基于il－1受体的拮抗剂和制造与使用的方法

专利名称：基于il－1受体的拮抗剂和制造与使用的方法
本申请是2001年3月22日提交的美国申请09/787,835的部份延续，后者是1999年9月22日提交的国际申请PCT/US99/22045的美国国家阶段申请，所述国际申请要求1999年5月19日提交的美国申请09/313,942(已授权的)的优先权，所述美国申请09/313,942要求1998年9月25日提交的美国临时申请60/101,858(现已放弃)的优先权。本申请通篇参考了各种出版物。这些完全公开的出版物此处引用作为参考。
背景技术：
细胞因子CNTF家族在众多的生理过程中起重要作用，这为拮抗剂和激动剂都提供了潜在的治疗应用。
发明概述本发明目的是生产用于治疗涉及细胞因子的疾病或病症的细胞因子拮抗剂。
本发明另一个目的是已公开的所述细胞因子拮抗剂在治疗涉及细胞因子的疾病或病症中的应用。
本发明的另一个目的是构建几个特异性的IL-1细胞因子拮抗剂，称为IL-1捕获者(Trap)，各具有不同的序列但都能够阻止IL-1和它的受体结合，因此用作IL-1的拮抗剂。
附图简述

图1人IL-1捕获者阻断外源施用的huIL-1的体内效应。在时间0时给BALB/c小鼠皮下注射huIL-1(0.3μg/kg)。在注射huIL-1之前24小时，用载体或150倍摩尔过量的huI L-1捕获者预先处理动物。在宰杀动物之前2小时(26小时)，第二次对小鼠注射huIL-1(0.3μg/kg)以再次刺激免疫反应。在各个时间点收集血液样品并检测血清中IL-1的水平(用平均值+/-SEM表示；n＝5每组)。
图2人IL-1捕获者阻断外源施用的人IL-1的体内效应。
图3人IL-1捕获者阻断发炎的关节中的IL-1的效应。
图4-5鼠科动物IL-1捕获者在酵母聚糖加速的胶原蛋白诱导的关节炎(Zymosan-Accelerated Collagen-Induced Arthritis)(CIA)模型中减轻关节炎症的严重程度。
图6在5pM浓度人IL-b存在的情况下，室温下孵育各种浓度的IL-1捕获者1649过夜。
发明详述本发明提供了编码能和细胞因子结合生成无功能复合物的融合多肽的分离的核酸分子，所述核酸分子包含(a)编码第一个融合多肽组件的核苷酸序列，所述多肽组件包含细胞因子受体特异性决定组件的细胞外结构域中的细胞因子结合部位的氨基酸序列；(b)编码第二个融合多肽组件的核苷酸序列，所述多肽组件包含细胞因子受体信号传导组件的细胞外结构域中的细胞因子结合部位的氨基酸序列；和(c)编码第三个融合多肽组件的核苷酸序列，所述组件包含多聚化组件的氨基酸序列。
“细胞因子结合部位”指的是结合细胞因子所必需的细胞外结构域的最小组成部分。本领域技术人员所接受的细胞因子受体的一个明确特征是存在两个包含经典的半胱氨酸的纤连蛋白样结构域和存在WSXWS盒(SEQ ID NO26)(Bazan(1990)PNAS 876934-6938)。编码细胞因子受体结合组件的细胞外结构域和信号传导组件的细胞外结构域的序列也可以用来创建本发明的融合多肽。类似地，可以使用更长的编码更大的细胞因子受体组件部位的序列。然而，由于考虑到比细胞外结构域更小的片段能行使与细胞因子结合的功能，因而本发明包含的融合多肽包含作为细胞因子结合部位的结合细胞因子所必需的细胞外结构域最小组成部分。
本发明包含细胞因子受体的“特异性决定组件”和细胞因子受体的“信号传导组件”。不考虑用来称呼细胞因子受体特定的组件或亚基的命名系统，本专业技术人员能识别出受体的哪个组件或亚基负责决定细胞因子的细胞靶向，于是可以知道哪个组件构成了“特异性决定组件”。类似地，不考虑所用的命名系统，本领域技术人员能够知道哪个组件或亚基可以构成“信号传导组件”。如此处所使用的，“信号传导组件”是天然存在的受体的组件，所述信号传导组件不是特异性决定组件并且在缺少特异性决定组件的情况下不与或微弱地与细胞因子结合。在天然存在的受体中，“信号传导组件”可参与信号传导。
在制备编码本发明的融合多肽的核酸序列中，所述融合多肽的第一，第二和第三组件编码在单链核酸上，当通过宿主载体系统表达时便产生单体类型的融合多肽。这样表达的单体，接着在多聚化组件(第三个融合多肽组件)间的相互作用下多聚化。用这种方式产生融合多肽避免了纯化异二聚体混合物(如果第一和第二组件由分开的分子产生而且接着多聚化将导致该异二聚体混合物)的需要。例如，于1995年11月28日颁发的美国专利5,470,952描述了作为CNTF或IL-6拮抗剂的异二聚体蛋白的生产。从由合适的alpha(a)和beta(b)组件共转染的细胞系中纯化异二聚体。接着使用诸如从制备型非变性聚丙酰胺凝胶中被动洗脱或使用高压阳离子交换层析等方法将异二聚体从同二聚体中分离出来。通过本发明方法可以避免对这个纯化步骤的需求。
此外，1996年4月18日公布的标题为二聚体IL-4抑制剂的PCT国际申请WO96/11213声称其申请者已经制备出同二聚体，其中二个IL-4受体通过一个多聚间隔子相连，和异二聚体，其中一个IL-4受体通过一个多聚间隔子与一个IL-2受体γ链相连。所描述的多聚间隔子是聚乙二醇。两个受体组件，IL-4R和IL-2Rγ是分开表达和纯化的。通过使用双功能的PEG试剂将组件连接在一起便产生了聚乙二醇化的(Pegylated)同二聚体和异二聚体。本发明的优势是它避免了对这种费时且昂贵的纯化和聚乙二醇化步骤的需要。
在本发明的一个实施方案中，编码第一个组件的核酸序列在编码第二个组件的核酸序列上游。在另一个本发明实施方案中，编码第一个组件的核酸序列在编码第二个组件的核酸序列下游。本发明更近一步的实施方案可以重新安排融合多肽的第一，第二和第三组件的顺序。例如，如果编码第一个组件的核酸序列称作1，编码第二个组件的核酸序列称作2，编码第三个组件的核酸序列称作3，那么组件在本发明的分离的核酸上从5’到3’读的顺序可以是下列六种组合中的任一种1，2，3；1，3，2；2，1，3；2，3，1；3，1，2；或3，2，1。
在本发明特定的实施方案中，被融合多肽结合的细胞因子是白细胞介素-1(IL-1)。
在本发明优选的实施方案中，多聚化组件包括免疫球蛋白衍生的结构域。更特别的是，免疫球蛋白衍生的结构域可能选自IgG的Fc结构域、IgG的重链和IgG的轻链。甚至更特别的是，免疫球蛋白的结构域可能选自IgG1或IgG4的Fc结构域、IgG1或IgG4的重链和IgG1或IgG4的轻链。在另一个实施方案中，多聚化组件可能是一个Fc结构域，其中去除了前五个氨基酸(包括一个半胱氨酸)便产生被称作Fc(DC1)的多聚化组件。或者，多聚化组件可能是其前五个氨基酸中的半胱氨酸已被另外的氨基酸(例如丝氨酸或丙氨酸)取代的Fc结构域。
本发明也提供了由本发明的分离的核苷酸编码的融合多肽。优选地，由于第三个组件(多聚化组件)的功能，融合多肽以多聚体的形式存在。在优选的实施方案中，所述多聚体是二聚体。合适的多聚化组件是编码免疫球蛋白重链铰链区的序列(Takahashi等人，(1982)Ce1129671-679)；免疫球蛋白基因序列和其中的部分序列。在优选的本发明实施方案中，免疫球蛋白基因序列，尤其是编码Fc结构域的序列，用来编码多聚化组件。
本发明也包括包含有此处所述的核酸分子的载体。
本发明的优选实施方案是编码具有SEQ ID NO2序列融合多肽的分离的具有SEQ ID NO1序列的核酸分子，其中融合多肽形成能与细胞因子结合形成无功能复合物的多聚体；编码具有SEQ ID NO4序列的融合多肽的分离的核酸分子，其具有SEQ ID NO3所列序列，其中融合多肽形成能结合细胞因子形成无功能复合物的多聚体；编码具有SEQ ID NO6序列的融合多肽的分离的核酸分子，其具有SEQ ID NO5所列序列，其中融合多肽形成能结合细胞因子形成无功能复合物的多聚体；以及由上述核酸分子编码的融合多肽。
其它本发明优选的实施方案是具有SEQ ID NO7，9，11，13，15，17，19，21和23所列序列的分离的核酸分子，它们分别编码具有SEQ IDNO8，10，12，14，16，18，20和22所列序列的融合多肽，其中各融合多肽形成能结合IL-1形成无功能复合物的多聚体。
本发明也提供了表达载体，所述载体包含此处描述的本发明核酸分子，其中该核酸分子有效地连接表达控制序列。本发明也提供了用来生产融合多肽的宿主-载体系统，所述宿主-载体系统包含本发明的表达载体，该载体被导入适合用来表达融合多肽的宿主细胞。合适的宿主细胞可以是细菌细胞，如大肠杆菌，酵母细胞，如巴斯德比赤氏酵母(pichiapastoris)，昆虫细胞，如草地夜蛾(Spodoptera frug iperda)、或哺乳动物细胞，如COS，CHO，293，BHK或NSO细胞。
本发明还提供了生产本发明融合多肽的方法通过在允许生产融合多肽的条件下培养此处描述的宿主-载体系统中的细胞和回收所产生的融合多肽以生产本发明的融合多肽。
根据本发明制备的sRα:β1异二聚体为它们的配基提供了有效的捕获者，它们在皮摩尔级范围能亲合结合这些配体而不产生有功能的中间体。此处描述的技术可用于为任何一种细胞因子开发细胞因子捕获物，其利用α组件(赋予特异性)和β组件(当与α特异性组件结合后，有着比单独使用其中任何一种组件时更高的对细胞因子的亲合力)。因而，根据本发明的拮抗剂包括白细胞介素-1(IL-1)的拮抗剂。
利用对本领域技术人员已知的方法可以制备α和β受体的细胞外结构域。可以通过克隆和在原核或真核表达系统中的表达来制备用于实现本发明的受体分子。可以使用任何种类的方法来表达和纯化重组受体基因。将编码该因子的基因亚克隆入细菌表达载体，诸如例如但不局限于PC110。
可以使用任何允许随后形成稳定的具有生物活性的蛋白技术纯化重组因子。例如但不局限于，所述因子可以以可溶性蛋白或包含体的形式从细胞中回收，然后可用8M盐酸胍和透析将蛋白从包含体中定量提取出来。为了进一步纯化因子，可使用传统的离子交换层析，疏水相互作用层析，反向层析或凝胶过滤。
正如公开的PCT申请WO93/10151(描述了β受体异二聚体的产生)所描述的那样，可使用已知的融合区域进行基因工程制备sRα:β异二聚体受体，或通过化学方法交联细胞外结构域来制备它们。所使用的结构域可以由α和β组件的完整细胞外结构域构成，或者它们可以由保持有与其配体形成复合体能力的其突变体或片段和sRα:β复合物上的其它组件形成。
在本发明的一个实施方案中，细胞外结构域可用亮氨酸拉链进行基因工程制备。已经显示人转录因子c-jun和c-fos的亮氨酸拉链结构域可以形成稳定的1∶1的化学计量的异二聚体(Bush等人，(1990)TrendsGenetics 636-40；Gentz等人，(1989)Science 2431695-1699)。尽管已经显示jun-jun同二聚体能够形成，但它们的稳定性比jun-fos异二聚体的弱1000倍。从未检测到Fos-fos同二聚体。
通过遗传工程形成嵌合基因将c-jun或c-fos的亮氨酸拉链结构域融合入上述受体组件的可溶性或细胞外结构域的C末端读码框内。融合可以是直接的或可以应用一个柔性的连接子结构域如人IgG的铰链区、或由小氨基酸(诸如甘氨酸，丝氨酸，苏氨酸或丙氨酸)以各种长度和组合构成的多肽连接子。另外，可使用His-His-His-His-His-His(His6)(SEQ ID NO25)标记嵌合蛋白，这样可通过金属螯合层析快速纯化该蛋白，和/或通过可获得抗体的抗原决定基标记，而允许通过蛋白质印迹法、免疫共沉淀或活性损耗/阻断生物鉴定对该蛋白进行检测。
在另一个实施方案中，用人IgG1的Fc结构域来制备sRα:β1异二聚体(Aruffo等人(1991)Cell 6735-44)。与前者相反，由于携带有Fc结构域的嵌合分子将表达为通过二硫键连接的同二聚体，所以异二聚体的形成必须通过生物化学方法获得。于是在有利于打断链间二硫键但不影响链内二硫键的条件下同二聚体将会减少。然后将具有不同细胞外组成部分的单体等摩尔量混合并氧化形成同和异二聚体的混合物。可以通过层析技术对这个混合物的组分进行分离。或者，通过遗传改造和表达由受体组件的可溶性或细胞外部位，其后连接hIgG的Fc结构域，再连接上述的c-jun或c-fos亮氨酸拉链(Kostelny等人，(1992)J.Immunol.1481547-1553))构成的分子，可以偏向性形成这种异二聚体。由于这些亮氨酸拉链主要形成异二聚体，它们可以用来驱动形成目的二聚体。对于描述过的使用亮氨酸拉链的嵌合蛋白，它们也可以使用金属螯合剂或抗原决定基标记。通过金属螯合层析可快速纯化这种带有标签的结构域，和/或通过抗体使用蛋白质印迹、免疫共沉淀或活性损耗/阻断生物鉴定方法来检测这种带有抗原决定基标签的结构域。
在另外的实施方案中，可使用驱动二聚体形成的其它免疫球蛋白来源的结构域来制备异二聚体。例如这样的结构域包括IgG的重链(Cg1和Cg4)以及人免疫球蛋白的kappa(K)和lambda(λ)轻链的恒定区。Cg和轻链的异二聚体化发生在Cg的CH1结构域和轻链(CL)的恒定区之间并且通过单个二硫键桥共价连接两个结构域而稳定。因此，可以使用这些免疫球蛋白的结构域制备构建体。或者，免疫球蛋白的结构域包括来源于驱动二聚体化的T细胞受体组件的结构域。
在本发明另一个实施方案中，通过表达利用柔性连接环的嵌合分子可以制备sRα:β1异二聚体。编码嵌合蛋白的DNA构建体设计为能表达通过柔性环以串连方式(“头对头”)融合在一起的二个可溶性或细胞外结构域。这个环可以是完全人造的(例如在某些间隔处被丝氨酸或苏氨酸插入打断的多聚甘氨酸重复)或从天然存在的蛋白(例如hIgG的铰链区)中“借来”。通过基因工程可以构建其中交换可溶性结构域或融合的细胞外结构域顺序的分子(例如sIL6Ra/环/sgp130或sgp130/环/sIL-6Ra)和/或其中改变环的长度和组成允许选择具有所需特征的分子。
或者，跟据本发明制造的异二聚体可以从用合适的α和β组件共转染的细胞系进行纯化。本领域技术人员使用已知方法从同二聚体中分离出异二聚体。例如，通过从制备型的非变性聚丙烯酰胺凝胶中被动洗脱可以回收有限量的异二聚体。或者，使用高压阳离子交换层析可以纯化异二聚体。使用Mono S阳离子交换柱可以获得高质量的纯化。
使用本领域技术人员已知的方法(例如参看Fingl等人，(1975)ThePharmacological Basis of Therapeutics，Goodman and Gilman，eds.Macmill an Publishing Co.，New York，pp.1-46)可以确定用来治疗IL-1相关疾病和病症的有效剂量。根据本发明使用的药物组合物包括上述的拮抗剂，所述拮抗剂在体内施用之前存在于药学可接受的液体、固体或半固体载体、连接到载体或靶向分子(例如抗体、激素、生长因子等)和/或包装入脂质体、微囊体和受控释放制剂内(包括拮抗剂表达细胞)。例如，药物组合物可能在含水溶液中(如无菌水、盐水、磷酸缓冲液或葡萄糖溶液)包含一种或更多种拮抗剂。或者，活性药剂可以包含在固体(例如石蜡)或半固体(例如凝胶状的)制剂中，所述制剂可以植入到需要这种治疗的病人体内。给药途径可以是任何一种本领域已知的给药模式，包括但不局限于静脉内地、鞘内地、皮下地，通过注射入所涉及的组织，动脉内地、鼻内地、经口地，或通过植入设备。
给药可以导致本发明活性药剂全身或局部分布。例如，在某些涉及神经系统长距区域的情况下，静脉内或皮下施用药剂可能比较理想。某些情况下，将包含有活性药剂的植入物植入受损的区域或附近。合适的植入物包括但不局限于明胶海绵、蜡或基于微颗粒的植入物。
实施例实施例1.克隆融合多肽组件通过利用组织cDNA的标准PCR技术(CLONTECH)进行PCR可获得人细胞因子受体细胞外结构域，将其克隆入表达载体pMT21(GeneticsInstitute，Inc.)并且用ABI 373A DNA测序列仪和Taq双脱氧终止子循环测序试剂盒(Applied Biosystems，Inc.，Fos ter City，CA))对该序列进行测序。对于IL-IRAcP，克隆来自Genbank序列AB006357的从1到1074位的核苷酸(对应氨基酸1-358)。对于IL-1RI，克隆来自Genbank序列X16896的从55到999位的核苷酸(对应氨基酸19-333)。
实施例2.生产融合多肽(细胞因子捕获者)通过标准的克隆和PCR技术由单个克隆的DNA(上面描述的)构建编码细胞因子捕获者的核酸序列。在每一个案例中，将所述序列构建入读码框内，使得编码第一个融合多肽组件的序列可以与编码第二个融合多肽组件的序列融合，其后连接一个作为多聚化组件的Fc结构域(铰链，人IgG1的CH2和CH3区域)。在某些情况下，将额外的核苷酸插入编码第一个和第二个融合多肽组件的序列之间的读码框内，为两个组件之间添加一个连接子区域。
实施例3.对IL-1捕获子的MRC5生物鉴定MRC5人肺成纤维细胞通过分泌IL-6对IL-1作出反应，于是可以用MRC5细胞来检测IL-1捕获者对IL-1依赖性的IL-6生成的阻断能力。IL1捕获子ISC569针对IL-1-RI.Fc进行测试，所述IL-1-RI.Fc是融入一个Fc结构域的IL-1 I型受体的细胞外结构。
将MRC5细胞以每毫升1×105个细胞悬浮在培养基里并将0.1ml细胞(每孔10,000个细胞)铺到96孔组织培养板的孔里。培养板在加湿的含5％CO2的培养箱中于37℃孵育24小时。
将IL-1捕获者和不同剂量的重组人IL-1预先孵育在96孔培养皿内并在37℃孵育2小时。然后将0.1ml该混合物加入到含有MRC5细胞的96孔板内，这样IL-1捕获者的终浓度为10nM而IL-1终浓度的范围是从2.4pM到5nM。对照孔只含捕获者或什么都不加。
然后将培养板放入加湿的含5％CO2的培养箱中于37℃条件下孵育24小时。收集上清液，根据产商说明使用R&D Systems QuantikineImmunoassay Kit检测IL-6的水平。
实施例4.在体内用IL-1捕获子阻断注射的IL-1IL-1是一个促炎细胞因子。已经显示在动物中系统性地给药IL-1会引发急性反应，包括短暂高血糖症、胰岛素分泌过少、发烧、食欲减退和增加的血清白细胞介素6(IL-6)水平(Reimers，1998)。因为小鼠对鼠和人的IL-1都会起反应，可以使用人IL-1并且可以估计人特异性IL-1拮抗剂在体内的结合效果。这个急性小鼠模型可以用来决定人IL-1捕获者拮抗外源施用的人IL-1引起的体内效应的能力。这个模型提供了人IL-1捕获者体内效应的快速指示并且可以用作帮助分子选择的检测方法。
实验设计给雄性C57BL/6小鼠皮下注射重组人IL-1β(rhIL-1β；0.3mg/kg)。在rhIL-1β给药前24小时，用载体、人IL-1捕获者569(50或150倍摩尔过量；分别为0.18或0.54mg/kg)或重组的鼠IL-1受体拮抗剂(rmIL-1ra；150或750倍摩尔过量；分别为45.8或229μg/kg)处理动物。施用rhIL-1β2小时后取血液样品并用小鼠IL-6ELISA方法检测血清中IL-6水平。外源给药的rhIL-1β显著地增加了血清中的IL-6水平。用50或150倍摩尔过量的hIL-1捕获者预处理阻断rhIL-1β诱导的IL-6。与此相反，注射150或750倍摩尔过量的rmIL-Ira都不会阻断IL-6的诱导。
结果外源施用人IL-1导致显著诱导的血清IL-6水平。在150倍摩尔过量时，人IL-1捕获者完全阻断IL-6的增加(图1)。而且，人IL-1捕获者的药效会持续至少另外24小时，甚至当重新施用IL-1时仍能阻止IL-6的增加(图1)。这种持续长时间的药效暗示在应用于长期治疗时没有必要每天注射IL-1捕获者。
在分开的实验中，IL-Ira在150倍或750倍摩尔过量时都没有明显地阻断IL6的诱导。因而，在这个例子中，IL-1捕获者似乎是一个更好的IL-1活性阻断剂。
实施例5.构建额外的单链IL-1捕获者此处描述的用于构建DNA载体的技术是本专业技术人员熟悉的标准生物学技术(参见例如Sambrook，J.，E.F.Fritsch And T.Maniatis.Molecular CloningA Laboratory Manual，第二版，Vols 1，2，和3，1989；Current Protocols in Molecular Biology，Eds.Ausubel等人，Greene Publ.Assoc.，Wiley Interscience，NY)。利用ABI 373ADNA测序列仪和Taq双脱氧终止子循环测序试剂盒(AppliedBiosystems，Inc.，Foster City，CA))标准技术对所有DNA序列进行测序。
(a)IL-1捕获者823序列-所述IL-1捕获者823序列由人IL-1RAcP细胞外结构域(对应于序列SEQ ID NO7中的核苷酸1-1077)，之后连接人IL-1RI的细胞外结构域(对应于序列SEQ ID NO7中的核苷酸1078-2013)，之后连接铰链区，人IgG1的CH2和CH3结构域(对应于序列SEQ ID NO7中的核苷酸2014-2703)的一部分构成，其中在核苷酸2017-2019含有由半胱氨酸变为甘氨酸(TGT-＞GGA)的突变。核酸序列编码的融合多肽序列为SEQ ID NO8。
(b)IL-1捕获者823-1198-B序列-所述IL-1捕获者823-1198-B序列由人IL-1RAcP细胞外结构域(对应于SEQ ID NO9的核苷酸1-1077)，之后连接人IL-1RI细胞外结构域(对应于序列SEQ ID NO9中的核苷酸1078-2013)，之后连接一段氨基酸片段(对应于SEQ ID NO9中的核苷酸2014-2019)，之后连接铰链区，人IgG4的CH2和CH3结构域(对应于序列SEQ ID NO9中的核苷酸2020-2709)构成。核酸序列编码融合的多肽序列为SEQ ID NO10所列。
(c)IL-1捕获者823-1267-C序列-所述IL-1捕获者823-1267-C序列由人IL-1RAcP细胞外结构域(对应于序列SEQ ID NO11中的核苷酸1-1077)，之后连接人IL-1RI细胞外结构域(对应于序列SEQ IDNO11中的核苷酸1078-2013)，之后连接一段氨基酸片段(对应于SEQID NO11中的核苷酸2014-2019)，之后连接铰链区，人IgG4的CH2和CH3结构域(对应于序列SEQ ID NO7中的核苷酸2020-2709)构成，其中包含在核苷酸2047(T＞C)将丝氨酸改变成脯氨酸的突变。核酸序列编码的融合多肽序列为SEQ ID NO12所列。
(d)IL-1捕获者570-FE序列-所述IL-1捕获者570-FE序列由人IL-1RI细胞外结构域(对应于序列SEQ ID NO1中的核苷酸1-996)，，之后连接人IL-1RAcP细胞外结构域(对应于序列SEQ ID NO1中的核苷酸997-2013)，之后连接铰链区，人IgG1的CH2和CH3结构域(对应于序列SEQ ID NO1中的核苷酸2014-2703)的一部分构成，其中包含在核苷酸2017-2019由半胱氨酸变为甘氨酸(TGT-＞GGA)的突变。核酸序列编码融合多肽为SEQ ID NO2所列序列。
(e)IL-1捕获者570-FE-B序列-所述IL-1捕获者570-FE-B序列由人IL-1RI细胞外结构域(对应于序列SEQ ID NO3中的核苷酸1-996)，之后连接人IL-1RAcP细胞外结构域(对应于序列SEQ ID NO3中的核苷酸997-2013)，之后连接一段氨基酸片段(对应于SEQ ID NO3中的核苷酸2014-2019)，之后连接铰链区，人IgG4的CH2和CH3结构域(对应于序列SEQ ID NO3中的核苷酸2020-2709)构成。核酸序列编码的融合多肽为SEQ ID NO4所列序列。
(f)IL-1捕获者570-FE-C序列-所述IL-1捕获者570-FE-C序列由人IL-1RI的细胞外结构域(对应于序列SEQ ID NO5中的核苷酸1-996)，之后连接人IL-RAcP细胞外结构域(对应于序列SEQ ID NO5中的核苷酸997-2013)，之后连接一段氨基酸片段(对应于SEQ ID NO5中的核苷酸2014-2019)，之后连接铰链区，人IgG4的CH2和CH3结构域(对应于序列SEQ ID NO7中的核苷酸2020-2709)构成，其中包含在核苷酸2047(T＞C)将丝氨酸改变成脯氨酸的突变。核酸序列编码的融合多肽为SEQ ID NO6所列序列。
(g)IL-1捕获者1647-CtF序列-所述IL-1捕获者1647-CtF序列由人IL-1RII细胞外结构域(对应于序列SEQ ID NO13中的核苷酸1-1044)，之后连接人IL-1RAcP细胞外结构域(对应于序列SEQ ID NO13中的核苷酸1045-2058)，之后连接铰链区，人IgG1的CH2和CH3结构域(对应于序列SEQ ID NO13中的核苷酸2059-2748)的一部分构成，其中包含在核苷酸2017-2019由半胱氨酸变为甘氨酸(TGT-＞GGA)的突变。核酸序列编码的融合多肽为SEQ ID NO14所列序列。
(h)IL-1捕获者1647-CtF-B序列-所述IL-1捕获者1647-CtF-B序列由人IL-1RII细胞外结构域(对应于序列SEQ ID NO15中的核苷酸1-1044)，之后连接人IL-1RAcP细胞外结构域(对应于序列SEQ IDNO15中的核苷酸1045-2058)，之后连接一段氨基酸片段(对应于EQID NO15中的核苷酸2059-2064)，之后连接铰链区，人IgG4的CH2和CH3结构域(对应于序列SEQ ID NO15中的核苷酸2065-2754)构成。核酸序列编码的融合多肽为SEQ ID NO16所列序列。
(i)IL-1捕获者1647-CtF-C序列-所述IL-1捕获者1647-CtF-C序列由人IL-1RII细胞外结构域(对应于序列SEQ ID NO17中的核苷酸1-1044)，之后连接人IL-1RAcP细胞外结构域(对应于序列SEQ IDNO17中的核苷酸1045-2058)，之后连接一段氨基酸片段(对应于SEQID NO17中的核苷酸2059-2064)，之后连接铰链区，人IgG4的CH2和CH3结构域(对应于序列SEQ ID NO17中的核苷酸2065-2754)构成，其中包含在核苷酸2092(T＞C)将丝氨酸改变成脯氨酸的突变。核酸序列编码的融合多肽为SEQ ID NO17所列序列。
(j)IL-1捕获者1649序列-所述IL-1捕获者1649序列由人IL-1RAcP细胞外结构域(对应于序列SEQ ID NO19中的核苷酸1-1074)，之后连接人IL-1RII细胞外结构域(对应于序列SEQ ID NO19中的核苷酸1075-2058)，之后连接铰链区，人IgG1的CH2和CH3结构域(对应于序列SEQ ID NO19中的核苷酸2059-2748)的一部分构成，其中包含在核苷酸2062-2064位点由半胱氨酸变为甘氨酸(TGT-＞GGA)的突变。核酸序列编码的融合多肽为SEQ ID NO20所列序列。
(k)IL-1捕获者1649-B序列-所述IL-1捕获者1649-B序列由人IL-1RAcP细胞外结构域(对应于序列SEQ ID NO21中的核苷酸1-1074)，之后连接人IL-1RII细胞外结构域(对应于序列SEQ ID NO21中的核苷酸1075-2058)，之后连接一段氨基酸片段(对应于核苷酸2059-2064)，之后连接铰链区，人IgG4的CH2和CH3结构域(对应于序列SEQ ID NO21中的核苷酸2065-2754)构成。核酸序列编码的融合多肽为SEQ ID NO22所列序列。
(1)IL-1捕获者1649-C序列-所述IL-1捕获者1649-C序列由人IL-1RAcP细胞外结构域(对应于序列SEQ ID NO23中的核苷酸1-1074)，之后连接人IL-1RII细胞外结构域(对应于序列SEQ ID NO23中的核苷酸1075-2058)，之后连接一段氨基酸片段(对应于SEQ ID NO23中的核苷酸2059-2064)，之后连接铰链区，人IgG4的CH2和CH3结构域(对应于序列SEQ ID NO23中的核苷酸2065-2754)构成，其中包含在核苷酸2092(T＞C)将丝氨酸改变成脯氨酸的突变。核酸序列编码的融合多肽为SEQ ID NO24所列序列。
除了上面所描述的序列外，下列对这些序列的修饰也是本主题发明所包括的。
1.对于IL1捕获者823，823-1198.B和823-1267.CAcP替换在核苷酸1043位从A到C的改变导致从赖氨酸到苏氨酸的氨基酸改变。SG插入在核苷酸1077和1078位之间插入核苷酸TCC GGA将在捕获者的两个受体结构域之间加上丝氨酸甘氨酸氨基酸片段。
2.对于IL1捕获者570-FE，570-FE.B和570-FE.CAcP替换在核苷酸1979位从A到C的改变导致从赖氨酸到苏氨酸的氨基酸改变。SG插入在核苷酸996和977位之间插入核苷酸TCC GGA将在捕获者的两个受体结构域之间加上丝氨酸甘氨酸氨基酸片段。
3.对于IL1捕获者1647-CtF，1647-CtF.B和1647-CtF.CAcP替换在核苷酸2027位从A到C的改变导致从赖氨酸到苏氨酸氨基酸的改变。SG插入在核苷酸1044和1045位之间插入核苷酸TCC GGA将在捕获者的两个受体结构域之间加上丝氨酸甘氨酸氨基酸片段。
4.对于IL1捕获者1649，1649-B和1649-CAcP替换在核苷酸1043位从A到C的改变导致从赖氨酸到苏氨酸的氨基酸改变。SG插入在核苷酸1074和1075位之间插入核苷酸TCC GGA将在捕获者的两个受体结构域之间加上丝氨酸甘氨酸氨基酸片段。
此外，本领域技术人员将认可构建其中Fc结构域源于不同的同种异型免疫球蛋白的IL-1捕获者是理想的。上面描述的修饰不会改变捕获者对IL1的结合能力。
例6.人IL-1捕获者阻止IL-1在发炎关节中的作用背景酵母聚糖(zymosan)是-种酵母细胞壁提取物，当它注射入膝盖时会在关节处引发急性炎症和上调IL-1β的水平(Joosten等人(1994)Clin Exp Immunol 97204-211.)。软骨细胞通过下调蛋白聚糖的合成对炎症和局部IL-1β作出反应，这种反应是促成关节处软骨渐近损坏的人关节炎的一个特征(Van den Berg等人(1982)Rheum Intl1165-169)。IL-1β的拮抗剂可以用来评估它们对酵母聚糖诱导的IL-1β上升的效应的阻断能力。
材料和方法通过经髌韧带麻痹的雄性C57BL/6小鼠右膝关节关节内(i.a.)注射酵母聚糖A(Sigma；300μg每10μ1)。通过髌韧带向其左膝关节关节内(i.a.)注射无菌PBS。在关节内注射之前24小时，用载体或hIL-1捕获子569(19mg/kg，皮下注射)处理动物。根据上面van den Berg等人(1982)描述的方法在注射酵母聚糖24小时之后去除小鼠髌骨以测量蛋白聚糖的合成。简而言之，将每个髌骨及其相连系的韧带放入含有10μCi/ml35S-硫酸盐(NEN DuPont)的培养基(含HEPES、HCO3、谷氨酰胺和青霉素/链霉素的RPMI)中于37℃，5％CO2条件下孵育3小时。孵育后，将组织清洗并用10％的福尔马琳(VWR)固定过夜。然后在将髌骨从周围组织分离出来之前将组织放入脱钙溶液(J.T.Baker)中放置4小时。然后将每个膝关节放在Solvable(Packard)中于50℃下孵育过夜。加入Utima Gold液体闪烁液(Packard)并且将样品用液体闪烁计数器计数。对每只动物测量的值为酵母聚糖关节的cpm/载体关节的cpm比值。
结果与载体注射相比，关节内注射酵母聚糖减少了近50％的蛋白聚糖的合成(图3)。在酵母聚糖注射之前施用hIL-1捕获者阻断了IL-1β的局部效应并且蛋白聚糖的合成恢复到对照的大约90％。这些数据显示hIL-1捕获者569皮下注射后能渗入关节中有效地中和IL-1在这些关节中的生物效应。
实施例7.在一个酵母聚糖加速的胶原蛋白诱导的关节炎(CIA)模型中，鼠IL-1捕获者减轻关节炎症的严重度背景已经显示IL-1涉及到类风湿性关节炎中炎症和软骨破坏的发展(Dinarello(1996)Blood 87(6)2095-2147；Wooley等人(1993)Arthritis & Rheumatism 36(9)1305-1314)。胶原蛋白诱导的关节炎(CIA)是与类风湿性关节炎相似的受到广泛研究的炎性多关节炎动物模型。普通组织病理特征包括关节的炎症和侵蚀、滑液超常增生和炎性细胞浸润(Joe等人(1999)Mol Med Today 5367-369)。由于前人的研究已经显示各种抗IL-1处理对减轻CIA动物中的关节炎症状有积极作用(van den Berg等人(1994)Clin Exp Immunol 95237-243；Joosten等人(1999)J Immunol 1635049-5055.；van de Loo等人(1992)J Rheumatol 19348-356.)，申请者在这种动物模型中检查了鼠IL-1捕获者(mIL-1捕获者)对关节炎症状发展进程的影响。人IL-1捕获者与啮齿动物的IL-1很少有交叉反应。mIL-1捕获者由鼠IL-1RAcP细胞外结构域之后连接鼠IL-IRI细胞外结构域，之后连接铰链，鼠科动物IgG2a的CH2和CH3结构域而构成。
材料和方法用100μg/50μl经完全和不完全弗式佐剂(2∶1∶1比例；Chondrex)乳化过的牛II型胶原蛋白(CII；Chondrex)在尾巴基部对雄性DBA-1小鼠进行皮内免疫并在第21天用经不完全弗式佐剂乳化过的II型胶原蛋白(100μg/50μl)进行皮内免疫加强。由于CIA在DBA-1小鼠体内以较低发生率经过较长的时期逐渐发生(Joosten等人，(1994)Clin Exp Immunol 97204-211)，申请者通过在第30天用3mg酵母聚糖(Sigma)腹膜内注射动物以同步化关节炎症状的起始。在注射酵母聚糖之前2小时，小鼠被随机分配到几个处理组并用载体或mIL-1捕获者(31或10mg/kg，3X/周，8次皮下注射)对其进行注射。由不知道处理组的人每周3次估量爪子的关节炎症状(ASI分值，如Wooley等人(1993)Arthritis & Rheumatism 36(9)1305-1314中所描述)。在第8次注射后24小时，杀死动物，测量此时的爪子宽度连同ASI分值。
结果相对那些接受mIL-1捕获者处理(图4)的在酵母聚糖注射10到15后症状达到最大值的动物，用载体处理的动物在皮下注射酵母聚糖后5天内ASI分值有了显著的增加。鼠IL-1捕获者以剂量依赖的方式起作用，因此接受10mg/kg捕获者处理的动物具有比那些接受31mg/kg捕获者处理的动物更严重的关节炎症状(更大的ASI分值)。然而，两个mIL-1捕获者处理组都具有显著低于载体处理组的关节炎症状。这种ASI分值的不同也反应在宰杀时动物爪子的宽度(图5)。接受mIL-1捕获者处理的动物有着与那些天然的没有用胶原蛋白免疫过的动物相似宽度的爪子。这些数据显示mIL-1捕获者能有效地中和IL-1并阻止发炎关节的发展。
实施例8.IL-1捕获者1649能阻断IL-1β的活性在室温下，将各种浓度的IL-1捕获者1649与5pM的人IL-1b共同孵育过夜。然后在37℃、5％CO2的条件下将该混合物加入到二个293-NFkB细胞(20,000细胞/孔)孔里孵育5小时。293-NFkB细胞含有一个稳定整合的具有荧光素酶基因(该基因被一个包含5个NFkB位点的启动子驱动)的报告质粒。IL-1b的加入导致荧光素酶基因表达的增加。在室温下将Steady-Glo Reagent(Promega)加入到细胞中过15分钟并且用照度计将荧光素酶基因表达定量为相对光单位(RLU)。IL-1捕获子1649显示IC50为32pM，该值暗示了约30pM的Kd(图6)。这些数据显示IL-1捕获子1649潜在地阻断IL-1。
本发明不局限于此处描述的具体实施方案的范围内。事实上，从前面的描述和附图来看，除了此处描述的修改，本发明的各种修改对本领域技术人员来说是明显的。这样的修改属于权利要求的范围内。
序列表<110>REGENERON PHARMACEUTICALS，INC.
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Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu690 695 700Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser705 710 715 720His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu725 730 735Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr740 745 750Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn755 760 765Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro770 775 780Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln785 790 795 800Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val805 810 815Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val820 825 830Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro835 840 845Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr850 855 860Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val865 870 875 880Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu885 890 895Ser Pro Gly Lys900<210>3<211>2709<212>DNA<213>人<400>3atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat60aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt120cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac180agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt240tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca300tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt360tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg420tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat480aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc540atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca600tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac660aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga720tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag780tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg840gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt900gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat960gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga1020ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca1080ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg1140atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc1200gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac1260actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc1320
ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa1380ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct1440tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat1500aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga1560aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact1620ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct1680aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc1740tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa1800cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa1860gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc1920agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag1980cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca2040tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg2700ggtaaatga2709<210>4<211>902<212>PRT<213>人<400>4Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser1 5 10 15Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val20 25 30Ser Ser Ala Asn GluIle Asp Val Arg Pro Cys Pro Leu Asn Pro Asn35 40 45Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro50 55 60Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu65 70 75 80Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val85 90 95Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe100 105 110Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys115 120 125Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met130 135 140Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr145 150 155 160Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val165 170 175Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn180 185 190Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile195 200 205
Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg210 215 220Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly225 230 235 240Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile245 250 255Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val260265 270Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg275 280 285Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe290 295 300Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp305 310 315 320Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys325 330 335Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp340 345 350Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe355 360 365Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp370 375 380Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro385 390 395 400Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr405 410 415Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr420 425 430Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser435 440 445Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu450 455 460Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro465 470 475 480Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile485 490 495Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu500 505 510Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr515 520 525Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys530 535 540Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro545 550 555 560Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile565 570 575Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val580 585 590Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val595 600 605Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg610 615 620Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg625 630 635 640Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala645 650 655Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser
660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu885 890 895Ser Leu Ser Leu Gly Lys900<210>5<211>2709<212>DNA<213>人<400>5atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat60aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt120cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac180agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt240tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca300tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt360tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg420tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat480aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc540atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca600tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac660aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga720tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag780tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg840gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt900gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat960gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga1020ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca1080ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg1140
atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc1200gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac1260actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc1320ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa1380ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct1440tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat1500aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga1560aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact1620ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct1680aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc1740tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa1800cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa1860gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc1920agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag1980cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca2040tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg2700ggtaaatga2709<210>6<211>902<212>PRT<213>人<400>6Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser1 5 10 15Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val20 25 30Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn35 40 45Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro50 55 60Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu65 70 75 80Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val85 90 95Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe100 105 110Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys115 120 125Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met130 135 140Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr145 150 155 160Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val165 170 175Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn
180 185 190Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile195 200 205Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg210 215 220Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly225 230 235 240Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile245 250 255Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val260 265 270Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg275 280 285Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe290 295 300Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp305 310 315 320Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys325 330 335Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp340 345 350Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe355 360 365Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp370 375 380Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro385 390 395 400Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr405 410 415Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr420 425 430Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser435 440 445Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu450 455 460Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro465 470 475 480Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile485 490 495Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu500 505 510Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr515 520 525Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys530 535 540Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro545 550 555 560Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile565 570 575Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val580 585 590Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val595 600 605Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg610 615 620Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg625 630 635 640
Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala645 650 655Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr835 840 845Thr Pr0 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu885 890 895Ser Leu Ser Leu Gly Lys900<210>7<211>2703<212>DNA<213>人<400>7atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa960
gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa1080tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt1140ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc1200aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg1260tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct1320tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat13 8 0aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc1440ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag1500gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc1560gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac1620ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa1680cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc1740cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg1800aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa1860aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag1920agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca1980gcatatatcc agttaatata tccagtcact aattccggag acaaaactca cacatgccca2040ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc2100aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc2160cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc2220aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc2280gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc2340ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag2400gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc2460ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg2520gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac2580agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg2640atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa2700tga 2703<210>8<211>900<212>PRT<213>人<400>8Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile355 360 365Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu370 375 380Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser385 390 395 400Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys405 410 415Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr420 425 430Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser435 440 445Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala450 455 460Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys465 470 475 480Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu485 490 495Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe500 505 510Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His515 520 525Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln530 535 540Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys545 550 555 560Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val565 570 575Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu580 585 590Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp595 600 605Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn
610 615 620Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu625 630 635 640Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His645 650 655Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser660 665 670Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu675 680 685Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu690 695 700Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser705 710 715 720His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu725 730 735Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr740 745 750Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn755 760 765Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro770 775 780Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln785 790 795 800Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val805 810 815Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val820 825 830Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro835 840 845Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr850 855 860Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val865 870 875 880Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu885 890 895Ser Pro Gly Lys900<210>9<211>2709<212>DNA<213>人<400>9atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag780
gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa1080tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt1140ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc1200aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg1260tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct1320tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat1380aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc1440ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag1500gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc1560gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac1620ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa1680cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc1740cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg1800aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa1860aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag1920agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca1980gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca2040tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg2700ggtaaatga2709<210>10<211>902<212>PRT<213>人<400>10Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile355 360 365Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu370 375 380Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser385 390 395 400Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys405 410 415Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr420 425 430Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser435 440 445Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala450 455 460Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys465 470 475 480Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu485 490 495Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe500 505 510Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His515 520 525Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln530 535 540Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys545 550 555 560Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val565 570 575Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu580 585 590
Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp595 600 605Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn610 615 620Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu625 630 635 640Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His645 650 655Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu885 890 895Ser Leu Ser Leu Gly Lys900<210>11<211>2709<212>DNA<213>人<400>11atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc600
attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa1080tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt1140ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc1200aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg1260tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct1320tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat1380aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc1440ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag1500gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc1560gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac1620ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa1680cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc1740cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtggl800aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa1860aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag1920agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca1980gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca2040tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg2700ggtaaatga2709<210>12<211>902<212>PRT<213>人<400>12Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile355 360 365Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu370 375 380Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser385 390 395 400Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys405 410 415Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr420 425 430Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser435 440 445Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala450 455 460Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys465 470 475 480Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu485 490 495Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe500 505 510Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His515 520 525Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln530 535 540Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys545 550 555 560Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val
565 570 575Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu580 585 590Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp595 600 605Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn610 615 620Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu625 630 635 640Ser Arg Phe Tyr Lys Hig Pro Phe Thr Cys Phe Ala Lys Asn Thr His645 650 655Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg850 855 860Leu Thr val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu885 890 895Ser Leu Ser Leu Gly Lys900<210>13<211>2748<212>DNA<213>人<400>13atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca60cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg120ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct180gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga240gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag300gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc360attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa420
attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt480gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat540gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa600gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc660actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt720tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg780tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac840atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa900aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg960cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca1020gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg1080aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac1140ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg1200actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt1260agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat1320acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt1380caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa1440tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa1500ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc1560gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt1620gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag1680gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg1740gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt1800ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc1860actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga1920actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt1980catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca2040gctccaagat acacagtgtc cggagacaaa actcacacat gcccaccgtg cccagcacct2100gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg2160atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag2220gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg2280gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac2340tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc2400gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc2460ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc2520tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag2580accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg2640gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg2700cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 2748<210>14<211>915<212>PRT<213>人<400>14Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu1 5 10 15Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly20 25 30Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu35 40 45Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg50 55 60Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly65 70 75 80Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu
85 90 95Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn100 105 110Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn115 120 125Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu130 135 140Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg145 150 155 160Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu165 170 175Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu180 185 190Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Va1195 200 205Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile210 215 220Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile225 230 235 240Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile245 250 255Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu260 265 270Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly275 280 285Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn290 295 300Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu305 310 315 320His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr325 330 335Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys340 345 350Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp355 360 365Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe370 375 380Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp385 390 395 400Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro405 410 415Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr420 425 430Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr435 440 445Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser450 455 460Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu465 470 475 480Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro485 490 495Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile500 505 510Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu515 520 525Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr530 535 540
Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys545 550 555 560Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro565 570 575Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile580 585 590Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val595 600 605Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val610 615 620Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg625 630 635 640Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg645 650 655Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala660 665 670Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly675 680 685Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly690 695 700Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met705 710 715 720Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His725 730 735Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val740 745 750His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr755 760 765Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly770 775 780Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile785 790 795 800Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val805 810 815Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser820 825 830Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu835 840 845Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro850 855 860Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val865 870 875 880Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met885 890 895His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser900 905 910Pro Gly Lys915<210>15<211>2754<212>DNA<213>人<400> 15atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca60cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg120
ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct180gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga240gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag300gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc360attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa420attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt480gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat540gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa600gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc660actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt720tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg780tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac840atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa900aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg960cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca1020gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg1080aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac1140ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg1200actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt1260agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat1320acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt1380caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa1440tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa1500ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc1560gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt1620gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag1680gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg1740gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt1800ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc1860actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga1920actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt1980catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca2040gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc atcatgccca2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754<210>16<211>917<212>PRT<213>人<400>16Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu1 5 10 15Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly20 25 30Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu35 40 45
Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg50 55 60Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly65 70 75 80Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu85 90 95Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn100 105 110Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn115 120 125Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu130 135 140Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg145 150 155 160Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu165 170 175Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu180 185 190Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val195 200 205Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile210 215 220Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile225 230 235 240Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile245 250 255Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu260 2652 70Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly275 280 285Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn290 295 300Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu305 310 315 320His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr325 330 335Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys340 345 350Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp355 360 365Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe370 375 380Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp385 390 395 400Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro405 410 415Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr420 425 430Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr435 440 445Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser450 455 460Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu465 470 475 480Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro485 490 495Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile
500 505 510Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu515 520 525Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr530 535 540Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys545 550 555 560Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro565 570 575Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile580 585 590Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val595 600 605Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val610 615 620Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg625 630 635 640Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg645 650 655Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala660 665 670Ala Lys Val Lys Gln Lys Val Pro Ala pro Arg Tyr Thr Val Ser Gly675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser900 905 910Leu Ser Leu Gly Lys915<210>17<211>2754<212>DNA
<213>人<400>17atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca60cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg120ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct180gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga240gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag300gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc360attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa420attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt480gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat540gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa600gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc660actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt720tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg780tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac840atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa900aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg960cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca1020gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg1080aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac1140ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg1200actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt1260agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat1320acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt1380caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa1440tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa1500ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc1560gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt1620gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag1680gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg1740gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt1800ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc1860actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga1920actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt1980catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca2040gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc accatgccca2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754<210>18<211>917<212>PRT<213>人<400>18Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu
1 5 10 15Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly20 25 30Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu35 40 45Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg50 55 60Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly65 70 75 80Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu85 90 95Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn100 105 110Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn115 120 125Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu130 135 140Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg145 150 155 160Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu165 170 175Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu180 185 190Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val195 200 205Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile210 215 220Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile225 230 235 240Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile245 250 255pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu260 265 270Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly275 280 285Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn290 295 300Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu305 310 315 320His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr325 330 335Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys340 345 350Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp355 360 365Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe370 375 380Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp385 390 395 400Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro405 410 415Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr420 425 430Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr435 440 445Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser450 455 460
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu465 470 475 480Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro485 490 495Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile500 505 510Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu515 520 525Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr530 535 540Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys545 550 555 560Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro565 570 575Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile580 585 590Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val595 600 605Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val610 615 620Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg625 630 635 640Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg645 650 655Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala660 665 670Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser900 905 910Leu Ser Leu Gly Lys
915<210>19<211>2748<212>DNA<213>人<400>19atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca1080ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa1140ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc1200ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa1260gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac1320tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag1380ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta1440accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa1500actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa1560tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct1620ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg1680agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc1740ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg1800ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag1860agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat1920gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg1980gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag2040gaagcctcct ccacgttctc cggagacaaa actcacacat gcccaccgtg cccagcacct2100gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg2160atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag2220gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg2280gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac2340tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc2400gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc2460ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc2520tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag2580accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg2640gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg2700cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 2748<210>20<211>915
<212>PRT<213>人<400>20Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe355 360 365Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val370 375 380Ala Leu Arg Cys Pro Gln val Pro Tyr Trp Leu Trp Ala Ser Val Ser385 390 395 400Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val405 410 415Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp
420 425 430Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr435 440 445Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe450 455 460Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu465 470 475 480Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe485 490 495Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu500 505 510Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr515 520 525His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg530 535 540Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg545 550 555 560Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val565 570 575Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu580 585 590Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr595 600 605Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro610 615 620Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn625 630 635 640Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu645 650 655Asp Leu His Met Asp Phe Lys cys Val Val His Asn Thr Leu Ser Phe660 665 670Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly675 680 685Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly690 695 700Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met705 710 715 720Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His725 730 735Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val740 745 750His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr755 760 765Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly770 775 780Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile785 790 795 800Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val805 810 815Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser820 825 830Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu835 840 845Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro850 855 860Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val865 870 875 880
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met885 890 895His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser900 905 910Pro Gly Lys915<210>21<211>2754<212>DNA<213>人<400>21atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca1080ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa1140ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc1200ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa1260gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac1320tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag1380ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta1440accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa1500actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa1560tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct1620ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg1680agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc1740ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg1800ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag1860agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat1920gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg1980gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag2040gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc atcatgccca2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta2640
accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754<210>22<211>917<212>PRT<213>人<400>22Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu LeuIle Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe355 360 365Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val370 375 380
Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser385 390 395 400Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val405 4l0 4l5Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp420 425 430Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr435 440 445Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe450 455 460Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu465 470 475 480Thr Leu Ser Thr Ser Gly Val Leu val Cys Pro Asp Leu Ser Glu Phe485 490 495Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu500 505 510Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr515 520 525His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg530 535 540Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg545 550 555 560Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val565 570 575Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu580 585 590Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr595 600 605Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro610 615 620Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn625 630 635 640Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu645 650 655Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe660 665 670Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser900 905 910Leu Ser Leu Gly Lys915<210>23<211>2754<212>DNA<213>人<400>23atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca1080ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa1140ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc1200ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa1260gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac1320tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag1380ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta1440accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa1500actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa1560tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct1620ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg1680agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc1740ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg1800ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag1860agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat1920gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg1980gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag2040gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc accatgccca2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac2340
caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754<210>24<211>917<212>PRT<213>人<400>24Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe355 360 365Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val370 375 380Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser385 390 395 400Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val405 410 415Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp420 425 430Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr435 440 445Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe450 455 460Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu465 470 475 480Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe485 490 495Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu500 505 510Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr515 520 525His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg530 535 540Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg545 550 555 560Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val565 570 575Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu580 585 590Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr595 600 605Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro610 615 620Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn625 630 635 640Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu645 650 655Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe660 665 670Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly675 680 685Glu Ser Lys Tyr Gly Pro Pro cys Pro Pro Cys Pro Ala Pro Glu Phe690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser900 905 910Leu Ser Leu Gly Lys915<210>25<211>6<212>PRT<213>人工序列<220>
<223>合成的<400>25His His His His His His1 5<210>26<211>5<212>PRT<213>人<220>
<221>变体<222>3<223>Xaa＝任何氨基酸<400>26Trp Ser Xaa Trp Ser1 权利要求
1.分离的核酸分子，其包含选自下列的序列SEQ ID NO1，3，5，7，9，11，13，15，17，19，21和23，其中所述分离的核酸分子编码的融合多肽形成能结合白细胞介素1(IL-1)而形成无功能复合物的多聚体。
2.权利要求1的分离的核酸分子，其编码分别选自下列的序列SEQ ID NO2，4，6，8，10，12，14，16，18，20，22，和24。
3.权利要求1的分离的核酸分子，其中该序列为SEQ ID NO7。
4.权利要求3的分离的核酸分子，其中该核酸分子编码包含序列SEQ ID NO8的融合多肽。
5.包含权利要求1到4中任一项的分离的核酸分子的载体。
6.包含有效地连接表达控制序列的权利要求1到4中任一项的分离的核酸分子的表达载体。
7.用于在合适的宿主细胞内生产融合多肽的宿主-载体系统，其包含权利要求6的表达载体。
8.权利要求7的宿主-载体系统，其中宿主细胞是细菌细胞、酵母细胞、昆虫细胞或哺乳动物细胞。
9.权利要求8的宿主-载体系统，其中宿主细胞是CHO细胞。
10.产生融合多肽的方法，包括在允许产生融合多肽的条件下培养权利要求8的宿主-载体系统的细胞，和回收这样产生的融合多肽。
11.权利要求1的分离的核酸，其中SEQ ID NO1，3或5的核酸包含一或多个的如下改变(a)核苷酸1979位由A变成C；并且(b)将核苷酸TCC GGA插入到核苷酸996和997位之间；
12.权利要求1的分离的核酸，其中SEQ ID NO7，9，或11的核酸包含一或多个如下改变(a)SEQ ID NO7，9，或11的核苷酸1043位由A变成C；并且(b)将核苷酸TCC GGA插入到核苷酸1077和1078位点之间。
13.权利要求1的分离的核酸，其中SEQ ID NO13，15或17的核酸包含一或多个的如下改变(a)核苷酸2027位由A变成C；(b)将核苷酸TCC GGA插入到核苷酸1044和1045位之间。
14.权利要求1的分离的核酸，其中SEQ ID NO19，21或23的核酸包含一或多个的如下改变(a)核苷酸1043位点由A变成C；且(b)将核苷酸TCC GGA插入到核苷酸1074和1075位点之间。
15.由权利要求1或11到14中的任一项的核酸分子编码的融合多肽。
16.融合多肽，其包含氨基酸序列SEQ ID NO2，4，6，8，10，12，14，16，18，20，22和24。
17.包含权利要求6的融合多肽的多聚体，其能与IL-1结合形成无功能复合物。
18.权利要求17的多聚体，其为二聚体。
19.权利要求18的多聚体，其中各融合蛋白具有SEQ ID NO8的序列。
全文摘要
本发明提供了能与白细胞介素－1(IL－1)结合而形成无功能复合物的融合多肽。本发明也提供了编码该融合多肽的核酸序列和制造与使用该融合多肽的方法。
文档编号A61K38/00GK1878871SQ200380102337
公开日2006年12月13日 申请日期2003年10月24日 优先权日2002年10月28日
发明者N·斯塔尔, G·D·扬科波洛斯 申请人:瑞泽恩制药公司