胞的功能响应从功能失调状态修复为抗原刺激状态。
在本申请中,术语“可变结构域”通常指抗体重链或轻链的氨基末端结构域。重链和轻链的可变结构域可以分别称为“VH”和“VL”。这些结构域通常是抗体的变化最大的部分(相对于相同类型的其它抗体),且包含抗原结合位点。
在本申请中,术语“可变”通常指在抗体之间可变结构域的某些区段在序列上存在很大差异的事实。V结构域介导抗原结合并决定特定抗体对其特定抗原的特异性。然而,可变性并非在整个可变结构域范围内均匀分布。相反,它集中在轻链和重链可变结构域中称为高变区(CDR或HVR)的三个区段中。可变结构域的更高度保守的部分称为框架区(FR)。天然重链和轻链的可变结构域各自包含四个FR区,大多数采用β-折叠构型,通过三个CDR连接,其形成环形连接,并且在一些情况下形成β-折叠结构的一部分。每条链中的CDR通过FR区紧密靠近地保持在一起,并且来自另一条链的CDR一同促进抗体的抗原结合位点的形成(参见Kabat et al,Sequences of Immunological Interest,Fifth Edition,NationalInstitute of Health,Bethesda,Md.(1991))。恒定结构域不直接参与抗体与抗原的结合,但显示出各种效应子功能,例如抗体参与抗体依赖性细胞毒性。
在本申请中,术语“抗体”通常指免疫球蛋白或其片段或其衍生物,涵盖包括抗原结合位点的任何多肽,无论其是在体外还是体内产生的。该术语包括但不限于多克隆的、单克隆的、单特异性的、多特异性的、非特异性的、人源化的、单链的、嵌合的、合成的、重组的、杂化的、突变的和移植的抗体。除非另外被术语“完整的”修饰,如在“完整的抗体”中,为了本发明的目的,术语“抗体”也包括抗体片段,比如Fab、F(ab')2、Fv、scFv、Fd、dAb和保持抗原结合功能(例如,特异性结合GITR)的其它抗体片段。通常,这样的片段应当包括抗原结合结构域。基本的4链抗体单元是由两个相同的轻(L)链和两个相同的重(H)链组成的异四聚体糖蛋白。IgM抗体由5个基本的异四聚体单元与另外一个称为J链的多肽组成,且含有10个抗原结合位点,而IgA抗体包括2-5个可以与J链相结合聚合形成多价组合的基本4链单元。就IgG而言,4链单元一般为约150,000道尔顿。每个L链通过一个共价二硫键与H链连接,而两个H链通过一个或多个取决于H链同种型的二硫键相互连接。每个H和L链还具有规则间隔的链内二硫化桥键。每个H链在N末端具有可变结构域(VH),对于α和γ链各自继之以三个恒定结构域(CH)、对于μ和ε同种型继之以四个CH结构域。每个L链在N末端具有可变结构域(VL),在其另一端具有恒定结构域。VL与VH对应,且CL与重链的第一恒定结构域(CH1)相对应。特定的氨基酸残基被认为在轻链和重链可变结构域之间形成界面。VH和VL配对一起形成单个抗原结合位点。对于不同类别抗体的结构和性质,参见例如Basic and ClinicalImmunology,8th Edition,Daniel P.Sties,Abba I.Terr and Tristram G.Parsolw(eds),Appleton&Lange,Norwalk,Conn.,1994,第71页和第6章。来自任何脊椎动物物种的L链可以基于其恒定结构域的氨基酸序列被分为两种明显不同的类型中的一种,称为κ和λ。取决于其重链(CH)恒定结构域的氨基酸序列,可以将免疫球蛋白分为不同的类别或同种型。存在五类免疫球蛋白:IgA、IgD、IgE、IgG和IgM,具有分别被命名为α、δ、ε、γ和μ的重链。基于CH序列和功能方面的相对小的差异,将γ和α类进一步分成亚类,例如,人表达下述亚类:IgG1、IgG2A、IgG2B、IgG3、IgG4、IgA1和IgK1。
在本申请中,术语“CDR”通常指抗体可变结构域的区域,其序列是高度可变的和/或形成结构定义环。通常,抗体包括六个CDR;在VH中三个(HCDR1、HCDR2、HCDR3),和在VL中三个(LCDR1、LCDR2、LCDR3)。在天然抗体中,HCDR3和LCDR3显示所述六个CDR的大多数多样性,并且特别地HCDR3被认为在赋予抗体的精细特异性方面起独特作用。参见,例如Xu etal,Immunity 13:37-45(2000);Johnson and Wu,in Methods in Molecular Biology248:1-25(Lo,ed.,Human Press,Totowa,N.J.,2003)。实际上,仅由重链组成的天然存在的骆驼抗体在缺乏轻链的情况功能正常且稳定。参见,例如,Hamers-Casterman et al.,Nature363:446-448(1993);Sheriff et al,Nature Struct.Biol.3:733-736(1996)。
在本申请中,术语“FR”通常指抗体可变结构域的更高度保守的部分,其被称为框架区。通常,天然重链和轻链的可变结构域各自包含四个FR区,即在VH中四个(H-FR1,H-FR2,H-FR3,和H-FR4),和在VL中四个(L-FR1,L-FR2,L-FR3,和L-FR4)。例如,本申请所述的分离的抗原结合蛋白的VL可以包括框架区L-FR1,L-FR2,L-FR3,和L-FR4。本申请所述的分离的抗原结合蛋白的VH可以包括框架区H-FR1,H-FR2,H-FR3,和H-FR4。
在本申请中,术语“抗原结合片段”通常指具有抗原结合活性的片段。在本申请中,所述抗原结合片段可以包括Fab,Fab’,F(ab)2、Fv片段、F(ab’)2,scFv,di-scFv和/或dAb。
在本申请中,术语“竞争结合”通常指抗体或其片段通过对另一种抗体(例如,参比抗体)进行变构调节,干扰另一种抗体直接地或间接地结合靶标/抗原(例如,GITR)的能力。例如,在本申请中,所述分离的抗原结合蛋白可以与参比抗体竞争结合GITR蛋白。此外,抗体或其片段能够干扰另一个抗体或其片段结合靶标的程度,且因此无论其是否可以被认为是根据本发明的阻断或竞争,都可以使用竞争性结合试验来确定。一种特别合适的定量竞争试验使用基于FACS或基于AlphaScreen方法测量标记的(例如,His标记的、生物素化的或放射性标记的)抗体或其片段和另一抗体或其片段之间在结合靶标方面的竞争。通常,竞争抗体或其片段为例如一种下述的:在竞争试验中结合靶标,使得在试验期间和在第二抗体或其片段的存在下,本发明的分离的抗原结合蛋白的所记录的取代达到由以给定量存在的所检测的潜在阻断抗体或其片段得到的最大理论取代(例如,由需要被阻断的冷(例如,未标记的)抗体或其片段取代)的至多100%(例如,在基于FACS的竞争试验中)。例如,竞争抗体或其片段具有在10%至100%之间,比如在50%至100%之间的所记录的取代。
在本申请中,术语“直接相连”与术语“间接相连”相对,术语“直接相连”通常是指直接连接。例如,所述直接相连可以为物质间没有间隔子而直接相连的情况。所述间隔子可以是连接子。例如,所述连接子可以为肽连接子。术语“间接相连”通常是指物质间不直接相连的情况。例如,所述间接相连可以为通过间隔子而连接的情况。例如,在本申请所述的分离的抗原结合蛋白中,所述L-FR1的C末端与所述LCDR1的N末端可以直接或间接相连。
在本申请中,术语“分离的核酸分子”通常指任何长度的分离形式的核苷酸,脱氧核糖核苷酸或核糖核苷酸,或从其天然环境分离的或人工合成的类似物。
在本申请中,术语“载体”通常指可将编码某蛋白的多聚核苷酸插入其中并使蛋白获得表达的一种核酸运载工具。载体可通过转化、转导或转染宿主细胞,使其携带的遗传物质元件在宿主细胞内表达得以表达。举例来说,载体包括:质粒;噬菌粒;柯斯质粒;人工染色体如酵母人工染色体(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。用作载体的动物病毒种类有逆转录酶病毒(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)。一种载体可能含有多种控制表达的元件,包括启动子序列、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。载体还有可能包括有协助其进入细胞的成分,如病毒颗粒、脂质体或蛋白外壳,但不仅仅只有这些物质。
在本申请中,术语“细胞”通常指可以是或已经是受试者质粒或载体的接受者的单个细胞、细胞系或细胞培养物,其包括本发明所述的核酸分子或本发明所述的载体。细胞可以包括单个细胞的后代。由于天然、偶然或有意的突变,后代可以不一定与原始母细胞完全相同(在总DNA互补体的形态上或在基因组上)。细胞可包括用本发明所述的载体在体外转染的细胞。细胞可以是细菌细胞(例如,大肠杆菌)、酵母细胞或其它真核细胞,例如COS细胞、中国仓鼠卵巢(CHO)细胞、HeLa细胞、HEK293细胞、COS-1细胞、NS0细胞或骨髓瘤细胞。在某些实施方案中,细胞为哺乳动物细胞。在某些实施方案中,哺乳动物细胞为HEK293细胞。
在本申请中,术语“药物组合物”通常指涉及适合施用于患者、例如人患者的组合物。例如,本申请所述的药物组合物,其可以包含本申请所述的分离的抗原结合蛋白、本申请所述的核酸分子、本申请所述的载体和/或本申请所述的细胞,以及任选地药学上可接受的佐剂。此外,所述药物组合物还可以包含一种或多种(药学上有效的)载剂、稳定剂、赋形剂、稀释剂、增溶剂、表面活性剂、乳化剂和/或防腐剂的合适的制剂。组合物的可接受成分在所用剂量和浓度下可以对接受者无毒。本发明的药物组合物包括但不限于液体、冷冻和冻干组合物。
在本申请中,术语“药学上可接受的佐剂”通常指与药物给药相容的任何和所有的溶剂、分散介质、包衣、等渗剂和吸收延迟剂等,通常安全、无毒,且既不是生物学上也非其它方面不合需要的。
在本申请中,术语“肿瘤”通常指由异常细胞生长形成的赘生物或实体病变。在本申请中,肿瘤可以是实体瘤或血液瘤。
在本申请中,术语“受试者”通常指人类或非人类动物,包括但不限于猫、狗、马、猪、奶牛、羊、兔、小鼠、大鼠或猴。
在本申请中,术语“包含”通常是指包括明确指定的特征,但不排除其他要素。
在本申请中,术语“约”通常是指在指定数值以上或以下0.5%-10%的范围内变动,例如在指定数值以上或以下0.5%、1%、1.5%、2%、2.5%、3%、3.5%、4%、4.5%、5%、5.5%、6%、6.5%、7%、7.5%、8%、8.5%、9%、9.5%、或10%的范围内变动。
分离的抗原结合蛋白
一方面,本申请提供了一种分离的抗原结合蛋白,其可以具有下述性质中的一种或多种:1)能够以7x10-12或更低的KD值结合源自人和猴的GITR蛋白,其中所述KD值通过BLI法测定;2)能够刺激免疫细胞增殖;3)能够刺激免疫细胞分泌IFN-γ,所述分泌在T细胞活性测定中测得;4)能够抑制肿瘤生长和/或肿瘤细胞增殖;5)能够激活GITR信号通路;6)能够抑制GITR与GITRL结合。
在本申请中,本申请所述的分离的抗原结合蛋白能够以7x10-12M或更低的KD值结合源自人和猴的GITR蛋白,其中所述KD值可以通过BLI法测定。例如,本申请所述的分离的抗原结合蛋白结合源自人的GITR蛋白的KD值可以为≤7x10-12M、≤6x10-12M、≤5x10-12M、≤4x10-12M、≤3x10-12M、≤2x10-12M、≤1x10-12M、≤0.5x10-12M、≤0.1x10-12M、≤0.01x10-12M、≤0.05x10-12M,或≤0.001x10-12M。又例如,本申请所述的分离的抗原结合蛋白结合源自猴的GITR蛋白的KD值可以为≤7x10-12M、≤6x10-12M、≤5x10-12M、≤4x10-12M、≤3x10-12M、≤2x10-12M、≤1x10-12M、≤0.5x10-12M、≤0.1x10-12M、≤0.01x10-12M、≤0.05x10-12M,或≤0.001x10-12M。此外,本申请所述的分离的抗原结合蛋白结合源自鼠的GITR蛋白的KD值可以为≤7x10-12M、≤6x10-12M、≤5x10-12M、≤4x10-12M、≤3x10-12M、≤2x10-12M、≤1x10-12M、≤0.5x10-12M、≤0.1x10-12M、≤0.01x10-12M、≤0.05x10-12M,或≤0.001x10-12M。
在本申请中,所述KD值还可以通过ELISA、竞争ELISA或BIACORE或KINEXA进行测定。
在本申请中,本申请所述的分离的抗原结合蛋白能够刺激免疫细胞增殖。例如本申请所述的分离的抗原结合蛋白能在体内或体外维持、提高、加速或延长免疫细胞增殖、生长和/或存活。可采用能检测细胞增殖、生长和/或存活的任何方法,例如细胞增殖试验或上皮屏障完整性试验(epithelialbarrier integrity assay)来测定本申请所述的分离的抗原结合蛋白能否刺激免疫细胞增殖。
在本申请中,所述免疫细胞可以选自下组一种或多种:淋巴细胞、天然杀伤细胞和髓样细胞。所述淋巴细胞可以为B细胞和/或T细胞。所述髓样细胞可以选自下组一种或多种:单核细胞、巨噬细胞、嗜曙红细胞、肥大细胞、嗜碱细胞和粒细胞。
在本申请中,本申请所述的分离的抗原结合蛋白能够刺激免疫细胞分泌IFN-γ,所述分泌可以在T细胞活性测定中测得,例如,可以采用ELISA、CBA或MSD法测定免疫细胞分泌的IFN-γ的含量。
在本申请中,本申请所述的分离的抗原结合蛋白能够抑制肿瘤生长和/或肿瘤细胞增殖,例如,能够使肿瘤体积减小至少约10%,至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%、至少约99%或100%。又例如,能够使肿瘤细胞数量减少至少约10%,至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%、至少约99%或100%。
在本申请中,本申请所述的分离的抗原结合蛋白能够激活GITR信号通路,使得本申请所述的分离的抗原结合蛋白能够阻断GITRL及其受体GITR之间的相互作用,将T细胞的功能响应从功能失调状态修复为抗原刺激状态。
在本申请中,本申请所述的分离的抗原结合蛋白能够抑制GITR与GITRL结合,阻断GITRL及其受体GITR之间的相互作用,将T细胞的功能响应从功能失调状态修复为抗原刺激状态。
在本申请中,本申请所述的分离的抗原结合蛋白可以包含氨基酸序列如SEQ IDNO:23所示的VH中的至少一个CDR。例如,本申请所述的分离的抗原结合蛋白,其可以包含氨基酸序列如SEQ ID NO:23所示的VH中的HCDR3。例如,本申请所述的分离的抗原结合蛋白,其可以包含氨基酸序列如SEQ ID NO:23所示的VH中的HCDR2。又例如,本申请所述的分离的抗原结合蛋白,其可以包含氨基酸序列如SEQ ID NO:23所示的VH中的HCDR1。
需要说明的是,在本申请中,本申请所述的分离的抗原结合蛋白的VL和/或VH中的CDR可以按照Kabat进行定义。
在本申请中,本申请所述的分离的抗原结合蛋白可以包含氨基酸序列如SEQ IDNO:24所示的VL中的至少一个CDR。例如,本申请所述的分离的抗原结合蛋白,其可以包含氨基酸序列如SEQ ID NO:24所示的VL中的LCDR1。例如,本申请所述的分离的抗原结合蛋白,其可以包含氨基酸序列如SEQ ID NO:24所示的VL中的LCDR2。又例如,本申请所述的分离的抗原结合蛋白,其可以包含氨基酸序列如SEQ ID NO:24所示的VL中的LCDR3。
本申请所述的分离的抗原结合蛋白中,所述HCDR3可以包含SEQ ID NO:4所示的氨基酸序列。
本申请所述的分离的抗原结合蛋白中,所述HCDR1可以包含SEQ ID NO:2所示的氨基酸序列。
本申请所述的分离的抗原结合蛋白中,所述HCDR2可以包含SEQ ID NO:3所示的氨基酸序列。
本申请所述的分离的抗原结合蛋白中,所述LCDR1可以包含SEQ ID NO:10所示的氨基酸序列。
本申请所述的分离的抗原结合蛋白中,所述LCDR2可以包含SEQ ID NO:11所示的氨基酸序列。
本申请所述的分离的抗原结合蛋白中,所述LCDR3可以包含SEQ ID NO:12所示的氨基酸序列。
在本申请中,本申请所述的分离的抗原结合蛋白,其可以包括抗体或其抗原结合片段。例如,本申请所述的分离的抗原结合蛋白可以包括但不限于重组抗体、单克隆抗体、人抗体、人源化抗体、嵌合抗体、双特异性抗体、单链抗体、双抗体、三抗体、四抗体、Fv片段、scFv片段、Fab片段、Fab'片段、F(ab')2片段和骆驼化单结构域抗体。
在本申请中,所述抗体可以为人源化抗体。换句话说,本申请所述的分离的抗原结合蛋白,其可以为免疫特异性结合至相关抗原(例如人类GITR))且包含基本上具有人类抗体的氨基酸序列的框架(FR)区及基本上具有非人类抗体的氨基酸序列的互补决定区(CDR)的抗体或其变异体、衍生物、类似物或片段。此处的“基本上”在CDR的情况下是指CDR的氨基酸序列与非人类抗体CDR的氨基酸序列至少80%、至少85%、至少90%、至少95%、至少98%或至少99%同一。所述人源化抗体基本上可以包含所有至少一个且通常两个可变域(Fab、Fab′、F(ab′)2、FabC、Fv),其中所有或基本上所有CDR区对应于非人类免疫球蛋白(即抗体)的CDR区且所有或基本上所有框架区为具有人类免疫球蛋白共有序列的框架区。例如,人源化抗体还包含至少一部分免疫球蛋白恒定区(例如,Fc),通常为人类免疫球蛋白的恒定区。在一些实施例中,人源化抗体含有轻链以及重链的至少可变域。抗体还可包括重链的CH1、铰链、CH2、CH3及CH4区。在一些实施例中,人源化抗体仅含人源化轻链。在一些实施例中,人源化抗体仅含人源化重链。在特定实施例中,人源化抗体仅含轻链和/或人源化重链的人源化可变域。
在本申请中,所述抗原结合片段可以包括Fab,Fab’,F(ab)2、Fv片段、F(ab’)2,scFv,di-scFv和/或dAb。
在本申请中,本申请所述的分离的抗原结合蛋白可以与参比抗体竞争结合GITR蛋白,其中所述参比抗体可以包含氨基酸序列如SEQ ID NO:23所示的VH中的HCDR1-3以及氨基酸序列如SEQ ID NO:24所示的VL中的LCDR1-3。
在本申请中,所述参比抗体的HCDR1-3可以分别包含SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的氨基酸序列,且所述参比抗体的LCDR1-3可以分别包含SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列。
在本申请中,所述参比抗体的轻链可变区可以包含SEQ ID NO:24所示的氨基酸序列;且所述参比抗体的重链可变区可以包含SEQ ID NO:23所示的氨基酸序列。
在本申请中,所述参比抗体的轻链可以包含SEQ ID NO:64、46-48中任一项所示的氨基酸序列;且所述参比抗体的重链可以包含SEQ ID NO:63、43-45中任一项所示的氨基酸序列。
在本申请中,本申请所述的分离的抗原结合蛋白的所述VL可以包括框架区L-FR1,L-FR2,L-FR3,和L-FR4。
例如,本申请所述的分离的抗原结合蛋白的所述L-FR1的C末端可以与所述LCDR1的N末端直接或间接相连,且所述L-FR1可以包含SEQ ID NO:39所示的氨基酸序列。
DIVMTQSPLSLPVX1LGX2X3ASISC(SEQ ID NO:39),其中,X1可以是S或T,X2可以是Q或D,X3可以是P或Q。
例如,本申请所述的分离的抗原结合蛋白的所述L-FR1可以包含SEQ ID NO:13、30、34中任一项所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的所述L-FR2可以位于所述LCDR1与所述LCDR2之间,且所述L-FR2可以包含SEQ ID NO:40所示的氨基酸序列。
WYLQX1PGQSPKLLIY(SEQ ID NO:40),其中,X1可以是R或K。
例如,本申请所述的分离的抗原结合蛋白的所述L-FR2可以包含SEQ ID NO:14、31中任一项所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的所述L-FR3可以位于所述LCDR2与所述LCDR3之间,且所述L-FR3可以包含SEQ ID NO:41所示的氨基酸序列。
GVPDRFSGSGSGTDFTLKISRVEAEDX1GVYYC(SEQ ID NO:41),其中,X1可以为L或V。
例如,本申请所述的分离的抗原结合蛋白的所述L-FR3可以包含SEQ ID NO:15、32中任一项所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的所述L-FR4的N末端可以与所述LCDR3的C末端相连,且所述L-FR4可以包含SEQ ID NO:42所示的氨基酸序列。
FGGGTKX1EIK(SEQ ID NO:42),其中,X1可以是V或L。
例如,本申请所述的分离的抗原结合蛋白的所述L-FR4可以包含SEQ ID NO:16、33中任一项所示的氨基酸序列。
在本申请中,本申请所述的分离的抗原结合蛋白的所述VL可以包含SEQ ID NO:24所示的氨基酸序列。
DIVMTQSPLSLPVX1LGX2X3ASISCRSSQTIVHSNGNTYLEWYLQX4PGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDX5GVYYCFQGSHVPWTFGGGTKX6EIK(SEQ ID NO:24),其中,X1可以是S或T,X2可以是Q或D,X3可以是P或Q,X4可以是R或K,X5可以为L或V,X6可以是V或L。
例如,本申请所述的分离的抗原结合蛋白的所述VL可以包含SEQ ID NO:9、20-22中任一项所示的氨基酸序列。
在本申请中,本申请所述的分离的抗原结合蛋白可以包括抗体轻链恒定区,且所述抗体轻链恒定区可以包括人Igκ恒定区。
在本申请中,本申请所述的分离的抗原结合蛋白的所述抗体轻链恒定区可以包含SEQ ID NO:55所示的氨基酸序列。
在本申请中,本申请所述的分离的抗原结合蛋白可以包含抗体轻链LC,且所述LC可以包含SEQ ID NO:64、46-48中任一项所示的氨基酸序列。
在本申请中,本申请所述的分离的抗原结合蛋白的所述VH可以包括框架区H-FR1,H-FR2,H-FR3,和H-FR4。
例如,本申请所述的分离的抗原结合蛋白的所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连,且所述H-FR1可以包含SEQ ID NO:35所示的氨基酸序列。
QVX1LQESGPX2X3X4X5PX6QTLX7LTCX8FSGFSLS(SEQ ID NO:35),其中,X1可以为T或Q,X2可以为G或T,X3可以为I或L,X4可以为L或V,X5可以为Q或K,X6可以为S或T,X7可以为S或T,X8可以为S或T。
例如,本申请所述的分离的抗原结合蛋白的所述H-FR1可以包含SEQ ID NO:5、25、29中任一项所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的所述H-FR2可以位于所述HCDR1与所述HCDR2之间,且所述H-FR2可以包含SEQ ID NO:36所示的氨基酸序列。
WIRQPX1GKGLEWLVLI(SEQ ID NO:36),其中,X1可以为P或S。
例如,本申请所述的分离的抗原结合蛋白的所述H-FR2可以包含SEQ ID NO:6、26中任一项所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的所述H-FR3可以位于所述HCDR2与所述HCDR3之间,且所述H-FR3可以包含SEQ ID NO:37所示的氨基酸序列。
LLTVX1KDTSX2NQVX3LX4IX5X6X7DX8X9DTATYYCAR(SEQ ID NO:37),其中,X1可以为S或T,X2可以为N或K,X3可以为F或V,X4可以为K或T,X5可以为A或T,X6可以为S或N,X7可以为V或M,X8可以为T或P,X9可以为A或V。
例如,本申请所述的分离的抗原结合蛋白的所述H-FR3可以包含SEQ ID NO:7、27中任一项所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的所述H-FR4的N末端可以与所述HCDR3的C末端相连,且所述H-FR4可以包含SEQ ID NO:38所示的氨基酸序列。
WGX1GTX2VTVSS(SEQ ID NO:38),其中,X1可以是Q或T,X2可以是M或T。
例如,本申请所述的分离的抗原结合蛋白的所述H-FR4可以包含SEQ ID NO:8、28中任一项所示的氨基酸序列。
在本申请中,本申请所述的分离的抗原结合蛋白的所述VH可以包含SEQ ID NO:23所示的氨基酸序列。
QVX1LQESGPX2X3X4X5PX6QTLX7LTCX8FSGFSLSTFGMGVGWIRQPX9GKGLEWLVLILWNDIKYYNPALKSLLTVX10KDTSX11NQVX12LX13IX14X15X16DX17X18DTATYYCARVDGYYGYFDVWGX19GTX20VTVSS(SEQID NO:23),其中,X1可以为T或Q,X2可以为G或T,X3可以为I或L,X4可以为L或V,X5可以为Q或K,X6可以为S或T,X7可以为S或T,X8可以为S或T,X9可以为P或S,X10可以为S或T,X11可以为N或K,X12可以为F或V,X13可以为K或T,X14可以为A或T,X15可以为S或N,X16可以为V或M,X17可以为T或P,X18可以为A或V,X19可以是Q或T,X20可以是M或T。
例如,本申请所述的分离的抗原结合蛋白的所述VH可以包含SEQ ID NO:1、17-19中任一项所示的氨基酸序列。
在本申请中,本申请所述的分离的抗原结合蛋白可以包括抗体重链恒定区,且所述抗体重链恒定区可以源自人IgG重链恒定区。在其他一些实施方式中,本申请所述的分离的抗原结合蛋白可以包括抗体重链恒定区,且所述抗体重链恒定区可以源自人IgG1重链恒定区。
在本申请中,本申请所述的分离的抗原结合蛋白的所述抗体重链恒定区可以包含SEQ ID NO:53所示的氨基酸序列。
在本申请中,本申请所述的分离的抗原结合蛋白可以包含抗体重链HC,且所述HC可以包含SEQ ID NO:63、43-45中任一项所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:13所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:15所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:5所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ ID NO:7所示的氨基酸序列。L-FR4可包含SEQ ID NO:8所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:30所示的氨基酸序列,L-FR2可包含SEQ ID NO:31所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:33所示的氨基酸序列,且H-FR1可包含SEQ ID NO:25所示的氨基酸序列。H-FR2可包含SEQ ID NO:26所示的氨基酸序列。L-FR3可包含SEQ IDNO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:30所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:25所示的氨基酸序列。H-FR2可包含SEQ ID NO:26所示的氨基酸序列。L-FR3可包含SEQ IDNO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:34所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:25所示的氨基酸序列。H-FR2可包含SEQ ID NO:26所示的氨基酸序列。L-FR3可包含SEQ IDNO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:30所示的氨基酸序列,L-FR2可包含SEQ ID NO:31所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:33所示的氨基酸序列,且H-FR1可包含SEQ ID NO:29所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ IDNO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:30所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:29所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ IDNO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:34所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:29所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ IDNO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:30所示的氨基酸序列,L-FR2可包含SEQ ID NO:31所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:33所示的氨基酸序列,且H-FR1可包含SEQ ID NO:29所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ IDNO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:30所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:29所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ IDNO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:34所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:29所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ IDNO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。
本申请所述的分离的抗原结合蛋白可包含抗体轻链可变区VL和抗体重链可变区VH。例如,所述VL可包含SEQ ID NO:9所示的氨基酸序列,所述VH可包含SEQ ID NO:1所示的氨基酸序列。
例如,所述VL可包含SEQ ID NO:20所示的氨基酸序列,所述VH可包含SEQ ID NO:17所示的氨基酸序列。
例如,所述VL可包含SEQ ID NO:21所示的氨基酸序列,所述VH可包含SEQ ID NO:17所示的氨基酸序列。
例如,所述VL可包含SEQ ID NO:22所示的氨基酸序列,所述VH可包含SEQ ID NO:17所示的氨基酸序列。
例如,所述VL可包含SEQ ID NO:20所示的氨基酸序列,所述VH可包含SEQ ID NO:18所示的氨基酸序列。
例如,所述VL可包含SEQ ID NO:21所示的氨基酸序列,所述VH可包含SEQ ID NO:18所示的氨基酸序列。
例如,所述VL可包含SEQ ID NO:22所示的氨基酸序列,所述VH可包含SEQ ID NO:18所示的氨基酸序列。
例如,所述VL可包含SEQ ID NO:20所示的氨基酸序列,所述VH可包含SEQ ID NO:19所示的氨基酸序列。
例如,所述VL可包含SEQ ID NO:21所示的氨基酸序列,所述VH可包含SEQ ID NO:19所示的氨基酸序列。
例如,所述VL可包含SEQ ID NO:22所示的氨基酸序列,所述VH可包含SEQ ID NO:19所示的氨基酸序列。
本申请所述的分离的抗原结合蛋白可包含抗体轻链和抗体重链。
例如,所述轻链可包含SEQ ID NO:64所示的氨基酸序列,所述重链可包含SEQ IDNO:63所示的氨基酸序列。
例如,所述轻链可包含SEQ ID NO:46所示的氨基酸序列,所述重链可包含SEQ IDNO:43所示的氨基酸序列。
例如,所述轻链可包含SEQ ID NO:47所示的氨基酸序列,所述重链可包含SEQ IDNO:43所示的氨基酸序列。
例如,所述轻链可包含SEQ ID NO:48所示的氨基酸序列,所述重链可包含SEQ IDNO:43所示的氨基酸序列。
例如,所述轻链可包含SEQ ID NO:46所示的氨基酸序列,所述重链可包含SEQ IDNO:44所示的氨基酸序列。
例如,所述轻链可包含SEQ ID NO:47所示的氨基酸序列,所述重链可包含SEQ IDNO:44所示的氨基酸序列。
例如,所述轻链可包含SEQ ID NO:48所示的氨基酸序列,所述重链可包含SEQ IDNO:44所示的氨基酸序列。
例如,所述轻链可包含SEQ ID NO:46所示的氨基酸序列,所述重链可包含SEQ IDNO:45所示的氨基酸序列。
例如,所述轻链可包含SEQ ID NO:47所示的氨基酸序列,所述重链可包含SEQ IDNO:45所示的氨基酸序列。
例如,所述轻链可包含SEQ ID NO:48所示的氨基酸序列,所述重链可包含SEQ IDNO:45所示的氨基酸序列。
在本申请中,所述的分离的抗原结合蛋白的HCDR1-3可以分别包含SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的氨基酸序列,且LCDR1-3可以分别包含SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列。其中,所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:13所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:15所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:5所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ ID NO:7所示的氨基酸序列。L-FR4可包含SEQ ID NO:8所示的氨基酸序列。所述VL可包含SEQ ID NO:9所示的氨基酸序列,所述VH可包含SEQ ID NO:1所示的氨基酸序列。所述轻链可包含SEQ ID NO:64所示的氨基酸序列,所述重链可包含SEQID NO:63所示的氨基酸序列。例如,所述分离的抗原结合蛋白可以为C3E2。
在本申请中,所述的分离的抗原结合蛋白的HCDR1-3可以分别包含SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的氨基酸序列,且LCDR1-3可以分别包含SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列。其中,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:30所示的氨基酸序列,L-FR2可包含SEQ ID NO:31所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:33所示的氨基酸序列,且H-FR1可包含SEQ ID NO:25所示的氨基酸序列。H-FR2可包含SEQ ID NO:26所示的氨基酸序列。L-FR3可包含SEQ ID NO:27所示的氨基酸序列。L-FR4可包含SEQ IDNO:28所示的氨基酸序列。所述VL可包含SEQ ID NO:20所示的氨基酸序列,所述VH可包含SEQ ID NO:17所示的氨基酸序列。所述轻链可包含SEQ ID NO:46所示的氨基酸序列,所述重链可包含SEQ ID NO:43所示的氨基酸序列。例如,所述分离的抗原结合蛋白可以为3E21-2。
在本申请中,所述的分离的抗原结合蛋白的HCDR1-3可以分别包含SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的氨基酸序列,且LCDR1-3可以分别包含SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列。其中,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:30所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:25所示的氨基酸序列。H-FR2可包含SEQ ID NO:26所示的氨基酸序列。L-FR3可包含SEQ ID NO:27所示的氨基酸序列。L-FR4可包含SEQ IDNO:28所示的氨基酸序列。所述VL可包含SEQ ID NO:21所示的氨基酸序列,所述VH可包含SEQ ID NO:17所示的氨基酸序列。所述轻链可包含SEQ ID NO:47所示的氨基酸序列,所述重链可包含SEQ ID NO:43所示的氨基酸序列。例如,所述分离的抗原结合蛋白可以为3E21-3。
在本申请中,所述的分离的抗原结合蛋白的HCDR1-3可以分别包含SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的氨基酸序列,且LCDR1-3可以分别包含SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列。其中,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:34所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:25所示的氨基酸序列。H-FR2可包含SEQ ID NO:26所示的氨基酸序列。L-FR3可包含SEQ ID NO:27所示的氨基酸序列。L-FR4可包含SEQ IDNO:28所示的氨基酸序列。所述VL可包含SEQ ID NO:22所示的氨基酸序列,所述VH可包含SEQ ID NO:17所示的氨基酸序列。所述轻链可包含SEQ ID NO:48所示的氨基酸序列,所述重链可包含SEQ ID NO:43所示的氨基酸序列。例如,所述分离的抗原结合蛋白可以为3E21-4。
在本申请中,所述的分离的抗原结合蛋白的HCDR1-3可以分别包含SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的氨基酸序列,且LCDR1-3可以分别包含SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列。其中,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:30所示的氨基酸序列,L-FR2可包含SEQ ID NO:31所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:33所示的氨基酸序列,且H-FR1可包含SEQ ID NO:29所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ ID NO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。所述VL可包含SEQ ID NO:20所示的氨基酸序列,所述VH可包含SEQID NO:18所示的氨基酸序列。所述轻链可包含SEQ ID NO:46所示的氨基酸序列,所述重链可包含SEQ ID NO:44所示的氨基酸序列。例如,所述分离的抗原结合蛋白可以为3E2 2-2。
在本申请中,所述的分离的抗原结合蛋白的HCDR1-3可以分别包含SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的氨基酸序列,且LCDR1-3可以分别包含SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列。其中,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:30所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:29所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ ID NO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。所述VL可包含SEQ ID NO:21所示的氨基酸序列,所述VH可包含SEQID NO:18所示的氨基酸序列。所述轻链可包含SEQ ID NO:47所示的氨基酸序列,所述重链可包含SEQ ID NO:44所示的氨基酸序列。例如,所述分离的抗原结合蛋白可以为3E2 2-3。
在本申请中,所述的分离的抗原结合蛋白的HCDR1-3可以分别包含SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的氨基酸序列,且LCDR1-3可以分别包含SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列。其中,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:34所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:29所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ ID NO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。所述VL可包含SEQ ID NO:22所示的氨基酸序列,所述VH可包含SEQID NO:18所示的氨基酸序列。所述轻链可包含SEQ ID NO:48所示的氨基酸序列,所述重链可包含SEQ ID NO:44所示的氨基酸序列。例如,所述分离的抗原结合蛋白可以为3E2 2-4。
在本申请中,所述的分离的抗原结合蛋白的HCDR1-3可以分别包含SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的氨基酸序列,且LCDR1-3可以分别包含SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列。其中,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:30所示的氨基酸序列,L-FR2可包含SEQ ID NO:31所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:33所示的氨基酸序列,且H-FR1可包含SEQ ID NO:29所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ ID NO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。所述VL可包含SEQ ID NO:20所示的氨基酸序列,所述VH可包含SEQID NO:19所示的氨基酸序列。所述轻链可包含SEQ ID NO:46所示的氨基酸序列,所述重链可包含SEQ ID NO:45所示的氨基酸序列。例如,所述分离的抗原结合蛋白可以为3E2 3-2。
在本申请中,所述的分离的抗原结合蛋白的HCDR1-3可以分别包含SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的氨基酸序列,且LCDR1-3可以分别包含SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列。其中,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:30所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:29所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ ID NO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。所述VL可包含SEQ ID NO:21所示的氨基酸序列,所述VH可包含SEQID NO:19所示的氨基酸序列。所述轻链可包含SEQ ID NO:47所示的氨基酸序列,所述重链可包含SEQ ID NO:45所示的氨基酸序列。例如,所述分离的抗原结合蛋白可以为3E2 3-3。
在本申请中,所述的分离的抗原结合蛋白的HCDR1-3可以分别包含SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的氨基酸序列,且LCDR1-3可以分别包含SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列。其中,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:34所示的氨基酸序列,L-FR2可包含SEQ ID NO:14所示的氨基酸序列,L-FR3可包含SEQ ID NO:32所示的氨基酸序列,L-FR4可包含SEQ ID NO:16所示的氨基酸序列,且H-FR1可包含SEQ ID NO:29所示的氨基酸序列。H-FR2可包含SEQ ID NO:6所示的氨基酸序列。L-FR3可包含SEQ ID NO:27所示的氨基酸序列。L-FR4可包含SEQ ID NO:28所示的氨基酸序列。所述VL可包含SEQ ID NO:22所示的氨基酸序列,所述VH可包含SEQID NO:19所示的氨基酸序列。所述轻链可包含SEQ ID NO:48所示的氨基酸序列,所述重链可包含SEQ ID NO:45所示的氨基酸序列。例如,所述分离的抗原结合蛋白可以为3E2 3-4。
核酸分子、载体、细胞、制备方法和药物组合物
另一方面,本申请还提供了分离的一种或多种核酸分子,其可以编码本申请所述的分离的抗原结合蛋白。本申请所述的分离的一种或多种核酸分子可以为任何长度的分离形式的核苷酸,脱氧核糖核苷酸或核糖核苷酸,或从其天然环境分离的或人工合成的类似物,但可以编码本申请所述的分离的抗原结合蛋白。
另一方面,本申请还提供了载体,其可以包含本申请所述的核酸分子。所述载体可通过转化、转导或转染宿主细胞,使其携带的遗传物质元件在宿主细胞内表达得以表达。例如,载体可以包括:质粒;噬菌粒;柯斯质粒;人工染色体如酵母人工染色体(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。用作载体的动物病毒种类有逆转录酶病毒(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)。又例如,所述载体可以含有多种控制表达的元件,包括启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外,所述载体还可以含有复制起始位点。此外,所述载体还可以包括有协助其进入细胞的成分,如病毒颗粒、脂质体或蛋白外壳,但不仅仅只有这些物质。
另一方面,本申请还提供了细胞,其可以包含本申请所述的核酸分子或本申请所述的载体。所述细胞可以包括单个细胞的后代。由于天然、偶然或有意的突变,后代可以不一定与原始母细胞完全相同(在总DNA互补体的形态上或在基因组上)。在某些实施方式中,所述细胞还可以包括用本发明所述的载体在体外转染的细胞。在某些实施方式中,所述细胞可以是细菌细胞(例如,大肠杆菌)、酵母细胞或其它真核细胞,例如COS细胞、中国仓鼠卵巢(CHO)细胞、HeLa细胞、HEK293细胞、COS-1细胞、NS0细胞或骨髓瘤细胞。在某些实施方案中,所述细胞可以为哺乳动物细胞。在某些实施方案中,所述哺乳动物细胞可以为HEK293细胞。
另一方面,本申请还提供了制备本申请所述的分离的抗原结合蛋白的方法,所述方法可以包括在使得本申请所述的分离的抗原结合蛋白表达的条件下,培养本申请所述的细胞。
另一方面,本申请还提供了药物组合物,其可以包含本申请所述的分离的抗原结合蛋白、本申请所述的核酸分子、本申请所述的载体和/或本申请所述的细胞,以及任选地药学上可接受的佐剂。
在某些实施方案中,所述药物组合物还可以包含一种或多种(药学上有效的)载剂、稳定剂、赋形剂、稀释剂、增溶剂、表面活性剂、乳化剂和/或防腐剂的合适的制剂。组合物的可接受成分在所用剂量和浓度下可以对接受者无毒。本发明的药物组合物包括但不限于液体、冷冻和冻干组合物。
在某些实施方案中,所述药学上可接受的佐剂可以包括与药物给药相容的任何和所有的溶剂、分散介质、包衣、等渗剂和吸收延迟剂,通常安全、无毒,且既不是生物学上也非其它方面不合需要的。
在某些实施方案中,所述药物组合物可以包含肠胃外、经皮、腔内、动脉内、鞘内和/或鼻内施用或直接注射到组织中。例如,所述药物组合物可以通过输注或注射施用于患者或者受试者。在某些实施方案中,所述药物组合物的施用可以通过不同的方式进行,例如静脉内、腹膜内、皮下、肌肉内、局部或真皮内施用。在某些实施方案中,所述药物组合物可以不间断施用。所述不间断(或连续)施用可以通过患者佩戴的小泵系统来实现,以测量流入患者体内的治疗剂,如WO2015/036583所述。
用途和应用
另一方面,本申请还提供了本申请所述的分离的抗原结合蛋白、本申请所述的核酸分子、本申请所述的载体、本申请所述的细胞和/或本申请所述的药物组合物在制备药物中的用途,所述药物可以用于预防、缓解和/或治疗肿瘤。
另一方面,本申请还提供了预防、缓解或治疗肿瘤的方法,所述方法可以包括向有需要的受试者施用本申请所述的分离的抗原结合蛋白。
另一方面,本申请所述的分离的抗原结合蛋白、本申请所述的核酸分子、本申请所述的载体、本申请所述的细胞和/或本申请所述的药物组合物,其可以用于预防、缓解或治疗肿瘤。
在本申请中,所述肿瘤可以是实体瘤或血液瘤。
在本申请中,所述受试者可以包括人类和非人类动物。例如,所述受试者可以包括但不限于猫、狗、马、猪、奶牛、羊、兔、小鼠、大鼠或猴。
另一方面,本申请还提供了抑制GITR与GITR配体GITRL结合的方法,所述方法可以包括施用本申请所述的分离的抗原结合蛋白。例如,施用本申请所述的分离的抗原结合蛋白后,受试者体内的GITRL及其受体GITR之间的相互作用可以被抑制,将T细胞的功能响应从功能失调状态修复为抗原刺激状态。
另一方面,本申请还提供了激活GITR的方法,所述方法可以包括施用本申请所述的分离的抗原结合蛋白。例如,施用本申请所述的分离的抗原结合蛋白后,受试者体内的GITRL及其受体GITR之间的相互作用可以被阻断,将T细胞的功能响应从功能失调状态修复为抗原刺激状态。
不欲被任何理论所限,下文中的实施例仅仅是为了阐释本申请的分离的抗原结合蛋白和用途等,而不用于限制本申请发明的范围。
实施例
实施例1.制备抗原蛋白
根据蛋白数据库Uniprot上人GITR的氨基酸序列(Q9Y5U5),其氨基酸序列如SEQID NO:49所示,得到人GITR胞外结构域的氨基酸序列(即Q9Y5U5中第1位残基至161位残基),其氨基酸序列如SEQ ID NO:50所示;根据数据库NCBI上食蟹猴GITR(即cynoGITR)的氨基酸序列(XP_005545180.1),其氨基酸序列如SEQ ID NO:51所示,得到食蟹猴GITR胞外结构域的氨基酸序列(即XP_005545180.1中第1位残基至155位残基),其氨基酸序列如SEQ IDNO:52所示;根据蛋白数据库Uniprot上人免疫球蛋白gamma1(IgG1)的重链恒定区氨基酸序列(P01857),其氨基酸序列如SEQ ID NO:53所示,得到人IgG1-Fc的结构域氨基酸序列(即P01857中第104位残基至330位残基),其氨基酸序列如SEQ ID NO:54所示;根据蛋白数据库Uniprot上小鼠免疫球蛋白gamma1(IgG1)的重链恒定区氨基酸序列(P01868),其氨基酸序列如SEQ ID NO:56所示,得到小鼠IgG1-Fc(muFc)的结构域氨基酸序列(即P01868中第98位残基至324位残基),其氨基酸序列如SEQ ID NO:57所示。利用DNAworks在线工具(http://helixweb.nih.gov/dnaworks/)设计对应的编码DNA序列得到以下3种融合蛋白的基因:人的GITR的胞外结构域与人的IgG1-Fc的结构域融合的融合蛋白(用hGITR-Fc表示,其氨基酸序列如SEQ ID NO:58所示)、人的GITR的胞外结构域与鼠的IgG1-Fc的结构域融合的融合蛋白(用hGITR-muFc表示,其氨基酸序列如SEQ ID NO:59所示)以及食蟹猴的GITR的胞外结构域与鼠的IgG1-Fc的结构域融合的融合蛋白(用cynoGITR-muFc表示,其氨基酸序列如SEQID NO:60所示)。编码hGITR-Fc的核苷酸序列如SEQ ID NO:65所示,编码hGITR-muFc的核苷酸序列如SEQ ID NO:66所示,编码cynoGITR-muFc的核苷酸序列如SEQ ID NO:67所示。
根据蛋白数据库Uniprot上信息得到增强型绿色荧光蛋白EGFP氨基酸序列(C5MKY7),利用DNAworks在线工具(http://helixweb.nih.gov/dnaworks/)设计对应的编码DNA序列得到以下2种与EGFP融合的融合蛋白的基因,即人的GITR的胞外结构域与EGFP融合的融合蛋白(用hGITR-EGFP表示,其氨基酸序列如SEQ ID NO:61所示)的基因和食蟹猴的GITR的胞外结构域与EGFP融合的融合蛋白(用cynoGITR-EGFP表示,其氨基酸序列如SEQ IDNO:62所示)的基因。编码hGITR-EGFP的核苷酸序列如SEQ ID NO:68所示,编码cynoGITR-EGFP的核苷酸序列如SEQ ID NO:69所示。
通过人工合成的方式得到上述DNA片段。合成好的基因序列分别经Fermentas公司的HindIII与PmeI双酶切亚克隆到商业化载体pcDNA4/myc-HisA(Invitrogen,V863-20)中,测序验证构建质粒的准确性,获得重组质粒DNA即:pcDNA4-hGITR-Fc、pcDNA4-hGITR-muFc、pcDNA4-cynoGITR-muFc、pcDNA4-hGITR-EGFP、pcDNA4-cynoGITR-EGFP。
将相关的EGFP重组质粒(即pcDNA4-hGITR-EGFP和pcDNA4-cynoGITR-EGFP)转染到HEK293(ATCC,CRL-1573TM)细胞中以制备hGITR-EGFP细胞和cynoGITR-EGFP细胞,转染48h后通过荧光激活信号分选(FACS)确认hGITR和cynoGITR的表达。
将pcDNA4-hGITR-Fc、pcDNA4-hGITR-muFc和pcDNA4-cynoGITR-muFc瞬时转染至HEK293细胞用于抗原蛋白生产。具体方法为:将重组质粒用Freestyle293培养基稀释并加入转化所需PEI(Polyethylenimine)溶液,将每组质粒/PEI混合物分别加入细胞悬液中,放置在37℃,10%CO2,90rpm中培养;培养5~6天后,收集瞬时表达培养上清液,通过ProteinA亲和层析法,初步纯化得到hGITR-Fc、hGITR-muFc和cynoGITR-muFc抗原蛋白样品,用于以下的各实施例。得到的抗原蛋白样品利用SDS-PAGE进行初步的检测,可以清晰的看到目的条带。
实施例2.利用杂交瘤的方法制备本申请所述的分离的抗原结合蛋白3E2
用实施例1制备的hGITR-muFc免疫小鼠,三次免疫后进行抗体效价检测,选择效价高的小鼠进行第四次免疫。从第四次免疫后的小鼠分离脾脏细胞,并将脾细胞和小鼠骨髓瘤细胞SP2/0进行融合。融合后的上清(即杂交瘤上清)进行ELISA结合检测,共得到382株可以结合GITR的杂交瘤克隆。具体的ELISA检测方法如下:在ELISA板上包被2μg/ml的hGITR-Fc,100μl/孔,4℃孵育过夜。用10mM,pH7.4的PBS/Tween(Tween体积分数为0.05%)洗一次,用含有3%BSA-PBS封闭,37℃孵育2h;洗版3次后加入杂交瘤上清,37℃孵育1h,洗版3次,加入anti-mouse IgG-HRP酶标二抗,37℃孵育1h,清洗后,用TMB底物对板进行显色,并在OD450nm处进行分光光度分析,挑选OD>0.8的克隆判定为阳性。
将所得的阳性克隆进行FACS结合检测和激活活性检测,挑选具有激活活性的抗体进行后续实验。FACS结合检测方法如下:取实施例1制备的hGITR-EGFP细胞,PBS洗两次,加入50μl杂交瘤上清液和50μl PBS,4℃孵育30min,PBS洗两次,加入anti-mouse Ig-PE,4℃孵育30min,PBS洗两次,重悬于300μlPBS中,流式细胞仪检测结果,共得到2株阳性克隆。
挑选2株结合能力强的克隆进行激活活性检测,激活活性检测方法如下:用anti-CD3(OKT3)包被48孔板,150μl/孔,0.3μg/ml,4℃过夜。次日,500μl/孔清洗包被的48孔板2次,接种Jurkat-GITR细胞(购于promega),1*105/孔,250μl/孔,分别加入不同浓度的上述2株结合能力强的克隆抗体、交联刺激,250μl/孔,6h后裂解细胞,用荧光素酶检测系统(Promega:E1500)检测最终得到1株单克隆抗体,对其进行亚克隆并对得到的单克隆(即为本申请所述的分离的抗原结合蛋白,用3E2表示)进行测序,3E2的VH氨基酸序列如SEQ IDNO:1所示,VL氨基酸序列如SEQ ID NO:9所示。编码3E2的VH的核苷酸序列如SEQ ID NO:70所示,编码3E2的VL的核苷酸序列如SEQ ID NO:71所示。
实施例3.本申请所述的分离的抗原结合蛋白C3E2的制备
根据蛋白数据库Uniprot上人免疫球蛋白gamma1(IgG1)的恒定区氨基酸序列(P01857),得到人IgG1重链恒定区氨基酸序列,其氨基酸序列如SEQ ID NO:53所示。利用DNAworks在线工具(http://helixweb.nih.gov/dnaworks/)设计对应的编码DNA序列得到人IgG1重链恒定区基因,将实施例2筛选得到的3E2蛋白的重链可变区VH序列与人IgG1重链恒定区基因序列拼接在一起,合成拼接好的基因,经Fermentas公司HindIII和PmeI双酶切亚克隆至载体pcDNA4/myc-HisA中得到抗体的重链表达质粒。
根据蛋白数据库Uniprot上人免疫球蛋白Kappa的恒定区氨基酸序列(P01934),得到人免疫球蛋白Kappa轻链恒定区氨基酸序列,其氨基酸序列如SEQ ID NO:55所示。利用DNAworks在线工具(http://helixweb.nih.gov/dnaworks/)设计对应的编码DNA序列得到人Kappa轻链恒定区基因,将实施例2筛选得到的3E2蛋白的轻链可变区VL序列与人Kappa轻链恒定区基因序列拼接在一起,合成拼接好的基因,经Fermentas公司HindIII和PmeI双酶切亚克隆至载体pcDNA4/myc-HisA中得到抗体的轻链表达质粒。
利用AidLab公司提供的质粒大提试剂盒(PL14)对上述得到的重链和轻链表达质粒进行质粒大提。将重组构建的轻链和重链质粒共转染HEK293细胞进行抗体表达。将重组表达质粒用Freestyle293培养基稀释并加入转化所需PEI(Polyethylenimine)溶液,将每组质粒/PEI混合物分别加入细胞悬液中,放置在37℃,10%CO2,90rpm中培养;同时补加50μg/LIGF-1。四小时后再补加EX293培养基,2mM谷氨酰胺(Glutamine)和50μg/LIGF-1,135rpm培养。二十四小时后加3.8mMVPA。培养5~6天后,收集瞬时表达培养上清液,通过ProteinA亲和层析法,纯化得到本申请所述的分离的抗原结合蛋白(用C3E2表示,其重链氨基酸序列如SEQ ID NO:63所示,其轻链氨基酸序列如SEQ ID NO:64所示),其表达量为42.5μg/ml。
实施例4.本申请所述的分离的抗原结合蛋白C3E2的表征
4.1.与细胞表面GITR结合能力检测(FACS)
取实施例1制备的hGITR-EGFP细胞和cynoGITR-EGFP细胞,PBS洗两次,加入10μg/ml的C3E2,4℃孵育30min,PBS洗两次,加入anti-human Ig-PE,4℃孵育30min,PBS洗两次,重悬于300μl的PBS中,流式细胞仪检测,结果如图1所示。其中,图1A-图1D分别表示阴性对照(仅加入PBS)、anti-human Ig-PE、C3E2结合hGITR(人GITR)、C3E2结合cynoGITR(猴GITR)的情况。
从图1可以看出,本申请所述的分离的抗原结合蛋白C3E2可以结合细胞表面的人和猴的GITR。
4.2.激活活性检测
用anti-CD3(OKT3)包被48孔板,105μl/孔,0.3μg/ml,4℃过夜。次日,500μl/孔清洗包被的48孔板2次,接种Jurkat-GITR细胞(promega),105μl/孔,250μl/孔,分别加入不同浓度的C3E2交联(crosslink)刺激,250μl/孔,6h后裂解细胞,用荧光素酶检测系统(Promega:E6110)检测,结果如图2所示。
从图2可以看出,本申请所述的分离的抗原结合蛋白C3E2的EC50值为0.5063,本申请所述的分离的抗原结合蛋白C3E2能激活下游的NFκB信号,具有好的激活活性。
4.3.激活T细胞活性检测
利用人淋巴细胞分离液(购于天津灏洋)密度梯度离心以从健康捐献者外周血浓缩白细胞中分离外周血单个核细胞PBMC,通过EasySep Negative Human CD4 Kit(干细胞:19052)来分离PBMC得到CD4+T细胞,PBS洗涤两次,计数,以每孔1.5*105细胞/孔加入到96孔板中。该96孔板预先用0.2μg/ml的anti-CD3抗体和C3E2包被,37℃孵育2h,加入0.2μg/ml的CD28,阴性对照为只加入anti-CD3的抗体或IgG,第二天PBS洗涤3次。将CD4+T细胞加入96孔板中后,将96孔板放入二氧化碳培养箱培养3d后收集细胞,流式细胞仪检测增殖情况,同时收集上清检测细胞因子变化。结果如图3和图4所示,图中的阴性对照表示只加入anti-CD3抗体,从图3和图4中可以看出,本申请所述的分离的抗原结合蛋白C3E2可刺激T细胞增殖,促进细胞因子IFN-γ的含量提高。
实施例5.本申请所述的分离的抗原结合蛋白3E2 1-2、3E2 1-3、3E2 1-4、3E2 2-2、3E22-3、3E2 2-4、3E2 3-2、3E2 3-3和3E2 3-4的制备及表征
5.1.制备本申请所述的分离的抗原结合蛋白
将实施例2制备的3E2用于人源化,通过改变重链和轻链可变区的框架区的某些氨基酸残基将抗体人源化,共得到表1所示的9株人源化抗体,即9种本申请所述的分离的抗原结合蛋白,分别用3E2 1-2、3E2 1-3、3E2 1-4、3E2 2-2、3E2 2-3、3E2 2-4、3E2 3-2、3E2 3-3和3E2 3-4表示。
表1.9株人源化抗体的重链和轻链的序列
将上述人源化的VH基因和VL基因进行合成,并且按照实施例3中C3E2的构建方法将VH和人IgG1重链恒定区组成抗体的重链,VL和人kappa轻链恒定区组成抗体的轻链。各基因克隆至pcDNA4/myc-HisA的载体中,得到重链表达质粒和轻链表达质粒。分别将重链表达质粒和轻链表达质粒按照表1进行配对后瞬时转染至HEK293(ATCC,CRL-1573TM)细胞系中用于蛋白生产。将重组表达质粒用Freestyle 293培养基稀释并加入转化所需PEI(Polyethylenimine)溶液,将每组质粒/PEI混合物分别加入细胞悬液中,放置在37℃,10%CO2,90rpm中培养;培养5~6天后,收集瞬时表达培养上清液,通过Protein A亲和层析法,初步纯化得到9种本申请所述的分离的抗原结合蛋白,即3E2 1-2、3E2 1-3、3E2 1-4、3E22-2、3E2 2-3、3E2 2-4、3E2 3-2、3E2 3-3和3E2 3-4,用于以下各实施例。得到的蛋白样品利用SDS-PAGE进行初步的检测,可以清晰的看到目的条带。上述9种本申请所述的分离的抗原结合蛋白的表达量如表2所示。
表2. 9种本申请所述的分离的抗原结合蛋白的表达量
名称 | 表达量(μg/ml) |
3E2 3-2 | 19.4 |
3E2 3-3 | 48 |
3E2 3-4 | 37.1 |
3E2 2-2 | 18.4 |
3E2 2-3 | 61.4 |
3E2 2-4 | 57.1 |
3E2 1-2 | 35.9 |
3E2 1-3 | 78.7 |
3E2 1-4 | 91 |
5.2.本申请所述的分离的抗原结合蛋白与人GITR蛋白结合能力检测(ELISA)
在ELISA板上包被5μg/ml的hGITR-muFc,100μl/孔,4℃孵育过夜。用10mM,pH7.4的PBS/Tween(0.05%)洗3次,用含有3%BSA的PBS封闭,37℃孵育2h;洗版3次后加入从10μg/ml开始3倍梯度稀释的上述9种本申请所述的分离的抗原结合蛋白,37℃孵育2h,洗版3次,加入anti-human IgG-HRP酶标二抗,37℃孵育1h,清洗后,用TMB底物进行显色,并在OD450nm处进行分光光度分析。结果如图5和图6所示,其中图5和图6中的各个蛋白的EC50值分别如表3和表4所示。从图5和图6以及表3和表4可以看出,人源化以后的抗体(即本申请所述的分离的抗原结合蛋白3E2 1-2、3E2 1-3、3E2 1-4、3E2 2-2、3E2 2-3、3E2 2-4、3E2 3-2、3E2 3-3和3E2 3-4)与亲本抗体(即本申请所述的分离的抗原结合蛋白C3E2)与抗原结合的亲和力相当。
表3.图5中的各个蛋白的EC50值
名称 | 人GITR EC50(ng/ml) |
C3E2 | 6.212 |
3E2 1-2 | 5.899 |
3E2 1-3 | 5.832 |
3E2 1-4 | 4.517 |
3E2 2-2 | 5.644 |
表4.图6中的各个蛋白的EC50值
名称 | 人GITR EC50(ng/ml) |
C3E2 | 6.721 |
3E2 2-3 | 4.711 |
3E2 2-4 | 4.800 |
3E2 3-2 | 5.275 |
3E2 3-3 | 6.041 |
3E2 3-4 | 6.435 |
5.3.本申请所述的分离的抗原结合蛋白与猴GITR蛋白结合能力检测(ELISA)
在ELISA板上包被5μg/ml实施例1制备的cynoGITR-muFc,100μl/孔,4℃孵育过夜。用10mM,pH 7.4的PBS/Tween(0.05%)洗3次,用含有3%BSA的PBS封闭,37℃孵育2h;洗版3次后加入从10μg/ml开始3倍梯度稀释的上述9种本申请所述的分离的抗原结合蛋白以及C3E2,37℃孵育2h,洗版3次,加入anti-human IgG-HRP酶标二抗,37℃孵育1h,清洗后,用TMB底物进行显色,并在OD450nm处进行分光光度分析。
结果如图7和图8所示,其中图7和图8中的各个蛋白的EC50值分别如表5和表6所示。从图7和图8以及表5和表6可以看出,人源化之后的抗体(即本申请所述的分离的抗原结合蛋白3E2 1-2、3E2 1-3、3E2 1-4、3E2 2-2、3E2 2-3、3E2 2-4、3E2 3-2、3E2 3-3和3E2 3-4)比亲本抗体(即本申请所述的分离的抗原结合蛋白C3E2)结合猴抗原的亲和力有所提高。
表5.图7中的各个蛋白的EC50值
名称 | 猴GITR EC50(ng/ml) |
C3E2 | 70.39 |
3E2 1-2 | 51.65 |
3E2 1-3 | 51.70 |
3E2 1-4 | 54.89 |
3E2 2-2 | 64.02 |
表6.图8中的各个蛋白的EC50值
名称 | 猴GITR EC50(ng/ml) |
C3E2 | 74.74 |
3E2 2-3 | 51.05 |
3E2 2-4 | 54.58 |
3E2 3-2 | 48.93 |
3E2 3-3 | 52.51 |
3E2 3-4 | 53.17 |
5.4.本申请所述的分离的抗原结合蛋白与人GITR蛋白结合动力学检测
采用BLI的方法,将上述9种本申请所述的分离的抗原结合蛋白以及C3E2以10μg/ml的浓度固化在AHC生物传感器上,同时将实施例1制备的hGITR-muFc从100nM进行2倍梯度稀释共5个梯度,将反应板放在Octet K2仪器上,同时将程序设置为Baseline 60s,Association 20s,Disscociation 300s,Baseline 2 30s,Loading 40s,custom 5s,程序结束后进行曲线拟合和参数换算。结果如表7所示,可以看出上述9种本申请所述的分离的抗原结合蛋白的KD值可以为7x10-12以下。
表7.本申请所述的分离的抗原结合蛋白与人GITR蛋白结合动力学检测结果
5.5.本申请所述的分离的抗原结合蛋白的激活活性检测(萤光素酶报告基因法)
取Jurkat-GITR-NF-kB稳定细胞株,加入胰酶消化2-3min后加入DMEM完全培养基终止消化,轻轻吹打细胞,转移细胞悬液接种到96孔板中,100μl/well,将上述9种本申请所述的分离的抗原结合蛋白以及C3E2从10μg/ml开始10倍稀释,将稀释后的抗体和anti-human crosslinking抗体(Jackson ImmunoResearch Laboratories:109-006-008)混合加入到96孔板中,对照组加入完全培养基,6h后裂解细胞,用荧光素酶检测系统(Promega:E6110)检测,结果如图9所示。
从图9可以看出上述9种本申请所述的分离的抗原结合蛋白激活下游信号通路的能力没有变化,从而表明人源化之后的抗体(即本申请所述的分离的抗原结合蛋白3E2 1-2、3E2 1-3、3E2 1-4、3E2 2-2、3E2 2-3、3E2 2-4、3E2 3-2、3E2 3-3和3E2 3-4)与亲本抗体(即本申请所述的分离的抗原结合蛋白C3E2)的激活活性相当,上述9种本申请所述的分离的抗原结合蛋白为激活性抗体。
5.6.本申请所述的分离的抗原结合蛋白激活T细胞活性检测
利用人淋巴细胞分离液(购于天津灏洋)密度梯度离心从健康捐献者外周血浓缩白细胞中分离外周血单个核细胞PBMC,通过EasySep Negative Human CD4 Kit(干细胞:19052)来分离PBMC得到CD4+T细胞,PBS洗涤两次,计数,以每孔1.5*105细胞/孔加入到96孔板中。该96孔板预先用0.2μg/ml的anti-CD3抗体和嵌合抗体包被,37℃孵育2h,加入0.2μg/ml的CD28,阴性对照为只加入anti-CD3的抗体和IgG,阳性对照为加入可溶的的anti-CD28的抗体(第二天和细胞一起加入),第二天PBS洗涤3次。将CD4+T细胞加入96孔板中后,将96孔板放入二氧化碳培养箱培养4d后收集细胞,流式细胞仪检测增殖情况,同时收集上清检测IFN-γ变化。结果如图10和图11所示,图中对照组表示上述阴性对照,可以看出,本申请所述的分离的抗原结合蛋白3E2 1-2,3E2 1-4、3E2 1-3和3E2 2-3均能刺激T细胞的增殖,且均能够增加IFN-γ的分泌,具有好的激活活性。
5.7.本申请所述的分离的抗原结合蛋白的稳定性检测(差示扫描量热法,DSC)
利用DSC的方法检测本申请所述的分离的抗原结合蛋白的热稳定性。为通过DSC正确地完成测试,采集了单独的缓冲液和有蛋白质的缓冲液的扫描结果。将本申请所述的分离的抗原结合蛋白稀释至1mg/ml(PBS缓冲液),采集数据的条件为:将DSC设定为扫描10-110℃,扫描速度为100℃每小时,每次扫描前有15min平衡。DSC样品室的提交为0.5ml。采集缓冲液和蛋白质的扫描结果后,可将从蛋白质扫描结果中减去缓冲液扫描结果,获得蛋白质在样品中的浓度,从而获得本申请所述的分离的抗原结合蛋白的Tm值,结果如图12、图13和图14所示,可以看出,3E2 1-3、3E2 1-4和3E2 2-3的Tm均在80℃以上,表现出优良的稳定性。
5.8.45℃加速稳定实验检测本申请所述的分离的抗原结合蛋白的稳定性
对本申请所述的分离的抗原结合蛋白进行45℃加速稳定实验,具体的实验方法为:将经protein A一步纯化的本申请所述的分离的抗原结合蛋白溶解于PBS中(pH7.4),并将该蛋白浓缩至2mg/ml,取100μg的浓缩后的该蛋白放入200μl的PCR管中,45℃水浴,于第0天,第7天,第14天收样进行SDS-PAGE检测和SEC-HPLC分析,结果如图15-图20所示(图15-17分别显示3E2 1-3、3E2 1-4和3E2 2-3的SDS-PAGE,图18-20分别显示3E2 1-3、3E2 1-4和3E2 2-3的SEC-HPLC),本申请所述的分离的抗原结合蛋白3E2 1-3、3E2 1-4和3E2 2-3在浓度为2mg/ml时,45℃条件下非常稳定。
前述详细说明是以解释和举例的方式提供的,并非要限制所附权利要求的范围。目前本申请所列举的实施方式的多种变化对本领域普通技术人员来说是显而易见的,且保留在所附的权利要求和其等同方案的范围内。
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<110> 苏州丁孚靶点生物技术有限公司
<120> 一种分离的抗原结合蛋白及其应用
<130> 0027-PA-033CN
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Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 10
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3E2LCDR1
<400> 10
Arg Ser Ser Gln Thr Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 11
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3E2LCDR2
<400> 11
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 12
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3E2LCDR3
<400> 12
Phe Gln Gly Ser His Val Pro Trp Thr
1 5
<210> 13
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3E2LFR1
<400> 13
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys
20
<210> 14
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3E2LFR2、VLV3中的L-FR2、VLV4中的L-FR2
<400> 14
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 15
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3E2LFR3
<400> 15
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys
20 25 30
<210> 16
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3E2LFR4、VLV3中的L-FR4、VLV4中的L-FR4
<400> 16
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 17
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VHV1
<400> 17
Gln Val Thr Leu Gln Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Phe
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Leu Val Leu Ile Leu Trp Asn Asp Ile Lys Tyr Tyr Asn Pro Ala
50 55 60
Leu Lys Ser Leu Leu Thr Val Thr Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Ile Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Val Asp Gly Tyr Tyr Gly Tyr Phe Asp Val Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 18
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VHV2
<400> 18
Gln Val Gln Leu Gln Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Phe
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Val Leu Ile Leu Trp Asn Asp Ile Lys Tyr Tyr Asn Pro Ala
50 55 60
Leu Lys Ser Leu Leu Thr Val Thr Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Ile Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Val Asp Gly Tyr Tyr Gly Tyr Phe Asp Val Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 19
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VHV3
<400> 19
Gln Val Gln Leu Gln Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Phe
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Val Leu Ile Leu Trp Asn Asp Ile Lys Tyr Tyr Asn Pro Ala
50 55 60
Leu Lys Ser Leu Leu Thr Val Thr Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Ile Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Val Asp Gly Tyr Tyr Gly Tyr Phe Asp Val Trp Gly Thr
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 20
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VLV2
<400> 20
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 21
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VLV3
<400> 21
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 22
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VLV4
<400> 22
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 23
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VH的通式(3E2的VH;VHV1~VHV3)
<220>
<221> X
<222> (3)..(3)
<223> X可以为T或Q
<220>
<221> X
<222> (10)..(10)
<223> X可以为G或T
<220>
<221> X
<222> (11)..(11)
<223> X可以为I或L
<220>
<221> X
<222> (12)..(12)
<223> X可以为L或V
<220>
<221> X
<222> (13)..(13)
<223> X可以为Q或K
<220>
<221> X
<222> (15)..(15)
<223> X可以为S或T
<220>
<221> X
<222> (19)..(19)
<223> X可以为S或T
<220>
<221> X
<222> (23)..(23)
<223> X可以为S或T
<220>
<221> X
<222> (43)..(43)
<223> X可以为P或S
<220>
<221> X
<222> (72)..(72)
<223> X可以为S或T
<220>
<221> X
<222> (77)..(77)
<223> X可以为N或K
<220>
<221> X
<222> (81)..(81)
<223> X可以为F或V
<220>
<221> X
<222> (83)..(83)
<223> X可以为K或T
<220>
<221> X
<222> (85)..(85)
<223> X可以为A或T
<220>
<221> X
<222> (86)..(86)
<223> X可以为S或N
<220>
<221> X
<222> (87)..(87)
<223> X可以为V或M
<220>
<221> X
<222> (89)..(89)
<223> X可以为T或P
<220>
<221> X
<222> (90)..(90)
<223> X可以为A或V
<220>
<221> X
<222> (112)..(112)
<223> X可以是Q或T
<220>
<221> X
<222> (115)..(115)
<223> X可以是M或T
<400> 23
Gln Val Xaa Leu Gln Glu Ser Gly Pro Xaa Xaa Xaa Xaa Pro Xaa Gln
1 5 10 15
Thr Leu Xaa Leu Thr Cys Xaa Phe Ser Gly Phe Ser Leu Ser Thr Phe
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Xaa Gly Lys Gly Leu Glu
35 40 45
Trp Leu Val Leu Ile Leu Trp Asn Asp Ile Lys Tyr Tyr Asn Pro Ala
50 55 60
Leu Lys Ser Leu Leu Thr Val Xaa Lys Asp Thr Ser Xaa Asn Gln Val
65 70 75 80
Xaa Leu Xaa Ile Xaa Xaa Xaa Asp Xaa Xaa Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Val Asp Gly Tyr Tyr Gly Tyr Phe Asp Val Trp Gly Xaa
100 105 110
Gly Thr Xaa Val Thr Val Ser Ser
115 120
<210> 24
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VL的通式(3E2的VL;VLV2~VLV4)
<220>
<221> X
<222> (14)..(14)
<223> X可以是S或T
<220>
<221> X
<222> (17)..(17)
<223> X可以是Q或D
<220>
<221> X
<222> (18)..(18)
<223> X可以是P或Q
<220>
<221> X
<222> (44)..(44)
<223> X可以是R或K
<220>
<221> X
<222> (88)..(88)
<223> X可以为L或V
<220>
<221> X
<222> (109)..(109)
<223> X可以是V或L
<400> 24
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Xaa Leu Gly
1 5 10 15
Xaa Xaa Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Xaa Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Xaa Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Xaa Glu Ile Lys
100 105 110
<210> 25
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VHV1中的H-FR1
<400> 25
Gln Val Thr Leu Gln Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser
20 25 30
<210> 26
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VHV1中的H-FR2
<400> 26
Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu Val Leu Ile
1 5 10 15
<210> 27
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VHV1中的H-FR3、VHV2中的H-FR3、VHV3中的H-FR3
<400> 27
Leu Leu Thr Val Thr Lys Asp Thr Ser Lys Asn Gln Val Val Leu Thr
1 5 10 15
Ile Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg
20 25 30
<210> 28
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VHV1中的H-FR4、VHV2中的H-FR4
<400> 28
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
1 5 10
<210> 29
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VHV2中的H-FR1、VHV3中的H-FR1
<400> 29
Gln Val Gln Leu Gln Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser
20 25 30
<210> 30
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VLV2中的L-FR1、VLV3中的L-FR1
<400> 30
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys
20
<210> 31
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VLV2中的L-FR2
<400> 31
Trp Tyr Leu Gln Arg Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 32
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VLV2中的L-FR3、VLV3中的L-FR3、VLV4中的L-FR3
<400> 32
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys
20 25 30
<210> 33
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VLV2中的L-FR4
<400> 33
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 34
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VLV4中的L-FR1
<400> 34
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys
20
<210> 35
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> H-FR1的通式(3E2的H-FR1;VHV1~VHV3中的H-FR1)
<220>
<221> X
<222> (3)..(3)
<223> X可以为T或Q
<220>
<221> X
<222> (10)..(10)
<223> X可以为G或T
<220>
<221> X
<222> (11)..(11)
<223> X可以为I或L
<220>
<221> X
<222> (12)..(12)
<223> X可以为L或V
<220>
<221> X
<222> (13)..(13)
<223> X可以为Q或K
<220>
<221> X
<222> (15)..(15)
<223> X可以为S或T
<220>
<221> X
<222> (19)..(19)
<223> X可以为S或T
<220>
<221> X
<222> (23)..(23)
<223> X可以为S或T
<400> 35
Gln Val Xaa Leu Gln Glu Ser Gly Pro Xaa Xaa Xaa Xaa Pro Xaa Gln
1 5 10 15
Thr Leu Xaa Leu Thr Cys Xaa Phe Ser Gly Phe Ser Leu Ser
20 25 30
<210> 36
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> H-FR2的通式(3E2的H-FR2;VHV1~VHV3中的H-FR2)
<220>
<221> X
<222> (6)..(6)
<223> X可以为P或S
<400> 36
Trp Ile Arg Gln Pro Xaa Gly Lys Gly Leu Glu Trp Leu Val Leu Ile
1 5 10 15
<210> 37
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> H-FR3的通式(3E2的H-FR3;VHV1~VHV3中的H-FR3)
<220>
<221> X
<222> (5)..(5)
<223> X可以为S或T
<220>
<221> X
<222> (10)..(10)
<223> X可以为N或K
<220>
<221> X
<222> (14)..(14)
<223> X可以为F或V
<220>
<221> X
<222> (16)..(16)
<223> X可以为K或T
<220>
<221> X
<222> (18)..(18)
<223> X可以为A或T
<220>
<221> X
<222> (19)..(19)
<223> X可以为S或N
<220>
<221> X
<222> (20)..(20)
<223> X可以为V或M
<220>
<221> X
<222> (22)..(22)
<223> X可以为T或P
<220>
<221> X
<222> (23)..(23)
<223> X可以为A或V
<400> 37
Leu Leu Thr Val Xaa Lys Asp Thr Ser Xaa Asn Gln Val Xaa Leu Xaa
1 5 10 15
Ile Xaa Xaa Xaa Asp Xaa Xaa Asp Thr Ala Thr Tyr Tyr Cys Ala Arg
20 25 30
<210> 38
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> H-FR4的通式(3E2的H-FR4;VHV1~VHV3中的H-FR4)
<220>
<221> X
<222> (3)..(3)
<223> X可以是Q或T
<220>
<221> X
<222> (6)..(6)
<223> X可以是M或T
<400> 38
Trp Gly Xaa Gly Thr Xaa Val Thr Val Ser Ser
1 5 10
<210> 39
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> L-FR1的通式(3E2的L-FR1;VLV2~VLV4中的L-FR1)
<220>
<221> X
<222> (14)..(14)
<223> X可以是S或T
<220>
<221> X
<222> (17)..(17)
<223> X可以是Q或D
<220>
<221> X
<222> (18)..(18)
<223> X可以是P或Q
<400> 39
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Xaa Leu Gly
1 5 10 15
Xaa Xaa Ala Ser Ile Ser Cys
20
<210> 40
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> L-FR2的通式(3E2的L-FR2;VLV2~VLV4中的L-FR2)
<220>
<221> X
<222> (5)..(5)
<223> X可以是R或K
<400> 40
Trp Tyr Leu Gln Xaa Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 41
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> L-FR3的通式(3E2的L-FR3;VLV2~VLV4中的L-FR3)
<220>
<221> X
<222> (27)..(27)
<223> X可以为L或V
<400> 41
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Xaa Gly Val Tyr Tyr Cys
20 25 30
<210> 42
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> L-FR4的通式(3E2的L-FR4;VLV2~VLV4中的L-FR4)
<220>
<221> X
<222> (7)..(7)
<223> X可以是V或L
<400> 42
Phe Gly Gly Gly Thr Lys Xaa Glu Ile Lys
1 5 10
<210> 43
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3E2 1-2/1-3/1-4 HC
<400> 43
Gln Val Thr Leu Gln Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Phe
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Leu Val Leu Ile Leu Trp Asn Asp Ile Lys Tyr Tyr Asn Pro Ala
50 55 60
Leu Lys Ser Leu Leu Thr Val Thr Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Ile Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Val Asp Gly Tyr Tyr Gly Tyr Phe Asp Val Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 44
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3E2 2-2/2-3/2-4 HC
<400> 44
Gln Val Gln Leu Gln Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Phe
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Val Leu Ile Leu Trp Asn Asp Ile Lys Tyr Tyr Asn Pro Ala
50 55 60
Leu Lys Ser Leu Leu Thr Val Thr Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Ile Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Val Asp Gly Tyr Tyr Gly Tyr Phe Asp Val Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 45
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3E2 3-2/3-3/3-4 HC
<400> 45
Gln Val Gln Leu Gln Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Phe
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Val Leu Ile Leu Trp Asn Asp Ile Lys Tyr Tyr Asn Pro Ala
50 55 60
Leu Lys Ser Leu Leu Thr Val Thr Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Ile Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Val Asp Gly Tyr Tyr Gly Tyr Phe Asp Val Trp Gly Thr
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 46
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3E2 1-2/2-2/3-2 LC
<400> 46
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 47
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3E2 1-3/2-3/3-3 LC
<400> 47
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 48
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3E2 1-4/2-4/3-4 LC
<400> 48
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 49
<211> 241
<212> PRT
<213> Homo sapiens
<400> 49
Met Ala Gln His Gly Ala Met Gly Ala Phe Arg Ala Leu Cys Gly Leu
1 5 10 15
Ala Leu Leu Cys Ala Leu Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro
20 25 30
Gly Cys Gly Pro Gly Arg Leu Leu Leu Gly Thr Gly Thr Asp Ala Arg
35 40 45
Cys Cys Arg Val His Thr Thr Arg Cys Cys Arg Asp Tyr Pro Gly Glu
50 55 60
Glu Cys Cys Ser Glu Trp Asp Cys Met Cys Val Gln Pro Glu Phe His
65 70 75 80
Cys Gly Asp Pro Cys Cys Thr Thr Cys Arg His His Pro Cys Pro Pro
85 90 95
Gly Gln Gly Val Gln Ser Gln Gly Lys Phe Ser Phe Gly Phe Gln Cys
100 105 110
Ile Asp Cys Ala Ser Gly Thr Phe Ser Gly Gly His Glu Gly His Cys
115 120 125
Lys Pro Trp Thr Asp Cys Thr Gln Phe Gly Phe Leu Thr Val Phe Pro
130 135 140
Gly Asn Lys Thr His Asn Ala Val Cys Val Pro Gly Ser Pro Pro Ala
145 150 155 160
Glu Pro Leu Gly Trp Leu Thr Val Val Leu Leu Ala Val Ala Ala Cys
165 170 175
Val Leu Leu Leu Thr Ser Ala Gln Leu Gly Leu His Ile Trp Gln Leu
180 185 190
Arg Ser Gln Cys Met Trp Pro Arg Glu Thr Gln Leu Leu Leu Glu Val
195 200 205
Pro Pro Ser Thr Glu Asp Ala Arg Ser Cys Gln Phe Pro Glu Glu Glu
210 215 220
Arg Gly Glu Arg Ser Ala Glu Glu Lys Gly Arg Leu Gly Asp Leu Trp
225 230 235 240
Val
<210> 50
<211> 161
<212> PRT
<213> Homo sapiens
<400> 50
Met Ala Gln His Gly Ala Met Gly Ala Phe Arg Ala Leu Cys Gly Leu
1 5 10 15
Ala Leu Leu Cys Ala Leu Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro
20 25 30
Gly Cys Gly Pro Gly Arg Leu Leu Leu Gly Thr Gly Thr Asp Ala Arg
35 40 45
Cys Cys Arg Val His Thr Thr Arg Cys Cys Arg Asp Tyr Pro Gly Glu
50 55 60
Glu Cys Cys Ser Glu Trp Asp Cys Met Cys Val Gln Pro Glu Phe His
65 70 75 80
Cys Gly Asp Pro Cys Cys Thr Thr Cys Arg His His Pro Cys Pro Pro
85 90 95
Gly Gln Gly Val Gln Ser Gln Gly Lys Phe Ser Phe Gly Phe Gln Cys
100 105 110
Ile Asp Cys Ala Ser Gly Thr Phe Ser Gly Gly His Glu Gly His Cys
115 120 125
Lys Pro Trp Thr Asp Cys Thr Gln Phe Gly Phe Leu Thr Val Phe Pro
130 135 140
Gly Asn Lys Thr His Asn Ala Val Cys Val Pro Gly Ser Pro Pro Ala
145 150 155 160
Glu
<210> 51
<211> 235
<212> PRT
<213> Macaca fascicularis
<400> 51
Met Cys Ala Cys Gly Thr Leu Cys Cys Leu Ala Leu Leu Cys Ala Ala
1 5 10 15
Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro Gly Cys Gly Pro Gly Arg
20 25 30
Leu Leu Leu Gly Thr Gly Lys Asp Ala Arg Cys Cys Arg Val His Pro
35 40 45
Thr Arg Cys Cys Arg Asp Tyr Gln Ser Glu Glu Cys Cys Ser Glu Trp
50 55 60
Asp Cys Val Cys Val Gln Pro Glu Phe His Cys Gly Asp Pro Cys Cys
65 70 75 80
Thr Thr Cys Gln His His Pro Cys Pro Ser Gly Gln Gly Val Gln Pro
85 90 95
Gln Gly Lys Phe Ser Phe Gly Phe Arg Cys Val Asp Cys Ala Leu Gly
100 105 110
Thr Phe Ser Arg Gly His Asp Gly His Cys Lys Pro Trp Thr Asp Cys
115 120 125
Thr Gln Phe Gly Phe Leu Thr Val Phe Pro Gly Asn Lys Thr His Asn
130 135 140
Ala Val Cys Val Pro Gly Ser Pro Pro Ala Glu Pro Pro Gly Trp Leu
145 150 155 160
Thr Ile Val Leu Leu Ala Val Ala Ala Cys Val Leu Leu Leu Thr Ser
165 170 175
Ala Gln Leu Gly Leu His Ile Trp Gln Leu Arg Ser Gln Pro Thr Gly
180 185 190
Pro Arg Glu Thr Gln Leu Leu Leu Glu Val Pro Pro Ser Thr Glu Asp
195 200 205
Ala Ser Ser Cys Gln Phe Pro Glu Glu Glu Arg Gly Glu Arg Leu Ala
210 215 220
Glu Glu Lys Gly Arg Leu Gly Asp Leu Trp Val
225 230 235
<210> 52
<211> 155
<212> PRT
<213> Macaca fascicularis
<400> 52
Met Cys Ala Cys Gly Thr Leu Cys Cys Leu Ala Leu Leu Cys Ala Ala
1 5 10 15
Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro Gly Cys Gly Pro Gly Arg
20 25 30
Leu Leu Leu Gly Thr Gly Lys Asp Ala Arg Cys Cys Arg Val His Pro
35 40 45
Thr Arg Cys Cys Arg Asp Tyr Gln Ser Glu Glu Cys Cys Ser Glu Trp
50 55 60
Asp Cys Val Cys Val Gln Pro Glu Phe His Cys Gly Asp Pro Cys Cys
65 70 75 80
Thr Thr Cys Gln His His Pro Cys Pro Ser Gly Gln Gly Val Gln Pro
85 90 95
Gln Gly Lys Phe Ser Phe Gly Phe Arg Cys Val Asp Cys Ala Leu Gly
100 105 110
Thr Phe Ser Arg Gly His Asp Gly His Cys Lys Pro Trp Thr Asp Cys
115 120 125
Thr Gln Phe Gly Phe Leu Thr Val Phe Pro Gly Asn Lys Thr His Asn
130 135 140
Ala Val Cys Val Pro Gly Ser Pro Pro Ala Glu
145 150 155
<210> 53
<211> 330
<212> PRT
<213> Homo sapiens
<400> 53
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 Lys
325 330
<210> 54
<211> 227
<212> PRT
<213> Homo sapiens
<400> 54
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 55
<211> 107
<212> PRT
<213> Homo sapiens
<400> 55
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> 56
<211> 324
<212> PRT
<213> Mus musculus
<400> 56
Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala
1 5 10 15
Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu
50 55 60
Ser Ser Ser Val Thr Val Pro Ser Ser Pro Arg Pro Ser Glu Thr Val
65 70 75 80
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
85 90 95
Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro
100 105 110
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
115 120 125
Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
130 135 140
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
145 150 155 160
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
165 170 175
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
180 185 190
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
195 200 205
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
210 215 220
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
225 230 235 240
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
245 250 255
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
260 265 270
Pro Ile Met Asn Thr Asn Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn
275 280 285
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
290 295 300
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
305 310 315 320
Ser Pro Gly Lys
<210> 57
<211> 227
<212> PRT
<213> Mus musculus
<400> 57
Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu
1 5 10 15
Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr
20 25 30
Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys
35 40 45
Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val
50 55 60
His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
65 70 75 80
Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val
115 120 125
Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser
130 135 140
Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu
145 150 155 160
Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro
165 170 175
Ile Met Asn Thr Asn Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val
180 185 190
Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu
195 200 205
His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser
210 215 220
Pro Gly Lys
225
<210> 58
<211> 388
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> hGITR-Fc
<400> 58
Met Ala Gln His Gly Ala Met Gly Ala Phe Arg Ala Leu Cys Gly Leu
1 5 10 15
Ala Leu Leu Cys Ala Leu Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro
20 25 30
Gly Cys Gly Pro Gly Arg Leu Leu Leu Gly Thr Gly Thr Asp Ala Arg
35 40 45
Cys Cys Arg Val His Thr Thr Arg Cys Cys Arg Asp Tyr Pro Gly Glu
50 55 60
Glu Cys Cys Ser Glu Trp Asp Cys Met Cys Val Gln Pro Glu Phe His
65 70 75 80
Cys Gly Asp Pro Cys Cys Thr Thr Cys Arg His His Pro Cys Pro Pro
85 90 95
Gly Gln Gly Val Gln Ser Gln Gly Lys Phe Ser Phe Gly Phe Gln Cys
100 105 110
Ile Asp Cys Ala Ser Gly Thr Phe Ser Gly Gly His Glu Gly His Cys
115 120 125
Lys Pro Trp Thr Asp Cys Thr Gln Phe Gly Phe Leu Thr Val Phe Pro
130 135 140
Gly Asn Lys Thr His Asn Ala Val Cys Val Pro Gly Ser Pro Pro Ala
145 150 155 160
Glu Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
165 170 175
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
180 185 190
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
195 200 205
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
210 215 220
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
225 230 235 240
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
245 250 255
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
260 265 270
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
275 280 285
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
290 295 300
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
305 310 315 320
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
325 330 335
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
340 345 350
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
355 360 365
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
370 375 380
Ser Pro Gly Lys
385
<210> 59
<211> 388
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> hGITR-muFc
<400> 59
Met Ala Gln His Gly Ala Met Gly Ala Phe Arg Ala Leu Cys Gly Leu
1 5 10 15
Ala Leu Leu Cys Ala Leu Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro
20 25 30
Gly Cys Gly Pro Gly Arg Leu Leu Leu Gly Thr Gly Thr Asp Ala Arg
35 40 45
Cys Cys Arg Val His Thr Thr Arg Cys Cys Arg Asp Tyr Pro Gly Glu
50 55 60
Glu Cys Cys Ser Glu Trp Asp Cys Met Cys Val Gln Pro Glu Phe His
65 70 75 80
Cys Gly Asp Pro Cys Cys Thr Thr Cys Arg His His Pro Cys Pro Pro
85 90 95
Gly Gln Gly Val Gln Ser Gln Gly Lys Phe Ser Phe Gly Phe Gln Cys
100 105 110
Ile Asp Cys Ala Ser Gly Thr Phe Ser Gly Gly His Glu Gly His Cys
115 120 125
Lys Pro Trp Thr Asp Cys Thr Gln Phe Gly Phe Leu Thr Val Phe Pro
130 135 140
Gly Asn Lys Thr His Asn Ala Val Cys Val Pro Gly Ser Pro Pro Ala
145 150 155 160
Glu Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro
165 170 175
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
180 185 190
Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
195 200 205
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
210 215 220
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
225 230 235 240
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
245 250 255
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
260 265 270
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
275 280 285
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
290 295 300
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
305 310 315 320
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
325 330 335
Pro Ile Met Asn Thr Asn Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn
340 345 350
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
355 360 365
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
370 375 380
Ser Pro Gly Lys
385
<210> 60
<211> 382
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> cynoGITR-muFc
<400> 60
Met Cys Ala Cys Gly Thr Leu Cys Cys Leu Ala Leu Leu Cys Ala Ala
1 5 10 15
Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro Gly Cys Gly Pro Gly Arg
20 25 30
Leu Leu Leu Gly Thr Gly Lys Asp Ala Arg Cys Cys Arg Val His Pro
35 40 45
Thr Arg Cys Cys Arg Asp Tyr Gln Ser Glu Glu Cys Cys Ser Glu Trp
50 55 60
Asp Cys Val Cys Val Gln Pro Glu Phe His Cys Gly Asp Pro Cys Cys
65 70 75 80
Thr Thr Cys Gln His His Pro Cys Pro Ser Gly Gln Gly Val Gln Pro
85 90 95
Gln Gly Lys Phe Ser Phe Gly Phe Arg Cys Val Asp Cys Ala Leu Gly
100 105 110
Thr Phe Ser Arg Gly His Asp Gly His Cys Lys Pro Trp Thr Asp Cys
115 120 125
Thr Gln Phe Gly Phe Leu Thr Val Phe Pro Gly Asn Lys Thr His Asn
130 135 140
Ala Val Cys Val Pro Gly Ser Pro Pro Ala Glu Val Pro Arg Asp Cys
145 150 155 160
Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe
165 170 175
Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro
180 185 190
Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val
195 200 205
Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr
210 215 220
Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu
225 230 235 240
Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys
245 250 255
Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser
260 265 270
Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro
275 280 285
Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile
290 295 300
Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly
305 310 315 320
Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asn Thr Asn
325 330 335
Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp
340 345 350
Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His
355 360 365
Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
370 375 380
<210> 61
<211> 400
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> hGITR-EGFP
<400> 61
Met Ala Gln His Gly Ala Met Gly Ala Phe Arg Ala Leu Cys Gly Leu
1 5 10 15
Ala Leu Leu Cys Ala Leu Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro
20 25 30
Gly Cys Gly Pro Gly Arg Leu Leu Leu Gly Thr Gly Thr Asp Ala Arg
35 40 45
Cys Cys Arg Val His Thr Thr Arg Cys Cys Arg Asp Tyr Pro Gly Glu
50 55 60
Glu Cys Cys Ser Glu Trp Asp Cys Met Cys Val Gln Pro Glu Phe His
65 70 75 80
Cys Gly Asp Pro Cys Cys Thr Thr Cys Arg His His Pro Cys Pro Pro
85 90 95
Gly Gln Gly Val Gln Ser Gln Gly Lys Phe Ser Phe Gly Phe Gln Cys
100 105 110
Ile Asp Cys Ala Ser Gly Thr Phe Ser Gly Gly His Glu Gly His Cys
115 120 125
Lys Pro Trp Thr Asp Cys Thr Gln Phe Gly Phe Leu Thr Val Phe Pro
130 135 140
Gly Asn Lys Thr His Asn Ala Val Cys Val Pro Gly Ser Pro Pro Ala
145 150 155 160
Glu Met Val Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile
165 170 175
Leu Val Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser
180 185 190
Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe
195 200 205
Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr
210 215 220
Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His Met
225 230 235 240
Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln
245 250 255
Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala
260 265 270
Glu Val Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys
275 280 285
Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu
290 295 300
Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile Met Ala Asp Lys Gln Lys
305 310 315 320
Asn Gly Ile Lys Val Asn Phe Lys Ile Arg His Asn Ile Glu Asp Gly
325 330 335
Ser Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly Asp
340 345 350
Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser Ala
355 360 365
Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu Glu
370 375 380
Phe Val Thr Ala Ala Gly Ile Thr Leu Gly Met Asp Glu Leu Tyr Lys
385 390 395 400
<210> 62
<211> 394
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> cynoGITR-EGFP
<400> 62
Met Cys Ala Cys Gly Thr Leu Cys Cys Leu Ala Leu Leu Cys Ala Ala
1 5 10 15
Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro Gly Cys Gly Pro Gly Arg
20 25 30
Leu Leu Leu Gly Thr Gly Lys Asp Ala Arg Cys Cys Arg Val His Pro
35 40 45
Thr Arg Cys Cys Arg Asp Tyr Gln Ser Glu Glu Cys Cys Ser Glu Trp
50 55 60
Asp Cys Val Cys Val Gln Pro Glu Phe His Cys Gly Asp Pro Cys Cys
65 70 75 80
Thr Thr Cys Gln His His Pro Cys Pro Ser Gly Gln Gly Val Gln Pro
85 90 95
Gln Gly Lys Phe Ser Phe Gly Phe Arg Cys Val Asp Cys Ala Leu Gly
100 105 110
Thr Phe Ser Arg Gly His Asp Gly His Cys Lys Pro Trp Thr Asp Cys
115 120 125
Thr Gln Phe Gly Phe Leu Thr Val Phe Pro Gly Asn Lys Thr His Asn
130 135 140
Ala Val Cys Val Pro Gly Ser Pro Pro Ala Glu Met Val Ser Lys Gly
145 150 155 160
Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly
165 170 175
Asp Val Asn Gly His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp
180 185 190
Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys
195 200 205
Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val
210 215 220
Gln Cys Phe Ser Arg Tyr Pro Asp His Met Lys Gln His Asp Phe Phe
225 230 235 240
Lys Ser Ala Met Pro Glu Gly Tyr Val Gln Glu Arg Thr Ile Phe Phe
245 250 255
Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly
260 265 270
Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu
275 280 285
Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His
290 295 300
Asn Val Tyr Ile Met Ala Asp Lys Gln Lys Asn Gly Ile Lys Val Asn
305 310 315 320
Phe Lys Ile Arg His Asn Ile Glu Asp Gly Ser Val Gln Leu Ala Asp
325 330 335
His Tyr Gln Gln Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro
340 345 350
Asp Asn His Tyr Leu Ser Thr Gln Ser Ala Leu Ser Lys Asp Pro Asn
355 360 365
Glu Lys Arg Asp His Met Val Leu Leu Glu Phe Val Thr Ala Ala Gly
370 375 380
Ile Thr Leu Gly Met Asp Glu Leu Tyr Lys
385 390
<210> 63
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> C3E2的重链
<400> 63
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Phe
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Val Leu Ile Leu Trp Asn Asp Ile Lys Tyr Tyr Asn Pro Ala
50 55 60
Leu Lys Ser Leu Leu Thr Val Ser Lys Asp Thr Ser Asn Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Ala Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Val Asp Gly Tyr Tyr Gly Tyr Phe Asp Val Trp Gly Thr
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 64
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> C3E2的轻链
<400> 64
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 65
<211> 1164
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码hGITR-Fc的核苷酸
<400> 65
atggcacagc acggggcgat gggcgcgttt cgggccctgt gcggcctggc gctgctgtgc 60
gcgctcagcc tgggtcagcg ccccaccggg ggtcccgggt gcggccctgg gcgcctcctg 120
cttgggacgg gaacggacgc gcgctgctgc cgggttcaca cgacgcgctg ctgccgcgat 180
tacccgggcg aggagtgctg ttccgagtgg gactgcatgt gtgtccagcc tgaattccac 240
tgcggagacc cttgctgcac gacctgccgg caccaccctt gtcccccagg ccagggggta 300
cagtcccagg ggaaattcag ttttggcttc cagtgtatcg actgtgcctc ggggaccttc 360
tccgggggcc acgaaggcca ctgcaaacct tggacagact gcacccagtt cgggtttctc 420
actgtgttcc ctgggaacaa gacccacaac gctgtgtgcg tcccagggtc cccgccggca 480
gaggataaga cacacacctg ccctccatgc cccgcacctg aactcctggg cgggccttcc 540
gttttcctgt ttcctcccaa gcccaaggat acactgatga ttagccgcac ccccgaagtc 600
acttgcgtgg tggtggatgt gagccatgaa gatccagaag ttaagtttaa ctggtatgtg 660
gacggggtcg aggtgcacaa tgctaaaaca aagcccaggg aggagcaata taactccaca 720
tacagagtgg tgtccgttct gacagtcctg caccaggact ggctgaacgg gaaggaatac 780
aagtgcaagg tgtctaataa ggcactgcca gcccccatag agaagacaat ctctaaagct 840
aaaggccaac cacgcgagcc tcaggtctac acactgccac catccaggga cgaactgacc 900
aagaatcagg tgagcctgac ttgtctcgtc aaaggattct acccaagcga catcgccgtg 960
gagtgggaat ccaacggcca accagagaac aactacaaga ccaccccacc agtcctggac 1020
tctgatggga gctttttcct gtattccaag ctgacagtgg acaagtctcg gtggcaacag 1080
ggcaacgtgt tcagctgctc cgtgatgcat gaagccctgc ataaccacta tacccagaaa 1140
agcctcagcc tgtcccccgg gaaa 1164
<210> 66
<211> 1164
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码hGITR-muFc的核苷酸
<400> 66
atggcacagc acggggcgat gggcgcgttt cgggccctgt gcggcctggc gctgctgtgc 60
gcgctcagcc tgggtcagcg ccccaccggg ggtcccgggt gcggccctgg gcgcctcctg 120
cttgggacgg gaacggacgc gcgctgctgc cgggttcaca cgacgcgctg ctgccgcgat 180
tacccgggcg aggagtgctg ttccgagtgg gactgcatgt gtgtccagcc tgaattccac 240
tgcggagacc cttgctgcac gacctgccgg caccaccctt gtcccccagg ccagggggta 300
cagtcccagg ggaaattcag ttttggcttc cagtgtatcg actgtgcctc ggggaccttc 360
tccgggggcc acgaaggcca ctgcaaacct tggacagact gcacccagtt cgggtttctc 420
actgtgttcc ctgggaacaa gacccacaac gctgtgtgcg tcccagggtc cccgccggca 480
gaggtgccca gggattgtgg ttgtaagcct tgcatatgta cagtcccaga agtatcatct 540
gtcttcatct tccccccaaa gcccaaggat gtgctcacca ttactctgac tcctaaggtc 600
acgtgtgttg tggtagacat cagcaaggat gatcccgagg tccagttcag ctggtttgta 660
gatgatgtgg aggtgcacac agctcagacg caaccccggg aggagcagtt caacagcact 720
ttccgctcag tcagtgaact tcccatcatg caccaggact ggctcaatgg caaggagttc 780
aaatgcaggg tcaacagtgc agctttccct gcccccatcg agaaaaccat ctccaaaacc 840
aaaggcagac cgaaggctcc acaggtgtac accattccac ctcccaagga gcagatggcc 900
aaggataaag tcagtctgac ctgcatgata acagacttct tccctgaaga cattactgtg 960
gagtggcagt ggaatgggca gccagcggag aactacaaga acactcagcc catcatgaac 1020
acgaatggct cttacttcgt ctacagcaag ctcaatgtgc agaagagcaa ctgggaggca 1080
ggaaatactt tcacctgctc tgtgttacat gagggcctgc acaaccacca tactgagaag 1140
agcctctccc actctcctgg gaaa 1164
<210> 67
<211> 1146
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码cynoGITR-muFc的核苷酸
<400> 67
atgtgtgcgt gcgggaccct gtgctgcctg gcgctgctgt gtgcggccag cctgggtcag 60
cgccccaccg ggggtcccgg gtgcggccct gggcgcctcc tgctcgggac gggaaaggac 120
gcacgctgct gccgcgttca cccgacgcgc tgctgccgcg attaccagag cgaggagtgc 180
tgctccgagt gggactgcgt gtgtgtccag cctgaattcc actgcggaga cccttgctgc 240
acgacctgcc agcaccaccc ttgcccctca ggccaggggg tgcagcccca ggggaaattc 300
agttttggct tcaggtgtgt cgactgtgcc ttggggacct tctccagggg ccacgacggc 360
cactgcaaac cttggacaga ctgcacccag tttgggtttc tcaccgtgtt ccctggaaac 420
aagacccaca acgccgtgtg cgtcccaggg tccccgccgg cagaggtgcc cagggattgt 480
ggttgtaagc cttgcatatg tacagtccca gaagtatcat ctgtcttcat cttcccccca 540
aagcccaagg atgtgctcac cattactctg actcctaagg tcacgtgtgt tgtggtagac 600
atcagcaagg atgatcccga ggtccagttc agctggtttg tagatgatgt ggaggtgcac 660
acagctcaga cgcaaccccg ggaggagcag ttcaacagca ctttccgctc agtcagtgaa 720
cttcccatca tgcaccagga ctggctcaat ggcaaggagt tcaaatgcag ggtcaacagt 780
gcagctttcc ctgcccccat cgagaaaacc atctccaaaa ccaaaggcag accgaaggct 840
ccacaggtgt acaccattcc acctcccaag gagcagatgg ccaaggataa agtcagtctg 900
acctgcatga taacagactt cttccctgaa gacattactg tggagtggca gtggaatggg 960
cagccagcgg agaactacaa gaacactcag cccatcatga acacgaatgg ctcttacttc 1020
gtctacagca agctcaatgt gcagaagagc aactgggagg caggaaatac tttcacctgc 1080
tctgtgttac atgagggcct gcacaaccac catactgaga agagcctctc ccactctcct 1140
gggaaa 1146
<210> 68
<211> 1200
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码hGITR-EGFP的核苷酸
<400> 68
atggcacagc acggggcgat gggcgcgttt cgggccctgt gcggcctggc gctgctgtgc 60
gcgctcagcc tgggtcagcg ccccaccggg ggtcccgggt gcggccctgg gcgcctcctg 120
cttgggacgg gaacggacgc gcgctgctgc cgggttcaca cgacgcgctg ctgccgcgat 180
tacccgggcg aggagtgctg ttccgagtgg gactgcatgt gtgtccagcc tgaattccac 240
tgcggagacc cttgctgcac gacctgccgg caccaccctt gtcccccagg ccagggggta 300
cagtcccagg ggaaattcag ttttggcttc cagtgtatcg actgtgcctc ggggaccttc 360
tccgggggcc acgaaggcca ctgcaaacct tggacagact gcacccagtt cgggtttctc 420
actgtgttcc ctgggaacaa gacccacaac gctgtgtgcg tcccagggtc cccgccggca 480
gagatggtga gcaagggcga ggagctgttc accggggtgg tgcccatcct ggtcgagctg 540
gacggcgacg taaacggcca caagttcagc gtgtccggcg agggcgaggg cgatgccacc 600
tacggcaagc tgaccctgaa gttcatctgc accaccggca agctgcccgt gccctggccc 660
accctcgtga ccaccctgac ctacggcgtg cagtgcttca gccgctaccc cgaccacatg 720
aagcagcacg acttcttcaa gtccgccatg cccgaaggct acgtccagga gcgcaccatc 780
ttcttcaagg acgacggcaa ctacaagacc cgcgccgagg tgaagttcga gggcgacacc 840
ctggtgaacc gcatcgagct gaagggcatc gacttcaagg aggacggcaa catcctgggg 900
cacaagctgg agtacaacta caacagccac aacgtctata tcatggccga caagcagaag 960
aacggcatca aggtgaactt caagatccgc cacaacatcg aggacggcag cgtgcagctc 1020
gccgaccact accagcagaa cacccccatc ggcgacggcc ccgtgctgct gcccgacaac 1080
cactacctga gcacccagtc cgccctgagc aaagacccca acgagaagcg cgatcacatg 1140
gtcctgctgg agttcgtgac cgccgccggg atcactctcg gcatggacga gctgtacaag 1200
<210> 69
<211> 1182
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码cynoGITR-EGFP的核苷酸
<400> 69
atgtgtgcgt gcgggaccct gtgctgcctg gcgctgctgt gtgcggccag cctgggtcag 60
cgccccaccg ggggtcccgg gtgcggccct gggcgcctcc tgctcgggac gggaaaggac 120
gcacgctgct gccgcgttca cccgacgcgc tgctgccgcg attaccagag cgaggagtgc 180
tgctccgagt gggactgcgt gtgtgtccag cctgaattcc actgcggaga cccttgctgc 240
acgacctgcc agcaccaccc ttgcccctca ggccaggggg tgcagcccca ggggaaattc 300
agttttggct tcaggtgtgt cgactgtgcc ttggggacct tctccagggg ccacgacggc 360
cactgcaaac cttggacaga ctgcacccag tttgggtttc tcaccgtgtt ccctggaaac 420
aagacccaca acgccgtgtg cgtcccaggg tccccgccgg cagagatggt gagcaagggc 480
gaggagctgt tcaccggggt ggtgcccatc ctggtcgagc tggacggcga cgtaaacggc 540
cacaagttca gcgtgtccgg cgagggcgag ggcgatgcca cctacggcaa gctgaccctg 600
aagttcatct gcaccaccgg caagctgccc gtgccctggc ccaccctcgt gaccaccctg 660
acctacggcg tgcagtgctt cagccgctac cccgaccaca tgaagcagca cgacttcttc 720
aagtccgcca tgcccgaagg ctacgtccag gagcgcacca tcttcttcaa ggacgacggc 780
aactacaaga cccgcgccga ggtgaagttc gagggcgaca ccctggtgaa ccgcatcgag 840
ctgaagggca tcgacttcaa ggaggacggc aacatcctgg ggcacaagct ggagtacaac 900
tacaacagcc acaacgtcta tatcatggcc gacaagcaga agaacggcat caaggtgaac 960
ttcaagatcc gccacaacat cgaggacggc agcgtgcagc tcgccgacca ctaccagcag 1020
aacaccccca tcggcgacgg ccccgtgctg ctgcccgaca accactacct gagcacccag 1080
tccgccctga gcaaagaccc caacgagaag cgcgatcaca tggtcctgct ggagttcgtg 1140
accgccgccg ggatcactct cggcatggac gagctgtaca ag 1182
<210> 70
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码3E2的VH的核苷酸
<400> 70
caggtccaac tgcaggagtc aggccctggg atactgcagc cctcccagac cctcagtctg 60
acttgttctt tctctgggtt ttcactgagc acttttggta tgggtgtagg ctggattcgt 120
cagccttcag ggaagggtct ggaatggctg gtactcattt tatggaatga tattaagtac 180
tataacccag ccctgaagag cctgctcaca gtctccaagg atacctccaa caaccaggtt 240
ttcctcaaga tcgccagtgt ggacaccgca gatactgcca catactactg tgctcgcgta 300
gatggttact acgggtactt cgatgtctgg ggcacaggga ccacggtcac cgtctcctca 360
<210> 71
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码3E2的VL的核苷酸
<400> 71
gatatcgtga tgacccaatc tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gaccattgta catagtaatg gaaacaccta tttagaatgg 120
tatctgcaga aaccaggcca gtctccaaag ctcctaatct acaaagtttc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttccg 300
tggacgttcg gtggaggcac caagctggaa atcaaa 336
<210> 72
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码VHV1的核苷酸
<400> 72
caagttactt tacaagaaag cggccctact ttagtgaagc ccacccagac tttaacttta 60
acttgtacct tcagcggctt ctctttaagc accttcggca tgggcgtggg ctggatcaga 120
cagcctcccg gtaagggttt agagtggctg gtgctgattt tatggaacga catcaagtac 180
tacaaccccg ctttaaagtc tttactgacc gtgaccaagg acaccagcaa gaaccaagtt 240
gtgctgacca tcaccaacat ggaccccgtg gacaccgcca catactactg cgctcgtgtg 300
gacggctact acggctactt cgacgtgtgg ggccaaggca ctatggtgac agtgagcagc 360
<210> 73
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码VHV2的核苷酸
<400> 73
caagttcagc tgcaagaaag cggccccaca ctggtgaagc ccacccagac tttaacttta 60
acttgtacct tcagcggctt ctctttaagc accttcggca tgggcgtggg ctggattcgt 120
cagcctagcg gcaagggttt agagtggctg gtgctgattt tatggaacga catcaagtac 180
tacaaccccg ctttaaagtc tttactgacc gtgaccaagg acaccagcaa gaaccaagtt 240
gtgctgacca tcaccaacat ggaccccgtg gacaccgcca cctactattg cgctcgtgtg 300
gacggctact acggctactt cgacgtgtgg ggccaaggta caatggtgac cgtgagcagc 360
<210> 74
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码VHV3的核苷酸
<400> 74
caagttcagc tgcaagaaag cggccccaca ctggtgaagc ccacccagac tttaacttta 60
acttgtacct tcagcggctt ctctttaagc accttcggca tgggcgtggg ctggattcgt 120
cagcctagcg gcaagggttt agagtggctg gtgctgattt tatggaacga catcaagtac 180
tacaaccccg ctttaaagtc tttactgacc gtgaccaagg acaccagcaa gaaccaagtt 240
gtgctgacca tcaccaacat ggaccccgtg gacaccgcca cctactattg cgctcgtgtg 300
gacggctact acggctactt cgacgtgtgg ggcaccggta caaccgtgac cgtgagcagc 360
<210> 75
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码VLV2的核苷酸
<400> 75
gacatcgtga tgacccagag ccctctgtct ttacccgtta ctttaggaca gcccgctagc 60
atcagctgtc gtagcagcca gaccatcgtg cacagcaacg gcaacaccta tttagagtgg 120
tacttacaga gacccggcca gagccccaag ctgctcatct acaaggtgag caatcgtttc 180
tccggcgtgc ccgatagatt tagcggcagc ggtagcggca ccgactttac tttaaagatc 240
agcagagtgg aggccgagga cgtgggcgtg tactactgct tccaaggtag ccatgtgcct 300
tggaccttcg gcggcggcac caaggtggag atcaag 336
<210> 76
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码VLV3的核苷酸
<400> 76
gacatcgtga tgacccagag ccctttatct ttacccgtta cactgggaca gcccgccagc 60
atcagctgtc gtagcagcca gaccatcgtg cacagcaacg gcaacaccta tttagagtgg 120
tatttacaga agcccggcca gagccccaag ctgctgatct acaaggtgag caatcgtttc 180
agcggcgtgc ccgacagatt cagcggaagc ggcagcggca ccgacttcac tttaaagatc 240
agcagagtgg aggccgagga cgtgggcgtg tactactgct tccaaggtag ccatgtgcct 300
tggaccttcg gaggcggcac caagctggag atcaag 336
<210> 77
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码VLV4的核苷酸
<400> 77
gacatcgtga tgacccagag ccctttatct ttacccgtta cactgggaga ccaggccagc 60
atcagctgtc gtagcagcca gaccatcgtg cacagcaacg gcaacaccta tttagagtgg 120
tatttacaga agcccggcca gagccccaag ctgctgatct acaaggtgag caatcgtttc 180
agcggcgtgc ccgacagatt cagcggaagc ggcagcggca ccgacttcac tttaaagatc 240
agcagagtgg aggccgagga cgtgggcgtg tactactgct tccaaggtag ccatgtgcct 300
tggaccttcg gaggcggcac caagctggag atcaag 336
Claims (45)
1.分离的抗原结合蛋白,其能够结合GITR蛋白,其包含VH和VL,其中所述VH包含HCDR1-3,其中所述VL包含LCDR1-3,其中所述HCDR3的氨基酸序列如SEQ ID NO:4所示,所述HCDR2的氨基酸序列如SEQ ID NO:3所示,所述HCDR1的氨基酸序列如SEQ ID NO:2,所述LCDR1的氨基酸序列如SEQ ID NO:10所示,所述LCDR2的氨基酸序列如SEQ ID NO:11所示,所述LCDR3的氨基酸序列如SEQ ID NO:12所示。
2.根据权利要求1所述的分离的抗原结合蛋白,其包括抗体或其抗原结合片段。
3.根据权利要求2所述的分离的抗原结合蛋白,其中所述抗原结合片段包括Fab,Fab’,F(ab)2、Fv片段、F(ab’)2,scFv和/或di-scFv。
4.根据权利要求2所述的分离的抗原结合蛋白,其中所述抗体为人源化抗体。
5.根据权利要求1所述的分离的抗原结合蛋白,其与参比抗体竞争结合GITR蛋白,其中所述参比抗体包含氨基酸序列如SEQ ID NO:23所示的VH中的HCDR1-3以及氨基酸序列如SEQ ID NO:24所示的VL中的LCDR1-3。
6.根据权利要求5所述的分离的抗原结合蛋白,其中所述参比抗体的HCDR1-3分别包含SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的氨基酸序列,且所述参比抗体的LCDR1-3分别包含SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12所示的氨基酸序列。
7.根据权利要求5所述的分离的抗原结合蛋白,其中所述参比抗体的轻链可变区包含SEQ ID NO:24所示的氨基酸序列;且所述参比抗体的重链可变区包含SEQ ID NO:23所示的氨基酸序列。
8.根据权利要求5所述的分离的抗原结合蛋白,其中所述参比抗体的轻链包含SEQ IDNO:64、46-48中任一项所示的氨基酸序列;且所述参比抗体的重链包含SEQ ID NO:63、43-45中任一项所示的氨基酸序列。
9.根据权利要求1-8中任一项所述的分离的抗原结合蛋白,其中所述VL包括框架区L-FR1,L-FR2,L-FR3,和L-FR4。
10.根据权利要求9所述的分离的抗原结合蛋白,其中所述L-FR1的C末端与所述LCDR1的N末端直接或间接相连,且所述L-FR1包含SEQ ID NO:39所示的氨基酸序列。
11.根据权利要求10所述的分离的抗原结合蛋白,其中所述L-FR1包含SEQ ID NO:13、30、34中任一项所示的氨基酸序列。
12.根据权利要求9所述的分离的抗原结合蛋白,其中所述L-FR2位于所述LCDR1与所述LCDR2之间,且所述L-FR2包含SEQ ID NO:40所示的氨基酸序列。
13.根据权利要求12所述的分离的抗原结合蛋白,其中所述L-FR2包含SEQ ID NO:14、31中任一项所示的氨基酸序列。
14.根据权利要求9所述的分离的抗原结合蛋白,其中所述L-FR3位于所述LCDR2与所述LCDR3之间,且所述L-FR3包含SEQ ID NO:41所示的氨基酸序列。
15.根据权利要求14所述的分离的抗原结合蛋白,其中所述L-FR3包含SEQ ID NO:15、32中任一项所示的氨基酸序列。
16.根据权利要求9所述的分离的抗原结合蛋白,其中所述L-FR4的N末端与所述LCDR3的C末端相连,且所述L-FR4包含SEQ ID NO:42所示的氨基酸序列。
17.根据权利要求16所述的分离的抗原结合蛋白,其中所述L-FR4包含SEQ ID NO:16、33中任一项所示的氨基酸序列。
18.根据权利要求1-8中任一项所述的分离的抗原结合蛋白,其中所述VL包含SEQ IDNO:24所示的氨基酸序列。
19.根据权利要求1-8中任一项所述的分离的抗原结合蛋白,其中所述VL包含SEQ IDNO:9、20-22中任一项所示的氨基酸序列。
20.根据权利要求1-8中任一项所述的分离的抗原结合蛋白,其包括抗体轻链恒定区,且所述抗体轻链恒定区包括人Igκ恒定区。
21.根据权利要求20所述的分离的抗原结合蛋白,其中所述抗体轻链恒定区包含SEQID NO:55所示的氨基酸序列。
22.根据权利要求1-8中任一项所述的分离的抗原结合蛋白,其包含抗体轻链LC,且所述LC包含SEQ ID NO:64、46-48中任一项所示的氨基酸序列。
23.根据权利要求1-8中任一项所述的分离的抗原结合蛋白,其中所述VH包括框架区H-FR1,H-FR2,H-FR3,和H-FR4。
24.根据权利要求23所述的分离的抗原结合蛋白,其中所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连,且所述H-FR1包含SEQ ID NO:35所示的氨基酸序列。
25.根据权利要求24所述的分离的抗原结合蛋白,其中所述H-FR1包含SEQ ID NO:5、25、29中任一项所示的氨基酸序列。
26.根据权利要求23所述的分离的抗原结合蛋白,其中所述H-FR2位于所述HCDR1与所述HCDR2之间,且所述H-FR2包含SEQ ID NO:36所示的氨基酸序列。
27.根据权利要求26所述的分离的抗原结合蛋白,其中所述H-FR2包含SEQ ID NO:6、26中任一项所示的氨基酸序列。
28.根据权利要求23所述的分离的抗原结合蛋白,其中所述H-FR3位于所述HCDR2与所述HCDR3之间,且所述H-FR3包含SEQ ID NO:37所示的氨基酸序列。
29.根据权利要求28所述的分离的抗原结合蛋白,其中所述H-FR3包含SEQ ID NO:7、27中任一项所示的氨基酸序列。
30.根据权利要求23所述的分离的抗原结合蛋白,其中所述H-FR4的N末端与所述HCDR3的C末端相连,且所述H-FR4包含SEQ ID NO:38所示的氨基酸序列。
31.根据权利要求30所述的分离的抗原结合蛋白,其中所述H-FR4包含SEQ ID NO:8、28中任一项所示的氨基酸序列。
32.根据权利要求1-8中任一项所述的分离的抗原结合蛋白,其中所述VH包含SEQ IDNO:23所示的氨基酸序列。
33.根据权利要求1-8中任一项所述的分离的抗原结合蛋白,其中所述VH包含SEQ IDNO:1、17-19中任一项所示的氨基酸序列。
34.根据权利要求1-8中任一项所述的分离的抗原结合蛋白,其包括抗体重链恒定区,且所述抗体重链恒定区源自人IgG重链恒定区。
35.根据权利要求1-8中任一项所述的分离的抗原结合蛋白,其包括抗体重链恒定区,且所述抗体重链恒定区源自人IgG1重链恒定区。
36.根据权利要求1-8中任一项所述的分离的抗原结合蛋白,其包括抗体重链恒定区,其中所述抗体重链恒定区包含SEQ ID NO:53所示的氨基酸序列。
37.根据权利要求1-8中任一项所述的分离的抗原结合蛋白,其包含抗体重链HC,且所述HC包含SEQ ID NO:63、43-45中任一项所示的氨基酸序列。
38.分离的一种或多种核酸分子,其编码权利要求1-37中任一项所述的分离的抗原结合蛋白。
39.载体,其包含根据权利要求38所述的核酸分子。
40.细胞,其包含根据权利要求38所述的核酸分子或根据权利要求39所述的载体。
41.制备权利要求1-37中任一项所述的分离的抗原结合蛋白的方法,所述方法包括在使得权利要求1-37中任一项所述的分离的抗原结合蛋白表达的条件下,培养根据权利要求40所述的细胞。
42.药物组合物,其包含权利要求1-37中任一项所述的分离的抗原结合蛋白、权利要求38所述的核酸分子、权利要求39所述的载体和/或权利要求40所述的细胞,以及任选地药学上可接受的佐剂。
43.权利要求1-37中任一项所述的分离的抗原结合蛋白、权利要求38所述的核酸分子、权利要求39所述的载体、权利要求40所述的细胞和/或权利要求42所述的药物组合物在制备药物中的用途,所述药物用于预防、缓解和/或治疗肿瘤。
44.一种非治疗目的的抑制GITR与GITR配体GITRL结合的方法,所述方法包括施用权利要求1-37中任一项所述的分离的抗原结合蛋白。
45.一种非治疗目的的激活GITR的方法,所述方法包括施用权利要求1-37中任一项所述的分离的抗原结合蛋白。
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