CN111936507B - Ox40抗原多肽及其用途 - Google Patents
Ox40抗原多肽及其用途 Download PDFInfo
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- CN111936507B CN111936507B CN201880091579.3A CN201880091579A CN111936507B CN 111936507 B CN111936507 B CN 111936507B CN 201880091579 A CN201880091579 A CN 201880091579A CN 111936507 B CN111936507 B CN 111936507B
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/525—Tumour necrosis factor [TNF]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
Abstract
提供一种分离的OX40抗原多肽,可用于制备特异性结合OX40的抗体,和/或能够抑制OX40配体与OX40相结合的抗体。
Description
技术领域
本申请涉及抗体领域,特别是用于制备特异性抗体的抗原多肽。具体而言,本申请涉及分离的OX40抗原多肽,以及其用于产生、识别或筛选免疫活性物质(例如抗体)的用途。
背景技术
T细胞活化需要两种信号协同作用:第一信号由T细胞抗原受体(TCR)识别抗原产生,经CD3分子将信号转导至细胞内,第一信号决定T细胞在适应性免疫应答中的特异性;第二信号是由抗原提呈细胞(APC)或者靶细胞表面的共刺激分子与T细胞表面的相应的协同刺激分子受体相互作用而产生。共刺激信号刺激抗原特异性T细胞增殖,并分化为效应T细胞。如果缺乏共刺激信号,T细胞则会进入无反应或自身免疫耐受状态,甚至进入程序性死亡。
OX40是TNFR受体超家族成员,是I型跨膜糖蛋白,OX40主要表达于活化的CD4+T细胞和CD8+T细胞上(Paterson等(1987)MolImmunol24:1281–1290)。OX40的胞外区由3个半胱氨酸富集域(CRD)和一个C端不完全CRD组成(DeanneM等(2006)Structure14:1321-1330)。OX40是次级共刺激分子。与CD28不同,OX40不表达于静息的T细胞表面,而在T细胞活化24-72小时有较高的表达。OX40的配体OX40L(TNFSF4,TXGP1,OX-40L,gp34或CD252)是II型跨膜糖蛋白,表达于活化的抗原提呈细胞,如树突状细胞、B细胞等(Godfrey,W.R等(1994)JExpMed180:757–762)。OX40/OX40L信号在T细胞的活化、增殖以及抑制凋亡过程中发挥着非常重要的作用。
研究表明激活型的OX40抗体能够有效地促进T细胞增殖和活化,并产生较好的抗肿瘤作用(Brendan D.Curti等(2013)CancerRes73:7189-7198)。
然而,人们对于激活型OX40抗体的作用位点及能够用于筛选和产生激活型OX40抗体的抗原表位仍了解甚少。因此,缺乏适当的手段来识别和筛选激活型OX40抗体,或者产生激活型OX40抗体,进而用于激活免疫系统或治疗疾病。
发明内容
本申请提供了一种分离的OX40抗原多肽。本申请的OX40抗原多肽能够特异性结合OX40激动性抗体,并且可用于产生所述OX40激动性抗体。所述OX40激动性抗体能够阻止OX40-OX40L六聚体的形成。本申请的OX40抗原多肽能够用于检测、识别和/或筛选OX40激动性抗体。在某些情形中,本申请的OX40抗原多肽还能够用于制备疫苗,例如癌症疫苗。因此,在某些情形中,本申请的OX40抗原多肽能够用于预防和/或治疗癌症。
一方面,本申请提供了一种分离的OX40抗原多肽,其可包含SEQ ID NO:1-32以及它们的片段或变体中的任一项或多项所示的氨基酸序列。
所述氨基酸序列的变体可包含:1)与SEQ ID NO:1-32中任一项所示的氨基酸序列具有至少80%(例如,至少85%,至少90%,至少91%,至少92%,至少93%,至少94%,至少95%,至少96%,至少97%,至少98%,至少99%,或至少100%)序列同源性的氨基酸序列;和/或2)在SEQ ID NO:1-32中任一项所示的氨基酸序列中经过取代、缺失或添加一个或几个(例如,1-2个,1-3个,1-4个,1-5个,1-6个,1-7个,1-8个,1-9个,1-10个,1-11个,1-12个或更多)氨基酸而获得的氨基酸序列。
在某些实施方式中,所述氨基酸序列的变体不包含突变G70A和/或突变F71A。在某些实施方式中,所述氨基酸序列的变体不包含残基G70和/或残基F71处的氨基酸突变。在本申请中,残基G70是指相应于SEQ ID NO:33所示氨基酸序列中第70位的残基G,残基F71是指相应于SEQ ID NO:33所示氨基酸序列中第71位的残基F。突变G70A是指将相应于SEQ IDNO:33所示氨基酸序列中第70位的残基G突变为A。突变F71A是指将相应于SEQ ID NO:33所示氨基酸序列中第71位的残基F突变为A。
在本申请中,“残基Xn”是指相应于SEQ ID NO:33所示氨基酸序列中第n位的残基X,其中n为正整数,X为任意氨基酸残基的缩写。
在本申请中,突变“XnY”是指将相应于SEQ ID NO:33所示氨基酸序列中第n位的残基X突变为Y,其中n为正整数,X和Y分别独立地为任意氨基酸残基的缩写,且X不同于Y。
在本申请中,某氨基酸序列中的某残基“相应于”另一氨基酸序列中的某残基通常是指,在优化条件下进行氨基酸序列比对时所获得的残基对应关系。所述序列比对可通过本领域技术人员了解的方式进行,例如,使用BLAST、BLAST-2、ALIGN、NEEDLE或Megalign(DNASTAR)软件等。本领域技术人员能够确定用于比对的适当参数,包括在所比较的全长序列中实现最优比对所需要的任何算法。例如,SEQ ID NO:2所示氨基酸序列中第1位至第7位的残基分别相应于SEQ ID NO:33所示氨基酸序列中第65位至第71位的残基。
在某些实施方式中,本申请所述的分离的OX40抗原多肽包含约4-160个(例如,至少5个,至少6个,至少7个,至少8个,至少9个,至少10个,至少15个,至少20个,至少25个,至少30个,至少35个,至少40个,至少45个,至少50个,至少55个,至少60个,至少65个,至少70个,至少75个,至少80个,至少85个,至少90个,至少95个,至少100个,至少110个,至少120个,至少130个,至少140个,至少150个,至少160个或更多个)氨基酸残基。
在某些实施方式中,本申请所述的分离的OX40抗原多肽源自OX40的细胞外结构域,其片段或变体。例如,其可源自人、食蟹猴、小鼠或大鼠OX40的细胞外结构域,其片段或变体。
在某些实施方式中,本申请所述的分离的OX40抗原多肽源自人OX40。例如,其可源自人OX40的细胞外结构域,其片段或变体。所述人OX40细胞外结构域的氨基酸序列可如SEQID NO:43所示。
在某些实施方式中,本申请的分离的OX40抗原多肽源自OX40(例如,人OX40)细胞外结构域中包含下组中一个或多个结构域或其片段的区域:半胱氨酸富集域1(CRD1)、半胱氨酸富集域2(CRD2)和半胱氨酸富集域3(CRD3)。在某些实施方式中,本申请的分离的OX40抗原多肽源自OX40(例如,人OX40)细胞外结构域中包含下组中一个或多个结构域或其片段的区域:半胱氨酸富集域1(CRD1)和半胱氨酸富集域2(CRD2)。在某些实施方式中,本申请的分离的OX40抗原多肽不包含OX40(例如,人OX40)细胞外结构域中的下列区域:半胱氨酸富集域3(CRD3)或半胱氨酸富集域4(CRD4)。
例如,本申请的分离的OX40抗原多肽可包含源自下组中的一个或多个结构域或其片段的区域:1)OX40(例如,人OX40)的CRD1的模块A1;2)OX40(例如,人OX40)的CRD1的模块B2;3)OX40(例如,人OX40)的CRD2的模块A1;和4)OX40(例如,人OX40)的CRD2的模块B2。
例如,人OX40的CRD1中模块A1的氨基酸序列可如SEQ ID NO:45所示,人OX40的CRD1中模块B2的氨基酸序列可如SEQ ID NO:46所示,人OX40的CRD1的氨基酸序列可如SEQID NO:47所示。人OX40的CRD2中模块A1的氨基酸序列可如SEQ ID NO:48所示,人OX40的CRD2中模块B2的氨基酸序列可如SEQ ID NO:49所示,人OX40的CRD2的氨基酸序列可如SEQID NO:50所示。
此外,人OX40的CRD3的氨基酸序列可如SEQ ID NO:51所示。人OX40的CRD4的氨基酸序列可如SEQ ID NO:52所示。
在某些实施方式中,本申请的分离的OX40抗原多肽具有免疫原性。
另一方面,本申请提供了一种融合蛋白或免疫缀合物,其包含本申请所述的分离的OX40抗原多肽。
另一方面,本申请提供了一种或多种分离的核酸分子,所述核酸分子可编码本申请所述的分离的OX40抗原多肽和/或本申请所述的融合蛋白或免疫缀合物。
在另一个方面,本申请提供了一种或多种载体,所述载体可包含本申请所述的一种或多种分离的核酸分子。
在另一个方面,本申请提供了一种或多种细胞(例如,宿主细胞)或非人生物体,其可包含或表达本申请所述的OX40抗原多肽、本申请所述的融合蛋白或免疫缀合物、本申请所述的一种或多种分离的核酸分子、和/或本申请所述的一种或多种载体。
在另一个方面,本申请提供了一种组合物(例如药物组合物),其可包含本申请所述的OX40抗原多肽、本申请所述的融合蛋白或免疫缀合物、本申请所述的核酸分子、本申请所述的载体、或本申请所述的细胞(例如,宿主细胞),以及任选地药学上可接受的佐剂。
在另一个方面,本申请提供了一种疫苗,其可包含一种或多种选自下列的物质以及任选地免疫原性载体:1)一种或多种本申请所述的OX40抗原多肽;2)本申请所述的融合蛋白或免疫缀合物;3)本申请所述的核酸分子;4)本申请所述的载体;5)本申请所述的细胞(例如,宿主细胞);和6)本申请所述的组合物(例如,药物组合物)。在某些实施方式中,所述疫苗为癌症疫苗。
在另一个方面,本申请提供了一种抗体,其能够特异性结合本申请所述的OX40抗原多肽。例如,所述抗体可以为OX40激动性抗体。在某些实施方式中,所述抗体为单克隆抗体。在某些实施方式中,所述抗体不包括DF004。在某些实施方式中,所述抗体基本上不结合包含突变G70A和/或突变F71A的OX40(例如,人OA40)变体。例如,所述抗体基本上不结合氨基酸序列如SEQ ID NO:35或SEQ ID NO:36所示的人OX40变体。
在另一个方面,本申请提供了一种药物组合物,其可包含本申请所述的抗体(例如,OX40激动性抗体),以及任选地药学上可接受的佐剂。
在另一个方面,本申请提供了一种用于产生OX40激动性抗体的方法。所述方法可以包括用本申请所述的OX40抗原多肽免疫动物。在某些实施方式中,所述方法还可包括分离与所述OX40抗原多肽特异性结合的抗体。
在另一个方面,本申请提供了用于筛选和/或检测OX40激动性抗体的方法。所述方法可包括使待筛选和/或待检测的候选抗体或其抗原结合片段、或者表达所述候选抗体或其抗原结合片段的细胞或细胞分泌物与本申请所述的OX40抗原多肽或本申请所述的融合蛋白或免疫缀合物接触。所述方法还可以包括判断所述候选抗体或其抗原结合片段是否与所述OX40抗原多肽特异性结合,且当检测到所述特异性结合时,将该候选抗体鉴别为OX40激动性抗体。例如,所述OX40激动性抗体可包括DF004。
在另一个方面,本申请提供了本申请所述的OX40抗原多肽或本申请所述的融合蛋白或免疫缀合物用于制备免疫活性物质的用途,所述免疫活性物质可包括OX40激动性抗体。
在另一个方面,本申请提供了本申请所述的OX40抗原多肽、本申请所述的融合蛋白或免疫缀合物或者本申请所述的抗体用于制备药物的用途,所述药物可用于预防和/或治疗癌症。
在另一个方面,本申请提供了一种阻止OX40-OX40L六聚体形成的方法,所述方法包括施用与本申请所述的OX40抗原多肽特异性结合的试剂。例如,与本申请所述的OX40抗原多肽特异性结合的试剂可以为OX40的激动剂。在某些实施方式中,与本申请所述的OX40抗原多肽特异性结合的试剂为OX40激动性抗体。
在另一个方面,本申请提供了所述OX40抗原多肽或本申请所述的融合蛋白或免疫缀合物用于制备试剂的用途,所述试剂可用于阻止OX40-OX40L六聚体的形成。在某些实施方式中,所述试剂能够作为激动剂激活OX40。例如,所述试剂可以为OX40激动性抗体。
在另一个方面,本申请提供了所述OX40抗原多肽或本申请所述的融合蛋白或免疫缀合物用于制备试剂的用途,所述试剂可用于检测、识别和/或筛选OX40激动性抗体。在某些实施方式中,所述OX40激动性抗体可包括DF004。
在另一个方面,本申请提供了预防和/或治疗受试者中的癌症的方法。所述方法可包括向所述受试者施用有效量的、选自下组的一种或多种物质:1)本申请所述的OX40抗原多肽;2)本申请所述的融合蛋白或免疫缀合物;3)本申请所述的核酸分子;4)本申请所述的载体;5)本申请所述的细胞(例如宿主细胞);6)本申请所述的药物组合物;和7)本申请所述的疫苗。
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公开的其它方面和优势。下文的详细描述中仅显示和描述了本公开的示例性实施方式。如本领域技术人员将认识到的,本公开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
图1显示了不同物种OX40片段的氨基酸序列比对结果。
图2显示了OX40与其配体OX40L形成的复合物,以及OX40与其激动性抗体形成的复合物。
图3显示了与OX40激动性抗体特异性结合的OX40表位序列,其中框内标示的是所述结合涉及的主要氨基酸残基。
图4显示了OX40表位多肽中的氨基酸序列突变对其与抗体的结合的影响。
图5显示了不同位置突变的OX40表位多肽与抗体结合的动力学参数检测结果。
图6A-6G显示了不同位置突变的OX40表位多肽与抗体结合的动力学曲线拟合结果。
具体实施方式
以下由特定的具体实例说明本发明的实施方式,本领域技术人员可通过本说明书所公开的内容了解本发明的其他优点及功效。
在本申请中,术语“抗体”通常是指一种能够特异性识别和/或中和特定抗原的多肽分子。例如,抗体可包含通过二硫键相互连接的至少两条重(H)链和两条轻(L)链组成的免疫球蛋白,并且包括任何包含其抗原结合部分的分子或片段。术语“抗体”包括单克隆抗体、抗体片段或抗体衍生物,包括但不限于人抗体、人源化抗体、嵌合抗体、单链抗体(例如,scFv),以及与抗原结合的抗体片段(例如,Fab、Fab’和(Fab)2片段)。术语“抗体”还包括抗体的所有重组体形式,例如在原核细胞中表达的抗体、未糖基化的抗体以及本文所述的任何与抗原结合的抗体片段及其衍生物。每条重链可由重链可变区(VH)和重链恒定区构成。每条轻链可由轻链可变区(VL)和轻链恒定区构成。VH和VL区可进一步被区分为称为互补决定区(CDR)的高变区,它们散布在称为框架区(FR)的更保守的区域中。每个VH和VL可由三个CDR和四个FR区构成,它们从氨基端至羧基端可按以下顺序排列:FR1、CRD1、FR2、CRD2、FR3、CRD3和FR4。重链和轻链的可变区含有与抗原相互作用的结合结构域。抗体的恒定区可介导该免疫球蛋白与宿主组织或因子的结合,所述宿主组织或因子包括免疫系统的多种细胞(例如,效应细胞)和经典补体系统的第一成分(Clq)。
在本申请中,术语“抗原结合部分”通常是指抗体中发挥特异性结合抗原功能的一个或多个片段。抗体的抗原结合功能可通过抗体的全长片段来实现。抗体的抗原结合功能也可通过以下的片段来实现:(1)Fab片段,即由VL、VH、CL和CH结构域组成的一价片段;(2)F(ab’)2片段,包含通过铰链区处的二硫键连接的两个Fab片段的二价片段;(3)由VH和CH结构域组成的Fd片段;(4)由抗体单臂的VL和VH结构域组成的Fv片段;(5)由VH结构域组成的dAb片段(Ward等,(1989)Nature 341:544-546);(6)分离的互补决定区(CDR)和(7)可任选地通过连接子连接的两个或两个以上分离的CDR的组合。此外,“抗原结合部分”还可包括由VL和VH配对形成的一价单链分子Fv(scFv)(参见Bird等(1988)Science 242:423-426;以及Huston等(1988)Proc.Natl.Acad.Sci.85:5879-5883)。所述“抗原结合部分”还可包括免疫球蛋白融合蛋白,所述融合蛋白包含选自以下的结合结构域:(1)与免疫球蛋白铰链区多肽融合的结合结构域多肽;(2)与铰链区融合的免疫球蛋白重链CH2恒定区;和(3)与CH2恒定区融合的免疫球蛋白重链CH3恒定区。
在本申请中,术语“OX40”通常是指OX40蛋白,可包括天然地或经遗传改造后含有OX40蛋白基因的细胞所表达的任何OX40蛋白及其变体、功能性片段、同工型(isoform)和种间同源物(species homologs)。OX40是一种I型跨膜糖蛋白,它通过与其配体OX40L相互作用形成多聚体(例如,六聚体)而发挥作用。例如,术语“OX40”可包括与UniProt登记号P43489.1具有至少80%氨基酸序列同一性、并且特异性结合OX40L的多肽或其片段。本申请中的术语“OX40”包括人OX40(hOX40),hOX40的变体、同工型和种间同源物,以及与hOX40具有至少一个共同表位的其类似物。例如,本申请的OX40蛋白可为人OX40蛋白。人OX40蛋白可包含如SEQ ID NO:xxx所示的氨基酸序列或该氨基酸序列的变体,例如,与其具有至少70%,至少75%,至少80%,至少85%,至少90%,至少91%,至少92%,至少93%,至少94%,至少95%,至少96%,至少97%,至少98%,至少99%或至少100%序列同源性的变体。
在本申请中,术语“单克隆抗体”通常是指由单一B细胞克隆产生的高度均一、仅针对某一特定抗原表位的抗体。单克隆抗体显示针对一种抗原表位的特异性和亲和性。例如,单克隆抗体可通过杂交瘤产生,所述杂交瘤可以为将具有分泌特异性抗体能力的B细胞和具有无限繁殖能力的骨髓瘤细胞融合后得到的杂交瘤细胞。
在本申请中,术语“表位”通常是指抗原决定簇,即指分子中被免疫系统识别(例如被抗体识别)的部分。例如,表位可以是被免疫系统识别的抗原上不连续的三维位点。表位通常由分子的化学活性表面基团(例如氨基酸或糖侧链)组成,并通常具有特定的三维结构特征以及特定的电荷特征。表位根据结构,可分为构象表位和非构象表位(线性表位)。构象表位与非构象表位的区别在于在变性溶剂存在下前者丧失结合,而后者则不会。只位于抗原物质表面、易与抗原识别受体或抗体结合的表位可称为功能性表位;位于分子内部、无免疫原性的表位可称为隐藏性表位。
在本申请中,术语“胞外结构域”通常是指蛋白质的细胞外结构域(extracellulardomain)。例如,OX40蛋白的胞外结构域通常可为基本不含跨膜和胞质结构域的OX40多肽形式。其中,跨膜的界定是根据本领域中用于鉴定疏水结构域类型的常规标准所鉴定的。跨膜的结构域的确切边界可有所不同,但是大部分是相似的。例如,所述OX40蛋白的胞外结构域可在跨膜结构域或细胞外结构域边界的任一侧含有约5个(或4个、3个、2个或1个)氨基酸。例如,所述OX40蛋白的胞外结构域可以带有相关的信号肽。
在本申请中,术语“分离的核酸分子”或“分离的核酸”通常是指从其天然环境中分离的或人工合成的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其类似物。
在本申请中,术语“载体”通常是指能够在合适的宿主中自我复制的核酸分子,其将插入的核酸分子转移到宿主细胞中和/或宿主细胞之间。所述载体可包括主要用于将DNA或RNA插入细胞中的载体、主要用于复制DNA或RNA的载体,以及主要用于DNA或RNA的转录和/或翻译的表达的载体。所述载体还包括具有多种上述功能的载体。所述载体可以是当引入合适的宿主细胞时能够转录并翻译成多肽的多核苷酸。通常,通过培养包含所述载体的合适的宿主细胞,所述载体可以产生期望的表达产物。
在本申请中,术语“宿主细胞”通常是指可以或已经含有包括本申请所述的核酸分子的质粒或载体,或者能够表达本申请所述的抗原多肽的个体细胞,细胞系或细胞培养物。所述宿主细胞可以包括单个宿主细胞的子代。由于天然的,意外的或故意的突变,子代细胞与原始亲本细胞在形态上或在基因组上可能不一定完全相同,但能够表达本申请所述的抗原多肽即可。所述宿主细胞可以通过使用本申请所述的载体体外转染细胞而得到。所述宿主细胞可以是原核细胞(例如大肠杆菌),也可以是真核细胞(例如酵母细胞,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)。在一些实施方案中,所述宿主细胞是哺乳动物细胞。在本申请中,术语“重组宿主细胞”通常指在其中引入了重组表达载体的细胞。所述重组宿主细胞不仅包括某种特定的细胞,还包括这些细胞的后代。
在本申请中,术语“肿瘤”通常是指哺乳动物中的机体(例如,细胞或其组成部分)在各种致瘤因子作用下,局部组织细胞增生所形成的赘生物。在本申请中,肿瘤可以包括淋巴瘤、母细胞瘤、肉瘤和血液肿瘤等。
在本申请中,术语“药学上可接受的佐剂”通常是指任何与所施用的活性成分相容的溶剂、分散介质、涂层、等渗剂和吸收延迟剂等佐剂、赋形剂或其它药物载体。
在本申请中,术语“受试者”通常是指任何人或非人动物。术语“非人动物”可包括所有脊椎动物,例如哺乳动物和非哺乳动物,例如非人灵长类动物、山羊、绵羊、狗、牛、鸡、两栖动物、爬行动物等。
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。
在本申请中,术语“OX40抗原多肽”、“OX40表位多肽”、“OX40多肽”、“OX40表位”等可互换地使用,通常是指源自OX40蛋白(例如人OX40)的多肽片段,其能够被OX40特异性抗体识别,与OX40特异性抗体结合和/或能够产生OX40特异性抗体。在本申请中“OX40抗原多肽”可由OX40蛋白上一段连续的氨基酸残基组成,也可指位于OX40蛋白上不连续位置的氨基酸残基的组合。
在本申请中,术语“免疫原性”通常是指能够刺激机体形成特异抗体或致敏淋巴细胞的能力。例如,可指抗原多肽能够刺激特定的免疫细胞,使免疫细胞活化、增殖、分化,最终产生免疫效应物质(例如,抗体)和/或致敏淋巴细胞的特性。术语“免疫原性”也可指抗原多肽刺激机体后,机体免疫系统能形成抗体或致敏T淋巴细胞的特异性免疫反应。
在本申请中,术语“非人生物体”通常是指除人类之外的生命形式。例如,“非人生物体”可包括植物、动物、微生物和/或病毒等,或者它们的有生命特征的部分。所述微生物可以是,例如细菌。所述动物可以是,例如脊椎动物(如哺乳动物)。在某些实施方式中,“非人生物体”包括非人灵长类动物、山羊、绵羊、狗、牛、鸡、两栖动物、爬行动物、大鼠、小鼠等。
在本申请中,术语“疫苗”通常是指用各类免疫原(例如,病原体或抗原多肽片段等)制作的、用于预防接种和/或治疗与该免疫原直接或间接相关的疾病或病症的生物制品。
在本申请中,术语“癌症疫苗”通常是指通过利用肿瘤细胞相关抗原(例如,抗原多肽或其组合),来激活受试者针对癌症的免疫系统的生物制品。
在本申请中,术语“激动性抗体”通常是指能够激活目标分子和/或增强其活性的抗体分子或其抗原结合片段。例如,本申请中的“激动性抗体”可以是特异性结合目标分子的抗体分子或其抗原结合片段,其中,所述抗体分子或其抗原结合片段与目标分子的结合使得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。在本申请中,“OX40激动性抗体”通常指能够特异性识别和/或结合OX40的抗体或其抗原结合片段,且所述抗体或其抗原结合片段特异性识别和/或结合OX40后能够使OX40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“免疫活性物质”通常是指能够产生免疫应答或者能够使机体产生特异性免疫反应的物质。免疫活性物质可以由效应细胞(例如,T细胞)或者其它细胞产生。常见的免疫活性物质可包括,例如抗体或其抗原结合片段、趋化因子、生长因子、免疫佐剂、细胞因子(例如干扰素、白介素、淋巴因子等)、细胞激素、炎性因子、病毒或其组成部分、细菌或其组成部分等。所述免疫应答或特异性免疫反应可包括,例如,增强抗体产生、增强体液应答、增强细胞免疫应答等。
在本申请中,术语“OX40-OX40L六聚体”通常是指由OX40与其配体OX40L构成的蛋白六聚体。例如,在本申请中,OX40-OX40L六聚体中可包含3个OX40蛋白分子以及3个OX40L蛋白分子。在某些实施方式中,每个OX40蛋白分子与2个OX40L蛋白分子结合,且每个OX40L蛋白分子与2个OX40蛋白分子结合。在某些实施方式中,OX40蛋白分子与OX40L蛋白分子交替排列而形成所述OX40-OX40L六聚体。
在本申请中,术语“激动剂”通常是指能够激活目标分子和/或增强其活性的物质或试剂。例如,本申请中的“激动剂”可以是激动性抗体或其它物质,所述激动剂可通过直接或间接与目标分子相结合而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。在本申请中,“OX40激动剂”通常指能够激活OX40和/或增强其活性的物质或试剂。例如,OX40激动剂可通过直接或间接与OX40相结合而使OX40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“阻止OX40-OX40L六聚体形成”通常是指使得OX40与其配体OX40L之间无法形成六聚体结构。在某些情形中,OX40与OX40L仍能够彼此结合,但是无法形成六聚体(例如,仅形成2聚体、3聚体、4聚体等)。在某些情形中,OX40与OX40L无法彼此结合或者结合后无法处于有活性的分子构象。
在本申请中,术语“序列同源性”通常是指两个或更多个多核苷酸序列间或者两个或更多个多肽序列间的序列相似性或可互换性。当使用计算机程序或软件(例如,EmbossNeedle或BestFit)来确定不同氨基酸序列间的序列同一性、相似性或同源性时,可使用默认的参数设置。也可以选择适当的记分矩阵,例如blosum45或blosum80,来优化同一性、相似性或同源性分数。在某些实施方式中,同源的多核苷酸包括下述多核苷酸:其能够在严紧条件下与对照多核苷酸序列杂交并且与对照多核苷酸序列相比具有至少60%、至少65%、至少70%、至少80%、至少90%、至少95%、至少97%、至少98%、至少99%甚至至少100%序列同一性。同源的多肽可以是下述多肽:当在优化条件下进行序列比对时,其与对照多肽序列具有至少80%、至少85%、至少90%、至少95%、至少97%、至少98%、至少99%、甚至至少100%的序列同一性。
为了确定序列同一性,可进行序列比对,其可通过本领域技术人员了解的各种方式进行,例如,使用BLAST、BLAST-2、ALIGN、NEEDLE或Megalign(DNASTAR)软件等。本领域技术人员能够确定用于比对的适当参数,包括在所比较的全长序列中实现最优比对所需要的任何算法。
在本申请中,术语“融合蛋白”通常是指下述多肽分子,其中一种多肽(例如本申请的OX40抗原多肽)的氨基酸序列直接或间接地(例如通过连接子)与另一种异源多肽的氨基酸序列相融合(例如,通过肽键)。
在本申请中,术语“免疫缀合物”通常是指通过将多肽(例如,本申请的OX40抗原多肽)与抗体或其片段(例如,抗体恒定区或抗体Fc区)相缀合而形成的蛋白类分子。
OX40抗原多肽、融合蛋白或免疫缀合物
一方面,本申请提供了一种分离的OX40抗原多肽。本申请所述的分离的OX40抗原多肽可包含SEQ ID NO:1-32以及它们的片段或变体中的任一项或多项所示的氨基酸序列。所述氨基酸序列的变体可包含:1)与SEQ ID NO:1-32中任一项所示的氨基酸序列具有至少80%(例如,至少85%,至少90%,至少91%,至少92%,至少93%,至少94%,至少95%,至少96%,至少97%,至少98%,至少99%,或至少100%)序列同源性的氨基酸序列;和/或2)在SEQ ID NO:1-32中任一项所示的氨基酸序列中经过取代、缺失或添加一个或几个(例如,1-2个,1-3个,1-4个,1-5个,1-6个,1-7个,1-8个,1-9个,1-10个,1-11个,1-12个或更多)氨基酸而获得的氨基酸序列。
在本申请中,所述氨基酸的取代可以是保守氨基酸取代或非保守氨基酸取代。经取代后的所述OX40抗原多肽仍能够被OX40激动性抗体(例如,DF004或其抗原结合片段)识别或结合(例如,特异性识别或结合),或者仍能够产生具有OX40激动性抗体(例如,DF004或其抗原结合片段)的一个或多个特征的抗体。
例如,所述氨基酸取代可以为非保守取代。所述非保守取代可包括以非保守的形式改变目标蛋白或多肽中的氨基酸残基,例如将具有某种侧链大小或某种特性(例如,亲水性)的氨基酸残基变为具有不同侧链大小或不同特性(例如,疏水性)的氨基酸残基。
所述氨基酸取代也可以为保守取代。所述保守取代可包括以保守的形式改变目标蛋白或多肽中的氨基酸残基,例如将具有某种侧链大小或某种特性(例如,亲水性)的氨基酸残基变为具有相同或相似侧链大小或者相同或相似特性(例如,仍为亲水性)的氨基酸残基。这样的保守取代通常不会对所产生的蛋白质的结构或功能带来很大影响。在本申请中,作为所述分离的OX40抗原多肽的氨基酸序列变体可包括不显著改变蛋白质结构或其功能(例如,产生或结合OX40激动性抗体的能力)的保守氨基酸取代。
作为示例,下述各组中每组内各氨基酸间的相互取代在本申请中可被认为是保守取代:
具有非极性侧链的氨基酸组:丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸和甲硫氨酸。
不带电荷、具有极性侧链的氨基酸组:甘氨酸、丝氨酸、苏氨酸,半胱氨酸,酪氨酸,天冬酰胺和谷氨酰胺。
带负电荷、具有极性侧链的氨基酸组:天冬氨酸和谷氨酸。
带正电荷的碱性氨基酸:赖氨酸、精氨酸和组氨酸。
带苯基的氨基酸:苯丙氨酸、色氨酸和酪氨酸。
在某些实施方式中,所述氨基酸序列的变体不包含突变G70A和/或突变F71A。在某些实施方式中,所述氨基酸序列的变体不包含残基G70和/或残基F71处的氨基酸突变。在本申请中,残基G70是指相应于SEQ ID NO:33所示氨基酸序列中第70位的残基G,残基F71是指相应于SEQ ID NO:33所示氨基酸序列中第71位的残基F。突变G70A是指将相应于SEQ IDNO:33所示氨基酸序列中第70位的残基G突变为A。突变F71A是指将相应于SEQ ID NO:33所示氨基酸序列中第71位的残基F突变为A。例如,所述OX40抗原多肽可源自OX40(例如人OX40),且其在相应于SEQ ID NO:33所示氨基酸序列中第70位的残基G处不包含氨基酸突变。例如,所述OX40抗原多肽可源自OX40(例如人OX40),且其在相应于SEQ ID NO:33所示氨基酸序列中第71位的残基F处不包含氨基酸突变。
在本申请中,某氨基酸序列中的某残基“相应于”另一氨基酸序列中的某残基通常是指,在优化条件下进行氨基酸序列比对时所获得的残基对应关系。所述序列比对可通过本领域技术人员了解的方式进行,例如,使用BLAST、BLAST-2、ALIGN、NEEDLE或Megalign(DNASTAR)软件等。本领域技术人员能够确定用于比对的适当参数,包括在所比较的全长序列中实现最优比对所需要的任何算法。例如,SEQ ID NO:2所示氨基酸序列中第1位至第7位的残基分别相应于SEQ ID NO:33所示氨基酸序列中第65位至第71位的残基。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:X1PCX2X3GF(SEQ ID NO:1),其中X1可以是R、A或H,X2可以是G或E,且X3可以是P或T。例如,所述分离的OX40抗原多肽可包含氨基酸序列RPCGPGF(SEQ ID NO:2)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:X1PCX2X3GFYNX4X5VX6X7X8X9C(SEQ ID NO:3),其中X1可以是R、A或H,X2可以是G或E,X3可以是P或T,X4可以是D或E,X5可以是V或A,X6可以是S或N,X7可以是S或Y,X8可以是K或D,X9可以是P或T。例如,所述分离的OX40抗原多肽可包含氨基酸序列RPCGPGFYNDVVSSKPC(SEQ ID NO:4)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:X1PCX2X3GFYNX4X5VX6X7X8X9CKX10CTX11CN(SEQ ID NO:5),其中X1可以是R、A或H,X2可以是G或E,X3可以是P或T,X4可以是D或E,X5可以是V或A,X6可以是S或N,X7可以是S或Y,X8可以是K或D,X9可以是P或T,X10可以是P、A或Q,且X11可以是W、A或Q。例如,所述分离的OX40抗原多肽可包含氨基酸序列RPCGPGFYNDVVSSKPCKPCTWCN(SEQ ID NO:6)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:X1PCX2X3GFYNX4X5VX6X7X8X9CKX10CTX11CNX12RSGSEX13KQX14CTX15TX16DTVC(SEQ ID NO:7),其中X1可以是R、A或H,X2可以是G或E,X3可以是P或T,X4可以是D或E,X5可以是V或A,X6可以是S或N,X7可以是S或Y,X8可以是K或D,X9可以是P或T,X10可以是P、A或Q,X11可以是W、A或Q,X12可以是L或H,X13可以是R或L,X14可以是L或N,X15可以是A或P,且X16可以是Q或E。例如,所述分离的OX40抗原多肽可包含氨基酸序列RPCGPGFYNDVVSSKPCKPCTWCNLRSGSERKQLCTATQDTVC(SEQ ID NO:8)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:GMVSRCX1X2X3X4X5TX6CX7PCX8X9GF(SEQ ID NO:9),其中X1可以是S或D,X2可以是R或H,X3可以是S或T,X4可以是Q或R,X5可以是N或D,X6可以是V或L,X7可以是R、A或H,X8可以是G或E,且X9可以是P或T。例如,所述分离的OX40抗原多肽可包含氨基酸序列GMVSRCSRSQNTVCRPCGPGF(SEQ ID NO:10)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:CX1ECX2PGX3GMVSRCX4X5X6X7X8TX9CX10PCX11X12GF(SEQ ID NO:11),其中X1可以是H或R,X2可以是R或Q,X3可以是N或H,X4可以是S或D,X5可以是R或H,X6可以是S或T,X7可以是Q或R,X8可以是N或D,X9可以是V或L,X10可以是R、A或H,X11可以是G或E,且X12可以是P或T。例如,所述分离的OX40抗原多肽可包含氨基酸序列CHECRPGNGMVSRCSRSQNTVCRPCGPGF(SEQ ID NO:12)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:LX1CVX2X3TYPSX4X5X6CCX7ECX8PGX9GMVSRCX10X11X12X13X14TX15CX16PCX17X18GF(SEQ ID NO:13),其中X1可以是H或N,X2可以是G或K,X3可以是D或H,X4可以是N或G,X5可以是D或H,X6可以是R或K,X7可以是H或R,X8可以是R或Q,X9可以是N或H,X10可以是S或D,X11可以是R或H,X12可以是S或T,X13可以是Q或R,X14可以是N或D,X15可以是V或L,X16可以是R、A或H,X17可以是G或E,且X18可以是P或T。例如,所述分离的OX40抗原多肽可包含氨基酸序列LHCVGDTYPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGF(SEQ ID NO:14)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:GMVSRCX1X2X3X4X5TX6CX7PCX8X9GFYNX10X11VX12X13X14X15C(SEQ ID NO:15),其中X1可以是S或D,X2可以是R或H,X3可以是S或T,X4可以是Q或R,X5可以是N或D,X6可以是V或L,X7可以是R、A或H,X8可以是G或E,X9可以是P或T,X10可以是D或E,X11可以是V或A,X12可以是S或N,X13可以是S或Y,X14可以是K或D,且X15可以是P或T。例如,所述分离的OX40抗原多肽可包含氨基酸序列GMVSRCSRSQNTVCRPCGPGFYNDVVSSKPC(SEQ ID NO:16)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:CX1ECX2PGX3GMVSRCX4X5X6X7X8TX9CX10PCX11X12GFYNX13X14VX15X16X17X18C(SEQ ID NO:17),其中X1可以是H或R,X2可以是R或Q,X3可以是N或H,X4可以是S或D,X5可以是R或H,X6可以是S或T,X7可以是Q或R,X8可以是N或D,X9可以是V或L,X10可以是R、A或H,X11可以是G或E,X12可以是P或T,X13可以是D或E,X14可以是V或A,X15可以是S或N,X16可以是S或Y,X17可以是K或D,且X18可以是P或T。例如,所述分离的OX40抗原多肽可包含氨基酸序列CHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPC(SEQ ID NO:18)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:LX1CVX2X3TYPSX4X5X6CCX7ECX8PGX9GMVSRCX10X11X12X13X14TX15CX16PCX17X18GFYNX19X20VX21X22X23X24C(SEQ IDNO:19),其中X1可以是H或N,X2可以是G或K,X3可以是D或H,X4可以是N或G,X5可以是D或H,X6可以是R或K,X7可以是H或R,X8可以是R或Q,X9可以是N或H,X10可以是S或D,X11可以是R或H,X12可以是S或T,X13可以是Q或R,X14可以是N或D,X15可以是V或L,X16可以是R、A或H,X17可以是G或E,X18可以是P或T,X19可以是D或E,X20可以是V或A,X21可以是S或N,X22可以是S或Y,X23可以是K或D,且X24可以是P或T。例如,所述分离的OX40抗原多肽可包含氨基酸序列LHCVGDTYPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPC(SEQ ID NO:20)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:GMVSRCX1X2X3X4X5TX6CX7PCX8X9GFYNX10X11VX12X13X14X15CKX16CTX17CN(SEQ ID NO:21),其中X1可以是S或D,X2可以是R或H,X3可以是S或T,X4可以是Q或R,X5可以是N或D,X6可以是V或L,X7可以是R、A或H,X8可以是G或E,X9可以是P或T,X10可以是D或E,X11可以是V或A,X12可以是S或N,X13可以是S或Y,X14可以是K或D,X15可以是P或T,X16可以是P、A或Q,且X17可以是W、A或Q。例如,所述分离的OX40抗原多肽可包含氨基酸序列GMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCN(SEQ IDNO:22)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:CX1ECX2PGX3GMVSRCX4X5X6X7X8TX9CX10PCX11X12GFYNX13X14VX15X16X17X18CKX19CTX20CN(SEQ ID NO:23),其中X1可以是H或R,X2可以是R或Q,X3可以是N或H,X4可以是S或D,X5可以是R或H,X6可以是S或T,X7可以是Q或R,X8可以是N或D,X9可以是V或L,X10可以是R、A或H,X11可以是G或E,X12可以是P或T,X13可以是D或E,X14可以是V或A,X15可以是S或N,X16可以是S或Y,X17可以是K或D,X18可以是P或T,X19可以是P、A或Q,且X20可以是W、A或Q。例如,所述分离的OX40抗原多肽可包含氨基酸序列CHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCN(SEQ ID NO:24)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:LX1CVX2X3TYPSX4X5X6CCX7ECX8PGX9GMVSRCX10X11X12X13X14TX15CX16PCX17X18GFYNX19X20VX21X22X23X24CKX25CTX2 6CN(SEQ ID NO:25),其中X1可以是H或N,X2可以是G或K,X3可以是D或H,X4可以是N或G,X5可以是D或H,X6可以是R或K,X7可以是H或R,X8可以是R或Q,X9可以是N或H,X10可以是S或D,X11可以是R或H,X12可以是S或T,X13可以是Q或R,X14可以是N或D,X15可以是V或L,X16可以是R、A或H,X17可以是G或E,X18可以是P或T,X19可以是D或E,X20可以是V或A,X21可以是S或N,X22可以是S或Y,X23可以是K或D,X24可以是P或T,X25可以是P、A或Q,且X26可以是W、A或Q。例如,所述分离的OX40抗原多肽可包含氨基酸序列LHCVGDTYPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCN(SEQ ID NO:26)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:GMVSRCX1X2X3X4X5TX6CX7PCX8X9GFYNX10X11VX12X13X14X15CKX16CTX17CNX18RSGSEX19KQX20CTX21TX22DTVC(SEQ IDNO:27),其中X1可以是S或D,X2可以是R或H,X3可以是S或T,X4可以是Q或R,X5可以是N或D,X6可以是V或L,X7可以是R、A或H,X8可以是G或E,X9可以是P或T,X10可以是D或E,X11可以是V或A,X12可以是S或N,X13可以是S或Y,X14可以是K或D,X15可以是P或T,X16可以是P、A或Q,X17可以是W、A或Q,X18可以是L或H,X19可以是R或L,X20可以是L或N,X21可以是A或P,且X22可以是Q或E。例如,所述分离的OX40抗原多肽可包含氨基酸序列GMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCNLRSGSERKQLCTATQDTVC(SEQ ID NO:28)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:CX1ECX2PGX3GMVSRCX4X5X6X7X8TX9CX10PCX11X12GFYNX13X14VX15X16X17X18CKX19CTX20CNX21RSGSEX22KQX23CTX24TX25DTVC(SEQ ID NO:29),其中X1可以是H或R,X2可以是R或Q,X3可以是N或H,X4可以是S或D,X5可以是R或H,X6可以是S或T,X7可以是Q或R,X8可以是N或D,X9可以是V或L,X10可以是R、A或H,X11可以是G或E,X12可以是P或T,X13可以是D或E,X14可以是V或A,X15可以是S或N,X16可以是S或Y,X17可以是K或D,X18可以是P或T,X19可以是P、A或Q,X20可以是W、A或Q,X21可以是L或H,X22可以是R或L,X23可以是L或N,X24可以是A或P,且X25可以是Q或E。例如,所述分离的OX40抗原多肽可包含氨基酸序列CHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCNLRSGSERKQLCTATQDTVC(SEQ ID NO:30)。
在某些实施方式中,本申请的分离的OX40抗原多肽包含氨基酸序列:LX1CVX2X3TYPSX4X5X6CCX7ECX8PGX9GMVSRCX10X11X12X13X14TX15CX16PCX17X18GFYNX19X20VX21X22X23X24CKX25CTX2 6CNX27RSGSEX28KQX29CTX30TX31DTVC(SEQ ID NO:31),其中X1可以是H或N,X2可以是G或K,X3可以是D或H,X4可以是N或G,X5可以是D或H,X6可以是R或K,X7可以是H或R,X8可以是R或Q,X9可以是N或H,X10可以是S或D,X11可以是R或H,X12可以是S或T,X13可以是Q或R,X14可以是N或D,X15可以是V或L,X16可以是R、A或H,X17可以是G或E,X18可以是P或T,X19可以是D或E,X20可以是V或A,X21可以是S或N,X22可以是S或Y,X23可以是K或D,X24可以是P或T,X25可以是P、A或Q,X26可以是W、A或Q,X27可以是L或H,X28可以是R或L,X29可以是L或N,X30可以是A或P,且X31可以是Q或E。例如,所述分离的OX40抗原多肽可包含氨基酸序列LHCVGDTYPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCNLRSGSERK QLCTATQDTVC(SEQ ID NO:32)。
在某些实施方式中,本申请所述的分离的OX40抗原多肽包含约4-160个(例如,至少5个,至少6个,至少7个,至少8个,至少9个,至少10个,至少15个,至少20个,至少25个,至少30个,至少35个,至少40个,至少45个,至少50个,至少55个,至少60个,至少65个,至少70个,至少75个,至少80个,至少85个,至少90个,至少95个,至少100个,至少110个,至少120个,至少130个,至少140个,至少150个,至少160个或更多个)氨基酸残基。
例如,本申请所述的分离的OX40抗原多肽可源自OX40的细胞外结构域,其片段或变体。例如,其可源自人、食蟹猴、小鼠或大鼠OX40的细胞外结构域,其片段或变体。在某些实施方式中,本申请所述的分离的OX40抗原多肽源自人OX40。例如,其可源自人OX40的细胞外结构域,其片段或变体。所述人OX40细胞外结构域的氨基酸序列可如SEQ ID NO:43所示。
例如,所述OX40抗原多肽可包含OX40(如人OX40)的细胞外结构域、其变体或部分,如一个或多个(例如,1个、2个、3个或4个)半胱氨酸富集域(CRD)、其变体或部分。
在某些实施方式中,本申请的分离的OX40抗原多肽源自OX40(例如,人OX40)细胞外结构域中包含下组中一个或多个结构域或其片段的区域:半胱氨酸富集域1(CRD1)、半胱氨酸富集域2(CRD2)和半胱氨酸富集域3(CRD3)。在某些实施方式中,本申请的分离的OX40抗原多肽源自OX40(例如,人OX40)细胞外结构域中包含下组中一个或多个结构域或其片段的区域:半胱氨酸富集域1(CRD1)和半胱氨酸富集域2(CRD2)。在某些实施方式中,本申请的分离的OX40抗原多肽不包含OX40(例如,人OX40)细胞外结构域中的下列区域:半胱氨酸富集域3(CRD3)或半胱氨酸富集域4(CRD4)。
在某些实施方式中,所述OX40抗原多肽包含OX40(例如人OX40)细胞外结构域中的CRD2区、其变体或其片段。在某些实施方式中,所述OX40抗原多肽还包含OX40(例如人OX40)细胞外结构域中的CRD1区、其变体或其片段。
在某些实施方式中,所述OX40抗原多肽不包含OX40(例如人OX40)细胞外结构域中的CRD3区或其片段。在某些实施方式中,所述OX40抗原多肽不包含OX40(例如人OX40)细胞外结构域中的CRD4区或其片段。
例如,本申请的分离的OX40抗原多肽可包含源自下组中的一个或多个结构域或其片段的区域:1)OX40(例如,人OX40)的CRD1的模块A1;2)OX40(例如,人OX40)的CRD1的模块B2;3)OX40(例如,人OX40)的CRD2的模块A1;和4)OX40(例如,人OX40)的CRD2的模块B2。在某些实施方式中,本申请的分离的OX40抗原多肽包含OX40(例如,人OX40)的CRD1的模块A1、其变体或片段。在某些实施方式中,本申请的分离的OX40抗原多肽包含OX40(例如,人OX40)的CRD1的模块B2、其变体或片段。在某些实施方式中,本申请的分离的OX40抗原多肽包含OX40(例如,人OX40)的CRD2的模块A1、其变体或片段。在某些实施方式中,本申请的分离的OX40抗原多肽包含OX40(例如,人OX40)的CRD2的模块B2、其变体或片段。
例如,人OX40的CRD1中模块A1的氨基酸序列可如SEQ ID NO:45所示,人OX40的CRD1中模块B2的氨基酸序列可如SEQ ID NO:46所示,人OX40的CRD1的氨基酸序列可如SEQID NO:47所示。人OX40的CRD2中模块A1的氨基酸序列可如SEQ ID NO:48所示,人OX40的CRD2中模块B2的氨基酸序列可如SEQ ID NO:49所示,人OX40的CRD2的氨基酸序列可如SEQID NO:50所示。
此外,人OX40的CRD3的氨基酸序列可如SEQ ID NO:51所示。人OX40的CRD4的氨基酸序列可如SEQ ID NO:52所示。
本申请的分离的OX40抗原多肽可具有免疫原性。例如,所述OX40抗原多肽能够刺激机体形成OX40特异性抗体和/或致敏淋巴细胞。
另一方面,本申请还提供了包含所述分离的OX40抗原多肽的融合蛋白或免疫缀合物。例如,可将所述分离的OX40抗原多肽与一种或多种异源多肽(例如,抗体或抗体的组成部分,或者其它抗原多肽)相融合,而得到所述融合蛋白或免疫缀合物。其中,用于与所述分离的OX40抗原多肽相融合的异源多肽可包含抗体(例如,IgG抗体)的恒定区或Fc区。在某些实施方式中,用于与所述分离的OX40抗原多肽相融合的异源多肽可包含其它抗原多肽,例如源自OX40(如人OX40)的其它抗原多肽。本申请所述的分离的OX40抗原多肽可直接(例如,在框内)或间接(例如,通过连接子,如肽连接子)与所述一种或多种异源多肽相连接、缀合或融合。可通过本领域技术人员已知的方法制备所述融合蛋白或免疫缀合物,例如可通过分子克隆和蛋白质重组表达的方法制备所述融合蛋白或免疫缀合物。
核酸、载体、细胞和制备方法
在另一个方面,本申请提供了一种或多种分离的核酸分子,所述核酸分子可编码本申请所述的分离的OX40抗原多肽和/或本申请所述的融合蛋白或免疫缀合物。
本申请所述的核酸分子可以为分离的。例如,其可以是通过以下方法产生或合成的:(i)在体外扩增的,例如通过聚合酶链式反应(PCR)扩增产生的,(ii)通过克隆重组产生的,(iii)纯化的,例如通过酶切和凝胶电泳分级分离,或者(iv)合成的,例如通过化学合成。在某些实施方式中,所述分离的核酸是通过重组DNA技术制备的核酸分子。
在本申请中,可以通过本领域已知的多种方法来制备编码所述OX40抗原多肽和/或所述融合蛋白或免疫缀合物的核酸,这些方法包括但不限于,采用限制性片段操作或采用合成性寡核苷酸的重叠延伸PCR,具体操作可参见Sambrook等人,Molecular Cloning,ALaboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,1989;和Ausube等人Current Protocols in Molecular Biology,GreenePublishing and Wiley-Interscience,New York N.Y.,1993。
在另一个方面,本申请提供了一种或多种载体,所述载体可包含本申请所述的一种或多种分离的核酸分子。此外,所述载体中还可包含其他基因,例如允许在适当的宿主细胞中和在适当的条件下选择该载体的标记基因。此外,所述载体还可包含允许编码区在适当宿主中正确表达的表达控制元件。这样的控制元件为本领域技术人员所熟知的,例如,可包括启动子、核糖体结合位点、增强子和调节基因转录或mRNA翻译的其他控制元件等。在某些实施方式中,所述表达控制序列为可调的元件。所述表达控制序列的具体结构可根据物种或细胞类型的功能而变化,但通常包含分别参与转录和翻译起始的5’非转录序列和5’及3’非翻译序列,例如TATA盒、加帽序列、CAAT序列等。例如,5’非转录表达控制序列可包含启动子区,启动子区可包含用于转录控制功能性连接核酸的启动子序列。所述表达控制序列还可包括增强子序列或上游活化子序列。在本申请中,适当的启动子可包括,例如用于SP6、T3和T7聚合酶的启动子、人U6RNA启动子、CMV启动子及其人工杂合启动子(如CMV),其中启动子的某部分可与其他细胞蛋白(如人GAPDH,甘油醛-3-磷酸脱氢酶)基因启动子的某部分融合,其可包含或不包含另外的内含子。本申请所述的一种或多种核酸分子可以与所述表达控制元件可操作地连接。
所述载体可以包括,例如质粒、粘粒、病毒、噬菌体或者在例如遗传工程中通常使用的其他载体。在某些实施方式中,所述载体为表达载体。
在另一个方面,本申请提供了一种或多种细胞(例如,宿主细胞)或非人生物体,其可包含或表达本申请所述的OX40抗原多肽、本申请所述的融合蛋白或免疫缀合物、本申请所述的一种或多种分离的核酸分子、或者本申请所述的一种或多种载体。例如,可将本申请所述的载体引入所述细胞(例如,宿主细胞)中,例如原核细胞(例如,细菌细胞)、CHO细胞、NS/0细胞、HEK293T细胞或HEK293A细胞,或者其他真核细胞,如来自植物的细胞、真菌或酵母细胞等。可通过本领域已知的方法将本申请所述的载体引入所述宿主细胞中,例如电穿孔、lipofectine转染、lipofectamin转染等。所述非人生物体可以为转基因的或遗传工程化的生物体,其可源自所述细胞(例如,宿主细胞)或者包含所述细胞(例如,宿主细胞)。
在另一个方面,本申请提供了制备所述OX40抗原多肽或者所述融合蛋白或免疫缀合物的方法。所述方法可包括,在使得所述OX40抗原多肽或者所述融合蛋白或免疫缀合物表达的条件下,培养本申请所述的细胞(例如,宿主细胞)。例如,可通过使用适当的培养基、适当的温度和培养时间等,这些方法是本领域普通技术人员所了解的。
在某些情形中,所述方法还可包括分离和/或纯化所述OX40抗原多肽或者所述融合蛋白或免疫缀合物的步骤。例如,可以采用蛋白G-琼脂糖或蛋白A-琼脂糖进行亲和层析,还可通过凝胶电泳和/或高效液相色谱等来纯化和分离本申请所述的OX40抗原多肽或者所述的融合蛋白或免疫缀合物。
组合物和疫苗
在另一个方面,本申请提供了一种组合物(例如药物组合物),其可包含本申请所述的OX40抗原多肽、本申请所述的融合蛋白或免疫缀合物、本申请所述的核酸分子、本申请所述的载体、或本申请所述的细胞(例如,宿主细胞),以及任选地药学上可接受的佐剂。
所述药学上可接受的佐剂可以包括缓冲剂、抗氧化剂、防腐剂、低分子量多肽、蛋白质、亲水聚合物、氨基酸、糖、螯合剂、反离子、金属复合物和/或非离子表面活性剂等。
在本申请中,可按照本领域的常规技术手段将所述药物组合物与可药用载体或稀释剂以及任何其他已知的辅剂和赋形剂配制在一起,例如按照Remington:The Scienceand Practice of Pharmacy,第十九版,Gennaro编辑,Mack Publishing Co.,Easton,PA,1995中公开的技术进行操作。
所述药物组合物可以用于在体内(例如,生物体内,如动物体内或人体内)或体外(例如分离的细胞或组织中)产生免疫活性物质。所述免疫活性物质可包括OX40特异性抗体,例如OX40激动性抗体,例如抗体DF004。在某些实施方式中,所述药物组合物用于抑制肿瘤生长(例如,血液瘤或实体肿瘤)。例如,本申请的药物组合物可以抑制或延缓疾病的发展或进展,可以减小肿瘤大小(甚至基本消除肿瘤),和/或可以减轻和/或稳定疾病状态。
例如,本申请所述的药物组合物可以为适于口服给药的形式,如片剂,胶囊剂,丸剂,粉剂,缓释制剂,溶液剂,混悬剂,或者用于肠胃外注射,如无菌溶液剂,混悬剂或乳剂,或者用于软膏或乳膏局部给药或作为栓剂直肠给药。所述药物组合物可以是适合精确剂量单次给药的单位剂量形式。所述药物组合物可以进一步包含常规的药物载体或赋形剂。此外,所述药物组合物可以包括其他药物或药剂,载体,佐剂等。
本申请所述的药物组合物可以包含治疗有效量的所述OX40抗原多肽或者所述融合蛋白或免疫缀合物。所述治疗有效量是能够产生免疫活性物质(例如,OX40特异性抗体,如OX40激动性抗体),和/或能够治疗或减缓疾病(例如肿瘤)发展或进展的量。所述剂量的具体量/浓度可以根据施用方法和患者需要而变化,并且可以基于例如患者体积,粘度和/或体重等来确定。应当理解的是,基于特定患者,制剂和/或疾病的状况,本领域技术人员(例如,医生或药剂师)可以方便地调整这些特定剂量。
本申请所述的药物组合物可以为疫苗(例如,癌症疫苗)。因此,在另一个方面,本申请提供了一种疫苗,其可包含一种或多种选自下列的物质以及任选地免疫原性载体:1)一种或多种本申请所述的OX40抗原多肽;2)本申请所述的融合蛋白或免疫缀合物;3)本申请所述的核酸分子;4)本申请所述的载体;5)本申请所述的细胞(例如,宿主细胞);和6)本申请所述的组合物(例如,药物组合物)。在某些实施方式中,所述疫苗为癌症疫苗。
本申请所述的疫苗(例如,癌症疫苗)还可以包含一种或多种其它的抗原(例如,肿瘤抗原)。所述其它的抗原可以包括一种或多种其它的OX40抗原多肽。所述疫苗可用于治疗受试者(例如,哺乳动物,比如人)中的一种或多种癌症(例如,血液癌或实体瘤,包括与T细胞、特别是CD4+和/或CD8+T细胞相关的癌症)。所述癌症可以包括但不限于,例如,黑色素瘤、脑癌、骨癌、白血病、淋巴瘤、上皮细胞癌、腺癌、胃肠道癌(如唇癌、口腔癌、食道癌、小肠癌、胃癌、结肠癌)、肝癌、膀胱癌、胰腺癌、卵巢癌、宫颈癌、肺癌、乳腺癌、皮肤癌、鳞状细胞癌、前列腺癌和/或肾细胞癌等。
可以通过化学合成或重组表达、纯化等方法制备本申请所述的分离的OX40抗原多肽或者所述融合蛋白或免疫缀合物,随后可将所述OX40抗原多肽或者所述融合蛋白或免疫缀合物与一种或多种其它肿瘤抗原和/或药学上可接受的佐剂进行混合而制备所述疫苗(例如,癌症疫苗)。
在某些情形中,所述疫苗中可包含一种或多种免疫原性载体或佐剂。例如,所述OX40抗原多肽、所述融合蛋白或免疫缀合物或其它肿瘤抗原可与一种或多种糖脂类似物相组合或结合,以增强其免疫效果。
这些疫苗或组合物可被用于免疫(例如,通过肌内或肠胃外施用)受试者(例如,动物或人,如鼠类、兔类、羊类等)。所述疫苗中也可包含一种或多种药学上可接受的佐剂,例如缓冲剂、抗氧化剂、防腐剂、低分子量多肽、蛋白质、亲水聚合物、氨基酸、糖、螯合剂、反离子、金属复合物和/或非离子表面活性剂等。
抗体及其产生、筛选方法及用途
在另一个方面,本申请提供了一种抗体,其能够特异性结合本申请所述的OX40抗原多肽。例如,所述抗体可以为OX40激动性抗体。在某些实施方式中,所述抗体为单克隆抗体。在某些实施方式中,所述抗体基本上不结合包含突变G70A和/或突变F71A的OX40(例如,人OA40)变体。例如,所述抗体可基本上不结合氨基酸序列如SEQ ID NO:35或SEQ ID NO:36所示的人OX40变体。
在某些实施方式中,所述抗体与DF004竞争结合本申请的所述OX40抗原多肽。在某些情形中,所述抗体可以不是DF004。
本申请所述的抗体DF004包含轻链和重链,所述轻链包含LCDR1、LCDR2和LCDR3,其中所述LCDR1的氨基酸序列如SEQ ID NO:63所示,所述LCDR2的氨基酸序列如SEQ ID NO:64所示且所述LCDR3的氨基酸序列如SEQ ID NO:65所示。所述重链包含HCDR1、HCDR2和HCDR3,其中所述HCDR1的氨基酸序列如SEQ ID NO:66所示,所述HCDR2的氨基酸序列如SEQ ID NO:67所示且所述HCDR3的氨基酸序列如SEQ ID NO:68所示。
本申请所述的抗体DF004的重链可变区氨基酸序列如SEQ ID NO:70所示,且其轻链可变区氨基酸序列如SEQ ID NO:69所示。
本申请所述的抗体DF004的重链氨基酸序列如SEQ ID NO:56所示,且其轻链氨基酸序列如SEQ ID NO:58所示。
在另一个方面,本申请提供了一种药物组合物,其可包含本申请所述的抗体(例如,OX40激动性抗体),以及任选地药学上可接受的佐剂。所述药学上可接受的佐剂可以包括缓冲剂、抗氧化剂、防腐剂、低分子量多肽、蛋白质、亲水聚合物、氨基酸、糖、螯合剂、反离子、金属复合物和/或非离子表面活性剂等。
在另一个方面,本申请提供了一种用于产生OX40激动性抗体的方法。所述方法可以包括施用(例如,向受试者,如待免疫的动物或人;或者在体外,例如向分离的细胞或组织)本申请所述的OX40抗原多肽或者本申请所述的融合蛋白或免疫缀合物。例如,所述方法可以包括用本申请所述的OX40抗原多肽免疫动物。在某些实施方式中,所述方法还包括分离与所述OX40抗原多肽特异性结合的抗体。
在另一个方面,本申请提供了本申请所述OX40抗原多肽或者本申请所述的融合蛋白或免疫缀合物用于制备免疫活性物质的用途,所述免疫活性物质可包括OX40激动性抗体。所产生的OX40激动性抗体可用于治疗疾病(例如,癌症,如血液癌或实体瘤,特别是与OX40的表达或调控相关的癌症)。因此,在某些实施方式中,本申请提供了所述OX40抗原多肽或者所述融合蛋白或免疫缀合物用于制备药物的用途,所述药物可用于治疗疾病(例如,癌症,如血液癌或实体瘤,特别是与OX40的表达或调控相关的癌症)。所述癌症可以包括但不限于,例如,黑色素瘤、脑癌、骨癌、白血病、淋巴瘤、上皮细胞癌、腺癌、胃肠道癌(如唇癌、口腔癌、食道癌、小肠癌、胃癌、结肠癌)、肝癌、膀胱癌、胰腺癌、卵巢癌、宫颈癌、肺癌、乳腺癌、皮肤癌、鳞状细胞癌、前列腺癌和/或肾细胞癌等。
能够利用本申请所述的OX40抗原多肽或者本申请所述的融合蛋白或免疫缀合物产生、制备、筛选和/或检测的抗体可包括天然产生的抗体以及通过重组方法制备的抗体。这些抗体可包括利用本领域已知的技术制备的多克隆抗体和单克隆抗体。这些抗体可以为OX40激动性抗体,例如,所述抗体能够激活OX40或增强其活性。所述抗体能够被用于治疗和/或预防与OX40和/或OX40L的表达或活性相关的疾病,例如肿瘤(如血液癌或实体瘤)。所述抗体也可被用于免疫测定中,例如用于对肿瘤组织和/或肿瘤微环境中的其它组织或细胞(如免疫细胞,例如表达OX40的免疫细胞)进行表征、识别或标记。
在利用本申请所述的OX40抗原多肽或者本申请所述的融合蛋白或免疫缀合物产生或制备抗体时,可采用本领域中常用的抗体制备方法。
例如,当所述产生或制备的抗体为多克隆抗体时,可采用本领域技术人员已知的方法,如Harlow等人,Antibodies:a Laboratory Manual,Cold spring HarborLaboratory Press,第二版(1988),其全文在此通过援引而并入。例如,可将本申请所述的OX40抗原多肽或者本申请所述的融合蛋白或免疫缀合物注射或以其它方式施用到宿主动物(包括但不限于,兔、小鼠、大鼠等)中,以诱导含有特异性针对所述OX40抗原、融合蛋白或免疫缀合物的多克隆抗体的血清的生成。所述OX40抗原、融合蛋白或免疫缀合物的施用可通过一次或多次注射来进行,需要的时候还可以施用免疫佐剂。依据宿主种类不同,各种佐剂可用于提高免疫应答,其包括但不限于,弗氏试剂(完全或不完全)、无机佐剂(如氢氧化铝)、表面活性物质(如溶血卵磷脂)、复合多元醇、聚阴离子、肽、油乳剂、匙孔血蓝蛋白、二硝基酚以及潜在有用的人佐剂如BCG(卡介苗)和短小棒状杆菌等。其它的可供使用的佐剂的例子包括MPL-TDM佐剂(单磷酸类脂A,合成的海藻糖二霉菌酸脂)。进行免疫的具体方案为本领域技术人员所知,并可通过能诱发所选动物宿主的免疫应答的任意方式进行。
例如,可通过多次皮下或腹膜内注射、或肌肉内或通过静脉输注将免疫原(具有或不具有佐剂)注射至宿主动物中。该免疫原可包括本申请的分离的OX40抗原多肽、本申请的融合蛋白或免疫缀合物等。可根据多肽的性质(即,疏水性比例、亲水性比例、稳定性、净电荷、等电点等),将所述免疫原(例如本申请的分离的OX40抗原多肽)与已知的、在待免疫的宿主动物中具有免疫原性的蛋白相缀合。可通过化学偶联、基于融合蛋白的方法、或其它本领域技术人员已知方法来实现所述缀合。所述在待免疫的宿主动物中具有免疫原性的蛋白可包括,例如匙孔血蓝蛋白、卵白蛋白、血清白蛋白、牛甲状腺蛋白、大豆胰蛋白抑制剂和混杂T辅助肽等。
当所述产生或制备的抗体为单克隆抗体时,可采用本领域技术人员已知的方法,例如杂交瘤技术(可参见美国专利4,376,110;Harlow等人,Antibodies:A LaboratoryManual,Cold Spring Harbor Laboratory Press,第二版(1988)以及Hammerling等人,Monoclonal Antibodies and T-Cell Hybridomas,Elsevier(1981))、重组DNA方法或本领域技术人员已知的其它方法进行制备。可用于制备单克隆抗体的方法的其它实例包括但不限于,人B-细胞杂交瘤技术、EBV-杂交瘤技术等。所产生的单克隆抗体可以是任意免疫球蛋白类别,包括IgG、IgM、IgE、IgA、IgD及其任意亚型。可在体外或体内培养用于产生单克隆抗体的杂交瘤。
在杂交瘤模型中,宿主(例如小鼠、人源化小鼠、具有人免疫系统的小鼠、仓鼠、兔、骆驼或任意其它合适的宿主动物)被免疫以诱发淋巴细胞,该淋巴细胞生成或能够生成特异性结合用于免疫的蛋白(例如本申请的分离的OX40抗原多肽,或者本申请的融合蛋白或免疫缀合物)的抗体。备选地,也可在体外对淋巴细胞进行免疫,然后可通过使用合适的融合剂(例如聚乙二醇)将淋巴细胞与骨髓瘤细胞进行融合,以形成杂交瘤。
一般而言,在制备用于产生抗体的杂交瘤时,如需要人源细胞,可使用外周血淋巴细胞(“PBL”)。如需要非人哺乳动物源细胞,可使用脾细胞或淋巴结细胞。然后,可通过使用合适的融合剂(例如聚乙二醇)将淋巴细胞与永生化细胞系相融合,以形成杂交瘤。永生化细胞系通常为被转化的哺乳动物细胞,特别是啮齿类动物、牛或人源骨髓瘤细胞。例如,可采用大鼠或小鼠的骨髓瘤细胞系。可在适当的培养基中培养所述杂交瘤细胞。例如,所述培养基可包含一种或多种抑制未融合的永生化细胞生长或存活的物质。例如,如果该亲代细胞缺乏次黄嘌呤鸟嘌呤磷酸核糖转移酶(HGPRT或HPRT),用于该杂交瘤的培养基通常会包含次黄嘌呤、氨基蝶呤和胸苷(“HAT培养基”),它们是阻止HGPRT-缺陷型细胞生长的物质。
例如,所使用的永生化细胞系可以是能够有效融合、支持所选抗体生成细胞稳定、高水平地产生抗体、并对培养基(例如HAT培养基)敏感的细胞系。这些骨髓瘤细胞系可包括鼠骨髓瘤细胞系,例如MOPC-21和MPC-11小鼠肿瘤细胞系,源自SP2/0的细胞系等。还可使用人骨髓瘤、鼠-人异源骨髓瘤细胞系、小鼠杂交瘤细胞系NSO等来制备抗体。
可通过免疫沉淀、放射性免疫测定(RIA)、酶联免疫吸附测定(ELISA)等体外结合试验来检测所产生的单克隆抗体与所述分离的OX40抗原多肽、所述融合蛋白或免疫缀合物的结合亲和力和/或结合特异性。这些技术在本领域技术人员的技能范围内。
当鉴定出能够生成具有所需结合特异性、亲和性和/或活性的抗体的杂交瘤后,可将该克隆通过有限稀释法进行亚克隆并以标准方法培养。合适的培养基可包括,例如,DMEM或RPMI-1640培养基。然后,可使用常规的免疫球蛋白纯化技术(例如,蛋白A-琼脂糖、羟基磷灰石层析、凝胶排阻层析、凝胶电泳、透析或亲和层析)从细胞培养物、宿主动物腹水或血清中分离由该亚克隆分泌的单克隆抗体。
也可通过其它方法,例如重组DNA方法制备或产生所述单克隆抗体。例如,可将由杂交瘤分离的DNA插入表达载体中,随后将其转染到宿主细胞(例如大肠杆菌细胞、NSO细胞、猿COS细胞、中国仓鼠卵巢(CHO)细胞或者其它情况下不会生成免疫球蛋白的骨髓瘤细胞)中,从而在该重组宿主细胞中合成所述单克隆抗体。
在另一个方面,本申请提供了一种阻止OX40-OX40L六聚体形成的方法,所述方法包括施用与本申请所述的OX40抗原多肽特异性结合的试剂。例如,在某些情形中,在体内或体外施用与本申请所述的OX40抗原多肽特异性结合的试剂后,OX40与OX40L无法再结合。在某些情形中,在体内或体外施用与本申请所述的OX40抗原多肽特异性结合的试剂后,OX40与OX40L仍能够彼此结合,但是无法形成六聚体(例如,仅行成2聚体、3聚体、4聚体等)。在某些情形中,OX40与OX40L无法彼此结合或者结合后无法处于有活性的分子构象。例如,与本申请所述的OX40抗原多肽特异性结合的试剂可以为OX40的激动剂。在某些实施方式中,与本申请所述的OX40抗原多肽特异性结合的试剂为OX40激动性抗体(例如,本申请所述的抗体DF004)。
在另一个方面,本申请提供了所述OX40抗原多肽或者所述融合蛋白或免疫缀合物用于制备试剂的用途,所述试剂可用于阻止OX40-OX40L六聚体的形成。在某些实施方式中,所述试剂能够作为激动剂激活OX40。例如,所述试剂可以包括或可以为OX40激动性抗体(例如,本申请所述的抗体DF004)。
在另一个方面,本申请提供了用于筛选和/或检测OX40激动性抗体的方法。所述方法可包括使待筛选和/或待检测的候选抗体或其抗原结合片段、或者表达所述候选抗体或其抗原结合片段的细胞或细胞分泌物与本申请所述的OX40抗原多肽或本申请所述的融合蛋白或免疫缀合物接触。所述方法还可以包括判断所述候选抗体或其抗原结合片段是否与所述OX40抗原多肽特异性结合,且当检测到所述特异性结合时,将该候选抗体鉴别为OX40激动性抗体。例如,所述OX40激动性抗体可包括DF004。
在另一个方面,本申请提供了所述OX40抗原多肽或者本申请所述的融合蛋白或免疫缀合物用于制备试剂的用途,所述试剂可用于检测、识别和/或筛选OX40激动性抗体。在某些实施方式中,所述OX40激动性抗体可包括DF004。
例如,可通过使待检测、识别和/或筛选的细胞、细胞分泌物、细胞培养混合物,或者包含待筛选/检测的抗体或其抗原结合片段的物质(例如,试剂或混合物)与本申请所述的分离的OX40抗原多肽接触,或者与本申请所述的融合蛋白或免疫缀合物接触,然后,根据其是否能够特异性结合本申请所述的分离的OX40抗原多肽(或者本申请所述融合蛋白或免疫缀合物中的所述OX40抗原多肽),来判断所述细胞、细胞分泌物、细胞培养混合物或者所述试剂或混合物中是否含有OX40激动性抗体或其抗原结合片段。在某些实施方式中,可通过此方法判断所述细胞、细胞分泌物、细胞培养混合物或者所述试剂或混合物中是否含有抗体DF004或其抗原结合片段。
可通过例如,免疫沉淀、放射性免疫测定(RIA)、酶联免疫吸附测定(ELISA)等体外结合试验来进行所述筛选和/或检测。
在另一个方面,本申请提供了预防和/或治疗受试者中的癌症的方法。所述方法可包括向所述受试者施用有效量的、选自下组的一种或多种物质:1)本申请所述的OX40抗原多肽;2)本申请所述的融合蛋白或免疫缀合物;3)本申请所述的核酸分子;4)本申请所述的载体;5)本申请所述的细胞(例如宿主细胞);6)本申请所述的药物组合物;和7)本申请所述的疫苗。所述癌症可以是例如血液癌或实体瘤,特别是与OX40的表达或调控相关的癌症。例如,所述癌症可以包括但不限于,黑色素瘤、脑癌、骨癌、白血病、淋巴瘤、上皮细胞癌、腺癌、胃肠道癌(如唇癌、口腔癌、食道癌、小肠癌、胃癌、结肠癌)、肝癌、膀胱癌、胰腺癌、卵巢癌、宫颈癌、肺癌、乳腺癌、皮肤癌、鳞状细胞癌、前列腺癌和/或肾细胞癌等。
下面将结合实施例对本申请所述发明的实施方式进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于示例性地说明本申请所述发明,而不应视为限定本申请所述发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1:DF004抗体的制备
构建表达载体
根据专利WO2017063162A1得到抗OX40激活性抗体DF004的重链和轻链的全长氨基酸序列,再利用DNAworks在线工具(http://helixweb.nih.gov/dnaworks/)设计对应的编码DNA序列,并通过人工合成方法获得DF004的轻链基因,命名为DF004-LC(核苷酸序列如SEQ ID NO:57所示)。按照同样的方法获得DF004的重链基因,命名为DF004-HC(核苷酸序列如SEQ ID NO:55所示)。将合成好的DF004-HC和DF004-LC分别经Thermo公司的HindIII和PmeI双酶切克隆至商业化载体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-DF004HC和pcDNA4-DF004LC。
宿主细胞转染和目标蛋白表达
转染前两天,准备600mL经悬浮驯化的HEK293(ATCC,CRL-1573TM)细胞用于瞬时转染,接种密度为0.8×106cells/mL。两天后取细胞悬液,离心后重悬于600mL Freestyle293培养基中。
将上述所得的2个重组质粒pcDNA4-DF004HC和pcDNA4-DF004LC用6mLFreestyle293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600mL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600mL EX293培养基,2mM谷氨酰胺和50μg/L IGF-1,135rpm培养。24小时后加3.8mM VPA。
培养5~6天后,收集1200mL的DF004抗体瞬时表达培养上清液,通过ProteinA亲和层析法,初步纯化得到DF004抗体样品。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。
实施例2:确定与DF004结合的OX40抗原表位
构建表达载体
从uniport数据库得到人OX40细胞外结构域的氨基酸序列(P43489,第1位到第170位,其氨基酸序列如SEQ ID NO:43所示),再利用DNAworks在线工具(http://helixweb.nih.gov/dnaworks/)设计对应的编码DNA序列,并通过人工合成方法获得编码OX40细胞外结构域的核酸分子,命名为OX40。将合成好的OX40核酸分子经Thermo公司的HindIII和AgeI双酶切克隆至商业化载体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-OX40-His(其中OX40-His的核苷酸序列如SEQ ID NO:60所示)。以实施例1构建的pcDNA-DF004HC为模板,利用PCR的方法(引物如下:SCDKTH-R:GCCGACCGGTGTGTGTCTTATCGCAGCT;DF004-VH-F:GCCGAAGCTTGCCACCATGGAGACAGACACACTCC;其核苷酸序列分别如SEQ ID NO:71、SEQ ID NO:72所示)获得DF004VH-CH1的序列,该序列经HindIII和AgeI双酶切克隆至商业化载体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-DF004VH-CH1-His(其中DF004VH-CH1-His的核苷酸序列如SEQ ID NO:62所示)。
宿主细胞转染和目标蛋白表达
转染前两天,准备600mL经悬浮驯化的HEK293(ATCC,CRL-1573TM)细胞用于瞬时转染,接种密度为0.8×106cells/mL。两天后取细胞悬液,离心后分别重悬于600mLFreestyle293培养基中。
将上述实施例中所得的重组表达载体分为两组,组1为200μg pcDNA4-OX40-His;组2为100ug pcDNA4-DF004-VH-CH1-His+100μg pcDNA4-DF004LC。每组质粒用6mLFreestyle293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600mL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600mL EX293培养基,2mM Glutamine和50μg/L IGF-1,135rpm培养。二十四小时后加3.8mM VPA。培养5~6天后,分别收集OX40-His(氨基酸序列如SEQ ID NO:59所示)和DF004Fab(DF004VH-CH1-His+DF004LC,其中DF004VH-CH1-His的氨基酸序列如SEQ ID NO:61所示)表达培养上清液,通过Ni-NTA柱亲和层析法,初步纯化得到OX40蛋白和DF004Fab蛋白。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。
OX40-DF004复合物的纯化和结晶
将OX40纯化后蛋白与DF004纯化后蛋白按摩尔比2:1比例混合,浓缩至2ml,进入HiLoad 16/600Superdex 75prep grade,用缓冲液E(10mM Tris-HCl pH7.4,150mM NaCl)洗脱样品,得到OX40和DF004Fab复合物。将OX40-DF004复合物浓缩至30mg/ml,以蛋白:池液=200nl:200nl比例筛选LMB板,结晶板置于25℃。晶体于(0.1M酒石酸钠钾,20%PEG 3350)长出晶体。对晶体条件优化,方案如下:0.1M酒石酸钠钾,10%~30%PEG 3350。优化后结果最佳为0.1M酒石酸钠钾,14%PEG 3350。进一步以上述条件为基础,加入甘油优化,方案如下:0.1M酒石酸钠钾,14%PEG 3350,5%~25%甘油。选取最佳条件0.1M酒石酸钠钾,14%PEG 3350,10%甘油,对复合物进行结晶。得到的晶体进行X射线衍射,对得到的衍射数据用CCP4软件进行处理,然后用PyMol软件做出示意图,结果如图2所示。
实施例3:对OX40抗原表位上关键结合位点的鉴定及验证
3.1构建OX40抗原关键结合位点表达载体
以实施例2中构建好的pcDNA4-OX40-His质粒为模板,利用重叠PCR的方法针对关键位点进行点突变,其中的关键位点突变策略分别为:W86A、R65A、P83A、A126V、G70A和F71A。点突变所用的引物见下表。
将重叠后的PCR产物分别经Thermo公司的HindIII和AgeI双酶切克隆至商业化载体pcDNA4/myc-HisA(Invitrogen,V863-20)中,获得重组质粒DNA即:pcDNA4-OX40W86A,pcDNA4-OX40R65A,pcDNA4-OX40P83A,pcDNA4-OX40A126V,pcDNA4-OX40G70A和pcDNA4-OX40F71A。通过测序验证所构建的上述重组质粒的准确性。
3.2宿主细胞转染和目标蛋白表达
转染前两天,准备6×600mL经悬浮驯化的HEK293(ATCC,CRL-1573TM)细胞用于瞬时转染,接种密度为0.8×106cells/mL。两天后取三份细胞悬液,离心后分别重悬于600mLFreestyle293培养基中。
将实施例3.1中所得的6个重组表达载体用6mL 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600mL细胞悬液中,放置在37℃,10%CO2,90rpm中培养;同时补加50μg/L IGF-1。四小时后再补加600mLEX293培养基,2mM Glutamine和50ug/L IGF-1,135rpm培养。二十四小时后加3.8mM VPA。
培养5~6天后,收集6×1200mL的OX40抗原瞬时表达培养上清液,通过Ni-NTA亲和层析法,纯化得到OX40点突变后的抗原,可以清晰的看到目的条带。
这些抗原分别命名为OX40-His W86A、OX40-His R65A、OX40-His P83A、OX40-HisG70A、OX40-His F71A和OX40-His A126V,其依次分别包含选自以下组的氨基酸序列:SEQID NO:87、SEQ ID NO:88、SEQ ID NO:89、SEQ ID NO:85、SEQ ID NO:86和SEQ ID NO:90。
3.3OX40抗原表位关键氨基酸的验证
以包被缓冲液(50mM Na2CO3,NaHCO3 pH9.6)稀释上述OX40-His的6种突变抗原(OX40-His W86A、OX40-His R65A、OX40-His P83A、OX40-His G70A、OX40-His F71A和OX40-His A126V)和野生型抗原OX40-His,稀释后的浓度为5μg/ml,100μl/孔,4℃过夜;洗板后,3%BSA-PBS37℃封闭2小时。洗板后将DF004抗体从10μg/ml开始,3倍稀释,共11个浓度,稀释液(1%BSA-PBS)作对照,37℃孵育2小时;洗板后加入羊抗人IgG-HRP(Goat anti-humanIgG-HRP conjugated,Sigma:A0170),37℃孵育1小时。洗板后加入加可溶性单组分TMB底物显色液,室温避光显色5-10min。加入2N H2SO4 50μL/孔,终止显色反应。置MD SpectraMaxPlus384酶标仪上读OD 450nm-650nm值,应用软件SoftMax Pro v5.4进行数据处理和作图分析,结果如图4所示。从结果中可以看出从结果中可以看出F71A的突变直接导致了OX40不与DF004结合,G70A突变导致OX40结合DF004的亲和力大幅度降低,其余突变基本上不破坏OX40与DF004的结合。
3.4通过BLI技术评价DF004结合不同OX40变体的动力学特征
以PBST(含有0.05%吐温20的PBS)将DF004抗体稀释至10ug/ml,将各OX40-His抗原变体稀释至500nM、250nM、125nM、62.5nM和31.25nM。分别吸取200μl PBST、DF004抗体稀释液、不同浓度的抗原稀释液和10mM pH1.7 Gly-HCl加入96孔板(Greinerbio-one,cat#655209)中,放入Octet K2卡槽中。使用AHC(fortebio,cat#18-5060)传感器,设置程序:运行1、PBST孔100s;2、DF004稀释液孔60s;3、PBST孔100s;4、抗原稀释液80s;5、PBST 300s;6、Gly-HCl 5s;7、Gly-HCl 5s;8、Gly-HCl 5s;9、Gly-HCl 5s;10、Gly-HCl 5s;11、Gly-HCl5s。用Data Analysis 9.0软件进行数据分析和动力学曲线拟合,结果如图5和图6A-6G所示。图6A-6G依次显示了变体OX40-His A126V、OX40-His P83A、OX40-His R65A、OX40-HisW86A、OX40-His F71A、OX40-His G70A和对照组野生型OX40-His的曲线拟合结果。从结果中可以看出变体OX40-His G70A与DF004亲和力大幅下降,变体OX40-His F71A的突变导致不与DF004结合,其余变体不破坏与DF004的结合。
尽管本申请所述发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。根据已经公开的所有教导,可以对某些细节进行各种修改和替换,这些改变均在本申请所述发明的保护范围之内。本申请所述发明的全部范围由所附权利要求及其任何等同实施方案给出。
序列表
<110> 苏州丁孚靶点生物技术有限公司
<120> OX40抗原多肽及其用途
<130> 0027-PA-009
<160> 90
<170> PatentIn version 3.5
<210> 1
<211> 7
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (1)..(1)
<223> R、A或H
<220>
<221> X2
<222> (4)..(4)
<223> G或E
<220>
<221> X3
<222> (5)..(5)
<223> P或T
<400> 1
Xaa Pro Cys Xaa Xaa Gly Phe
1 5
<210> 2
<211> 7
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 2
Arg Pro Cys Gly Pro Gly Phe
1 5
<210> 3
<211> 17
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (1)..(1)
<223> R、A或H
<220>
<221> X2
<222> (4)..(4)
<223> G或E
<220>
<221> X3
<222> (5)..(5)
<223> P或T
<220>
<221> X4
<222> (10)..(10)
<223> D或E
<220>
<221> X5
<222> (11)..(11)
<223> V或A
<220>
<221> X6
<222> (13)..(13)
<223> S或N
<220>
<221> X7
<222> (14)..(14)
<223> S或Y
<220>
<221> X8
<222> (15)..(15)
<223> K或D
<220>
<221> X9
<222> (16)..(16)
<223> P或T
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Xaa Pro Cys Xaa Xaa Gly Phe Tyr Asn Xaa Xaa Val Xaa Xaa Xaa Xaa
1 5 10 15
Cys
<210> 4
<211> 17
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 4
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
1 5 10 15
Cys
<210> 5
<211> 24
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (1)..(1)
<223> R、A或H
<220>
<221> X2
<222> (4)..(4)
<223> G或E
<220>
<221> X3
<222> (5)..(5)
<223> P或T
<220>
<221> X4
<222> (10)..(10)
<223> D或E
<220>
<221> X5
<222> (11)..(11)
<223> V或A
<220>
<221> X6
<222> (13)..(13)
<223> S或N
<220>
<221> X7
<222> (14)..(14)
<223> S或Y
<220>
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<222> (15)..(15)
<223> K或D
<220>
<221> X9
<222> (16)..(16)
<223> P或T
<220>
<221> X10
<222> (19)..(19)
<223> P、A或Q
<220>
<221> X11
<222> (22)..(22)
<223> W、A或Q
<400> 5
Xaa Pro Cys Xaa Xaa Gly Phe Tyr Asn Xaa Xaa Val Xaa Xaa Xaa Xaa
1 5 10 15
Cys Lys Xaa Cys Thr Xaa Cys Asn
20
<210> 6
<211> 24
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 6
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
1 5 10 15
Cys Lys Pro Cys Thr Trp Cys Asn
20
<210> 7
<211> 43
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (1)..(1)
<223> R、A或H
<220>
<221> X2
<222> (4)..(4)
<223> G或E
<220>
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<222> (5)..(5)
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<220>
<221> X4
<222> (10)..(10)
<223> D或E
<220>
<221> X5
<222> (11)..(11)
<223> V或A
<220>
<221> X6
<222> (13)..(13)
<223> S或N
<220>
<221> X7
<222> (14)..(14)
<223> S或Y
<220>
<221> X8
<222> (15)..(15)
<223> K或D
<220>
<221> X9
<222> (16)..(16)
<223> P或T
<220>
<221> X10
<222> (19)..(19)
<223> P、A或Q
<220>
<221> X11
<222> (22)..(22)
<223> W、A或Q
<220>
<221> X12
<222> (25)..(25)
<223> L或H
<220>
<221> X13
<222> (31)..(31)
<223> R或L
<220>
<221> X14
<222> (34)..(34)
<223> L或N
<220>
<221> X15
<222> (37)..(37)
<223> A或P
<220>
<221> X16
<222> (39)..(39)
<223> Q或E
<400> 7
Xaa Pro Cys Xaa Xaa Gly Phe Tyr Asn Xaa Xaa Val Xaa Xaa Xaa Xaa
1 5 10 15
Cys Lys Xaa Cys Thr Xaa Cys Asn Xaa Arg Ser Gly Ser Glu Xaa Lys
20 25 30
Gln Xaa Cys Thr Xaa Thr Xaa Asp Thr Val Cys
35 40
<210> 8
<211> 43
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 8
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
1 5 10 15
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
20 25 30
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys
35 40
<210> 9
<211> 21
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (7)..(7)
<223> S或D
<220>
<221> X2
<222> (8)..(8)
<223> R或H
<220>
<221> X3
<222> (9)..(9)
<223> S或T
<220>
<221> X4
<222> (10)..(10)
<223> Q或R
<220>
<221> X5
<222> (11)..(11)
<223> N或D
<220>
<221> X6
<222> (13)..(13)
<223> V或L
<220>
<221> X7
<222> (15)..(15)
<223> R、A或H
<220>
<221> X8
<222> (18)..(18)
<223> G或E
<220>
<221> X9
<222> (19)..(19)
<223> P或T
<400> 9
Gly Met Val Ser Arg Cys Xaa Xaa Xaa Xaa Xaa Thr Xaa Cys Xaa Pro
1 5 10 15
Cys Xaa Xaa Gly Phe
20
<210> 10
<211> 21
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 10
Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys Arg Pro
1 5 10 15
Cys Gly Pro Gly Phe
20
<210> 11
<211> 29
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (2)..(2)
<223> H或R
<220>
<221> X2
<222> (5)..(5)
<223> R或Q
<220>
<221> X3
<222> (8)..(8)
<223> N或H
<220>
<221> X4
<222> (15)..(15)
<223> S或D
<220>
<221> X5
<222> (16)..(16)
<223> R或H
<220>
<221> X6
<222> (17)..(17)
<223> S或T
<220>
<221> X7
<222> (18)..(18)
<223> Q或R
<220>
<221> X8
<222> (19)..(19)
<223> N或D
<220>
<221> X9
<222> (21)..(21)
<223> V或L
<220>
<221> X10
<222> (23)..(23)
<223> R、A或H
<220>
<221> X11
<222> (26)..(26)
<223> G或E
<220>
<221> X12
<222> (27)..(27)
<223> P或T
<400> 11
Cys Xaa Glu Cys Xaa Pro Gly Xaa Gly Met Val Ser Arg Cys Xaa Xaa
1 5 10 15
Xaa Xaa Xaa Thr Xaa Cys Xaa Pro Cys Xaa Xaa Gly Phe
20 25
<210> 12
<211> 29
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 12
Cys His Glu Cys Arg Pro Gly Asn Gly Met Val Ser Arg Cys Ser Arg
1 5 10 15
Ser Gln Asn Thr Val Cys Arg Pro Cys Gly Pro Gly Phe
20 25
<210> 13
<211> 43
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (2)..(2)
<223> H或N
<220>
<221> X2
<222> (5)..(5)
<223> G或K
<220>
<221> X3
<222> (6)..(6)
<223> D或H
<220>
<221> X4
<222> (11)..(11)
<223> N或G
<220>
<221> X5
<222> (12)..(12)
<223> D或H
<220>
<221> X6
<222> (13)..(13)
<223> R或K
<220>
<221> X7
<222> (16)..(16)
<223> H或R
<220>
<221> X8
<222> (19)..(19)
<223> R或Q
<220>
<221> X9
<222> (22)..(22)
<223> N或H
<220>
<221> X10
<222> (29)..(29)
<223> S或D
<220>
<221> X11
<222> (30)..(30)
<223> R或H
<220>
<221> X12
<222> (31)..(31)
<223> S或T
<220>
<221> X13
<222> (32)..(32)
<223> Q或R
<220>
<221> X14
<222> (33)..(33)
<223> N或D
<220>
<221> X15
<222> (35)..(35)
<223> V或L
<220>
<221> X16
<222> (37)..(37)
<223> R、A或H
<220>
<221> X17
<222> (40)..(40)
<223> G或E
<220>
<221> X18
<222> (41)..(41)
<223> P或T
<400> 13
Leu Xaa Cys Val Xaa Xaa Thr Tyr Pro Ser Xaa Xaa Xaa Cys Cys Xaa
1 5 10 15
Glu Cys Xaa Pro Gly Xaa Gly Met Val Ser Arg Cys Xaa Xaa Xaa Xaa
20 25 30
Xaa Thr Xaa Cys Xaa Pro Cys Xaa Xaa Gly Phe
35 40
<210> 14
<211> 43
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 14
Leu His Cys Val Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His
1 5 10 15
Glu Cys Arg Pro Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln
20 25 30
Asn Thr Val Cys Arg Pro Cys Gly Pro Gly Phe
35 40
<210> 15
<211> 31
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (7)..(7)
<223> S或D
<220>
<221> X2
<222> (8)..(8)
<223> R或H
<220>
<221> X3
<222> (9)..(9)
<223> S或T
<220>
<221> X4
<222> (10)..(10)
<223> Q或R
<220>
<221> X5
<222> (11)..(11)
<223> N或D
<220>
<221> X6
<222> (13)..(13)
<223> V或L
<220>
<221> X7
<222> (15)..(15)
<223> R、A或H
<220>
<221> X8
<222> (18)..(18)
<223> G或E
<220>
<221> X9
<222> (19)..(19)
<223> P或T
<220>
<221> X10
<222> (24)..(24)
<223> D或E
<220>
<221> X11
<222> (25)..(25)
<223> V或A
<220>
<221> X12
<222> (27)..(27)
<223> S或N
<220>
<221> X13
<222> (28)..(28)
<223> S或Y
<220>
<221> X14
<222> (29)..(29)
<223> K或D
<220>
<221> X15
<222> (30)..(30)
<223> P或T
<400> 15
Gly Met Val Ser Arg Cys Xaa Xaa Xaa Xaa Xaa Thr Xaa Cys Xaa Pro
1 5 10 15
Cys Xaa Xaa Gly Phe Tyr Asn Xaa Xaa Val Xaa Xaa Xaa Xaa Cys
20 25 30
<210> 16
<211> 31
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 16
Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys Arg Pro
1 5 10 15
Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro Cys
20 25 30
<210> 17
<211> 39
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (2)..(2)
<223> H或R
<220>
<221> X2
<222> (5)..(5)
<223> R或Q
<220>
<221> X3
<222> (8)..(8)
<223> N或H
<220>
<221> X4
<222> (15)..(15)
<223> S或D
<220>
<221> X5
<222> (16)..(16)
<223> R或H
<220>
<221> X6
<222> (17)..(17)
<223> S或T
<220>
<221> X7
<222> (18)..(18)
<223> Q或R
<220>
<221> X8
<222> (19)..(19)
<223> N或D
<220>
<221> X9
<222> (21)..(21)
<223> V或L
<220>
<221> X10
<222> (23)..(23)
<223> R、A或H
<220>
<221> X11
<222> (26)..(26)
<223> G或E
<220>
<221> X12
<222> (27)..(27)
<223> P或T
<220>
<221> X13
<222> (32)..(32)
<223> D或E
<220>
<221> X14
<222> (33)..(33)
<223> V或A
<220>
<221> X15
<222> (35)..(35)
<223> S或N
<220>
<221> X16
<222> (36)..(36)
<223> S或Y
<220>
<221> X17
<222> (37)..(37)
<223> K或D
<220>
<221> X18
<222> (38)..(38)
<223> P或T
<400> 17
Cys Xaa Glu Cys Xaa Pro Gly Xaa Gly Met Val Ser Arg Cys Xaa Xaa
1 5 10 15
Xaa Xaa Xaa Thr Xaa Cys Xaa Pro Cys Xaa Xaa Gly Phe Tyr Asn Xaa
20 25 30
Xaa Val Xaa Xaa Xaa Xaa Cys
35
<210> 18
<211> 39
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 18
Cys His Glu Cys Arg Pro Gly Asn Gly Met Val Ser Arg Cys Ser Arg
1 5 10 15
Ser Gln Asn Thr Val Cys Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp
20 25 30
Val Val Ser Ser Lys Pro Cys
35
<210> 19
<211> 53
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (2)..(2)
<223> H或N
<220>
<221> X2
<222> (5)..(5)
<223> G或K
<220>
<221> X3
<222> (6)..(6)
<223> D或H
<220>
<221> X4
<222> (11)..(11)
<223> N或G
<220>
<221> X5
<222> (12)..(12)
<223> D或H
<220>
<221> X6
<222> (13)..(13)
<223> R或K
<220>
<221> X7
<222> (16)..(16)
<223> H或R
<220>
<221> X8
<222> (19)..(19)
<223> R或Q
<220>
<221> X9
<222> (22)..(22)
<223> N或H
<220>
<221> X10
<222> (29)..(29)
<223> S或D
<220>
<221> X11
<222> (30)..(30)
<223> R或H
<220>
<221> X12
<222> (31)..(31)
<223> S或T
<220>
<221> X13
<222> (32)..(32)
<223> Q或R
<220>
<221> X14
<222> (33)..(33)
<223> N或D
<220>
<221> X15
<222> (35)..(35)
<223> V或L
<220>
<221> X16
<222> (37)..(37)
<223> R、A或H
<220>
<221> X17
<222> (40)..(40)
<223> G或E
<220>
<221> X18
<222> (41)..(41)
<223> P或T
<220>
<221> X19
<222> (46)..(46)
<223> D或E
<220>
<221> X20
<222> (47)..(47)
<223> V或A
<220>
<221> X21
<222> (49)..(49)
<223> S或N
<220>
<221> X22
<222> (50)..(50)
<223> S或Y
<220>
<221> X23
<222> (51)..(51)
<223> K或D
<220>
<221> X24
<222> (52)..(52)
<223> P或T
<400> 19
Leu Xaa Cys Val Xaa Xaa Thr Tyr Pro Ser Xaa Xaa Xaa Cys Cys Xaa
1 5 10 15
Glu Cys Xaa Pro Gly Xaa Gly Met Val Ser Arg Cys Xaa Xaa Xaa Xaa
20 25 30
Xaa Thr Xaa Cys Xaa Pro Cys Xaa Xaa Gly Phe Tyr Asn Xaa Xaa Val
35 40 45
Xaa Xaa Xaa Xaa Cys
50
<210> 20
<211> 53
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 20
Leu His Cys Val Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His
1 5 10 15
Glu Cys Arg Pro Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln
20 25 30
Asn Thr Val Cys Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val
35 40 45
Ser Ser Lys Pro Cys
50
<210> 21
<211> 38
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (7)..(7)
<223> S或D
<220>
<221> X2
<222> (8)..(8)
<223> R或H
<220>
<221> X3
<222> (9)..(9)
<223> S或T
<220>
<221> X4
<222> (10)..(10)
<223> Q或R
<220>
<221> X5
<222> (11)..(11)
<223> N或D
<220>
<221> X6
<222> (13)..(13)
<223> V或L
<220>
<221> X7
<222> (15)..(15)
<223> R、A或H
<220>
<221> X8
<222> (18)..(18)
<223> G或E
<220>
<221> X9
<222> (19)..(19)
<223> P或T
<220>
<221> X10
<222> (24)..(24)
<223> D或E
<220>
<221> X11
<222> (25)..(25)
<223> V或A
<220>
<221> X12
<222> (27)..(27)
<223> S或N
<220>
<221> X13
<222> (28)..(28)
<223> S或Y
<220>
<221> X14
<222> (29)..(29)
<223> K或D
<220>
<221> X15
<222> (30)..(30)
<223> P或T
<220>
<221> X16
<222> (33)..(33)
<223> P、A或Q
<220>
<221> X17
<222> (36)..(36)
<223> W、A或Q
<400> 21
Gly Met Val Ser Arg Cys Xaa Xaa Xaa Xaa Xaa Thr Xaa Cys Xaa Pro
1 5 10 15
Cys Xaa Xaa Gly Phe Tyr Asn Xaa Xaa Val Xaa Xaa Xaa Xaa Cys Lys
20 25 30
Xaa Cys Thr Xaa Cys Asn
35
<210> 22
<211> 38
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 22
Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys Arg Pro
1 5 10 15
Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro Cys Lys
20 25 30
Pro Cys Thr Trp Cys Asn
35
<210> 23
<211> 46
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (2)..(2)
<223> H或R
<220>
<221> X2
<222> (5)..(5)
<223> R或Q
<220>
<221> X3
<222> (8)..(8)
<223> N或H
<220>
<221> X4
<222> (15)..(15)
<223> S或D
<220>
<221> X5
<222> (16)..(16)
<223> R或H
<220>
<221> X6
<222> (17)..(17)
<223> S或T
<220>
<221> X7
<222> (18)..(18)
<223> Q或R
<220>
<221> X8
<222> (19)..(19)
<223> N或D
<220>
<221> X9
<222> (21)..(21)
<223> V或L
<220>
<221> X10
<222> (23)..(23)
<223> R、A或H
<220>
<221> X11
<222> (26)..(26)
<223> G或E
<220>
<221> X12
<222> (27)..(27)
<223> P或T
<220>
<221> X13
<222> (32)..(32)
<223> D或E
<220>
<221> X14
<222> (33)..(33)
<223> V或A
<220>
<221> X15
<222> (35)..(35)
<223> S或N
<220>
<221> X16
<222> (36)..(36)
<223> S或Y
<220>
<221> X17
<222> (37)..(37)
<223> K或D
<220>
<221> X18
<222> (38)..(38)
<223> P或T
<220>
<221> X19
<222> (41)..(41)
<223> P、A或Q
<220>
<221> X20
<222> (44)..(44)
<223> W、A或Q
<400> 23
Cys Xaa Glu Cys Xaa Pro Gly Xaa Gly Met Val Ser Arg Cys Xaa Xaa
1 5 10 15
Xaa Xaa Xaa Thr Xaa Cys Xaa Pro Cys Xaa Xaa Gly Phe Tyr Asn Xaa
20 25 30
Xaa Val Xaa Xaa Xaa Xaa Cys Lys Xaa Cys Thr Xaa Cys Asn
35 40 45
<210> 24
<211> 46
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 24
Cys His Glu Cys Arg Pro Gly Asn Gly Met Val Ser Arg Cys Ser Arg
1 5 10 15
Ser Gln Asn Thr Val Cys Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp
20 25 30
Val Val Ser Ser Lys Pro Cys Lys Pro Cys Thr Trp Cys Asn
35 40 45
<210> 25
<211> 60
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (2)..(2)
<223> H或N
<220>
<221> X2
<222> (5)..(5)
<223> G或K
<220>
<221> X3
<222> (6)..(6)
<223> D或H
<220>
<221> X4
<222> (11)..(11)
<223> N或G
<220>
<221> X5
<222> (12)..(12)
<223> D或H
<220>
<221> X6
<222> (13)..(13)
<223> R或K
<220>
<221> X7
<222> (16)..(16)
<223> H或R
<220>
<221> X8
<222> (19)..(19)
<223> R或Q
<220>
<221> X9
<222> (22)..(22)
<223> N或H
<220>
<221> X10
<222> (29)..(29)
<223> S或D
<220>
<221> X11
<222> (30)..(30)
<223> R或H
<220>
<221> X12
<222> (31)..(31)
<223> S或T
<220>
<221> X13
<222> (32)..(32)
<223> Q或R
<220>
<221> X14
<222> (33)..(33)
<223> N或D
<220>
<221> X15
<222> (35)..(35)
<223> V或L
<220>
<221> X16
<222> (37)..(37)
<223> R、A或H
<220>
<221> X17
<222> (40)..(40)
<223> G或E
<220>
<221> X18
<222> (41)..(41)
<223> P或T
<220>
<221> X19
<222> (46)..(46)
<223> D或E
<220>
<221> X20
<222> (47)..(47)
<223> V或A
<220>
<221> X21
<222> (49)..(49)
<223> S或N
<220>
<221> X22
<222> (50)..(50)
<223> S或Y
<220>
<221> X23
<222> (51)..(51)
<223> K或D
<220>
<221> X24
<222> (52)..(52)
<223> P或T
<220>
<221> X25
<222> (55)..(55)
<223> P、A或Q
<220>
<221> X26
<222> (58)..(58)
<223> W、A或Q
<400> 25
Leu Xaa Cys Val Xaa Xaa Thr Tyr Pro Ser Xaa Xaa Xaa Cys Cys Xaa
1 5 10 15
Glu Cys Xaa Pro Gly Xaa Gly Met Val Ser Arg Cys Xaa Xaa Xaa Xaa
20 25 30
Xaa Thr Xaa Cys Xaa Pro Cys Xaa Xaa Gly Phe Tyr Asn Xaa Xaa Val
35 40 45
Xaa Xaa Xaa Xaa Cys Lys Xaa Cys Thr Xaa Cys Asn
50 55 60
<210> 26
<211> 60
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 26
Leu His Cys Val Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His
1 5 10 15
Glu Cys Arg Pro Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln
20 25 30
Asn Thr Val Cys Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val
35 40 45
Ser Ser Lys Pro Cys Lys Pro Cys Thr Trp Cys Asn
50 55 60
<210> 27
<211> 57
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (7)..(7)
<223> S或D
<220>
<221> X2
<222> (8)..(8)
<223> R或H
<220>
<221> X3
<222> (9)..(9)
<223> S或T
<220>
<221> X4
<222> (10)..(10)
<223> Q或R
<220>
<221> X5
<222> (11)..(11)
<223> N或D
<220>
<221> X6
<222> (13)..(13)
<223> V或L
<220>
<221> X7
<222> (15)..(15)
<223> R、A或H
<220>
<221> X8
<222> (18)..(18)
<223> G或E
<220>
<221> X9
<222> (19)..(19)
<223> P或T
<220>
<221> X10
<222> (24)..(24)
<223> D或E
<220>
<221> X11
<222> (25)..(25)
<223> V或A
<220>
<221> X12
<222> (27)..(27)
<223> S或N
<220>
<221> X13
<222> (28)..(28)
<223> S或Y
<220>
<221> X14
<222> (29)..(29)
<223> K或D
<220>
<221> X15
<222> (30)..(30)
<223> P或T
<220>
<221> X16
<222> (33)..(33)
<223> P、A或Q
<220>
<221> X17
<222> (36)..(36)
<223> W、A或Q
<220>
<221> X18
<222> (39)..(39)
<223> L或H
<220>
<221> X19
<222> (45)..(45)
<223> R或L
<220>
<221> X20
<222> (48)..(48)
<223> L或N
<220>
<221> X21
<222> (51)..(51)
<223> A或P
<220>
<221> X22
<222> (53)..(53)
<223> Q或E
<400> 27
Gly Met Val Ser Arg Cys Xaa Xaa Xaa Xaa Xaa Thr Xaa Cys Xaa Pro
1 5 10 15
Cys Xaa Xaa Gly Phe Tyr Asn Xaa Xaa Val Xaa Xaa Xaa Xaa Cys Lys
20 25 30
Xaa Cys Thr Xaa Cys Asn Xaa Arg Ser Gly Ser Glu Xaa Lys Gln Xaa
35 40 45
Cys Thr Xaa Thr Xaa Asp Thr Val Cys
50 55
<210> 28
<211> 57
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 28
Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys Arg Pro
1 5 10 15
Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro Cys Lys
20 25 30
Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys Gln Leu
35 40 45
Cys Thr Ala Thr Gln Asp Thr Val Cys
50 55
<210> 29
<211> 65
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (2)..(2)
<223> H或R
<220>
<221> X2
<222> (5)..(5)
<223> R或Q
<220>
<221> X3
<222> (8)..(8)
<223> N或H
<220>
<221> X4
<222> (15)..(15)
<223> S或D
<220>
<221> X5
<222> (16)..(16)
<223> R或H
<220>
<221> X6
<222> (17)..(17)
<223> S或T
<220>
<221> X7
<222> (18)..(18)
<223> Q或R
<220>
<221> X8
<222> (19)..(19)
<223> N或D
<220>
<221> X9
<222> (21)..(21)
<223> V或L
<220>
<221> X10
<222> (23)..(23)
<223> R、A或H
<220>
<221> X11
<222> (26)..(26)
<223> G或E
<220>
<221> X12
<222> (27)..(27)
<223> P或T
<220>
<221> X13
<222> (32)..(32)
<223> D或E
<220>
<221> X14
<222> (33)..(33)
<223> V或A
<220>
<221> X15
<222> (35)..(35)
<223> S或N
<220>
<221> X16
<222> (36)..(36)
<223> S或Y
<220>
<221> X17
<222> (37)..(37)
<223> K或D
<220>
<221> X18
<222> (38)..(38)
<223> P或T
<220>
<221> X19
<222> (41)..(41)
<223> P、A或Q
<220>
<221> X20
<222> (44)..(44)
<223> W、A或Q
<220>
<221> X21
<222> (47)..(47)
<223> L或H
<220>
<221> X22
<222> (53)..(53)
<223> R或L
<220>
<221> X23
<222> (56)..(56)
<223> L或N
<220>
<221> X24
<222> (59)..(59)
<223> A或P
<220>
<221> X25
<222> (61)..(61)
<223> Q或E
<400> 29
Cys Xaa Glu Cys Xaa Pro Gly Xaa Gly Met Val Ser Arg Cys Xaa Xaa
1 5 10 15
Xaa Xaa Xaa Thr Xaa Cys Xaa Pro Cys Xaa Xaa Gly Phe Tyr Asn Xaa
20 25 30
Xaa Val Xaa Xaa Xaa Xaa Cys Lys Xaa Cys Thr Xaa Cys Asn Xaa Arg
35 40 45
Ser Gly Ser Glu Xaa Lys Gln Xaa Cys Thr Xaa Thr Xaa Asp Thr Val
50 55 60
Cys
65
<210> 30
<211> 65
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 30
Cys His Glu Cys Arg Pro Gly Asn Gly Met Val Ser Arg Cys Ser Arg
1 5 10 15
Ser Gln Asn Thr Val Cys Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp
20 25 30
Val Val Ser Ser Lys Pro Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg
35 40 45
Ser Gly Ser Glu Arg Lys Gln Leu Cys Thr Ala Thr Gln Asp Thr Val
50 55 60
Cys
65
<210> 31
<211> 79
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40抗原多肽
<220>
<221> X1
<222> (2)..(2)
<223> H或N
<220>
<221> X2
<222> (5)..(5)
<223> G或K
<220>
<221> X3
<222> (6)..(6)
<223> D或H
<220>
<221> X4
<222> (11)..(11)
<223> N或G
<220>
<221> X5
<222> (12)..(12)
<223> D或H
<220>
<221> X6
<222> (13)..(13)
<223> R或K
<220>
<221> X7
<222> (16)..(16)
<223> H或R
<220>
<221> X8
<222> (19)..(19)
<223> R或Q
<220>
<221> X9
<222> (22)..(22)
<223> N或H
<220>
<221> X10
<222> (29)..(29)
<223> S或D
<220>
<221> X11
<222> (30)..(30)
<223> R或H
<220>
<221> X12
<222> (31)..(31)
<223> S或T
<220>
<221> X13
<222> (32)..(32)
<223> Q或R
<220>
<221> X14
<222> (33)..(33)
<223> N或D
<220>
<221> X15
<222> (35)..(35)
<223> V或L
<220>
<221> X16
<222> (37)..(37)
<223> R、A或H
<220>
<221> X17
<222> (40)..(40)
<223> G或E
<220>
<221> X18
<222> (41)..(41)
<223> P或T
<220>
<221> X19
<222> (46)..(46)
<223> D或E
<220>
<221> X20
<222> (47)..(47)
<223> V或A
<220>
<221> X21
<222> (49)..(49)
<223> S或N
<220>
<221> X22
<222> (50)..(50)
<223> S或Y
<220>
<221> X23
<222> (51)..(51)
<223> K或D
<220>
<221> X24
<222> (52)..(52)
<223> P或T
<220>
<221> X25
<222> (55)..(55)
<223> P、A或Q
<220>
<221> X26
<222> (58)..(58)
<223> W、A或Q
<220>
<221> X27
<222> (61)..(61)
<223> L或H
<220>
<221> X28
<222> (67)..(67)
<223> R或L
<220>
<221> X29
<222> (70)..(70)
<223> L或N
<220>
<221> X30
<222> (73)..(73)
<223> A或P
<220>
<221> X31
<222> (75)..(75)
<223> Q或E
<400> 31
Leu Xaa Cys Val Xaa Xaa Thr Tyr Pro Ser Xaa Xaa Xaa Cys Cys Xaa
1 5 10 15
Glu Cys Xaa Pro Gly Xaa Gly Met Val Ser Arg Cys Xaa Xaa Xaa Xaa
20 25 30
Xaa Thr Xaa Cys Xaa Pro Cys Xaa Xaa Gly Phe Tyr Asn Xaa Xaa Val
35 40 45
Xaa Xaa Xaa Xaa Cys Lys Xaa Cys Thr Xaa Cys Asn Xaa Arg Ser Gly
50 55 60
Ser Glu Xaa Lys Gln Xaa Cys Thr Xaa Thr Xaa Asp Thr Val Cys
65 70 75
<210> 32
<211> 79
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40抗原多肽
<400> 32
Leu His Cys Val Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His
1 5 10 15
Glu Cys Arg Pro Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln
20 25 30
Asn Thr Val Cys Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val
35 40 45
Ser Ser Lys Pro Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly
50 55 60
Ser Glu Arg Lys Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys
65 70 75
<210> 33
<211> 277
<212> PRT
<213> 人 (Homo sapiens)
<400> 33
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro
165 170 175
Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr
180 185 190
Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu
195 200 205
Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val
210 215 220
Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu
225 230 235 240
Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
245 250 255
Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser
260 265 270
Thr Leu Ala Lys Ile
275
<210> 34
<211> 834
<212> DNA
<213> 人 (Homo sapiens)
<400> 34
atgtgcgtgg gggctcggcg gctgggccgc gggccgtgtg cggctctgct cctcctgggc 60
ctggggctga gcaccgtgac ggggctccac tgtgtcgggg acacctaccc cagcaacgac 120
cggtgctgcc acgagtgcag gccaggcaac gggatggtga gccgctgcag ccgctcccag 180
aacacggtgt gccgtccgtg cgggccgggc ttctacaacg acgtggtcag ctccaagccg 240
tgcaagccct gcacgtggtg taacctcaga agtgggagtg agcggaagca gctgtgcacg 300
gccacacagg acacagtctg ccgctgccgg gcgggcaccc agcccctgga cagctacaag 360
cctggagttg actgtgcccc ctgccctcca gggcacttct ccccaggcga caaccaggcc 420
tgcaagccct ggaccaactg caccttggct gggaagcaca ccctgcagcc ggccagcaat 480
agctcggacg caatctgtga ggacagggac cccccagcca cgcagcccca ggagacccag 540
ggccccccgg ccaggcccat cactgtccag cccactgaag cctggcccag aacctcacag 600
ggaccctcca cccggcccgt ggaggtcccc gggggccgtg cggttgccgc catcctgggc 660
ctgggcctgg tgctggggct gctgggcccc ctggccatcc tgctggccct gtacctgctc 720
cggagggacc agaggctgcc ccccgatgcc cacaagcccc ctgggggagg cagtttccgg 780
acccccatcc aagaggagca ggccgacgcc cactccaccc tggccaagat ctga 834
<210> 35
<211> 277
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 G70A
<400> 35
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Ala Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro
165 170 175
Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr
180 185 190
Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu
195 200 205
Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val
210 215 220
Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu
225 230 235 240
Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
245 250 255
Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser
260 265 270
Thr Leu Ala Lys Ile
275
<210> 36
<211> 277
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 F71A
<400> 36
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Gly Ala Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro
165 170 175
Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr
180 185 190
Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu
195 200 205
Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val
210 215 220
Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu
225 230 235 240
Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
245 250 255
Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser
260 265 270
Thr Leu Ala Lys Ile
275
<210> 37
<211> 277
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 W86A
<400> 37
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Ala Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro
165 170 175
Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr
180 185 190
Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu
195 200 205
Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val
210 215 220
Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu
225 230 235 240
Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
245 250 255
Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser
260 265 270
Thr Leu Ala Lys Ile
275
<210> 38
<211> 277
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 R65A
<400> 38
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Ala Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro
165 170 175
Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr
180 185 190
Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu
195 200 205
Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val
210 215 220
Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu
225 230 235 240
Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
245 250 255
Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser
260 265 270
Thr Leu Ala Lys Ile
275
<210> 39
<211> 277
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 P83A
<400> 39
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Ala Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro
165 170 175
Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr
180 185 190
Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu
195 200 205
Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val
210 215 220
Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu
225 230 235 240
Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
245 250 255
Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser
260 265 270
Thr Leu Ala Lys Ile
275
<210> 40
<211> 277
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 A126V
<400> 40
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Val Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro
165 170 175
Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr
180 185 190
Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu
195 200 205
Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val
210 215 220
Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu
225 230 235 240
Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
245 250 255
Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser
260 265 270
Thr Leu Ala Lys Ile
275
<210> 41
<211> 272
<212> PRT
<213> 小鼠 (Mus musculus)
<400> 41
Met Tyr Val Trp Val Gln Gln Pro Thr Ala Leu Leu Leu Leu Ala Leu
1 5 10 15
Thr Leu Gly Val Thr Ala Arg Arg Leu Asn Cys Val Lys His Thr Tyr
20 25 30
Pro Ser Gly His Lys Cys Cys Arg Glu Cys Gln Pro Gly His Gly Met
35 40 45
Val Ser Arg Cys Asp His Thr Arg Asp Thr Leu Cys His Pro Cys Glu
50 55 60
Thr Gly Phe Tyr Asn Glu Ala Val Asn Tyr Asp Thr Cys Lys Gln Cys
65 70 75 80
Thr Gln Cys Asn His Arg Ser Gly Ser Glu Leu Lys Gln Asn Cys Thr
85 90 95
Pro Thr Gln Asp Thr Val Cys Arg Cys Arg Pro Gly Thr Gln Pro Arg
100 105 110
Gln Asp Ser Gly Tyr Lys Leu Gly Val Asp Cys Val Pro Cys Pro Pro
115 120 125
Gly His Phe Ser Pro Gly Asn Asn Gln Ala Cys Lys Pro Trp Thr Asn
130 135 140
Cys Thr Leu Ser Gly Lys Gln Thr Arg His Pro Ala Ser Asp Ser Leu
145 150 155 160
Asp Ala Val Cys Glu Asp Arg Ser Leu Leu Ala Thr Leu Leu Trp Glu
165 170 175
Thr Gln Arg Pro Thr Phe Arg Pro Thr Thr Val Gln Ser Thr Thr Val
180 185 190
Trp Pro Arg Thr Ser Glu Leu Pro Ser Pro Pro Thr Leu Val Thr Pro
195 200 205
Glu Gly Pro Ala Phe Ala Val Leu Leu Gly Leu Gly Leu Gly Leu Leu
210 215 220
Ala Pro Leu Thr Val Leu Leu Ala Leu Tyr Leu Leu Arg Lys Ala Trp
225 230 235 240
Arg Leu Pro Asn Thr Pro Lys Pro Cys Trp Gly Asn Ser Phe Arg Thr
245 250 255
Pro Ile Gln Glu Glu His Thr Asp Ala His Phe Thr Leu Ala Lys Ile
260 265 270
<210> 42
<211> 271
<212> PRT
<213> 大鼠 (Rattus norvegicus)
<400> 42
Met Tyr Val Trp Val Gln Gln Pro Thr Ala Phe Leu Leu Leu Gly Leu
1 5 10 15
Ser Leu Gly Val Thr Val Lys Leu Asn Cys Val Lys Asp Thr Tyr Pro
20 25 30
Ser Gly His Lys Cys Cys Arg Glu Cys Gln Pro Gly His Gly Met Val
35 40 45
Ser Arg Cys Asp His Thr Arg Asp Thr Val Cys His Pro Cys Glu Pro
50 55 60
Gly Phe Tyr Asn Glu Ala Val Asn Tyr Asp Thr Cys Lys Gln Cys Thr
65 70 75 80
Gln Cys Asn His Arg Ser Gly Ser Glu Leu Lys Gln Asn Cys Thr Pro
85 90 95
Thr Glu Asp Thr Val Cys Gln Cys Arg Pro Gly Thr Gln Pro Arg Gln
100 105 110
Asp Ser Ser His Lys Leu Gly Val Asp Cys Val Pro Cys Pro Pro Gly
115 120 125
His Phe Ser Pro Gly Ser Asn Gln Ala Cys Lys Pro Trp Thr Asn Cys
130 135 140
Thr Leu Ser Gly Lys Gln Ile Arg His Pro Ala Ser Asn Ser Leu Asp
145 150 155 160
Thr Val Cys Glu Asp Arg Ser Leu Leu Ala Thr Leu Leu Trp Glu Thr
165 170 175
Gln Arg Thr Thr Phe Arg Pro Thr Thr Val Pro Ser Thr Thr Val Trp
180 185 190
Pro Arg Thr Ser Gln Leu Pro Ser Thr Pro Thr Leu Val Ala Pro Glu
195 200 205
Gly Pro Ala Phe Ala Val Ile Leu Gly Leu Gly Leu Gly Leu Leu Ala
210 215 220
Pro Leu Thr Val Leu Leu Ala Leu Tyr Leu Leu Arg Lys Ala Trp Arg
225 230 235 240
Ser Pro Asn Thr Pro Lys Pro Cys Trp Gly Asn Ser Phe Arg Thr Pro
245 250 255
Ile Gln Glu Glu Gln Thr Asp Thr His Phe Thr Leu Ala Lys Ile
260 265 270
<210> 43
<211> 216
<212> PRT
<213> 人 (Homo sapiens)
<400> 43
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro
165 170 175
Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr
180 185 190
Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu
195 200 205
Val Pro Gly Gly Arg Ala Val Ala
210 215
<210> 44
<211> 648
<212> DNA
<213> 人 (Homo sapiens)
<400> 44
atgtgcgtgg gggctcggcg gctgggccgc gggccgtgtg cggctctgct cctcctgggc 60
ctggggctga gcaccgtgac ggggctccac tgtgtcgggg acacctaccc cagcaacgac 120
cggtgctgcc acgagtgcag gccaggcaac gggatggtga gccgctgcag ccgctcccag 180
aacacggtgt gccgtccgtg cgggccgggc ttctacaacg acgtggtcag ctccaagccg 240
tgcaagccct gcacgtggtg taacctcaga agtgggagtg agcggaagca gctgtgcacg 300
gccacacagg acacagtctg ccgctgccgg gcgggcaccc agcccctgga cagctacaag 360
cctggagttg actgtgcccc ctgccctcca gggcacttct ccccaggcga caaccaggcc 420
tgcaagccct ggaccaactg caccttggct gggaagcaca ccctgcagcc ggccagcaat 480
agctcggacg caatctgtga ggacagggac cccccagcca cgcagcccca ggagacccag 540
ggccccccgg ccaggcccat cactgtccag cccactgaag cctggcccag aacctcacag 600
ggaccctcca cccggcccgt ggaggtcccc gggggccgtg cggttgcc 648
<210> 45
<211> 12
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 CRD1 A1
<400> 45
Cys Val Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys
1 5 10
<210> 46
<211> 19
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 CRD1 B2
<400> 46
Cys Arg Pro Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn
1 5 10 15
Thr Val Cys
<210> 47
<211> 36
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 CRD1
<400> 47
Leu His Cys Val Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His
1 5 10 15
Glu Cys Arg Pro Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln
20 25 30
Asn Thr Val Cys
35
<210> 48
<211> 15
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 CRD2 A1
<400> 48
Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro Cys
1 5 10 15
<210> 49
<211> 21
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 CRD2 B2
<400> 49
Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys Gln Leu Cys Thr Ala Thr
1 5 10 15
Gln Asp Thr Val Cys
20
<210> 50
<211> 41
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 CRD2
<400> 50
Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro Cys Lys
1 5 10 15
Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys Gln Leu
20 25 30
Cys Thr Ala Thr Gln Asp Thr Val Cys
35 40
<210> 51
<211> 18
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 CRD3
<400> 51
Cys Arg Ala Gly Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp
1 5 10 15
Cys Ala
<210> 52
<211> 40
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人OX40 CRD4
<400> 52
Cys Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro
1 5 10 15
Trp Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser
20 25 30
Asn Ser Ser Asp Ala Ile Cys Glu
35 40
<210> 53
<211> 28
<212> PRT
<213> 人 (Homo sapiens)
<400> 53
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly
20 25
<210> 54
<211> 84
<212> DNA
<213> 人 (Homo sapiens)
<400> 54
atgtgcgtgg gggctcggcg gctgggccgc gggccgtgtg cggctctgct cctcctgggc 60
ctggggctga gcaccgtgac gggg 84
<210> 55
<211> 1347
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004 重链核苷酸
<400> 55
caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60
acctgtgcca tctccgggga cagtgtctct agcaacagtg tctcttggga ctggatcagg 120
cagtccccct cgaggggcct tgagtggctg ggaaggacat actataggtc caagtggtat 180
aatgagtatg cagtatctgt ggaaagtcga ataaccatca acccagacac atccaagaac 240
cagttctccc tgcaactgaa ctctgtgact cccgaggaca cggctatata tttctgtgta 300
agaaatgact acttcttcga tctctggggc cgtggtaccc tggtcaccgt ctcctcagcc 360
agcactaagg ggccctctgt gtttccactc gccccttcta gcaaaagcac ttccggaggc 420
actgcagcac tcgggtgtct ggtcaaagat tatttccctg agccagtcac cgtgagctgg 480
aactctggcg ccctcacctc cggggttcac acctttccag ccgtcctgca gtcctccggc 540
ctgtactccc tgagcagcgt cgttaccgtg ccatcctctt ctctggggac ccagacatac 600
atctgcaatg tcaaccataa gcctagcaac accaaggtgg acaaaaaggt cgagccaaag 660
agctgcgata agacacacac ctgccctcca tgccccgcac ctgaactcct gggcgggcct 720
tccgttttcc tgtttcctcc caagcccaag gatacactga tgattagccg cacccccgaa 780
gtcacttgcg tggtggtgga tgtgagccat gaagatccag aagttaagtt taactggtat 840
gtggacgggg tcgaggtgca caatgctaaa acaaagccca gggaggagca atataactcc 900
acatacagag tggtgtccgt tctgacagtc ctgcaccagg actggctgaa cgggaaggaa 960
tacaagtgca aggtgtctaa taaggcactg ccagccccca tagagaagac aatctctaaa 1020
gctaaaggcc aaccacgcga gcctcaggtc tacacactgc caccatccag ggacgaactg 1080
accaagaatc aggtgagcct gacttgtctc gtcaaaggat tctacccaag cgacatcgcc 1140
gtggagtggg aatccaacgg ccaaccagag aacaactaca agaccacccc accagtcctg 1200
gactctgatg ggagcttttt cctgtattcc aagctgacag tggacaagtc tcggtggcaa 1260
cagggcaacg tgttcagctg ctccgtgatg catgaagccc tgcataacca ctatacccag 1320
aaaagcctca gcctgtcccc cgggaaa 1347
<210> 56
<211> 449
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004 重链氨基酸
<400> 56
Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn
20 25 30
Ser Val Ser Trp Asp Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu
35 40 45
Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Glu Tyr Ala
50 55 60
Val Ser Val Glu Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn
65 70 75 80
Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Ile
85 90 95
Tyr Phe Cys Val Arg Asn Asp Tyr Phe Phe Asp Leu Trp Gly Arg Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 57
<211> 648
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004 轻链核苷酸
<400> 57
gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttggc agctacttag cctggtatca acagaaacct 120
ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctcccgg gtacactttt 300
ggccagggga ccaagctgga gatcaaacgt acggtggctg caccatctgt cttcatcttc 360
ccgccatctg atgagcagtt gaaatctggt accgctagcg ttgtgtgcct gctgaataac 420
ttttatccac gggaggctaa ggtgcagtgg aaagtggaca atgccctcca gagcggaaat 480
agccaagagt ccgttaccga acaggactct aaagactcta catactccct gtcctccaca 540
ctgaccctct ccaaggccga ctatgagaaa cacaaggttt acgcatgcga ggtcacacac 600
cagggactct cctctcccgt gaccaagagc ttcaaccggg gagaatgc 648
<210> 58
<211> 216
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004 轻链氨基酸
<400> 58
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Gly Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val
100 105 110
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
115 120 125
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
130 135 140
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
145 150 155 160
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
165 170 175
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
180 185 190
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
195 200 205
Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 59
<211> 176
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40-His 抗原
<400> 59
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp His His His His His His
165 170 175
<210> 60
<211> 528
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40-His 抗原 核苷酸
<400> 60
atgtgcgtgg gggctcggcg gctgggccgc gggccgtgtg cggctctgct cctcctgggc 60
ctggggctga gcaccgtgac ggggctccac tgtgtcgggg acacctaccc cagcaacgac 120
cggtgctgcc acgagtgcag gccaggcaac gggatggtga gccgctgcag ccgctcccag 180
aacacggtgt gccgtccgtg cgggccgggc ttctacaacg acgtggtcag ctccaagccg 240
tgcaagccct gcacgtggtg taacctcaga agtgggagtg agcggaagca gctgtgcacg 300
gccacacagg acacagtctg ccgctgccgg gcgggcaccc agcccctgga cagctacaag 360
cctggagttg actgtgcccc ctgccctcca gggcacttct ccccaggcga caaccaggcc 420
tgcaagccct ggaccaactg caccttggct gggaagcaca ccctgcagcc ggccagcaat 480
agctcggacg caatctgtga ggacagggac catcatcacc atcaccat 528
<210> 61
<211> 232
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004VH-CH1-CHis
<400> 61
Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn
20 25 30
Ser Val Ser Trp Asp Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu
35 40 45
Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Glu Tyr Ala
50 55 60
Val Ser Val Glu Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn
65 70 75 80
Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Ile
85 90 95
Tyr Phe Cys Val Arg Asn Asp Tyr Phe Phe Asp Leu Trp Gly Arg Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His His His His His His His
225 230
<210> 62
<211> 696
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004VH-CH1-CHis 核苷酸
<400> 62
caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60
acctgtgcca tctccgggga cagtgtctct agcaacagtg tctcttggga ctggatcagg 120
cagtccccct cgaggggcct tgagtggctg ggaaggacat actataggtc caagtggtat 180
aatgagtatg cagtatctgt ggaaagtcga ataaccatca acccagacac atccaagaac 240
cagttctccc tgcaactgaa ctctgtgact cccgaggaca cggctatata tttctgtgta 300
agaaatgact acttcttcga tctctggggc cgtggtaccc tggtcaccgt ctcctcagcc 360
agcactaagg ggccctctgt gtttccactc gccccttcta gcaaaagcac ttccggaggc 420
actgcagcac tcgggtgtct ggtcaaagat tatttccctg agccagtcac cgtgagctgg 480
aactctggcg ccctcacctc cggggttcac acctttccag ccgtcctgca gtcctccggc 540
ctgtactccc tgagcagcgt cgttaccgtg ccatcctctt ctctggggac ccagacatac 600
atctgcaatg tcaaccataa gcctagcaac accaaggtgg acaaaaaggt cgagccaaag 660
agctgcgata agacacacca tcatcaccat caccat 696
<210> 63
<211> 11
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004 LCDR1
<400> 63
Arg Ala Ser Gln Ser Val Gly Ser Tyr Leu Ala
1 5 10
<210> 64
<211> 7
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004 LCDR2
<400> 64
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 65
<211> 11
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004 LCDR3
<400> 65
Gln Gln Arg Ser Asn Trp Pro Pro Gly Tyr Thr
1 5 10
<210> 66
<211> 7
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004 HCDR1
<400> 66
Ser Asn Ser Val Ser Trp Asp
1 5
<210> 67
<211> 18
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004 HCDR2
<400> 67
Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Glu Tyr Ala Val Ser Val
1 5 10 15
Glu Ser
<210> 68
<211> 7
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004 HCDR3
<400> 68
Asn Asp Tyr Phe Phe Asp Leu
1 5
<210> 69
<211> 109
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004 VL
<400> 69
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Gly Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 70
<211> 119
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004 VH
<400> 70
Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn
20 25 30
Ser Val Ser Trp Asp Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu
35 40 45
Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Glu Tyr Ala
50 55 60
Val Ser Val Glu Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn
65 70 75 80
Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Ile
85 90 95
Tyr Phe Cys Val Arg Asn Asp Tyr Phe Phe Asp Leu Trp Gly Arg Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 71
<211> 28
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> SCDKTH-R
<400> 71
gccgaccggt gtgtgtctta tcgcagct 28
<210> 72
<211> 35
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> DF004-VH-F
<400> 72
gccgaagctt gccaccatgg agacagacac actcc 35
<210> 73
<211> 21
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> W86A-OF
<400> 73
ccctgcacgg cgtgtaacct c 21
<210> 74
<211> 21
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> W86A-OR
<400> 74
gaggttacac gccgtgcagg g 21
<210> 75
<211> 22
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> R65A-OF
<400> 75
cacggtgtgc gctccgtgcg gg 22
<210> 76
<211> 22
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> R65A-OR
<400> 76
cccgcacgga gcgcacaccg tg 22
<210> 77
<211> 20
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> P83A-OF
<400> 77
cgtgcaaggc ctgcacgtgg 20
<210> 78
<211> 20
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> P83A-OR
<400> 78
ccacgtgcag gccttgcacg 20
<210> 79
<211> 20
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> G70A-OF
<400> 79
gggccggcct tctacaacga 20
<210> 80
<211> 20
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> G70A-OR
<400> 80
tcgttgtaga aggccggccc 20
<210> 81
<211> 20
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> F71A-OF
<400> 81
gccgggcgcc tacaacgacg 20
<210> 82
<211> 20
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> F71A-OR
<400> 82
cgtcgttgta ggcgcccggc 20
<210> 83
<211> 23
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> A126V-OF
<400> 83
gttccctgcc ctccagggca ctt 23
<210> 84
<211> 20
<212> DNA
<213> 人工序列 (Artificial Sequence)
<220>
<223> A126V-OR
<400> 84
acagtcaact ccaggcttgt 20
<210> 85
<211> 176
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40-His G70A
<400> 85
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Ala Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp His His His His His His
165 170 175
<210> 86
<211> 176
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40-His F71A
<400> 86
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Gly Ala Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp His His His His His His
165 170 175
<210> 87
<211> 176
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40-His W86A
<400> 87
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Ala Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp His His His His His His
165 170 175
<210> 88
<211> 176
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40-His R65A
<400> 88
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Ala Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp His His His His His His
165 170 175
<210> 89
<211> 176
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40-His P83A
<400> 89
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Ala Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Ala Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp His His His His His His
165 170 175
<210> 90
<211> 176
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> OX40-His A126V
<400> 90
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
1 5 10 15
Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
20 25 30
Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
35 40 45
Gly Asn Gly Met Val Ser Arg Cys Ser Arg Ser Gln Asn Thr Val Cys
50 55 60
Arg Pro Cys Gly Pro Gly Phe Tyr Asn Asp Val Val Ser Ser Lys Pro
65 70 75 80
Cys Lys Pro Cys Thr Trp Cys Asn Leu Arg Ser Gly Ser Glu Arg Lys
85 90 95
Gln Leu Cys Thr Ala Thr Gln Asp Thr Val Cys Arg Cys Arg Ala Gly
100 105 110
Thr Gln Pro Leu Asp Ser Tyr Lys Pro Gly Val Asp Cys Val Pro Cys
115 120 125
Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
130 135 140
Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp His His His His His His
165 170 175
Claims (12)
1.分离的OX40抗原多肽,其氨基酸序列如SEQ ID NO:37、38、39、40中任一项所示。
2.融合蛋白或免疫缀合物,其包含权利要求1所述的分离的OX40抗原多肽。
3.分离的核酸分子,其编码权利要求1所述的分离的OX40抗原多肽和/或权利要求2所述的融合蛋白或免疫缀合物。
4.载体,其包含权利要求3所述的分离的核酸分子。
5.细胞,其包含或表达权利要求1所述的OX40抗原多肽,权利要求2所述的融合蛋白或免疫缀合物,权利要求3所述的核酸分子或权利要求4所述的载体。
6.药物组合物,其包含权利要求1所述的OX40抗原多肽,权利要求2所述的融合蛋白或免疫缀合物,权利要求3所述的核酸分子,权利要求4所述的载体,或权利要求5所述的细胞,以及任选地药学上可接受的佐剂。
7.疫苗,其包含一种或多种选自下列的物质以及任选地免疫原性载体:
1)一种或多种权利要求1所述的OX40抗原多肽;
2)权利要求2所述的融合蛋白或免疫缀合物;
3)权利要求3所述的核酸分子;
4)权利要求4所述的载体;
5)权利要求5所述的细胞;和
6)权利要求6所述的药物组合物。
8.根据权利要求7所述的疫苗,其为癌症疫苗。
9.筛选、识别和/或检测OX40激动性抗体的方法,其包括:
使待筛选、识别和/或检测的候选抗体或其抗原结合片段、表达所述候选抗体或其抗原结合片段的细胞、或者包含所述候选抗体或其抗原结合片段的混合物与权利要求1所述的OX40抗原多肽或权利要求2所述的融合蛋白或免疫缀合物接触,并且
判断所述候选抗体或其抗原结合片段是否与所述OX40抗原多肽特异性结合,且当检测到所述特异性结合时,将该候选抗体鉴别为OX40激动性抗体。
10.权利要求1所述的OX40抗原多肽或权利要求2所述的融合蛋白或免疫缀合物用于制备药物的用途,其中所述药物用于预防和/或治疗癌症。
11.非诊断治疗性目的的阻止OX40-OX40L六聚体形成的方法,包括施用与权利要求1所述的OX40抗原多肽特异性结合的试剂。
12.权利要求1所述的OX40抗原多肽或者权利要求2所述的融合蛋白或免疫缀合物用于制备试剂的用途,所述试剂用于检测、识别和/或筛选OX40激动性抗体。
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BR112022020742A2 (pt) * | 2020-04-17 | 2022-12-20 | Hutchison Medipharma Ltd | Anticorpo anti-ox40 e usos do mesmo |
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US10106619B2 (en) * | 2006-10-04 | 2018-10-23 | La Jolla Institute For Allergy And Immunology | Virus vaccination and treatment methods with OX40 agonist compositions |
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GB201403775D0 (en) * | 2014-03-04 | 2014-04-16 | Kymab Ltd | Antibodies, uses & methods |
TW201619200A (zh) * | 2014-10-10 | 2016-06-01 | 麥迪紐有限責任公司 | 人類化抗-ox40抗體及其用途 |
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