CN114957434A - 用于治疗自身免疫性疾病的多肽 - Google Patents
用于治疗自身免疫性疾病的多肽 Download PDFInfo
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- CN114957434A CN114957434A CN202110205336.1A CN202110205336A CN114957434A CN 114957434 A CN114957434 A CN 114957434A CN 202110205336 A CN202110205336 A CN 202110205336A CN 114957434 A CN114957434 A CN 114957434A
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Abstract
本发明涉及疾病治疗领域。具体而言,本发明提供了用于治疗自身免疫性疾病(例如系统性红斑狼疮、1型糖尿病、类风湿性关节炎)的多肽或其变体,包含此类多肽或其变体的融合蛋白,以及此类多肽或其变体和融合蛋白的医药用途。本发明还涉及可用于治疗自身免疫性疾病(例如系统性红斑狼疮、1型糖尿病、类风湿性关节炎)或减轻自身免疫性疾病的一种或多种症状的药物组合物,其包含本发明的多肽或其变体或融合蛋白。
Description
技术领域
本发明涉及疾病治疗领域。具体而言,本发明提供了用于治疗自身免疫性疾病(例如系统性红斑狼疮、1型糖尿病、类风湿性关节炎)的多肽或其变体,包含此类多肽或其变体的融合蛋白,以及此类多肽或其变体和融合蛋白的医药用途。本发明还涉及可用于治疗自身免疫性疾病(例如系统性红斑狼疮、1型糖尿病、类风湿性关节炎)或减轻自身免疫性疾病的一种或多种症状的药物组合物,其包含本发明的多肽或其变体或融合蛋白。
背景技术
自身免疫性疾病是由免疫系统自我耐受性受损或丧失而引起器官和组织损伤的一系列疾病。包括如系统性红斑狼疮(SLE)、1型糖尿病、类风湿性关节炎(RA)等。自身免疫疾病的患者免疫功能异常活化,攻击机体正常组织和器官,可累及全身多个系统发生疾病。
系统性红斑狼疮,英文systemic lupus erythematosus,简称SLE。系统性红斑狼疮属于自身免疫类疾病,常发生于20-40岁女性。本病病因至今尚未明确,大量研究显示遗传、内分泌、感染、免疫异常和一些环境因素与本病的发病可能有关。在遗传因素、环境因素、雌激素水平等各种因素相互作用下,患者T淋巴细胞减少、抑制性T细胞功能降低、B细胞过度增生,产生大量的自身抗体,并与体内相应的自身抗原结合形成相应的免疫复合物,沉积在皮肤、关节、小血管、肾小球等部位,引起急慢性炎症及组织坏死(如狼疮肾炎),或抗体直接与组织细胞抗原作用,引起细胞破坏(如红细胞、淋巴细胞及血小板壁的特异性抗原与相应的自身抗体结合,分别引起溶血性贫血、淋巴细胞减少症和血小板减少症),从而导致机体的多系统损害。
SLE的诊断主要依靠临床表现、实验室检查、组织病理学和影像学检查。1997年美国风湿病协会(ACR)修订的SLE分类标准中,明确将血液学异常、免疫学异常和自身抗体阳性等实验室检查列入了诊断标准。由于系统性红斑狼疮患者常存在血液系统异常和肾脏损伤等,血常规检查可有贫血、白细胞计数减少、血小板降低等症状;尿液分析可显示蛋白尿、血尿、细胞和颗粒管型。目前临床开展的系统性红斑狼疮相关自身抗体常规检测项目主要有抗核抗体(ANA)、抗双链脱氧核糖核酸抗体(抗dsDNA抗体)、抗可溶性抗原抗体(抗ENA抗体)(包括抗Sm、抗U1RNP、抗SSA/Ro、抗SSB/La、抗rRNP、抗Scl-70和抗Jo-1等)、抗核小体抗体和抗磷脂抗体等。ACR修订的SLE分类标准中,免疫学异常和自身抗体阳性包括:抗Sm抗体、抗dsDNA抗体、抗磷脂抗体和ANA阳性。
1型糖尿病,英文type 1 diabetes mellitus,简称T1DM。T1DM是一种自身免疫性疾病,是由胰岛中的β细胞被免疫系统破坏引起的,T1DM可以在任何年龄发生,但通常最常见于青春期,并在青春期左右开始发作。研究表明遗传因素和环境因素在T1DM发病中都起作用,但尚不清楚T1DM的确切病因。目前T1MD的主要治疗方式依然是终身注射胰岛素控制血糖。
类风湿性关节炎,英文rheumatoid arthritis,简称RA。RA的特征为导致促炎细胞因子如肿瘤坏死因子α(TNF)白细胞介素1(IL-1)的过量产生的免疫系统的不平衡和抗炎细胞因子例如IL-10、IL-11的缺乏。RA通过滑膜发炎表征,滑膜炎进展为软骨破坏、骨侵蚀和随后的关节变形。RA的原发症状为是关节发炎、肿胀、移动困难和疼。在RA的后期,发炎细胞产生的酶会消化骨骼和软骨。长期的损伤导致关节的慢性疼痛、机能丧失、变形和甚至寿命变短。尽管近几年抗TNF治疗在治疗RA中已取得了不错的进展,但其只能用于部分患者,至少三分之一的RA患者不产生反应。因此成功的治疗关节炎仍然是一个未得到解决的医学需要。
自身免疫性疾病具有很强的异质性,不论采用中医还是西医治疗绝大多数患者均不可能根治,只能通过药物缓解病情,长期服药会带来明显的毒副作用,给患者和家属带来巨大的经济和精神负担,因此开发新的治疗自身免疫性疾病方案和药物具有重要的社会和经济意义。
发明内容
热休克蛋白(Heat shock protein,HSP)是一类在生物进化中高度保守且广泛存在于原核及真核生物中的蛋白质。HSP根据同源程度及分子量大小可分为HSP110、HSP90、HSP70、HSP60、HSP40、小分子HSP及泛素等多个亚家族。人类热休克蛋白90家族(HSP90)包括HSP90α,HSP90β,gp96(grp94)和Trap-1四个成员。gp96(GRP94)为内质网HSP90家族的代表,与细胞质HSP90高度同源,主要生物学功能有:分子伴侣,参与新合成蛋白的折叠与组装;与细胞内的其他肽类蛋白质尤其是变性蛋白的结合,参与细胞的抗损伤、修复和热耐受过程;参与蛋白质水解过程;结合抗原肽,加工提呈肿瘤抗原及维持细胞内环境稳定等作用;对细胞的生长、发育、分化及死亡具有一定的调节作用。
已有研究报道,全长gp96虽然可以活化调节性T细胞(Treg),然而其还具有强大的活化效应CD4+T、CD8+T细胞、B细胞等功能,不能特异性单独靶向调节性T细胞,因此全长gp96在治疗自身免疫性疾病中有可能活化免疫系统,导致治疗效果不佳,甚至有可能加重自身免疫疾病。
本申请的发明人经过大量的研究后出人意料地发现,全长gp96的特定多肽片段具有特异性单独靶向调节性T细胞、且不靶向效应T细胞及B细胞的活性,从而特别适用于自身免疫性疾病的治疗,具有重要临床应用价值。
分离的多肽或其变体
在一个方面,本发明提供了一种分离的多肽或其变体,其中,所述多肽由gp96蛋白的至少136个连续氨基酸残基组成,且包含:gp96蛋白的第578-713位氨基酸残基;
其中,所述变体与其所源自的多肽相异仅在于1个或几个(例如,1个、2个、3个、4个或5个)氨基酸残基的置换、缺失或添加,且保留了其所源自的多肽的生物学功能。
在本文中,本发明的多肽或其变体的生物学功能包括但不限于,诱导调节性T细胞活化,不诱导或基本不诱导效应T细胞和B细胞活化,治疗自身免疫性疾病,降低抗双链DNA抗体的水平,降低尿蛋白的水平,和/或降低血糖。
本领域技术人员已知,在mRNA的翻译过程中,由于起始密码子的作用,所产生的多肽链第一位经常为起始密码子编码的氨基酸(例如,甲硫氨酸(M))。因此,本发明的多肽或其变体不仅囊括在其N末端不包含起始密码子编码的氨基酸(例如,甲硫氨酸)的氨基酸序列,也囊括在其N末端包含起始密码子编码的氨基酸(例如,甲硫氨酸)的氨基酸序列。
在某些实施方案中,所述gp96蛋白为人源。在某些实施方案中,所述gp96蛋白具有如SEQ ID NO:7所示的氨基酸序列。
在某些实施方案中,本发明的分离的多肽由gp96蛋白的不多于254个的连续氨基酸残基组成,例如,由不多于250个,240个,230个,226个,224个,220个,210个,200个,196个,194个,190个,180个,170个,166个,164个,160个,150个,140个或136个的连续氨基酸残基组成。
在某些实施方案中,所述变体与其所源自的多肽相异仅在于1个或几个(例如,1个、2个、3个、4个或5个)氨基酸残基的置换、缺失或添加,所述置换是保守置换。
在某些实施方案中,所述变体与其所源自的多肽相异仅在于1个、2个或3个氨基酸残基的置换、缺失或添加。在某些实施方案中,所述置换包括将所述氨基酸残基替换为丙氨酸(A)。
在某些实施方案中,本发明的多肽包含:gp96蛋白的第578-713位氨基酸残基、第578-743位氨基酸残基、第578-773位氨基酸残基、第578-803位氨基酸残基、第550-713位氨基酸残基、第550-743位氨基酸残基、第550-773位氨基酸残基或第550-803位氨基酸残基。
在某些实施方案中,所述分离的多肽包含选自下列的氨基酸序列,或由其组成:SEQ ID NOs:30、31、32、33、37、42、43、44。此处所示序列在其N端包含起始密码子编码的甲硫氨酸。本领域技术人员理解,所述分离的多肽也可以包含在其N端不包含起始密码子编码的甲硫氨酸的上述氨基酸序列,或由其组成。
在某些实施方案中,所述变体包含选自下列的氨基酸序列,或由其组成:SEQ IDNOs:55-62。此处所示序列在其N端包含起始密码子编码的甲硫氨酸。本领域技术人员理解,所述变体也可以包含在其N端不包含起始密码子编码的甲硫氨酸的上述氨基酸序列,或由其组成。
融合蛋白
在另一方面,本发明提供了一种融合蛋白,其包含本发明的分离的多肽(或其变体)和另外的多肽。
在某些实施方案中,所述另外的多肽选自蛋白标签、靶向部分或其任意组合。
在本文中,蛋白标签是本领域熟知的,其实例包括但不限于His、Flag、GST、MBP、HA、Myc、GFP或生物素,并且本领域技术人员已知如何根据期望目的(例如,纯化、检测或示踪)选择合适的蛋白标签。
在本文中,术语“靶向部分”是指,能够将本发明的多肽(或其变体)引导至所期望的位置的结构域,所述期望的位置可以为特定的组织、特定的细胞、甚至特定的细胞内位置(例如细胞核、核糖体、内质网、溶酶体或过氧化物酶体)。本领域技术人员已知如何通过期望位置的特性设计相应的靶向结构域。在某些实施方案中,所述靶向部分包括配体、受体或抗体或其结合结构域。
在某些实施方案中,所述另外的多肽任选地通过接头连接至本发明的多肽(或其变体)的N端或C端。在某些实施方案中,所述接头为包含一个或多个(例如,1个,2个,3个,4个或5个)氨基酸(如,Gly或Ser)的序列。
多肽及融合蛋白的制备
本发明的多肽或其变体或融合蛋白不受其产生方式的限定,例如,其可以通过基因工程方法(重组技术)产生,也可以通过化学合成方法产生。
在另一方面,本发明提供了一种分离的核酸分子,其包含编码本发明的多肽或其变体或融合蛋白的核苷酸序列。
在某些实施方案中,所述分离的核酸分子包含选自下列的核苷酸序列:(i)SEQ IDNOs:13-16、20、25-27、47-54任一项所示的序列;(ii)与(i)所述序列相比具有至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少99%的序列同一性的序列;(iii)在严格条件下与(i)或(ii)中所述的序列杂交的序列;或(iv)(i)或(ii)中所述的序列的互补序列。
在另一方面,本发明还提供了一种载体,其包含如上所述的分离的核酸分子。本发明的载体可以是克隆载体,也可以是表达载体。在某些实施方案中,本发明的载体是例如质粒,粘粒,噬菌体,柯斯质粒等等。
在另一方面,本发明还提供了包含本发明的分离的核酸分子或载体的宿主细胞。此类宿主细胞包括但不限于,原核细胞例如大肠杆菌细胞,以及真核细胞例如酵母细胞,昆虫细胞(例如Sf9细胞),植物细胞和动物细胞(如哺乳动物细胞,例如小鼠细胞、人细胞等)。
在另一方面,本发明还提供了制备本发明的多肽或其变体或融合蛋白的方法,其包括,在允许所述多肽或其变体或融合蛋白表达的条件下,培养本发明的宿主细胞,和从培养的宿主细胞培养物中回收所述多肽或其变体或融合蛋白。
药物组合物
在另一方面,本发明提供了一种药物组合物,其包含本发明的分离的多肽(或其变体)、融合蛋白、分离的核酸分子、载体或宿主细胞,以及药学上可接受的载体和/或赋形剂。
在某些实施方案中,所述药物组合物包含本发明的分离的多肽(或其变体)或融合蛋白中的一种或多种。
本发明的多肽(或其变体)、融合蛋白或药物组合物可以配制成医学领域已知的任何剂型,例如,片剂、丸剂、混悬剂、乳剂、溶液、凝胶剂、胶囊剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射剂(包括注射液、冻干粉剂)等形式。在一些实施方案中,本发明的多肽(或其变体)、融合蛋白或药物组合物可以配制成注射液或冻干粉剂。
此外,本发明的多肽(或其变体)或融合蛋白可以以单位剂量形式存在于药物组合物中,以便于施用。
本发明的多肽(或其变体)、融合蛋白或药物组合物可以通过本领域已知的任何合适的方法来施用,包括但不限于,口服、口腔、舌下、眼球、局部、肠胃外、直肠、叶鞘内、内胞浆网槽内、腹股沟、膀胱内、局部(如,粉剂、药膏或滴剂),或鼻腔途径。但是,对于许多治疗用途而言,优选的给药途径/方式是胃肠外给药(例如静脉注射,皮下注射,腹膜内注射,肌内注射)。技术人员应理解,给药途径和/或方式将根据预期目的而发生变化。在一个优选的实施方案中,本发明的多肽(或其变体)、融合蛋白或药物组合物通过静脉输注或注射给予。
本发明所提供的多肽(或其变体)、融合蛋白或药物组合物可以单独使用或联合使用,也可以与另外的药学活性剂(例如抗炎药物或免疫抑制剂)联合使用。这种另外的药学活性剂可以在施用本发明的多肽(或其变体)、融合蛋白或药物组合物之前、同时或之后施用。
在某些实施方案中,所述药物组合物任选地还包含另外的药学活性剂,例如具有治疗自身免疫性疾病活性的药物。在某些实施方案中,所述另外的药学活性剂选自抗炎药物或免疫抑制剂,例如非甾体抗炎药、甾体抗炎药、致炎性细胞因子的抗体或拮抗剂、抗炎细胞因子等。
治疗用途
本申请的发明人首次发现,gp96的C末端结构域或其活性片段能够特异性活化调节性T细胞,而不活化效应T细胞及B细胞的活性,从而特别适用于自身免疫性疾病的治疗。
因此,在另一方面,本发明还涉及gp96的C末端结构域或其活性片段或其变体、或本发明的分离的多肽(或其变体)、融合蛋白、分离的核酸分子、载体或宿主细胞在制备药物中的用途,所述药物用于在受试者中预防和/或治疗自身免疫性疾病、或降低抗双链DNA抗体的水平、或降低尿蛋白的水平、或降低血糖。
在某些实施方案中,所述C末端结构域由gp96蛋白的第550-803位氨基酸残基组成。在某些实施方案中,所述C末端结构域具有如SEQ ID NO:30所示的序列。
在某些实施方案中,所述gp96的C末端结构域的活性片段或其变体选自本发明的分离的多肽或其变体。
在某些实施方案中,所述药物包含所述gp96的C末端结构域或其活性片段或其变体、本发明的分离的多肽(或其变体)或融合蛋白中的一种或多种。
在某些实施方案中,所述自身免疫性疾病可以选自系统性红斑狼疮、1型糖尿病、类风湿性关节炎、多发性硬化症、银屑病、炎症性肠病、溃疡性结肠炎、克罗恩病、重症肌无力或多发性肌炎。
在某些实施方案中,所述药物用于预防和/或治疗系统性红斑狼疮或缓解系统性红斑狼疮的一种或多种症状(例如降低抗双链DNA抗体的水平,和/或降低尿蛋白的水平)。
在某些实施方案中,所述药物用于预防和/或治疗1型糖尿病或缓解1型糖尿病的一种或多种症状(例如降低血糖)。
在某些实施方案中,所述药物用于预防和/或治疗类风湿性关节炎或缓解类风湿性关节炎的一种或多种症状(例如减轻关节肿胀、压痛和/或疼痛)。
在某些实施方案中,所述受试者可以为哺乳动物,例如人或鼠。在某些实施方案中,所述受试者患有或被怀疑患有自身免疫性疾病,或者具有患上述疾病的风险。在某些实施方案中,所述受试者患有或被怀疑患有系统性红斑狼疮,或者具有患上述疾病的风险。在某些实施方案中,所述受试者患有或被怀疑患有1型糖尿病,或者具有患上述疾病的风险。在某些实施方案中,所述受试者患有或被怀疑患有类风湿性关节炎,或者具有患上述疾病的风险。
术语定义
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的病毒学、生物化学、免疫学实验室操作步骤均为相应领域内广泛使用的常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
如本文中所使用的,术语“gp96”又称为Grp94,是位于细胞内质网膜上的热休克蛋白90家族中的一员。gp96蛋白由N端结构域(N末端ATP结合结构域)、M结构域(带电中间结构域)以及C端结构域(C末端同源二聚结构域)组成。gp96是本领域技术人员公知的,其序列可参见各种公共数据库,例如NCBI GENBANK数据库登录号:AAH66656.1。
如本文中所使用的,当提及gp96蛋白的氨基酸序列时,其使用SEQ ID NO:7所示的序列来进行描述。例如,表述“gp96蛋白的第578-713位氨基酸残基”是指,SEQ ID NO:7所示的多肽的第578-713位氨基酸残基。然而,本领域技术人员理解,在gp96的氨基酸序列中,可天然产生或人工引入突变或变异,而不影响其生物学功能。因此,在本发明中,术语“gp96”及其类似表述应包括所有此类序列,包括例如SEQ ID NO:7所示的序列以及其天然或人工的变体。并且,当描述gp96蛋白的序列片段时,其不仅包括SEQ ID NO:7的序列片段,还包括其天然或人工变体中的相应序列片段。例如,表述“gp96蛋白的第578-713位氨基酸残基”包括,SEQ ID NO:7的第578-713位氨基酸残基,以及其变体(天然或人工)中的相应片段。根据本发明,表述“相应序列片段”或“相应片段”是指,当对序列进行最优比对时,即当序列进行比对以获得最高百分数同一性时,进行比较的序列中位于等同位置的片段。
如本文中所使用的,术语“分离的”或“被分离的”指的是,从天然状态下经人工手段获得的。如果自然界中出现某一种“分离”的物质或成分,那么可能是其所处的天然环境发生了改变,或从天然环境下分离出该物质,或二者情况均有发生。例如,某一活体动物体内天然存在某种未被分离的多聚核苷酸或多肽,而从这种天然状态下分离出来的高纯度的相同的多聚核苷酸或多肽即称之为分离的。术语“分离的”或“被分离的”不排除混有人工或合成的物质,也不排除存在不影响物质活性的其它不纯物质。
如本文中所使用的,术语“载体(vector)”是指,可将多聚核苷酸插入其中的一种核酸运载工具。当载体能使插入的多核苷酸编码的蛋白获得表达时,载体称为表达载体。载体可以通过转化,转导或者转染导入宿主细胞,使其携带的遗传物质元件在宿主细胞中获得表达。载体是本领域技术人员公知的,包括但不限于:质粒;噬菌粒;柯斯质粒;人工染色体,例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。可用作载体的动物病毒包括但不限于,逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。一种载体可以含有多种控制表达的元件,包括但不限于,启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外,载体还可含有复制起始位点。
如本文中所使用的,术语“宿主细胞”是指,可用于导入载体的细胞,其包括但不限于,如大肠杆菌或枯草菌等的原核细胞,如酵母细胞或曲霉菌等的真菌细胞,如S2果蝇细胞或Sf9等的昆虫细胞,或者如纤维原细胞,CHO细胞,COS细胞,NSO细胞,HeLa细胞,BHK细胞,HEK 293细胞或人细胞等的动物细胞。
如本文中所使用的,对于杂交的“严格条件”是指形成特异性杂交体但不形成非特异性杂交体的条件。典型的严格条件例如可以举出在钾浓度约25mM~约50mM以及镁浓度约1.0mM~约5.0mM中进行杂交的条件。作为示例,严格条件可以指在Tris-HCl(pH8.6)、25mM的KCl以及1.5mM的MgCl2下进行杂交的条件,但不限于此。本领域技术人员能够通过改变杂交反应、杂交反应液的盐浓度等来容易地选择这样的条件。
如本文中所使用的,术语“同一性”用于指两个多肽之间或两个核酸之间序列的匹配情况。当两个进行比较的序列中的某个位置都被相同的碱基或氨基酸单体亚单元占据时(例如,两个DNA分子的每一个中的某个位置都被腺嘌呤占据,或两个多肽的每一个中的某个位置都被赖氨酸占据),那么各分子在该位置上是同一的。两个序列之间的“百分数同一性”是由这两个序列共有的匹配位置数目除以进行比较的位置数目×100的函数。例如,如果两个序列的10个位置中有6个匹配,那么这两个序列具有60%的同一性。例如,DNA序列CTGACT和CAGGTT共有50%的同一性(总共6个位置中有3个位置匹配)。通常,在将两个序列比对以产生最大同一性时进行比较。这样的比对可通过使用,例如,可通过计算机程序例如Align程序(DNAstar,Inc.)方便地进行的Needleman等人(1970)J.Mol.Biol.48:443-453的方法来实现。还可使用已整合入ALIGN程序(版本2.0)的E.Meyers和W.Miller(Comput.ApplBiosci.,4:11-17(1988))的算法,使用PAM120权重残基表(weight residue table)、12的缺口长度罚分和4的缺口罚分来测定两个氨基酸序列之间的百分数同一性。此外,可使用已整合入GCG软件包(可在www.gcg.com上获得)的GAP程序中的Needleman和Wunsch(J MoIBiol.48:444-453(1970))算法,使用Blossum 62矩阵或PAM250矩阵以及16、14、12、10、8、6或4的缺口权重(gap weight)和1、2、3、4、5或6的长度权重来测定两个氨基酸序列之间的百分数同一性。
如本文中所使用的,术语“保守置换”意指不会不利地影响或改变包含氨基酸序列的蛋白/多肽的预期性质的氨基酸置换。例如,可通过本领域内已知的标准技术例如定点诱变和PCR介导的诱变引入保守置换。保守氨基酸置换包括用具有相似侧链的氨基酸残基替代氨基酸残基的置换,例如用在物理学上或功能上与相应的氨基酸残基相似(例如具有相似大小、形状、电荷、化学性质,包括形成共价键或氢键的能力等)的残基进行的置换。已在本领域内定义了具有相似侧链的氨基酸残基的家族。这些家族包括具有碱性侧链(例如,赖氨酸、精氨酸和组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β分支侧链(例如,苏氨酸、缬氨酸、异亮氨酸)和芳香族侧链(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。因此,优选用来自相同侧链家族的另一个氨基酸残基替代相应的氨基酸残基。鉴定氨基酸保守置换的方法在本领域内是熟知的(参见,例如,Brummell等人,Biochem.32:1180-1187(1993);Kobayashi等人Protein Eng.12(10):879-884(1999);和Burks等人Proc.NatlAcad.Set USA 94:412-417(1997),其通过引用并入本文)。
本文涉及的二十个常规氨基酸的编写遵循常规用法。参见例如,Immunology-ASynthesis(2nd Edition,E.S.Golub and D.R.Gren,Eds.,Sinauer Associates,Sunderland,Mass.(1991)),其以引用的方式并入本文中。在本发明中,术语“多肽”和“蛋白质”具有相同的含义且可互换使用。并且在本发明中,氨基酸通常用本领域公知的单字母和三字母缩写来表示。例如,丙氨酸可用A或Ala表示。
如本文中所使用的,术语“受试者”包括但不限于各种动物,特别是哺乳动物,例如人。在某些实施方案中,所述受试者(例如人)患有自身免疫性疾病。
如本文中所使用的,术语“药学上可接受的载体和/或赋形剂”是指,在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂,其是本领域公知的(参见例如Remington's Pharmaceutical Sciences.Edited by Gennaro AR,19thed.Pennsylvania:Mack Publishing Company,1995),并且包括但不限于:pH调节剂,表面活性剂,离子强度增强剂,维持渗透压的试剂,延迟吸收的试剂,稀释剂,佐剂,防腐剂,稳定剂等。例如,pH调节剂包括但不限于磷酸盐缓冲液。表面活性剂包括但不限于阳离子,阴离子或者非离子型表面活性剂,例如Tween-80。离子强度增强剂包括但不限于氯化钠。维持渗透压的试剂包括但不限于糖、NaCl及其类似物。延迟吸收的试剂包括但不限于单硬脂酸盐和明胶。稀释剂包括但不限于水,水性缓冲液(如缓冲盐水),醇和多元醇(如甘油)等。佐剂包括但不限于铝佐剂(例如氢氧化铝),弗氏佐剂(例如完全弗氏佐剂)等。防腐剂包括但不限于各种抗细菌试剂和抗真菌试剂,例如硫柳汞,2-苯氧乙醇,对羟苯甲酸酯,三氯叔丁醇,苯酚,山梨酸等。稳定剂具有本领域技术人员通常理解的含义,其能够稳定药物中的活性成分的期望活性(例如对PSD-95泛素化的抑制活性),包括但不限于谷氨酸钠,明胶,SPGA,糖类(如山梨醇,甘露醇,淀粉,蔗糖,乳糖,葡聚糖,或葡萄糖),氨基酸(如谷氨酸,甘氨酸),蛋白质(如干燥乳清,白蛋白或酪蛋白)或其降解产物(如乳白蛋白水解物)等。
如本文中所使用的,术语“治疗”是指,治疗或治愈疾病(例如自身免疫性疾病),延缓疾病的一种或多种症状的发作,和/或延缓疾病的发展。
如本文中所使用的,术语“有效量”是指,可以有效实现预期目的的量。例如,治疗有效量可以是有效地或足以治疗或治愈疾病(例如自身免疫性疾病),延缓疾病的一种或多种症状的发作和/或延缓疾病发展的量。这样的有效量可以由本领域技术人员或医生容易地确定,并且可以与预期目的、受试者的一般健康状况、年龄、性别、体重、待治疗的疾病的严重程度、并发症、施用方式等相关。这样的有效量的确定完全在本领域技术人员的能力范围内。
如本文中所使用的,本发明的多肽或其变体的生物学功能包括但不限于选自下列的一种或多种:
1)诱导调节性T细胞活化;
2)不诱导效应T细胞和B细胞活化;
3)在受试者中治疗自身免疫性疾病(例如系统性红斑狼疮、1型糖尿病、类风湿性关节炎);
4)在受试者中降低抗双链DNA抗体的水平;
5)在受试者中降低尿蛋白的水平;
6)在受试者中降低血糖。
有益效果
与现有技术相比,本发明的多肽(或其变体)和含有所述多肽(或其变体)的融合蛋白具有显著的有利方面。特别地,本发明的多肽(或其变体)和融合蛋白可特异性诱导调节性T细胞活化,且不诱导效应T细胞及B细胞活化,从而避免了全长gp96蛋白可能加重自身免疫性疾病进展的潜在风险。此外,本发明的多肽(或其变体)和融合蛋白诱导调节性T细胞活化的能力明显优于全长gp96蛋白,具有更优的免疫调节活性。因此,本发明的多肽(或其变体)和融合蛋白特别适用于自身免疫性疾病的治疗,具有重大的临床价值。
下面将结合附图和实施例对本发明的实施方案进行详细描述,但是本领域技术人员将理解,下列附图和实施例仅用于说明本发明,而不是对本发明的范围的限定。根据附图和优选实施方案的下列详细描述,本发明的各种目的和有利方面对于本领域技术人员来说将变得显然。
附图说明
图1为100μg不同gp96蛋白片段免疫小鼠后小鼠的调节性T细胞(Tregs)百分比(%CD3+CD4+CD25+Foxp3+Tregs/CD3+CD4+T细胞)。*,P<0.05;**,P<0.01
图2为300μg不同gp96蛋白片段免疫小鼠后小鼠的调节性T细胞(Tregs)百分比(%CD3+CD4+CD25+Foxp3+Tregs/CD3+CD4+T细胞)。*,P<0.05;***,P<0.001
图3为500μg不同gp96蛋白片段免疫小鼠后小鼠的调节性T细胞(Tregs)百分比(%CD3+CD4+CD25+Foxp3+Tregs/CD3+CD4+T细胞)。*,P<0.05;***,P<0.001
图4为300μg不同多肽片段和全长gp96免疫小鼠后小鼠的调节性T细胞(Tregs)百分比(%CD3+CD4+CD25+Foxp3+Tregs/CD3+CD4+T细胞)。**,peptides与gp96组相比P<0.01
图5为30μg或300μg不同多肽片段和全长gp96联合卵清白蛋白(NP-OVA)免疫小鼠后活化的CD4+T细胞百分比(INFγ+CD4+T/CD4+T)。**,P<0.01;***,P<0.001
图6为30μg或300μg不同多肽片段和全长gp96联合卵清白蛋白(NP-OVA)免疫小鼠后活化的CD8+T细胞百分比(INFγ+CD8+T/CD8+T)。**,P<0.01;***,P<0.001
图7为300μg不同多肽片段和全长gp96免疫小鼠后小鼠血清中的抗OVA抗体IgG的水平。**,P<0.01
图8为100μg、300μg或500μg不同多肽片段和全长gp96免疫Lyn(-/-)小鼠后小鼠血清中抗dsDNA抗体的水平。相同剂量下,gp96组与PBS组相比P<0.001(“***”),peptide组与gp96组相比P<0.05(“*”)
图9为100μg、300μg或500μg不同多肽片段和全长gp96免疫Lyn(-/-)小鼠后小鼠尿液中蛋白的水平。相同剂量下,gp96组与PBS组相比P<0.001(“***”),peptide组与gp96组相比P<0.05(“*”)
图10为100μg、300μg或500μg不同多肽片段和全长gp96免疫后NOD小鼠预防模型T1D患病率。相同剂量下,peptide组与gp96组相比P<0.05(“*”)或P<0.01(“**”)
图11为100μg、300μg或500μg不同多肽片段和全长gp96免疫后NOD小鼠预防模型血液中的血糖水平。相同剂量下,peptide组与gp96组相比P<0.05(“*”)
图12为100μg、300μg或500μg不同多肽片段和全长gp96免疫后NOD小鼠预防模型脾脏细胞中活化的CD8+T细胞百分比(INFγ+CD8+T/CD8+T)。相同剂量下,peptide组与gp96组相比P<0.05(“*”)
图13为300μg不同多肽片段和全长gp96免疫后NOD小鼠治疗模型血液中的血糖水平。相同剂量下,peptide组与gp96组相比P<0.05(“*”)
图14为300μg Peptide 1和其氨基酸缺失和替换突变免疫后NOD小鼠治疗模型血液中的血糖水平。
图15为300μg Peptide 15和其氨基酸缺失和替换突变免疫后NOD小鼠治疗模型血液中的血糖水平。
图16为不同多肽片段和全长gp96免疫后诱导性小鼠关节炎症模型中的类风湿性炎症指数检测结果。
序列信息
表1:本申请涉及的序列的信息描述于下面的表中。
具体实施方式
现参照下列意在举例说明本发明(而非限定本发明)的实施例来描述本发明。
本领域技术人员知晓,实施例以举例方式描述本发明,且不意欲限制本申请所要求保护的范围。实施例中的实验方法,如无特殊说明,均为常规方法。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。实施例中的定量实验,均设置三次重复实验,结果取平均值。
以下实施例中所涉及的实验材料来源如下:
雌性Lyn(-/-)敲除鼠系统性红斑狼疮模型参见如下文献:Hibbs ML,etal.Multiple defects in the immune system of Lyn-deficient mice,culminating inautoimmune disease.Cell(1995)83(2):301–11;Yu CC,Yen TS,Lowell CA,DeFrancoAL.Lupus-like kidney disease in mice deficient in the Src family tyrosinekinases Lyn and Fyn.Curr Biol.2001 Jan 9;11(1):34-8.
雌性NOD/LTJ小鼠参见如下文献:Terry L.et al.I The Nonobese DiabeticMouse as a Model of Autoimmune Diabetes:Immune Dysregulation Gets theNOD.Immunity,December,1997,Vol.7,727-738;Michelle Solomon,Nora Sarvetnick,etal.The Pathogenesis of Diabetes in the NOD Mouse.Immunology,2004,84:239-64.
Sf9细胞购自Invitrogen公司,目录号:11496-015;
pFastBacTM1质粒购自Invitrogen公司,产品目录号:10359-016;
DH10BacTM感受态细胞购自Invitrogen公司,产品目录号:10361-012;
Insect-XPRESSTM Protein-free Insect Cells medium with L-Glutamine购自LONZA公司,产品目录号:12-730Q;
超滤管购自Merck Millipore公司,产品目录号:UFC905096;
ELISA试剂盒购自eBioscience公司,产品目录号:BMS614INST;
Ni亲和层析预装柱购自阿拉丁公司,产品目录号:N5289-01;
Superdex 200 10/300 GL分子筛层析柱购自GE公司,产品目录号:17517501;
大肠杆菌DH10Bac感受态细胞购自北京原平皓生物技术有限公司,产品目录号:CL108-01。
实施例1:全长gp96或不同gp96截短体的制备
1.重组质粒的构建。
含有全长gp96或不同gp96截短体的编码序列的重组质粒pFastBac1-DNAs由金斯瑞生物科技股份有限公司合成。所涉及的全长gp96或不同gp96截短体的氨基酸序列及编码核酸序列参见表1。将重组质粒分别转化至DH10BacTM感受态细胞,经重组筛选得到重组杆粒DNA。所有gp96蛋白片段和多肽的C端都带有6xHis标签,标签的DNA序列为CACCACCACCATCACCAC(SEQ ID NO:63)。
2.全长gp96或不同gp96截短体的表达。
2.1将重组杆粒DNA共转染贴壁Sf9细胞(每8×105个Sf9细胞约转染2μg重组质粒;共转染过程中,转染试剂为Cellfectin II reagent(购自Life technologies,产品目录号:10362-100)),27℃孵育72h,离心,上清液即为P1代病毒。
2.2将Sf9细胞悬浮液1(含8×106个Sf9细胞)27℃培养1~5h,得到贴壁培养细胞;然后向所述贴壁培养细胞中加入P1代病毒(剂量为0.05~0.1MOI),27℃孵育72h,4000rpm离心5min,上清液即为P2代病毒。
2.3向Sf9细胞悬浮液2(含8×106个Sf9细胞)中加入P2代病毒(剂量为0.05~0.1MOI),27℃、100~120rpm培养72h,4000rpm离心5min,上清液即为P3代病毒。
3.全长gp96或不同gp96截短体的纯化。
3.1向300ml的Sf9细胞悬浮液3(含Sf9细胞2~4×106个/ml)中加入P3代病毒(剂量为0.05MOI),27℃、100~120rpm培养72~96h,得到悬浮液。
3.2取所述悬浮液,7000rpm离心20min,获得上清液1。
3.3取所述上清液1,经0.22mm滤膜过滤,获得上样液。
3.4将所述上样液上样于Ni亲和层析柱。上样流速控制在1ml/min,然后用不含咪唑的Tris-HCl缓冲液冲洗,再用含有咪唑的Tris-HCl缓冲液洗脱并收获洗脱液。将洗脱液用截留分子量为10KD的超滤管进行超滤浓缩,得到1ml左右的浓缩液。所述浓缩液即含有重组gp96 C端蛋白。
3.5将步骤4得到的浓缩液上样于Superdex 200 10/300 GL分子筛层析柱(流速为0.25ml/min),然后用pH7.5、含150mM NaCl的PBS缓冲液洗涤(流速为0.25ml/min),收集为相应蛋白峰的穿透液,通过SDS-PAGE检测相应的蛋白,并利用抗His-tag抗体(购自上海碧云天生物技术有限公司)通过western blotting进一步对纯化的蛋白进行鉴定。进一步采用截留分子量为10KD的超滤管进行超滤浓缩,得到分别含有不同gp96蛋白片段和多肽的溶液。采用BCA法测定蛋白和多肽的溶液中的蛋白浓度,最后分装,蛋白浓度为1mg/ml,贮存于-80℃。
实施例2:全长gp96或不同gp96截短体诱导小鼠调节性T细胞活性的评价
本实施例考察gp96全长蛋白(SEQ ID NO:7)、截短体gp96-N(SEQ ID NO:8)、gp96-M(SEQ ID NO:10)、gp96-N+M(SEQ ID NO:9)、gp96-C(SEQ ID NO:11)及gp96-C+M(SEQ IDNO:12)诱导小鼠产生调节性T细胞的情况。在以上各蛋白或多肽的C端添加6xHis标签。其中,gp96-N对应于全长蛋白的第550-578位氨基酸残基;gp96-M对应于全长蛋白的第578-713位氨基酸残基;gp96-C对应于全长蛋白的第713-803位氨基酸残基。
1、小鼠分组免疫
将105只六周龄体重为14~16g的C57BL/6小鼠(购自北京维通利华实验动物技术有限公司)随机分成gp96处理组、gp96-N处理组、gp96-M处理组、重组gp96-N+M处理组重组、gp96-C处理组、gp96-C+M处理组和对照组(每组5只小鼠),分别进行如下处理:
gp96-N处理组:小鼠生长至第9周龄,腹部皮下注射实施例1制备获得的经纯化的gp96-N的溶液,记为实验第1天;实验第8天后,再次腹部皮下注射实施例1制备获得的经纯化的gp96 N的溶液;实验第22天,再次腹部皮下注射实施例1制备获得的经纯化的gp96-N的溶液。每次注射剂量均为100μg,300μg或500μg gp96-N/只小鼠。
gp96-M处理组:小鼠生长至第9周龄,腹部皮下注射实施例1制备获得的经纯化的gp96-M的溶液,记为实验第1天;实验第8天后,再次腹部皮下注射实施例1制备获得的经纯化的gp96-M的溶液;实验第22天,再次腹部皮下注射实施例1制备获得的经纯化的gp96-M的溶液。每次注射剂量均为100μg,300μg或500μg gp96-M/只。
gp96-N+M处理组:小鼠生长至第9周龄,腹部皮下注射实施例1制备获得的经纯化的gp96-N+M的溶液,记为实验第1天;实验第8天后,再次腹部皮下注射实施例1制备获得的经纯化的gp96-N+M溶液;实验第22天,再次腹部皮下注射实施例1制备的经纯化的gp96-N+M的溶液。每次注射剂量均为100μg,300μg或500μg gp96-N+M/只。
gp96-C处理组:小鼠生长至第9周龄,腹部皮下注射实施例1制备的经纯化的gp96-C,记为实验第1天;实验第8天后,再次腹部皮下注射实施例1制备的经纯化的gp96-C的溶液;实验第22天,再次腹部皮下注射实施例1制备的经纯化的gp96-C的溶液。每次注射剂量均为100μg,300μg或500μg gp96-C/只。
gp96-C+M处理组:小鼠生长至第9周龄,腹部皮下注射实施例1制备的经纯化的gp96-C+M,记为实验第1天;实验第8天后,再次腹部皮下注射实施例1制备的经纯化的gp96-C+M的溶液;实验第22天,再次腹部皮下注射实施例1制备的经纯化的gp96 C-3的溶液。每次注射剂量均为100μg,300μg或500μg gp96-C+M/只。
全长gp96处理组:小鼠生长至第9周龄,腹部皮下注射实施例1制备的经纯化的gp96-C+M,记为实验第1天;实验第8天后,再次腹部皮下注射实施例1制备的经纯化的gp96-C+M的溶液;实验第22天,再次腹部皮下注射实施例1制备的全长gp96的溶液。每次注射剂量均为100μg,300μg或500μg gp96/只。
对照组:实验第1天腹部皮下注射pH7.2、0.01mol/L PBS缓冲液,实验第8天,再次腹部皮下注射pH7.2、0.01mol/L PBS缓冲液;实验第22天,再次腹部皮下注射pH7.2、0.01mol/L PBS缓冲液。每次注射PBS剂量均为100μl/只,300μg或500μl/只。
2、免疫效果评价
在第25天处死小鼠,取小鼠脾脏分离制备小鼠脾脏淋巴细胞,利用流式细胞仪分析小鼠的调节性T细胞(Tregs)百分比(%CD3+CD4+CD25+Foxp3+Tregs/CD3+CD4+T细胞)。调节性T细胞的分离和检测方法详见Xinghui Li,et al.2013.Induction of regulatory Tcells by high-dose gp96 suppresses murine liver immune hyperactivation.PLoSOne.8(7):e68997。
检测结果如图1-3所示,图1-3分别为100μg、300μg和500μg不同gp96蛋白片段免疫小鼠后小鼠的调节性T细胞(Tregs)百分比。结果表明,100μg,300μg或500μg gp96-C、gp96-C+M蛋白免疫的小鼠调节性T细胞的百分比显著高于对照组(PBS)或gp96-N、gp96-M、gp96-N+M免疫组(P<0.05或P<0.001),而且gp96-C和gp96-C+M蛋白免疫组调节性T细胞水平明显高于全长gp96免疫组(P<0.05),而gp96-N、gp96-M、gp96-N+M蛋白和对照组处理小鼠的调节性T细胞百分比无显著差异。
实施例3:基于gp96蛋白的C端结构域的不同截短体的制备及其诱导小鼠调节性T细胞活性的评价
1、不同多肽片段的设计
gp96全长的C末端共有255个氨基酸残基,分别截除分成17个不同的多肽片段:Peptide 1-Peptide 17,它们的氨基酸序列分别如SEQ ID NOs:30-46所示。在以上各多肽的C端添加6xHis标签,利用实施例1中的方法分别表达和制备上述17种多肽。
2、小鼠分组免疫
将95只六周龄体重为14~16g的C57BL/6小鼠随机分成19组,分别设Peptide 1-Peptide 17实验组、PBS和gp96对照组,每组5只小鼠。
小鼠生长至第9周龄,实验第1天腹部皮下注射相应的蛋白(多肽)或PBS,实验第8天,再次腹部皮下注射;实验第22天,再次腹部皮下注射。每次注射剂量均为300μg/只。
3、效果评价
第25天处死小鼠,取小鼠脾脏分离制备小鼠脾脏淋巴细胞,利用流式细胞仪分析不同重组多肽片段免疫后小鼠调节性T细胞百分比。调节性T细胞的分离和检测方法如实施例2。
检测结果如图4,结果表明,Peptide 1、Peptide 2、Peptide 3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15处理组,小鼠调节性细胞的百分比显著高于对照组(PBS)(P<0.001),且均高于全长gp96处理组(P<0.01)。并且可以看出,Peptide 15所包含的氨基酸序列(gp96全长蛋白的第578-713位氨基酸残基)是活化调节性T细胞的必要序列。
实施例4:基于gp96蛋白的C端结构域的不同截短体诱导小鼠效应T细胞活性的评价
1、小鼠分组免疫
将110只六周龄体重为14~16g的C57BL/6小鼠随机分成22组,分别设Peptide 1、Peptide 2、Peptide 3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽、全长gp96联合卵清白蛋白(NP-OVA)(购自北京博奥派克生物科技有限公司,货号:T-5051-100*100mg)实验组、单独NP-OVA或PBS对照组(每组5只小鼠)。
小鼠生长至第9周龄,实验第1天腹部皮下注射相应的多肽或全长gp96联合NP-OVA,或单独NP-OVA或PBS免疫,实验第8天,再次腹部皮下注射;实验第22天,再次腹部皮下注射。每次注射多肽或全长gp96注射剂量均为30μg或300μg/只小鼠,OVA蛋白的剂量为20μg/只小鼠。
2、效果评价
在第25天处死小鼠,分离小鼠的脾脏细胞,利用流式细胞仪分析免疫后小鼠活化的CD4+T细胞、CD8+T细胞百分比。活化的CD4+T细胞、CD8+T细胞的分离和检测方法详见Xinghui Li,et al.2013.Induction of regulatory T cells by high-dose gp96suppresses murine liver immune hyperactivation.PLoS One.8(7):e68997。
活化的CD4+T细胞、CD8+T细胞百分比检测结果分别如图5和图6所示,结果表明,30μg和300μg免疫剂量的Peptide 1、Peptide 2、Peptide 3、Peptide 4、Peptide 8、Peptide13、Peptide 14、Peptide 15多肽片段处理组中小鼠活化的CD4+T细胞和CD8+T细胞的百分比均与对照组(PBS)无明显差异,而30μg免疫剂量的全长gp96组小鼠活化的CD4+T细胞和CD8+T细胞的百分比显著高于对照组(PBS)(P<0.001)和OVA免疫组(P<0.01),300μg免疫剂量的全长gp96组小鼠活化的CD4+T细胞和CD8+T细胞的百分比显著高于对照组(PBS)(P<0.01),这表明多肽片段免疫不会活化效应T细胞,而全长gp96可明显活化效应T细胞。
进一步通过ELISA检测300μg不同多肽片段和全长gp96免疫小鼠后小鼠血清中的抗OVA抗体IgG的水平,检测方法详见Bettina Eide Holm,et al.2015.Antibldies withspecificity for native and denatured forms of ovalbumin differ in reactivitybetween enzyme-linked immunosorbent assays.APMIS.123(2):136-45。
检测结果如图7所示,结果表明300μg免疫剂量的Peptide 1、Peptide 2、Peptide3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽片段处理组中小鼠血清抗OVA抗体水平与对照组(PBS)无明显差异,并明显低于全长gp96免疫小鼠(所有P<0.05),这表明多肽片段免疫不会活化效应B细胞。
实施例5:基于gp96蛋白的C端结构域的不同截短体在治疗系统性红斑狼疮中的应用
1、小鼠分组免疫
将300只六周龄体重为14~16g的雌性Lyn(-/-)小鼠随机分成Peptide 1、Peptide2、Peptide 3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽、全长gp96免疫组和对照组(PBS)(每组10只),分别进行如下处理:小鼠生长至第7周龄、第8周龄、第10周龄、第12周龄、第14周龄、第16周龄时,分别在小鼠腹部皮下注射实施例1和实施例3制备的经纯化的重组多肽、全长gp96或PBS,每次注射剂量/只小鼠为100μg、300μg或500μg。
小鼠生长至20周龄时,眼眶取血200μl。室温静置30min,3000rpm离心20min,取上清。
2、抗双链DNA抗体滴度的分析
血清中抗双链DNA抗体的水平采用酶联免疫吸附(ELISA)方法测定,步骤如下:
2.1向96孔酶标板(购自Nunc,Rochester NY,USA)中加入2.5μg/ml的小牛胸腺dsDNA标准品(购自Sigma Aldrich,USA,货号:D8899-1MG),每孔100μl。4℃包被过夜。
2.2加入2%牛血清白蛋白(购自Invitrogen,USA)100μl,37℃孵育60分钟。
2.3加入血清样本50μl(1:50比例稀释)和抗dsDNA抗体标准品(购自ChemiconInternational,USA,clone号:16-13),37℃孵育60分钟。
2.4弃去孔内液体,每孔加入200μl的1×洗涤液(PBST,PBS按0.1%加入Triton-X100),静置30秒,甩干,重复洗涤5次。最后在吸水纸上拍干。
2.5加入HRP标记的抗小鼠二抗(购自中杉金桥,1:5000稀释),每孔50μl。37℃孵育60分钟。
2.6弃去孔内液体,每孔加入200μl的1×洗涤液,静置30秒,甩干,重复洗涤5次。最后在吸水纸上拍干。
2.7每孔加入100μl底物(1×TMB ELISA Substrate Solution,购自eBioscience,货号:00-4201-56)。37℃孵育15分钟。
2.8弃去孔内液体,每孔加入50μl终止液(2M H2SO4),混匀,酶标仪上450nm波长下读数。测定应在加终止液后15分钟以内进行。
3、尿蛋白的测定
尿蛋白检测试剂盒购自南京建成生物工程研究所(货号:C035-2)
3.1取三个管,分别标记为空白管,标准管和测定管。空白管加入双蒸水0.05ml,CBB试剂3.0ml。标准管加入563mg/L蛋白标准液0.05ml,CBB试剂3.0ml。测定管加入尿液样本0.05ml,CBB试剂3.0ml。
3.2充分混匀,放置5分钟。分光光度计用波长595nm检测各管的吸光度。
尿蛋白浓度(mg/L)=(测定OD值-空白OD值)/(标准OD值-空白OD值)×标准品浓度
4、效果评价
小鼠的抗双链DNA抗体检测结果见图8。结果表明,Peptide 1、Peptide 2、Peptide3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽治疗小鼠的抗双链DNA抗体滴度显著小于对照组(PBS)(P<0.001),同时也明显低于全长gp96治疗组(P<0.05)。这说明多肽治疗系统性红斑狼疮的效果优于全长gp96。
小鼠的尿蛋白检测结果见图9。结果表明,Peptide 1、Peptide 2、Peptide 3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽治疗小鼠的尿蛋白水平显著低于对照组(PBS)(P<0.001),同时也明显低于全长gp96治疗组(P<0.05)。这说明多肽治疗系统性红斑狼疮的效果优于全长gp96。
实施例6:基于gp96蛋白的C端结构域的不同截短体在预防1型糖尿病中的应用
1、小鼠免疫
将300只六周龄体重为14~16g的NOD小鼠预防模型随机分成Peptide 1、Peptide2、Peptide 3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽、全长gp96免疫组和对照组(PBS)(每组10只),分别进行如下处理:小鼠生长至第7周龄、第8周龄、第10周龄、第12周龄、第14周龄时,分别在小鼠腹部皮下注射实施例1和实施例3制备的经纯化的重组多肽、全长gp96或PBS,每次注射剂量/只小鼠分别为100μg、300μg或500μg。
从NOD小鼠第9周龄开始监测小鼠血糖值,取小鼠尾静脉血1滴,用血糖仪(德国罗氏公司ACCU-Performa)参照说明书测定血糖值,并统计患病率。以血糖值>13.3mmol/L且持续2次以上诊断为糖尿病(T1D)。
2、效果评价
小鼠患病指数结果见图10,结果表明,Peptide 1、Peptide 2、Peptide 3、Peptide4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽免疫小鼠T1D的患病率明显低于全长gp96免疫小鼠(P<0.05或P<0.01),对照小鼠(PBS)在11-14周龄均发病。
小鼠血糖浓度检测结果见图11,结果表明,Peptide 1、Peptide 2、Peptide 3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽免疫的小鼠的血糖浓度显著低于全长gp96免疫组(P<0.05)。
在小鼠20周龄时处死小鼠,分离小鼠的脾脏细胞,利用流式细胞仪分析免疫后小鼠活化的CD8+T细胞百分比,检测结果见图12。结果表明,Peptide 1、Peptide 2、Peptide3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽片段处理组中小鼠活化的CD8+T细胞的百分比明显低于全长gp96组小鼠(P<0.05)。
上述结果表明,上述多肽对1型糖尿病的预防效果明显优于全长gp96。
实施例7:基于gp96蛋白的C端结构域的不同截短体在治疗1型糖尿病中的应用
1、小鼠免疫
将100只六周龄体重为14~16g的NOD小鼠治疗模型随机分成Peptide 1、Peptide2、Peptide 3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽、全长gp96免疫组和对照组(PBS)(每组10只),分别进行如下处理:小鼠生长至第14周龄、第15周龄、第17周龄、第19周龄、第21周龄时,分别在小鼠腹部皮下注射实施例1和实施例3制备的经纯化的多肽、全长gp96或PBS,每次注射剂量/只小鼠为300μg。
2、效果评价
小鼠血糖浓度检测结果见图13。结果表明,Peptide 1、Peptide 2、Peptide 3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽免疫后小鼠的血糖浓度随着时间变化而逐渐降低,最终浓度显著低于对照组(PBS)(P<0.001),同时所有多肽免疫组小鼠血糖水平也明显低于全长gp96免疫组(P<0.05)。
上述结果表明,用多肽免疫小鼠,能够有效的治疗小鼠的TID,其治疗效果优于全长gp96。
实施例8:突变多肽片段在治疗1型糖尿病中的应用
1、突变多肽片段的表达
将上述Peptide 1和Peptide 15多肽随机选取三个氨基酸位点突变为丙氨酸(Ala),分别记做Peptide 1m-1(SEQ ID NO:55)、Peptide 1m-2(SEQ ID NO:56)、Peptide15m-1(SEQ ID NO:59)、Peptide 15m-2(SEQ ID NO:60),再将Peptide 1、Peptide 15中三个氨基酸位点缺失,分别记做Peptide 1d-1(SEQ ID NO:57)、Peptide 1d-2(SEQ ID NO:58)、Peptide15d-1(SEQ ID NO:61)、Peptide15d-2(SEQ ID NO:62)。在以上各蛋白或多肽的C端添加6xHis标签。重组质粒由金斯瑞生物科技股份有限公司合成,然后按实施例1进行多肽的表达和纯化。
2、小鼠免疫
将60只六周龄体重为14~16g的NOD小鼠治疗模型随机分成Peptide 1、Peptide1m-1、Peptide 1m-2、Peptide 1d-1、Peptide 1d-2、Peptide 15、Peptide 15m-1、Peptide15m-2、Peptide 15d-1、Peptide 15d-2多肽免疫组(每组10只),分别进行如下处理:小鼠生长至第14周龄、第15周龄、第17周龄、第19周龄、第21周龄时,分别在小鼠腹部皮下注射按实施例1方法制备的多肽,每次注射剂量/只小鼠为300μg。
3、效果评价
Peptide 1氨基酸缺失和替换突变多肽免疫小鼠血糖浓度检测结果见图14,结果表明,突变的多肽免疫后小鼠的血糖浓度与未突变多肽没有明显区别,说明突变多肽和未突变多肽具有相同的治疗功能。
Peptide 15氨基酸缺失和替换突变多肽免疫小鼠血糖浓度检测结果见图15,结果表明,突变后的多肽免疫后小鼠的血糖浓度与未突变多肽没有明显区别,说明某些突变多肽和未突变多肽具有相同的治疗功能。
上述结果表明,本发明的多肽能够在一定程度上耐受氨基酸突变,维持其治疗自身免疫性疾病的活性。
实施例9:基于gp96蛋白的C端结构域的不同截短体在治疗诱导性小鼠关节炎症中的应用
1、小鼠分组免疫
将310只六周龄体重为14~16g的雌性DBA/1小鼠(北京维通利华实验动物技术有限公司)随机分成Peptide 1、Peptide 2、Peptide 3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽、全长gp96免疫组、对照组(PBS)和模型组(每组10只),除10只正常对照组外,其余300只小鼠进行CIA造模。将10mg牛Ⅱ型胶原溶于0.01mmol/L的醋酸溶液5mL,4℃摇床过夜,取5mL含2mg/mL的完全弗氏佐剂等体积混合,充分乳化制得抗原乳剂,并置于冰箱4℃保存备用。首次免疫于小鼠尾根部皮下注射抗原乳剂0.1mL,造模第21天使用0.1mLⅡ型胶原和不完全弗氏佐剂混合的乳剂进行加强免疫一次,正常组同法注射等体积的生理盐水。二次免疫后的第8天分别进行如下处理:小鼠生长至第10周龄、第11周龄、第13周龄,分别在小鼠腹部皮下注射实施例1和实施例3制备的重组多肽、全长gp96或PBS,每次注射剂量/只小鼠为100μg、300μg或500μg。
指标检测,关节炎指数:小鼠给药后第0、5、10、15、20、25、30天给予关节炎症指数评分,评分标准:0分:没有明显的关节红肿;1分:踝关节或趾关节轻度红肿;2分:从趾关节到踝关节轻度红肿;3分:从趾关节到踝关节中度红胀;4分:严重的踝关节到整个足掌的红肿,每只小鼠最高评分16分。足掌厚度:小鼠给药后第0、5、10、15、20、25、30天给予选取肿胀的足掌给予测肿胀的厚度,用游标卡尺选取肿胀最甚处测量,单位为mm。
2、效果评价
小鼠关节炎症指数结果见图16,结果表明,Peptide 1、Peptide 2、Peptide 3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽免疫后小鼠的关节炎症指数显著低于模型组(P<0.001),同时也低于全长gp96治疗组(P<0.05)。此外,足掌厚度的检测结果显示,Peptide 1、Peptide 2、Peptide 3、Peptide 4、Peptide 8、Peptide 13、Peptide 14、Peptide 15多肽免疫后小鼠的足掌厚度显著低于模型组(P<0.001),同时也低于全长gp96治疗组(P<0.05)。注射剂量为100μg或500μg的小鼠治疗类风湿也得到类似的治疗结果。上述结果表明,用多肽免疫小鼠,能够有效的治疗小鼠的诱导性关节炎症,其治疗效果优于全长gp96。
尽管本发明的具体实施方式已经得到详细的描述,但本领域技术人员将理解:根据已经公布的所有教导,可以对细节进行各种修改和变动,并且这些改变均在本发明的保护范围之内。本发明的全部分为由所附权利要求及其任何等同物给出。
SEQUENCE LISTING
<110> 佛山热休生物技术有限公司
<120> 用于治疗自身免疫性疾病的多肽
<130> IDC200566
<160> 63
<170> PatentIn version 3.5
<210> 1
<211> 2412
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码全长gp96的核苷酸序列
<400> 1
atgagggccc tgtgggtgct gggcctctgc tgcgtcctgc tgaccttcgg gtcggtcaga 60
gctgacgatg aagttgatgt ggatggtaca gtagaagagg atctgggtaa aagtagagaa 120
ggatcaagga cggatgatga agtagtacag agagaggaag aagctattca gttggatgga 180
ttaaatgcat cacaaataag agaacttaga gagaagtcgg aaaagtttgc cttccaagcc 240
gaagttaaca gaatgatgaa acttatcatc aattcattgt ataaaaataa agagattttc 300
ctgagagaac tgatttcaaa tgcttctgat gctttagata agataaggct aatatcactg 360
actgatgaaa atgctctttc tggaaatgag gaactaacag tcaaaattaa gtgtgataag 420
gagaagaacc tgctgcatgt cacagacacc ggtgtaggaa tgaccagaga agagttggtt 480
aaaaaccttg gtaccatagc caaatctggg acaagcgagt ttttaaacaa aatgactgaa 540
gcacaggaag atggccagtc aacttctgaa ttgattggcc agtttggtgt cggtttctat 600
tccgccttcc ttgtagcaga taaggttatt gtcacttcaa aacacaacaa cgatacccag 660
cacatctggg agtctgactc caatgaattt tctgtaattg ctgacccaag aggaaacact 720
ctaggacggg gaacgacaat tacccttgtc ttaaaagaag aagcatctga ttaccttgaa 780
ttggatacaa ttaaaaatct cgtcaaaaaa tattcacagt tcataaactt tcctatttat 840
gtatggagca gcaagactga aactgttgag gagcccatgg aggaagaaga agcagccaaa 900
gaagagaaag aagaatctga tgatgaagct gcagtagagg aagaagaaga agaaaagaaa 960
ccaaagacta aaaaagttga aaaaactgtc tgggactggg aacttatgaa tgatatcaaa 1020
ccaatatggc agagaccatc aaaagaagta gaagaagatg aatacaaagc tttctacaaa 1080
tcattttcaa aggaaagtga tgaccccatg gcttatattc actttactgc tgaaggggaa 1140
gttaccttca aatcaatttt atttgtaccc acatctgctc cacgtggtct gtttgacgaa 1200
tatggatcta aaaagagcga ttacattaag ctctatgtgc gccgtgtatt catcacagac 1260
gacttccatg atatgatgcc taaatacctc aattttgtca agggtgtggt ggactcagat 1320
gatctcccct tgaatgtttc ccgcgagact cttcagcaac ataaactgct taaggtgatt 1380
aggaagaagc ttgttcgtaa aacgctggac atgatcaaga agattgctga tgataaatac 1440
aatgatactt tttggaaaga atttggtacc aacatcaagc ttggtgtgat tgaagaccac 1500
tcgaatcgaa cacgtcttgc taaacttctt aggttccagt cttctcatca tccaactgac 1560
attactagcc tagaccagta tgtggaaaga atgaaggaaa aacaagacaa aatctacttc 1620
atggctgggt ccagcagaaa agaggctgaa tcttctccat ttgttgagcg acttctgaaa 1680
aagggctatg aagttattta cctcacagaa cctgtggatg aatactgtat tcaggccctt 1740
cccgaatttg atgggaagag gttccagaat gttgccaagg aaggagtgaa gttcgatgaa 1800
agtgagaaaa ctaaggagag tcgtgaagca gttgagaaag aatttgagcc tctgctgaat 1860
tggatgaaag ataaagccct taaggacaag attgaaaagg ctgtggtgtc tcagcgcctg 1920
acagaatctc cgtgtgcttt ggtggccagc cagtacggat ggtctggcaa catggagaga 1980
atcatgaaag cacaagcgta ccaaacgggc aaggacatct ctacaaatta ctatgcgagt 2040
cagaagaaaa catttgaaat taatcccaga cacccgctga tcagagacat gcttcgacga 2100
attaaggaag atgaagatga taaaacagtt ttggatcttg ctgtggtttt gtttgaaaca 2160
gcaacgcttc ggtcagggta tcttttacca gacactaaag catatggaga tagaatagaa 2220
agaatgcttc gcctcagttt gaacattgac cctgatgcaa aggtggaaga agagcccgaa 2280
gaagaacctg aagagacagc agaagacaca acagaagaca cagagcaaga cgaagatgaa 2340
gaaatggatg tgggaacaga tgaagaagaa gaaacagcaa aggaatctac agctgaaaaa 2400
gatgaattgt aa 2412
<210> 2
<211> 93
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码gp96-N的核苷酸序列
<400> 2
atggaatcct cccccttcgt ggagcgtctg ctcaagaagg gctacgaagt gatctatctg 60
accgaacccg tggacgagta ttgcatccaa taa 93
<210> 3
<211> 498
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码gp96-N+M的核苷酸序列
<400> 3
atggaatcct cccccttcgt ggagcgtctg ctcaagaagg gctacgaagt gatctatctg 60
accgaacccg tggacgagta ttgcatccaa gctctccccg agttcgatgg caagcgcttc 120
cagaacgtgg ccaaggaggg cgtcaaattc gatgagagcg agaagaccaa ggagagccgc 180
gaagccgtgg agaaagagtt tgagcctctg ctcaactgga tgaaagacaa ggccctcaaa 240
gacaagatcg aaaaggccgt ggtgtcccag cgtctcactg aaagcccttg cgctctggtg 300
gccagccagt acggttggag cggcaatatg gagcgtatca tgaaggctca agcttaccaa 360
accggcaagg acatctccac caactactac gcctcccaaa agaagacctt cgagatcaac 420
cctcgccatc ctctgatccg cgatatgctg cgccgtatca aggaagatga ggacgacaag 480
accgtgctgg acctctaa 498
<210> 4
<211> 414
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码gp96-M的核苷酸序列
<400> 4
atgcaagctc tccccgagtt cgatggcaag cgcttccaga acgtggccaa ggagggcgtc 60
aaattcgatg agagcgagaa gaccaaggag agccgcgaag ccgtggagaa agagtttgag 120
cctctgctca actggatgaa agacaaggcc ctcaaagaca agatcgaaaa ggccgtggtg 180
tcccagcgtc tcactgaaag cccttgcgct ctggtggcca gccagtacgg ttggagcggc 240
aatatggagc gtatcatgaa ggctcaagct taccaaaccg gcaaggacat ctccaccaac 300
tactacgcct cccaaaagaa gaccttcgag atcaaccctc gccatcctct gatccgcgat 360
atgctgcgcc gtatcaagga agatgaggac gacaagaccg tgctggacct ctaa 414
<210> 5
<211> 276
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码gp96-C的核苷酸序列
<400> 5
atggctgtgg tgctgttcga gaccgccact ctgcgctccg gttatctgct ccccgacacc 60
aaggcctacg gcgatcgtat tgagcgtatg ctgcgtctgt ctctgaatat cgaccccgac 120
gccaaggtgg aggaagaacc cgaggaagaa cccgaggaga ccgctgaaga taccaccgag 180
gacactgaac aagacgaaga cgaggagatg gatgtgggta ccgacgagga ggaagagact 240
gctaaggaat ccaccgccga gaaggacgag ctgtaa 276
<210> 6
<211> 684
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码gp96-C+M的核苷酸序列
<400> 6
atgcaagctc tccccgagtt cgatggcaag cgcttccaga acgtggccaa ggagggcgtc 60
aaattcgatg agagcgagaa gaccaaggag agccgcgaag ccgtggagaa agagtttgag 120
cctctgctca actggatgaa agacaaggcc ctcaaagaca agatcgaaaa ggccgtggtg 180
tcccagcgtc tcactgaaag cccttgcgct ctggtggcca gccagtacgg ttggagcggc 240
aatatggagc gtatcatgaa ggctcaagct taccaaaccg gcaaggacat ctccaccaac 300
tactacgcct cccaaaagaa gaccttcgag atcaaccctc gccatcctct gatccgcgat 360
atgctgcgcc gtatcaagga agatgaggac gacaagaccg tgctggacct cgctgtggtg 420
ctgttcgaga ccgccactct gcgctccggt tatctgctcc ccgacaccaa ggcctacggc 480
gatcgtattg agcgtatgct gcgtctgtct ctgaatatcg accccgacgc caaggtggag 540
gaagaacccg aggaagaacc cgaggagacc gctgaagata ccaccgagga cactgaacaa 600
gacgaagacg aggagatgga tgtgggtacc gacgaggagg aagagactgc taaggaatcc 660
accgccgaga aggacgagct gtaa 684
<210> 7
<211> 803
<212> PRT
<213> Artificial Sequence
<220>
<223> 全长gp96氨基酸序列
<400> 7
Met Arg Ala Leu Trp Val Leu Gly Leu Cys Cys Val Leu Leu Thr Phe
1 5 10 15
Gly Ser Val Arg Ala Asp Asp Glu Val Asp Val Asp Gly Thr Val Glu
20 25 30
Glu Asp Leu Gly Lys Ser Arg Glu Gly Ser Arg Thr Asp Asp Glu Val
35 40 45
Val Gln Arg Glu Glu Glu Ala Ile Gln Leu Asp Gly Leu Asn Ala Ser
50 55 60
Gln Ile Arg Glu Leu Arg Glu Lys Ser Glu Lys Phe Ala Phe Gln Ala
65 70 75 80
Glu Val Asn Arg Met Met Lys Leu Ile Ile Asn Ser Leu Tyr Lys Asn
85 90 95
Lys Glu Ile Phe Leu Arg Glu Leu Ile Ser Asn Ala Ser Asp Ala Leu
100 105 110
Asp Lys Ile Arg Leu Ile Ser Leu Thr Asp Glu Asn Ala Leu Ser Gly
115 120 125
Asn Glu Glu Leu Thr Val Lys Ile Lys Cys Asp Lys Glu Lys Asn Leu
130 135 140
Leu His Val Thr Asp Thr Gly Val Gly Met Thr Arg Glu Glu Leu Val
145 150 155 160
Lys Asn Leu Gly Thr Ile Ala Lys Ser Gly Thr Ser Glu Phe Leu Asn
165 170 175
Lys Met Thr Glu Ala Gln Glu Asp Gly Gln Ser Thr Ser Glu Leu Ile
180 185 190
Gly Gln Phe Gly Val Gly Phe Tyr Ser Ala Phe Leu Val Ala Asp Lys
195 200 205
Val Ile Val Thr Ser Lys His Asn Asn Asp Thr Gln His Ile Trp Glu
210 215 220
Ser Asp Ser Asn Glu Phe Ser Val Ile Ala Asp Pro Arg Gly Asn Thr
225 230 235 240
Leu Gly Arg Gly Thr Thr Ile Thr Leu Val Leu Lys Glu Glu Ala Ser
245 250 255
Asp Tyr Leu Glu Leu Asp Thr Ile Lys Asn Leu Val Lys Lys Tyr Ser
260 265 270
Gln Phe Ile Asn Phe Pro Ile Tyr Val Trp Ser Ser Lys Thr Glu Thr
275 280 285
Val Glu Glu Pro Met Glu Glu Glu Glu Ala Ala Lys Glu Glu Lys Glu
290 295 300
Glu Ser Asp Asp Glu Ala Ala Val Glu Glu Glu Glu Glu Glu Lys Lys
305 310 315 320
Pro Lys Thr Lys Lys Val Glu Lys Thr Val Trp Asp Trp Glu Leu Met
325 330 335
Asn Asp Ile Lys Pro Ile Trp Gln Arg Pro Ser Lys Glu Val Glu Glu
340 345 350
Asp Glu Tyr Lys Ala Phe Tyr Lys Ser Phe Ser Lys Glu Ser Asp Asp
355 360 365
Pro Met Ala Tyr Ile His Phe Thr Ala Glu Gly Glu Val Thr Phe Lys
370 375 380
Ser Ile Leu Phe Val Pro Thr Ser Ala Pro Arg Gly Leu Phe Asp Glu
385 390 395 400
Tyr Gly Ser Lys Lys Ser Asp Tyr Ile Lys Leu Tyr Val Arg Arg Val
405 410 415
Phe Ile Thr Asp Asp Phe His Asp Met Met Pro Lys Tyr Leu Asn Phe
420 425 430
Val Lys Gly Val Val Asp Ser Asp Asp Leu Pro Leu Asn Val Ser Arg
435 440 445
Glu Thr Leu Gln Gln His Lys Leu Leu Lys Val Ile Arg Lys Lys Leu
450 455 460
Val Arg Lys Thr Leu Asp Met Ile Lys Lys Ile Ala Asp Asp Lys Tyr
465 470 475 480
Asn Asp Thr Phe Trp Lys Glu Phe Gly Thr Asn Ile Lys Leu Gly Val
485 490 495
Ile Glu Asp His Ser Asn Arg Thr Arg Leu Ala Lys Leu Leu Arg Phe
500 505 510
Gln Ser Ser His His Pro Thr Asp Ile Thr Ser Leu Asp Gln Tyr Val
515 520 525
Glu Arg Met Lys Glu Lys Gln Asp Lys Ile Tyr Phe Met Ala Gly Ser
530 535 540
Ser Arg Lys Glu Ala Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys
545 550 555 560
Lys Gly Tyr Glu Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys
565 570 575
Ile Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala
580 585 590
Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg
595 600 605
Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp
610 615 620
Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu
625 630 635 640
Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly
645 650 655
Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp
660 665 670
Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn
675 680 685
Pro Arg His Pro Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp
690 695 700
Glu Asp Asp Lys Thr Val Leu Asp Leu Ala Val Val Leu Phe Glu Thr
705 710 715 720
Ala Thr Leu Arg Ser Gly Tyr Leu Leu Pro Asp Thr Lys Ala Tyr Gly
725 730 735
Asp Arg Ile Glu Arg Met Leu Arg Leu Ser Leu Asn Ile Asp Pro Asp
740 745 750
Ala Lys Val Glu Glu Glu Pro Glu Glu Glu Pro Glu Glu Thr Ala Glu
755 760 765
Asp Thr Thr Glu Asp Thr Glu Gln Asp Glu Asp Glu Glu Met Asp Val
770 775 780
Gly Thr Asp Glu Glu Glu Glu Thr Ala Lys Glu Ser Thr Ala Glu Lys
785 790 795 800
Asp Glu Leu
<210> 8
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> gp96-N氨基酸序列
<400> 8
Met Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys Lys Gly Tyr Glu
1 5 10 15
Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys Ile Gln
20 25 30
<210> 9
<211> 165
<212> PRT
<213> Artificial Sequence
<220>
<223> gp96-N+M氨基酸序列
<400> 9
Met Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys Lys Gly Tyr Glu
1 5 10 15
Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys Ile Gln Ala Leu
20 25 30
Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala Lys Glu Gly Val
35 40 45
Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg Glu Ala Val Glu
50 55 60
Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp Lys Ala Leu Lys
65 70 75 80
Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu Thr Glu Ser Pro
85 90 95
Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly Asn Met Glu Arg
100 105 110
Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp Ile Ser Thr Asn
115 120 125
Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn Pro Arg His Pro
130 135 140
Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp Glu Asp Asp Lys
145 150 155 160
Thr Val Leu Asp Leu
165
<210> 10
<211> 137
<212> PRT
<213> Artificial Sequence
<220>
<223> gp96-M氨基酸序列
<400> 10
Met Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala
1 5 10 15
Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg
20 25 30
Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp
35 40 45
Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu
50 55 60
Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly
65 70 75 80
Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp
85 90 95
Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn
100 105 110
Pro Arg His Pro Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp
115 120 125
Glu Asp Asp Lys Thr Val Leu Asp Leu
130 135
<210> 11
<211> 91
<212> PRT
<213> Artificial Sequence
<220>
<223> gp96-C氨基酸序列
<400> 11
Met Ala Val Val Leu Phe Glu Thr Ala Thr Leu Arg Ser Gly Tyr Leu
1 5 10 15
Leu Pro Asp Thr Lys Ala Tyr Gly Asp Arg Ile Glu Arg Met Leu Arg
20 25 30
Leu Ser Leu Asn Ile Asp Pro Asp Ala Lys Val Glu Glu Glu Pro Glu
35 40 45
Glu Glu Pro Glu Glu Thr Ala Glu Asp Thr Thr Glu Asp Thr Glu Gln
50 55 60
Asp Glu Asp Glu Glu Met Asp Val Gly Thr Asp Glu Glu Glu Glu Thr
65 70 75 80
Ala Lys Glu Ser Thr Ala Glu Lys Asp Glu Leu
85 90
<210> 12
<211> 227
<212> PRT
<213> Artificial Sequence
<220>
<223> gp96-C+M氨基酸序列
<400> 12
Met Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala
1 5 10 15
Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg
20 25 30
Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp
35 40 45
Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu
50 55 60
Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly
65 70 75 80
Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp
85 90 95
Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn
100 105 110
Pro Arg His Pro Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp
115 120 125
Glu Asp Asp Lys Thr Val Leu Asp Leu Ala Val Val Leu Phe Glu Thr
130 135 140
Ala Thr Leu Arg Ser Gly Tyr Leu Leu Pro Asp Thr Lys Ala Tyr Gly
145 150 155 160
Asp Arg Ile Glu Arg Met Leu Arg Leu Ser Leu Asn Ile Asp Pro Asp
165 170 175
Ala Lys Val Glu Glu Glu Pro Glu Glu Glu Pro Glu Glu Thr Ala Glu
180 185 190
Asp Thr Thr Glu Asp Thr Glu Gln Asp Glu Asp Glu Glu Met Asp Val
195 200 205
Gly Thr Asp Glu Glu Glu Glu Thr Ala Lys Glu Ser Thr Ala Glu Lys
210 215 220
Asp Glu Leu
225
<210> 13
<211> 768
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 1的核苷酸序列
<400> 13
atggaatcct cccccttcgt ggagcgtctg ctcaagaagg gctacgaagt gatctatctg 60
accgaacccg tggacgagta ttgcatccaa gctctccccg agttcgatgg caagcgcttc 120
cagaacgtgg ccaaggaggg cgtcaaattc gatgagagcg agaagaccaa ggagagccgc 180
gaagccgtgg agaaagagtt tgagcctctg ctcaactgga tgaaagacaa ggccctcaaa 240
gacaagatcg aaaaggccgt ggtgtcccag cgtctcactg aaagcccttg cgctctggtg 300
gccagccagt acggttggag cggcaatatg gagcgtatca tgaaggctca agcttaccaa 360
accggcaagg acatctccac caactactac gcctcccaaa agaagacctt cgagatcaac 420
cctcgccatc ctctgatccg cgatatgctg cgccgtatca aggaagatga ggacgacaag 480
accgtgctgg acctcgctgt ggtgctgttc gagaccgcca ctctgcgctc cggttatctg 540
ctccccgaca ccaaggccta cggcgatcgt attgagcgta tgctgcgtct gtctctgaat 600
atcgaccccg acgccaaggt ggaggaagaa cccgaggaag aacccgagga gaccgctgaa 660
gataccaccg aggacactga acaagacgaa gacgaggaga tggatgtggg taccgacgag 720
gaggaagaga ctgctaagga atccaccgcc gagaaggacg agctgtaa 768
<210> 14
<211> 678
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 2的核苷酸序列
<400> 14
atggaatcct cccccttcgt ggagcgtctg ctcaagaagg gctacgaagt gatctatctg 60
accgaacccg tggacgagta ttgcatccaa gctctccccg agttcgatgg caagcgcttc 120
cagaacgtgg ccaaggaggg cgtcaaattc gatgagagcg agaagaccaa ggagagccgc 180
gaagccgtgg agaaagagtt tgagcctctg ctcaactgga tgaaagacaa ggccctcaaa 240
gacaagatcg aaaaggccgt ggtgtcccag cgtctcactg aaagcccttg cgctctggtg 300
gccagccagt acggttggag cggcaatatg gagcgtatca tgaaggctca agcttaccaa 360
accggcaagg acatctccac caactactac gcctcccaaa agaagacctt cgagatcaac 420
cctcgccatc ctctgatccg cgatatgctg cgccgtatca aggaagatga ggacgacaag 480
accgtgctgg acctcgctgt ggtgctgttc gagaccgcca ctctgcgctc cggttatctg 540
ctccccgaca ccaaggccta cggcgatcgt attgagcgta tgctgcgtct gtctctgaat 600
atcgaccccg acgccaaggt ggaggaagaa cccgaggaag aacccgagga gaccgctgaa 660
gataccaccg aggactaa 678
<210> 15
<211> 588
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 3的核苷酸序列
<400> 15
atggaatcct cccccttcgt ggagcgtctg ctcaagaagg gctacgaagt gatctatctg 60
accgaacccg tggacgagta ttgcatccaa gctctccccg agttcgatgg caagcgcttc 120
cagaacgtgg ccaaggaggg cgtcaaattc gatgagagcg agaagaccaa ggagagccgc 180
gaagccgtgg agaaagagtt tgagcctctg ctcaactgga tgaaagacaa ggccctcaaa 240
gacaagatcg aaaaggccgt ggtgtcccag cgtctcactg aaagcccttg cgctctggtg 300
gccagccagt acggttggag cggcaatatg gagcgtatca tgaaggctca agcttaccaa 360
accggcaagg acatctccac caactactac gcctcccaaa agaagacctt cgagatcaac 420
cctcgccatc ctctgatccg cgatatgctg cgccgtatca aggaagatga ggacgacaag 480
accgtgctgg acctcgctgt ggtgctgttc gagaccgcca ctctgcgctc cggttatctg 540
ctccccgaca ccaaggccta cggcgatcgt attgagcgta tgctgtaa 588
<210> 16
<211> 498
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 4的核苷酸序列
<400> 16
atggaatcct cccccttcgt ggagcgtctg ctcaagaagg gctacgaagt gatctatctg 60
accgaacccg tggacgagta ttgcatccaa gctctccccg agttcgatgg caagcgcttc 120
cagaacgtgg ccaaggaggg cgtcaaattc gatgagagcg agaagaccaa ggagagccgc 180
gaagccgtgg agaaagagtt tgagcctctg ctcaactgga tgaaagacaa ggccctcaaa 240
gacaagatcg aaaaggccgt ggtgtcccag cgtctcactg aaagcccttg cgctctggtg 300
gccagccagt acggttggag cggcaatatg gagcgtatca tgaaggctca agcttaccaa 360
accggcaagg acatctccac caactactac gcctcccaaa agaagacctt cgagatcaac 420
cctcgccatc ctctgatccg cgatatgctg cgccgtatca aggaagatga ggacgacaag 480
accgtgctgg acctctaa 498
<210> 17
<211> 408
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 5的核苷酸序列
<400> 17
atggaatcct cccccttcgt ggagcgtctg ctcaagaagg gctacgaagt gatctatctg 60
accgaacccg tggacgagta ttgcatccaa gctctccccg agttcgatgg caagcgcttc 120
cagaacgtgg ccaaggaggg cgtcaaattc gatgagagcg agaagaccaa ggagagccgc 180
gaagccgtgg agaaagagtt tgagcctctg ctcaactgga tgaaagacaa ggccctcaaa 240
gacaagatcg aaaaggccgt ggtgtcccag cgtctcactg aaagcccttg cgctctggtg 300
gccagccagt acggttggag cggcaatatg gagcgtatca tgaaggctca agcttaccaa 360
accggcaagg acatctccac caactactac gcctcccaaa agaagtaa 408
<210> 18
<211> 318
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 6的核苷酸序列
<400> 18
atggaatcct cccccttcgt ggagcgtctg ctcaagaagg gctacgaagt gatctatctg 60
accgaacccg tggacgagta ttgcatccaa gctctccccg agttcgatgg caagcgcttc 120
cagaacgtgg ccaaggaggg cgtcaaattc gatgagagcg agaagaccaa ggagagccgc 180
gaagccgtgg agaaagagtt tgagcctctg ctcaactgga tgaaagacaa ggccctcaaa 240
gacaagatcg aaaaggccgt ggtgtcccag cgtctcactg aaagcccttg cgctctggtg 300
gccagccagt acggttaa 318
<210> 19
<211> 228
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 7的核苷酸序列
<400> 19
atggaacccg tggacgagta ttgcatccaa gctctccccg agttcgatgg caagcgcttc 60
cagaacgtgg ccaaggaggg cgtcaaattc gatgagagcg agaagaccaa ggagagccgc 120
gaagccgtgg agaaagagtt tgagcctctg ctcaactgga tgaaagacaa ggccctcaaa 180
gacaagatcg aaaaggccgt ggtgtcccag cgtctcactg aaagctaa 228
<210> 20
<211> 684
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 8的核苷酸序列
<400> 20
atgcaagctc tccccgagtt cgatggcaag cgcttccaga acgtggccaa ggagggcgtc 60
aaattcgatg agagcgagaa gaccaaggag agccgcgaag ccgtggagaa agagtttgag 120
cctctgctca actggatgaa agacaaggcc ctcaaagaca agatcgaaaa ggccgtggtg 180
tcccagcgtc tcactgaaag cccttgcgct ctggtggcca gccagtacgg ttggagcggc 240
aatatggagc gtatcatgaa ggctcaagct taccaaaccg gcaaggacat ctccaccaac 300
tactacgcct cccaaaagaa gaccttcgag atcaaccctc gccatcctct gatccgcgat 360
atgctgcgcc gtatcaagga agatgaggac gacaagaccg tgctggacct cgctgtggtg 420
ctgttcgaga ccgccactct gcgctccggt tatctgctcc ccgacaccaa ggcctacggc 480
gatcgtattg agcgtatgct gcgtctgtct ctgaatatcg accccgacgc caaggtggag 540
gaagaacccg aggaagaacc cgaggagacc gctgaagata ccaccgagga cactgaacaa 600
gacgaagacg aggagatgga tgtgggtacc gacgaggagg aagagactgc taaggaatcc 660
accgccgaga aggacgagct gtaa 684
<210> 21
<211> 594
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 9的核苷酸序列
<400> 21
atgcgcgaag ccgtggagaa agagtttgag cctctgctca actggatgaa agacaaggcc 60
ctcaaagaca agatcgaaaa ggccgtggtg tcccagcgtc tcactgaaag cccttgcgct 120
ctggtggcca gccagtacgg ttggagcggc aatatggagc gtatcatgaa ggctcaagct 180
taccaaaccg gcaaggacat ctccaccaac tactacgcct cccaaaagaa gaccttcgag 240
atcaaccctc gccatcctct gatccgcgat atgctgcgcc gtatcaagga agatgaggac 300
gacaagaccg tgctggacct cgctgtggtg ctgttcgaga ccgccactct gcgctccggt 360
tatctgctcc ccgacaccaa ggcctacggc gatcgtattg agcgtatgct gcgtctgtct 420
ctgaatatcg accccgacgc caaggtggag gaagaacccg aggaagaacc cgaggagacc 480
gctgaagata ccaccgagga cactgaacaa gacgaagacg aggagatgga tgtgggtacc 540
gacgaggagg aagagactgc taaggaatcc accgccgaga aggacgagct gtaa 594
<210> 22
<211> 504
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 10的核苷酸序列
<400> 22
atgcagcgtc tcactgaaag cccttgcgct ctggtggcca gccagtacgg ttggagcggc 60
aatatggagc gtatcatgaa ggctcaagct taccaaaccg gcaaggacat ctccaccaac 120
tactacgcct cccaaaagaa gaccttcgag atcaaccctc gccatcctct gatccgcgat 180
atgctgcgcc gtatcaagga agatgaggac gacaagaccg tgctggacct cgctgtggtg 240
ctgttcgaga ccgccactct gcgctccggt tatctgctcc ccgacaccaa ggcctacggc 300
gatcgtattg agcgtatgct gcgtctgtct ctgaatatcg accccgacgc caaggtggag 360
gaagaacccg aggaagaacc cgaggagacc gctgaagata ccaccgagga cactgaacaa 420
gacgaagacg aggagatgga tgtgggtacc gacgaggagg aagagactgc taaggaatcc 480
accgccgaga aggacgagct gtaa 504
<210> 23
<211> 414
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 11的核苷酸序列
<400> 23
atgcaaaccg gcaaggacat ctccaccaac tactacgcct cccaaaagaa gaccttcgag 60
atcaaccctc gccatcctct gatccgcgat atgctgcgcc gtatcaagga agatgaggac 120
gacaagaccg tgctggacct cgctgtggtg ctgttcgaga ccgccactct gcgctccggt 180
tatctgctcc ccgacaccaa ggcctacggc gatcgtattg agcgtatgct gcgtctgtct 240
ctgaatatcg accccgacgc caaggtggag gaagaacccg aggaagaacc cgaggagacc 300
gctgaagata ccaccgagga cactgaacaa gacgaagacg aggagatgga tgtgggtacc 360
gacgaggagg aagagactgc taaggaatcc accgccgaga aggacgagct gtaa 414
<210> 24
<211> 324
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 12的核苷酸序列
<400> 24
atgctgcgcc gtatcaagga agatgaggac gacaagaccg tgctggacct cgctgtggtg 60
ctgttcgaga ccgccactct gcgctccggt tatctgctcc ccgacaccaa ggcctacggc 120
gatcgtattg agcgtatgct gcgtctgtct ctgaatatcg accccgacgc caaggtggag 180
gaagaacccg aggaagaacc cgaggagacc gctgaagata ccaccgagga cactgaacaa 240
gacgaagacg aggagatgga tgtgggtacc gacgaggagg aagagactgc taaggaatcc 300
accgccgaga aggacgagct gtaa 324
<210> 25
<211> 594
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 13的核苷酸序列
<400> 25
atgcaagctc tccccgagtt cgatggcaag cgcttccaga acgtggccaa ggagggcgtc 60
aaattcgatg agagcgagaa gaccaaggag agccgcgaag ccgtggagaa agagtttgag 120
cctctgctca actggatgaa agacaaggcc ctcaaagaca agatcgaaaa ggccgtggtg 180
tcccagcgtc tcactgaaag cccttgcgct ctggtggcca gccagtacgg ttggagcggc 240
aatatggagc gtatcatgaa ggctcaagct taccaaaccg gcaaggacat ctccaccaac 300
tactacgcct cccaaaagaa gaccttcgag atcaaccctc gccatcctct gatccgcgat 360
atgctgcgcc gtatcaagga agatgaggac gacaagaccg tgctggacct cgctgtggtg 420
ctgttcgaga ccgccactct gcgctccggt tatctgctcc ccgacaccaa ggcctacggc 480
gatcgtattg agcgtatgct gcgtctgtct ctgaatatcg accccgacgc caaggtggag 540
gaagaacccg aggaagaacc cgaggagacc gctgaagata ccaccgagga ctaa 594
<210> 26
<211> 504
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 14的核苷酸序列
<400> 26
atgcaagctc tccccgagtt cgatggcaag cgcttccaga acgtggccaa ggagggcgtc 60
aaattcgatg agagcgagaa gaccaaggag agccgcgaag ccgtggagaa agagtttgag 120
cctctgctca actggatgaa agacaaggcc ctcaaagaca agatcgaaaa ggccgtggtg 180
tcccagcgtc tcactgaaag cccttgcgct ctggtggcca gccagtacgg ttggagcggc 240
aatatggagc gtatcatgaa ggctcaagct taccaaaccg gcaaggacat ctccaccaac 300
tactacgcct cccaaaagaa gaccttcgag atcaaccctc gccatcctct gatccgcgat 360
atgctgcgcc gtatcaagga agatgaggac gacaagaccg tgctggacct cgctgtggtg 420
ctgttcgaga ccgccactct gcgctccggt tatctgctcc ccgacaccaa ggcctacggc 480
gatcgtattg agcgtatgct gtaa 504
<210> 27
<211> 414
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 15的核苷酸序列
<400> 27
atgcaagctc tccccgagtt cgatggcaag cgcttccaga acgtggccaa ggagggcgtc 60
aaattcgatg agagcgagaa gaccaaggag agccgcgaag ccgtggagaa agagtttgag 120
cctctgctca actggatgaa agacaaggcc ctcaaagaca agatcgaaaa ggccgtggtg 180
tcccagcgtc tcactgaaag cccttgcgct ctggtggcca gccagtacgg ttggagcggc 240
aatatggagc gtatcatgaa ggctcaagct taccaaaccg gcaaggacat ctccaccaac 300
tactacgcct cccaaaagaa gaccttcgag atcaaccctc gccatcctct gatccgcgat 360
atgctgcgcc gtatcaagga agatgaggac gacaagaccg tgctggacct ctaa 414
<210> 28
<211> 324
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 16的核苷酸序列
<400> 28
atgcaagctc tccccgagtt cgatggcaag cgcttccaga acgtggccaa ggagggcgtc 60
aaattcgatg agagcgagaa gaccaaggag agccgcgaag ccgtggagaa agagtttgag 120
cctctgctca actggatgaa agacaaggcc ctcaaagaca agatcgaaaa ggccgtggtg 180
tcccagcgtc tcactgaaag cccttgcgct ctggtggcca gccagtacgg ttggagcggc 240
aatatggagc gtatcatgaa ggctcaagct taccaaaccg gcaaggacat ctccaccaac 300
tactacgcct cccaaaagaa gtaa 324
<210> 29
<211> 234
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 17的核苷酸序列
<400> 29
atgcaagctc tccccgagtt cgatggcaag cgcttccaga acgtggccaa ggagggcgtc 60
aaattcgatg agagcgagaa gaccaaggag agccgcgaag ccgtggagaa agagtttgag 120
cctctgctca actggatgaa agacaaggcc ctcaaagaca agatcgaaaa ggccgtggtg 180
tcccagcgtc tcactgaaag cccttgcgct ctggtggcca gccagtacgg ttaa 234
<210> 30
<211> 255
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 1氨基酸序列
<400> 30
Met Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys Lys Gly Tyr Glu
1 5 10 15
Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys Ile Gln Ala Leu
20 25 30
Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala Lys Glu Gly Val
35 40 45
Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg Glu Ala Val Glu
50 55 60
Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp Lys Ala Leu Lys
65 70 75 80
Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu Thr Glu Ser Pro
85 90 95
Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly Asn Met Glu Arg
100 105 110
Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp Ile Ser Thr Asn
115 120 125
Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn Pro Arg His Pro
130 135 140
Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp Glu Asp Asp Lys
145 150 155 160
Thr Val Leu Asp Leu Ala Val Val Leu Phe Glu Thr Ala Thr Leu Arg
165 170 175
Ser Gly Tyr Leu Leu Pro Asp Thr Lys Ala Tyr Gly Asp Arg Ile Glu
180 185 190
Arg Met Leu Arg Leu Ser Leu Asn Ile Asp Pro Asp Ala Lys Val Glu
195 200 205
Glu Glu Pro Glu Glu Glu Pro Glu Glu Thr Ala Glu Asp Thr Thr Glu
210 215 220
Asp Thr Glu Gln Asp Glu Asp Glu Glu Met Asp Val Gly Thr Asp Glu
225 230 235 240
Glu Glu Glu Thr Ala Lys Glu Ser Thr Ala Glu Lys Asp Glu Leu
245 250 255
<210> 31
<211> 225
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 2氨基酸序列
<400> 31
Met Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys Lys Gly Tyr Glu
1 5 10 15
Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys Ile Gln Ala Leu
20 25 30
Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala Lys Glu Gly Val
35 40 45
Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg Glu Ala Val Glu
50 55 60
Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp Lys Ala Leu Lys
65 70 75 80
Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu Thr Glu Ser Pro
85 90 95
Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly Asn Met Glu Arg
100 105 110
Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp Ile Ser Thr Asn
115 120 125
Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn Pro Arg His Pro
130 135 140
Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp Glu Asp Asp Lys
145 150 155 160
Thr Val Leu Asp Leu Ala Val Val Leu Phe Glu Thr Ala Thr Leu Arg
165 170 175
Ser Gly Tyr Leu Leu Pro Asp Thr Lys Ala Tyr Gly Asp Arg Ile Glu
180 185 190
Arg Met Leu Arg Leu Ser Leu Asn Ile Asp Pro Asp Ala Lys Val Glu
195 200 205
Glu Glu Pro Glu Glu Glu Pro Glu Glu Thr Ala Glu Asp Thr Thr Glu
210 215 220
Asp
225
<210> 32
<211> 195
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 3氨基酸序列
<400> 32
Met Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys Lys Gly Tyr Glu
1 5 10 15
Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys Ile Gln Ala Leu
20 25 30
Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala Lys Glu Gly Val
35 40 45
Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg Glu Ala Val Glu
50 55 60
Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp Lys Ala Leu Lys
65 70 75 80
Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu Thr Glu Ser Pro
85 90 95
Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly Asn Met Glu Arg
100 105 110
Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp Ile Ser Thr Asn
115 120 125
Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn Pro Arg His Pro
130 135 140
Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp Glu Asp Asp Lys
145 150 155 160
Thr Val Leu Asp Leu Ala Val Val Leu Phe Glu Thr Ala Thr Leu Arg
165 170 175
Ser Gly Tyr Leu Leu Pro Asp Thr Lys Ala Tyr Gly Asp Arg Ile Glu
180 185 190
Arg Met Leu
195
<210> 33
<211> 165
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 4氨基酸序列
<400> 33
Met Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys Lys Gly Tyr Glu
1 5 10 15
Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys Ile Gln Ala Leu
20 25 30
Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala Lys Glu Gly Val
35 40 45
Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg Glu Ala Val Glu
50 55 60
Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp Lys Ala Leu Lys
65 70 75 80
Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu Thr Glu Ser Pro
85 90 95
Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly Asn Met Glu Arg
100 105 110
Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp Ile Ser Thr Asn
115 120 125
Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn Pro Arg His Pro
130 135 140
Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp Glu Asp Asp Lys
145 150 155 160
Thr Val Leu Asp Leu
165
<210> 34
<211> 135
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 5氨基酸序列
<400> 34
Met Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys Lys Gly Tyr Glu
1 5 10 15
Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys Ile Gln Ala Leu
20 25 30
Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala Lys Glu Gly Val
35 40 45
Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg Glu Ala Val Glu
50 55 60
Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp Lys Ala Leu Lys
65 70 75 80
Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu Thr Glu Ser Pro
85 90 95
Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly Asn Met Glu Arg
100 105 110
Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp Ile Ser Thr Asn
115 120 125
Tyr Tyr Ala Ser Gln Lys Lys
130 135
<210> 35
<211> 105
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 6氨基酸序列
<400> 35
Met Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys Lys Gly Tyr Glu
1 5 10 15
Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys Ile Gln Ala Leu
20 25 30
Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala Lys Glu Gly Val
35 40 45
Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg Glu Ala Val Glu
50 55 60
Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp Lys Ala Leu Lys
65 70 75 80
Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu Thr Glu Ser Pro
85 90 95
Cys Ala Leu Val Ala Ser Gln Tyr Gly
100 105
<210> 36
<211> 75
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 7氨基酸序列
<400> 36
Met Glu Pro Val Asp Glu Tyr Cys Ile Gln Ala Leu Pro Glu Phe Asp
1 5 10 15
Gly Lys Arg Phe Gln Asn Val Ala Lys Glu Gly Val Lys Phe Asp Glu
20 25 30
Ser Glu Lys Thr Lys Glu Ser Arg Glu Ala Val Glu Lys Glu Phe Glu
35 40 45
Pro Leu Leu Asn Trp Met Lys Asp Lys Ala Leu Lys Asp Lys Ile Glu
50 55 60
Lys Ala Val Val Ser Gln Arg Leu Thr Glu Ser
65 70 75
<210> 37
<211> 227
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 8氨基酸序列
<400> 37
Met Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala
1 5 10 15
Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg
20 25 30
Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp
35 40 45
Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu
50 55 60
Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly
65 70 75 80
Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp
85 90 95
Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn
100 105 110
Pro Arg His Pro Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp
115 120 125
Glu Asp Asp Lys Thr Val Leu Asp Leu Ala Val Val Leu Phe Glu Thr
130 135 140
Ala Thr Leu Arg Ser Gly Tyr Leu Leu Pro Asp Thr Lys Ala Tyr Gly
145 150 155 160
Asp Arg Ile Glu Arg Met Leu Arg Leu Ser Leu Asn Ile Asp Pro Asp
165 170 175
Ala Lys Val Glu Glu Glu Pro Glu Glu Glu Pro Glu Glu Thr Ala Glu
180 185 190
Asp Thr Thr Glu Asp Thr Glu Gln Asp Glu Asp Glu Glu Met Asp Val
195 200 205
Gly Thr Asp Glu Glu Glu Glu Thr Ala Lys Glu Ser Thr Ala Glu Lys
210 215 220
Asp Glu Leu
225
<210> 38
<211> 197
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 9氨基酸序列
<400> 38
Met Arg Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met
1 5 10 15
Lys Asp Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln
20 25 30
Arg Leu Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp
35 40 45
Ser Gly Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly
50 55 60
Lys Asp Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu
65 70 75 80
Ile Asn Pro Arg His Pro Leu Ile Arg Asp Met Leu Arg Arg Ile Lys
85 90 95
Glu Asp Glu Asp Asp Lys Thr Val Leu Asp Leu Ala Val Val Leu Phe
100 105 110
Glu Thr Ala Thr Leu Arg Ser Gly Tyr Leu Leu Pro Asp Thr Lys Ala
115 120 125
Tyr Gly Asp Arg Ile Glu Arg Met Leu Arg Leu Ser Leu Asn Ile Asp
130 135 140
Pro Asp Ala Lys Val Glu Glu Glu Pro Glu Glu Glu Pro Glu Glu Thr
145 150 155 160
Ala Glu Asp Thr Thr Glu Asp Thr Glu Gln Asp Glu Asp Glu Glu Met
165 170 175
Asp Val Gly Thr Asp Glu Glu Glu Glu Thr Ala Lys Glu Ser Thr Ala
180 185 190
Glu Lys Asp Glu Leu
195
<210> 39
<211> 167
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 10氨基酸序列
<400> 39
Met Gln Arg Leu Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr
1 5 10 15
Gly Trp Ser Gly Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln
20 25 30
Thr Gly Lys Asp Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr
35 40 45
Phe Glu Ile Asn Pro Arg His Pro Leu Ile Arg Asp Met Leu Arg Arg
50 55 60
Ile Lys Glu Asp Glu Asp Asp Lys Thr Val Leu Asp Leu Ala Val Val
65 70 75 80
Leu Phe Glu Thr Ala Thr Leu Arg Ser Gly Tyr Leu Leu Pro Asp Thr
85 90 95
Lys Ala Tyr Gly Asp Arg Ile Glu Arg Met Leu Arg Leu Ser Leu Asn
100 105 110
Ile Asp Pro Asp Ala Lys Val Glu Glu Glu Pro Glu Glu Glu Pro Glu
115 120 125
Glu Thr Ala Glu Asp Thr Thr Glu Asp Thr Glu Gln Asp Glu Asp Glu
130 135 140
Glu Met Asp Val Gly Thr Asp Glu Glu Glu Glu Thr Ala Lys Glu Ser
145 150 155 160
Thr Ala Glu Lys Asp Glu Leu
165
<210> 40
<211> 137
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 11氨基酸序列
<400> 40
Met Gln Thr Gly Lys Asp Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys
1 5 10 15
Lys Thr Phe Glu Ile Asn Pro Arg His Pro Leu Ile Arg Asp Met Leu
20 25 30
Arg Arg Ile Lys Glu Asp Glu Asp Asp Lys Thr Val Leu Asp Leu Ala
35 40 45
Val Val Leu Phe Glu Thr Ala Thr Leu Arg Ser Gly Tyr Leu Leu Pro
50 55 60
Asp Thr Lys Ala Tyr Gly Asp Arg Ile Glu Arg Met Leu Arg Leu Ser
65 70 75 80
Leu Asn Ile Asp Pro Asp Ala Lys Val Glu Glu Glu Pro Glu Glu Glu
85 90 95
Pro Glu Glu Thr Ala Glu Asp Thr Thr Glu Asp Thr Glu Gln Asp Glu
100 105 110
Asp Glu Glu Met Asp Val Gly Thr Asp Glu Glu Glu Glu Thr Ala Lys
115 120 125
Glu Ser Thr Ala Glu Lys Asp Glu Leu
130 135
<210> 41
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 12氨基酸序列
<400> 41
Met Leu Arg Arg Ile Lys Glu Asp Glu Asp Asp Lys Thr Val Leu Asp
1 5 10 15
Leu Ala Val Val Leu Phe Glu Thr Ala Thr Leu Arg Ser Gly Tyr Leu
20 25 30
Leu Pro Asp Thr Lys Ala Tyr Gly Asp Arg Ile Glu Arg Met Leu Arg
35 40 45
Leu Ser Leu Asn Ile Asp Pro Asp Ala Lys Val Glu Glu Glu Pro Glu
50 55 60
Glu Glu Pro Glu Glu Thr Ala Glu Asp Thr Thr Glu Asp Thr Glu Gln
65 70 75 80
Asp Glu Asp Glu Glu Met Asp Val Gly Thr Asp Glu Glu Glu Glu Thr
85 90 95
Ala Lys Glu Ser Thr Ala Glu Lys Asp Glu Leu
100 105
<210> 42
<211> 197
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 13氨基酸序列
<400> 42
Met Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala
1 5 10 15
Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg
20 25 30
Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp
35 40 45
Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu
50 55 60
Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly
65 70 75 80
Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp
85 90 95
Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn
100 105 110
Pro Arg His Pro Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp
115 120 125
Glu Asp Asp Lys Thr Val Leu Asp Leu Ala Val Val Leu Phe Glu Thr
130 135 140
Ala Thr Leu Arg Ser Gly Tyr Leu Leu Pro Asp Thr Lys Ala Tyr Gly
145 150 155 160
Asp Arg Ile Glu Arg Met Leu Arg Leu Ser Leu Asn Ile Asp Pro Asp
165 170 175
Ala Lys Val Glu Glu Glu Pro Glu Glu Glu Pro Glu Glu Thr Ala Glu
180 185 190
Asp Thr Thr Glu Asp
195
<210> 43
<211> 167
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 14氨基酸序列
<400> 43
Met Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala
1 5 10 15
Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg
20 25 30
Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp
35 40 45
Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu
50 55 60
Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly
65 70 75 80
Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp
85 90 95
Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn
100 105 110
Pro Arg His Pro Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp
115 120 125
Glu Asp Asp Lys Thr Val Leu Asp Leu Ala Val Val Leu Phe Glu Thr
130 135 140
Ala Thr Leu Arg Ser Gly Tyr Leu Leu Pro Asp Thr Lys Ala Tyr Gly
145 150 155 160
Asp Arg Ile Glu Arg Met Leu
165
<210> 44
<211> 137
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 15氨基酸序列
<400> 44
Met Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala
1 5 10 15
Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg
20 25 30
Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp
35 40 45
Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu
50 55 60
Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly
65 70 75 80
Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp
85 90 95
Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn
100 105 110
Pro Arg His Pro Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp
115 120 125
Glu Asp Asp Lys Thr Val Leu Asp Leu
130 135
<210> 45
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 16氨基酸序列
<400> 45
Met Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala
1 5 10 15
Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg
20 25 30
Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp
35 40 45
Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu
50 55 60
Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly
65 70 75 80
Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp
85 90 95
Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys
100 105
<210> 46
<211> 77
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide 17氨基酸序列
<400> 46
Met Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala
1 5 10 15
Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg
20 25 30
Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp
35 40 45
Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu
50 55 60
Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly
65 70 75
<210> 47
<211> 768
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 1m-1的核苷酸序列
<400> 47
atggaatcct cccccttcgt ggagcgtctg ctcaagaagg gctacgaagt gatctatctg 60
accgaacccg tggacgagta ttgcatccaa gctctccccg agttcgatgg caagcgcttc 120
cagaacgtgg ccaaggaggg cgtcaaattc gatgagagcg agaagaccaa ggagagcgcg 180
gaagccgtgg agaaagagtt tgagcctctg ctcaactgga tgaaagacaa ggccctcaaa 240
gacaagatcg aaaaggccgt ggtgtcccag cgtctcactg aaagcccttg cgctctggtg 300
gccagccagt acggttggag cggcaatatg gagcgtatca tgaaggctca agcttaccaa 360
accggcaagg acatctccac caactactac gcctcccaaa agaagacctt cgagatcaac 420
cctcgccatc ctctgatccg cgatatggca cgccgtatca aggaagatga ggacgacaag 480
accgtgctgg acctcgctgt ggtgctgttc gagaccgcca ctctgcgctc cggttatctg 540
ctccccgaca ccaaggccta cggcgatcgt attgagcgta tgctgcgtct gtctctgaat 600
atcgaccccg acgccaaggt ggaggaagaa cccgaggaag aacccgagga gaccgctgaa 660
gataccaccg aggacactga acaagacgaa gacgaggaga tggatgtggg taccgacgca 720
gaggaagaga ctgctaagga atccaccgcc gagaaggacg agctgtaa 768
<210> 48
<211> 768
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 1m-2的核苷酸序列
<400> 48
atggaatcct cccccttcgt ggagcgtctg ctcaagaagg gctacgaagt gatctatctg 60
accgaacccg tggacgagta ttgcatcgcc gctctccccg agttcgatgg caagcgcttc 120
cagaacgtgg ccaaggaggg cgtcaaattc gatgagagcg agaagaccaa ggagagccgc 180
gaagccgtgg agaaagagtt tgagcctctg ctcaactgga tgaaagacaa ggccctcaaa 240
gacaagatcg aaaaggccgt ggtgtcccag cgtctcactg aaagcccttg cgctctggtg 300
gccagccagt acggttggag cggcaatatg gagcgtatca tgaaggctca agcttaccaa 360
accggcaagg acatctccac caactactac gcctcccaaa agaagacctt cgagatcgcg 420
cctcgccatc ctctgatccg cgatatgctg cgccgtatca aggaagatga ggacgacaag 480
accgtgctgg acctcgctgt ggtgctgttc gagaccgcca ctctgcgctc cggttatctg 540
ctccccgaca ccaaggccta cggcgatcgt attgagcgta tgctgcgtct gtctctgaat 600
atcgaccccg acgccaaggt ggaggaagaa cccgaggaag aacccgagga gaccgctgaa 660
gataccaccg aggacactga acaagacgaa gacgaggcga tggatgtggg taccgacgag 720
gaggaagaga ctgctaagga atccaccgcc gagaaggacg agctgtaa 768
<210> 49
<211> 759
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 1d-1的核苷酸序列
<400> 49
atggaatcct cccccttcgt ggagcgtctg ctcaagaagg gctacgaagt gatctatctg 60
accgaacccg tggacgagta ttgcatcgct ctccccgagt tcgatggcaa gcgcttccag 120
aacgtggcca aggagggcgt caaattcgat gagagcgaga agaccaagga gagccgcgaa 180
gccgtggaga aagagtttga gcctctgctc aactggatga aagacaaggc cctcaaagac 240
aagatcgaaa aggccgtggt gtcccagcgt ctcactgaaa gcccttgcgc tctggtggcc 300
agccagtacg gttggagcgg caatatggag cgtatcatga aggctcaagc ttaccaaacc 360
ggcaaggaca tctccaccaa ctactacgcc tcccaaaaga agaccttcga gatccctcgc 420
catcctctga tccgcgatat gctgcgccgt atcaaggaag atgaggacga caagaccgtg 480
ctggacctcg ctgtggtgct gttcgagacc gccactctgc gctccggtta tctgctcccc 540
gacaccaagg cctacggcga tcgtattgag cgtatgctgc gtctgtctct gaatatcgac 600
cccgacgcca aggtggagga agaacccgag gaagaacccg aggagaccgc tgaagatacc 660
accgaggaca ctgaacaaga cgacgaggag atggatgtgg gtaccgacga ggaggaagag 720
actgctaagg aatccaccgc cgagaaggac gagctgtaa 759
<210> 50
<211> 759
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 1d-2的核苷酸序列
<400> 50
atggaatcct cccccttcgt ggagcgtctg ctcaagaagg gctacgaagt gatctatctg 60
accgaacccg tggacgagta ttgcatccaa gctctccccg agttcgatgg caagcgccag 120
aacgtggcca aggagggcgt caaattcgat gagagcgaga agaccaagga gagccgcgaa 180
gccgtggaga aagagtttga gcctctgctc aactggatga aagacaaggc cctcaaagac 240
aagatcgaaa aggccgtggt gtcccgtctc actgaaagcc cttgcgctct ggtggccagc 300
cagtacggtt ggagcggcaa tatggagcgt atcatgaagg ctcaagctta ccaaaccggc 360
aaggacatct ccaccaacta ctacgcctcc caaaagaaga ccttcgagat caaccctcgc 420
catcctctga tccgcgatat gctgcgccgt atcaaggaag atgaggacga caagaccgtg 480
ctggacctcg ctgtggtgct gttcgagacc gccactctgc gctccggtta tctgctcccc 540
gacaccaagg cctacggcga tcgtattgag cgtatgctgc gtctgtctct gaatatcgac 600
cccgacgcca aggtggagga agaacccgag gaagaacccg aggagaccgc tgaagatacc 660
accgaggaca ctgaacaaga cgaagacgag gagatggatg tgggtaccga cgaggaagag 720
actgctaagg aatccaccgc cgagaaggac gagctgtaa 759
<210> 51
<211> 414
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 15m-1的核苷酸序列
<400> 51
atgcaagctc tccccgagtt cgatggcgca cgcttccaga acgtggccaa ggagggcgtc 60
aaattcgatg agagcgagaa gaccaaggag agccgcgaag ccgtggagaa agagtttgag 120
cctctgctca actggatgaa agacaaggcc ctcaaagaca agatcgaaaa ggccgtggcg 180
tcccagcgtc tcactgaaag cccttgcgct ctggtggcca gccagtacgg ttggagcggc 240
aatatggagc gtatcatgaa ggctcaagct taccaaaccg gcaaggacat ctccaccaac 300
tactacgcct cccaaaagaa gaccttcgcg atcaaccctc gccatcctct gatccgcgat 360
atgctgcgcc gtatcaagga agatgaggac gacaagaccg tgctggacct ctaa 414
<210> 52
<211> 414
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 15m-2的核苷酸序列
<400> 52
atgcaagctc tccccgagtt cgatggcaag cgcttccaga acgtggccaa ggagggcgcg 60
aaattcgatg agagcgagaa gaccaaggag agccgcgaag ccgtggagaa agagtttgag 120
cctctgctca actggatgaa agacaaggcc ctcaaagaca agatcgaaaa ggccgtggtg 180
tcccagcgtc tcactgaaag cccttgcgct ctggtggcca gccagtacgg ttggagcggc 240
aatatggagc gtatcatgaa ggctcaagct taccaaaccg gcaaggacat ctccaccaac 300
tactacgcct cccaaaagaa gaccttcgcg atcaaccctc gccatcctct gatccgcgca 360
atgctgcgcc gtatcaagga agatgaggac gacaagaccg tgctggacct ctaa 414
<210> 53
<211> 405
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 15d-1的核苷酸序列
<400> 53
atgcaagctc tccccgagtt cgatggcaag cgcttccaga acgtggccaa ggagggcgtc 60
aaattcgatg agagcgagaa gaccaagagc cgcgaagccg tggagaaaga gtttgagcct 120
ctgctcaact ggatgaaaga caaggccctc aaagacaaga tcgaaaaggc cgtggtgtcc 180
cagcgtctca ctgaaagccc ttgcgctctg gtggccagcc agtacggttg gagcggcaat 240
atggagcgta tcatgaaggc tcaataccaa accggcaagg acatctccac caactactac 300
gcctcccaaa agaagacctt cgagatcaac cctcgccatc ctctgatccg cgatatgctg 360
cgccgtatca aggaagatga ggacaagacc gtgctggacc tctaa 405
<210> 54
<211> 405
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码Peptide 15d-2的核苷酸序列
<400> 54
atgcaagctc tccccgagtt cgatggcaag cgcttccaga acgtggccaa ggagggcgtc 60
aaattcgatg agagcgagaa gaccaaggag agccgcgaag ccgtggagaa agagtttcct 120
ctgctcaact ggatgaaaga caaggccctc aaagacaaga tcgaaaaggc cgtggtgtcc 180
cagcgtctca ctgaaagccc ttgcgctctg gtggccagcc agtacggttg gagcggcaat 240
atggagcgta tcatgaaggc tcaagcttac caaaccggca aggacatctc caccaactac 300
tacgcctccc aaaagaagac cttcgagatc aaccctcgcc atcctctgat ccgcatgctg 360
cgccgtatca aggaagatga ggacaagacc gtgctggacc tctaa 405
<210> 55
<211> 255
<212> PRT
<213> Artificial Sequence
<220>
<223> 1m-1氨基酸序列
<400> 55
Met Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys Lys Gly Tyr Glu
1 5 10 15
Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys Ile Gln Ala Leu
20 25 30
Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala Lys Glu Gly Val
35 40 45
Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Ala Glu Ala Val Glu
50 55 60
Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp Lys Ala Leu Lys
65 70 75 80
Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu Thr Glu Ser Pro
85 90 95
Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly Asn Met Glu Arg
100 105 110
Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp Ile Ser Thr Asn
115 120 125
Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn Pro Arg His Pro
130 135 140
Leu Ile Arg Asp Met Ala Arg Arg Ile Lys Glu Asp Glu Asp Asp Lys
145 150 155 160
Thr Val Leu Asp Leu Ala Val Val Leu Phe Glu Thr Ala Thr Leu Arg
165 170 175
Ser Gly Tyr Leu Leu Pro Asp Thr Lys Ala Tyr Gly Asp Arg Ile Glu
180 185 190
Arg Met Leu Arg Leu Ser Leu Asn Ile Asp Pro Asp Ala Lys Val Glu
195 200 205
Glu Glu Pro Glu Glu Glu Pro Glu Glu Thr Ala Glu Asp Thr Thr Glu
210 215 220
Asp Thr Glu Gln Asp Glu Asp Glu Glu Met Asp Val Gly Thr Asp Ala
225 230 235 240
Glu Glu Glu Thr Ala Lys Glu Ser Thr Ala Glu Lys Asp Glu Leu
245 250 255
<210> 56
<211> 255
<212> PRT
<213> Artificial Sequence
<220>
<223> 1m-2氨基酸序列
<400> 56
Met Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys Lys Gly Tyr Glu
1 5 10 15
Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys Ile Ala Ala Leu
20 25 30
Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala Lys Glu Gly Val
35 40 45
Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg Glu Ala Val Glu
50 55 60
Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp Lys Ala Leu Lys
65 70 75 80
Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu Thr Glu Ser Pro
85 90 95
Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly Asn Met Glu Arg
100 105 110
Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp Ile Ser Thr Asn
115 120 125
Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Ala Pro Arg His Pro
130 135 140
Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp Glu Asp Asp Lys
145 150 155 160
Thr Val Leu Asp Leu Ala Val Val Leu Phe Glu Thr Ala Thr Leu Arg
165 170 175
Ser Gly Tyr Leu Leu Pro Asp Thr Lys Ala Tyr Gly Asp Arg Ile Glu
180 185 190
Arg Met Leu Arg Leu Ser Leu Asn Ile Asp Pro Asp Ala Lys Val Glu
195 200 205
Glu Glu Pro Glu Glu Glu Pro Glu Glu Thr Ala Glu Asp Thr Thr Glu
210 215 220
Asp Thr Glu Gln Asp Glu Asp Glu Ala Met Asp Val Gly Thr Asp Glu
225 230 235 240
Glu Glu Glu Thr Ala Lys Glu Ser Thr Ala Glu Lys Asp Glu Leu
245 250 255
<210> 57
<211> 252
<212> PRT
<213> Artificial Sequence
<220>
<223> 1d-1氨基酸序列
<400> 57
Met Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys Lys Gly Tyr Glu
1 5 10 15
Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys Ile Ala Leu Pro
20 25 30
Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala Lys Glu Gly Val Lys
35 40 45
Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg Glu Ala Val Glu Lys
50 55 60
Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp Lys Ala Leu Lys Asp
65 70 75 80
Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu Thr Glu Ser Pro Cys
85 90 95
Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly Asn Met Glu Arg Ile
100 105 110
Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp Ile Ser Thr Asn Tyr
115 120 125
Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Pro Arg His Pro Leu Ile
130 135 140
Arg Asp Met Leu Arg Arg Ile Lys Glu Asp Glu Asp Asp Lys Thr Val
145 150 155 160
Leu Asp Leu Ala Val Val Leu Phe Glu Thr Ala Thr Leu Arg Ser Gly
165 170 175
Tyr Leu Leu Pro Asp Thr Lys Ala Tyr Gly Asp Arg Ile Glu Arg Met
180 185 190
Leu Arg Leu Ser Leu Asn Ile Asp Pro Asp Ala Lys Val Glu Glu Glu
195 200 205
Pro Glu Glu Glu Pro Glu Glu Thr Ala Glu Asp Thr Thr Glu Asp Thr
210 215 220
Glu Gln Asp Asp Glu Glu Met Asp Val Gly Thr Asp Glu Glu Glu Glu
225 230 235 240
Thr Ala Lys Glu Ser Thr Ala Glu Lys Asp Glu Leu
245 250
<210> 58
<211> 252
<212> PRT
<213> Artificial Sequence
<220>
<223> 1d-2氨基酸序列
<400> 58
Met Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys Lys Gly Tyr Glu
1 5 10 15
Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys Ile Gln Ala Leu
20 25 30
Pro Glu Phe Asp Gly Lys Arg Gln Asn Val Ala Lys Glu Gly Val Lys
35 40 45
Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg Glu Ala Val Glu Lys
50 55 60
Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp Lys Ala Leu Lys Asp
65 70 75 80
Lys Ile Glu Lys Ala Val Val Ser Arg Leu Thr Glu Ser Pro Cys Ala
85 90 95
Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly Asn Met Glu Arg Ile Met
100 105 110
Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp Ile Ser Thr Asn Tyr Tyr
115 120 125
Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn Pro Arg His Pro Leu Ile
130 135 140
Arg Asp Met Leu Arg Arg Ile Lys Glu Asp Glu Asp Asp Lys Thr Val
145 150 155 160
Leu Asp Leu Ala Val Val Leu Phe Glu Thr Ala Thr Leu Arg Ser Gly
165 170 175
Tyr Leu Leu Pro Asp Thr Lys Ala Tyr Gly Asp Arg Ile Glu Arg Met
180 185 190
Leu Arg Leu Ser Leu Asn Ile Asp Pro Asp Ala Lys Val Glu Glu Glu
195 200 205
Pro Glu Glu Glu Pro Glu Glu Thr Ala Glu Asp Thr Thr Glu Asp Thr
210 215 220
Glu Gln Asp Glu Asp Glu Glu Met Asp Val Gly Thr Asp Glu Glu Glu
225 230 235 240
Thr Ala Lys Glu Ser Thr Ala Glu Lys Asp Glu Leu
245 250
<210> 59
<211> 137
<212> PRT
<213> Artificial Sequence
<220>
<223> 15m-1氨基酸序列
<400> 59
Met Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Ala Gln Asn Val Ala
1 5 10 15
Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg
20 25 30
Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp
35 40 45
Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Ala Arg Leu
50 55 60
Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly
65 70 75 80
Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp
85 90 95
Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Ala
100 105 110
Pro Arg His Pro Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp
115 120 125
Glu Asp Asp Lys Thr Val Leu Asp Leu
130 135
<210> 60
<211> 137
<212> PRT
<213> Artificial Sequence
<220>
<223> 15m-2氨基酸序列
<400> 60
Met Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala
1 5 10 15
Lys Glu Gly Val Lys Ala Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg
20 25 30
Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp
35 40 45
Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu
50 55 60
Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly
65 70 75 80
Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp
85 90 95
Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Ala
100 105 110
Pro Arg His Pro Leu Ile Arg Asp Met Ala Arg Arg Ile Lys Glu Asp
115 120 125
Glu Asp Asp Lys Thr Val Leu Asp Leu
130 135
<210> 61
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> 15d-1氨基酸序列
<400> 61
Met Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala
1 5 10 15
Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Glu
20 25 30
Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp Lys
35 40 45
Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu Thr
50 55 60
Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly Asn
65 70 75 80
Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Thr Gly Lys Asp Ile Ser
85 90 95
Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn Pro Arg
100 105 110
His Pro Leu Ile Arg Asp Met Arg Arg Ile Lys Glu Asp Glu Asp Asp
115 120 125
Lys Thr Val Leu Asp Leu
130
<210> 62
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> 15d-2氨基酸序列
<400> 62
Met Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala
1 5 10 15
Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg
20 25 30
Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Asn Trp Met Lys Asp Lys
35 40 45
Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu Thr
50 55 60
Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly Asn
65 70 75 80
Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Thr Gly Lys Asp Ile Ser
85 90 95
Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn Pro Arg
100 105 110
His Pro Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp Glu Asp
115 120 125
Asp Thr Val Leu Asp Leu
130
<210> 63
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> 6xHis标签的核苷酸序列
<400> 63
caccaccacc atcaccac
18
Claims (18)
1.一种分离的多肽或其变体,其中,所述多肽由gp96蛋白的至少136个连续氨基酸残基组成,且包含:gp96蛋白的第578-713位氨基酸残基;
其中,所述变体与其所源自的多肽相异仅在于1个或几个(例如,1个、2个、3个、4个或5个)氨基酸残基的置换、缺失或添加,且保留了其所源自的多肽的生物学功能(例如诱导调节性T细胞活化,不诱导效应T细胞和B细胞活化,预防和/或治疗自身免疫性疾病,降低抗双链DNA抗体的水平,降低尿蛋白的水平,和/或降低血糖)。
2.权利要求1所述的分离的多肽或其变体,其中,所述分离的多肽包含:gp96蛋白的第578-713位氨基酸残基、第578-743位氨基酸残基、第578-773位氨基酸残基、第578-803位氨基酸残基、第550-713位氨基酸残基、第550-743位氨基酸残基、第550-773位氨基酸残基或第550-803位氨基酸残基。
3.权利要求1或2所述的分离的多肽或其变体,其中,所述gp96蛋白具有如SEQ ID NO:7所示的序列。
4.权利要求1-3任一项所述的分离的多肽或其变体,其中,所述分离的多肽包含选自下列的氨基酸序列:SEQ ID NOs:30、31、32、33、37、42、43、44。
5.权利要求1-4任一项所述分离的多肽或其变体,其中,所述变体与其所源自的多肽相异仅在于1个、2个或3个氨基酸残基的置换、缺失或添加;
优选地,所述置换包括将所述氨基酸残基替换为丙氨酸(A)。
6.权利要求1-5任一项所述的分离的多肽或其变体,其中,所述变体包含选自下列的氨基酸序列:SEQ ID NOs:55-62。
7.一种融合蛋白,其包含权利要求1-6任一项所述的分离的多肽或其变体和另外的多肽;
优选地,所述另外的多肽任选地通过接头连接至所述多肽或其变体的N端或C端;
优选地,所述另外的多肽选自蛋白标签、靶向部分或其任意组合。
8.一种分离的核酸分子,其包含编码权利要求1-6任一项所述的分离的多肽或其变体,或权利要求7所述的融合蛋白的核苷酸序列;
优选地,所述分离的核酸分子包含选自下列的核苷酸序列:(i)SEQ ID NOs:13-16、20、25-27、47-54任一项所示的序列;(ii)与(i)所述序列相比具有至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少99%的序列同一性的序列;(iii)在严格条件下与(i)或(ii)中所述的序列杂交的序列;或(iv)(i)或(ii)中所述的序列的互补序列。
9.一种载体,其包含权利要求8所述的分离的核酸分子。
10.一种宿主细胞,其包含权利要求8所述的分离的核酸分子或权利要求9所述的载体。
11.一种药物组合物,其包含权利要求1-6任一项所述的分离的多肽或其变体、权利要求7所述的融合蛋白、权利要求8所述的分离的核酸分子、权利要求9所述的载体或权利要求10所述的宿主细胞,以及药学上可接受的载体和/或赋形剂;
优选地,所述药物组合物包含权利要求1-6任一项所述的分离的多肽或其变体、权利要求7所述的融合蛋白中的一种或多种。
12.权利要求11所述的药物组合物,其中,所述药物组合物任选地还包含另外的药学活性剂;
优选地,所述另外的药学活性剂为具有治疗自身免疫性疾病活性的药物,例如抗炎药物或免疫抑制剂。
13.权利要求1-6任一项所述的分离的多肽或其变体、权利要求7所述的融合蛋白、权利要求8所述的分离的核酸分子、权利要求9所述的载体或权利要求10所述的宿主细胞、或权利要求11或12所述的药物组合物在制备药物中的用途,所述药物用于:
(i)在受试者中预防和/或治疗自身免疫性疾病;
(ii)在受试者中降低抗双链DNA抗体的水平;
(iii)在受试者中降低尿蛋白的水平;和/或
(iv)在受试者中降低血糖。
14.gp96蛋白的C末端结构域或其活性片段或其变体在制备药物中的用途,所述药物用于:
(i)在受试者中预防和/或治疗自身免疫性疾病;
(ii)在受试者中降低抗双链DNA抗体的水平;
(iii)在受试者中降低尿蛋白的水平;和/或
(iv)在受试者中降低血糖。
15.权利要求14所述的用途,其中,所述活性片段包含gp96蛋白的第578-713位氨基酸残基;
优选地,所述活性片段包含:gp96蛋白的第578-713位氨基酸残基、第578-743位氨基酸残基、第578-773位氨基酸残基、第578-803位氨基酸残基、第550-713位氨基酸残基、第550-743位氨基酸残基、或第550-773位氨基酸残基;
优选地,所述活性片段包含选自下列的氨基酸序列:SEQ ID NOs:31、32、33、37、42、43、44。
16.权利要求14或15所述的用途,其中,所述变体与其所源自的多肽相异仅在于1个或几个(例如,1个、2个、3个、4个或5个)氨基酸残基的置换、缺失或添加,且保留了其所源自的多肽的生物学功能(例如诱导调节性T细胞活化,不诱导效应T细胞和B细胞活化的活性,预防和/或治疗自身免疫性疾病,降低抗双链DNA抗体的水平,降低尿蛋白的水平,和/或降低血糖);
优选地,所述变体与其所源自的多肽相异仅在于1个、2个或3个氨基酸残基的置换、缺失或添加;优选地,所述置换包括将所述氨基酸残基替换为丙氨酸(A);
优选地,所述变体包含选自下列的氨基酸序列:SEQ ID NOs:55-62。
17.权利要求13-16任一项所述的用途,其中,所述自身免疫性疾病选自系统性红斑狼疮、1型糖尿病、类风湿性关节炎、多发性硬化症、银屑病、炎症性肠病、溃疡性结肠炎、克罗恩病、重症肌无力或多发性肌炎。
18.权利要求13-17任一项所述的用途,其中,所述受试者是哺乳动物,例如人或鼠。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110189188A1 (en) * | 2008-03-13 | 2011-08-04 | Compugen Ltd. | Novel gp96 derived peptides |
CN105749251A (zh) * | 2016-04-08 | 2016-07-13 | 中国科学院微生物研究所 | 热休克蛋白gp96在预防和治疗1型糖尿病中的应用 |
CN105963681A (zh) * | 2016-05-09 | 2016-09-28 | 中国科学院微生物研究所 | 热休克蛋白gp96在治疗系统性红斑狼疮中的应用 |
CN106039287A (zh) * | 2016-06-28 | 2016-10-26 | 中国科学院微生物研究所 | 热休克蛋白gp96在治疗类风湿性关节炎中的应用 |
CN106975072A (zh) * | 2017-03-16 | 2017-07-25 | 北京热休生物技术有限公司 | 热休克蛋白gp96在治疗自身免疫性溶血性贫血中的应用 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN106913863B (zh) * | 2017-03-16 | 2020-10-27 | 北京热休生物技术有限公司 | NUP188蛋白的多肽与热休克蛋白gp96的复合物在制备治疗与预防癌症药物中的应用 |
CN106822869B (zh) * | 2017-03-16 | 2020-10-30 | 北京热休生物技术有限公司 | DEF8蛋白的多肽与热休克蛋白gp96的复合物在制备治疗与预防癌症药物中的应用 |
CN106890315B (zh) * | 2017-03-16 | 2019-09-06 | 北京热休生物技术有限公司 | Apo-e蛋白及其多肽在治疗与预防癌症中的应用 |
CN106983855A (zh) * | 2017-03-16 | 2017-07-28 | 北京热休生物技术有限公司 | 热休克蛋白gp96在治疗重症肌无力症中的应用 |
-
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- 2021-09-18 WO PCT/CN2021/119376 patent/WO2022179093A1/zh active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110189188A1 (en) * | 2008-03-13 | 2011-08-04 | Compugen Ltd. | Novel gp96 derived peptides |
CN105749251A (zh) * | 2016-04-08 | 2016-07-13 | 中国科学院微生物研究所 | 热休克蛋白gp96在预防和治疗1型糖尿病中的应用 |
CN105963681A (zh) * | 2016-05-09 | 2016-09-28 | 中国科学院微生物研究所 | 热休克蛋白gp96在治疗系统性红斑狼疮中的应用 |
CN106039287A (zh) * | 2016-06-28 | 2016-10-26 | 中国科学院微生物研究所 | 热休克蛋白gp96在治疗类风湿性关节炎中的应用 |
CN106975072A (zh) * | 2017-03-16 | 2017-07-25 | 北京热休生物技术有限公司 | 热休克蛋白gp96在治疗自身免疫性溶血性贫血中的应用 |
Non-Patent Citations (3)
Title |
---|
WEIWEI LIU等: "Interaction of Toll-Like Receptors with the Molecular Chaperone Gp96 Is Essential for Its Activation of Cytotoxic T Lymphocyte Response", PLOS ONE, vol. 11, no. 05 * |
刘振: "高剂量热休克蛋白gp96及其氨基端片段对调节性T细胞介导CTL反应的影响", 中国优秀硕士学位论文全文数据库 医药卫生科技辑, no. 08 * |
陈密;李星辉;郑华国;孟颂东;: "高剂量热休克蛋白gp96通过激活调节性T细胞预防1型糖尿病", 生物工程学报, no. 12 * |
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