CN1878871A - 基于il－1受体的拮抗剂和制造与使用的方法 - Google Patents
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Abstract
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。
Description
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。
发明背景
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 NO：26)(Bazan(1990)PNAS 87：6934-6938)。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)Ce1129：671-679)；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 NO：2序列融合多肽的分离的具有SEQ ID NO：1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 NO：4序列的融合多肽的分离的核酸分子，其具有SEQ ID NO：3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 NO：6序列的融合多肽的分离的核酸分子，其具有SEQ ID NO：5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 NO：7，9，11，13，15，17，19，21和23所列序列的分离的核酸分子，它们分别编码具有SEQ IDNO：8，10，12，14，16，18，20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 6：36-40；Gentz等人，(1989)Science 243：1695-1699)。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 NO：25)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 67：35-44)。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.148：1547-1553))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-1
IL-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 Cloning：A 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 NO：7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 NO：7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 NO：7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 NO：8。
(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 NO：9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 NO：9中的核苷酸1078-2013)，之后连接一段氨基酸片段(对应于SEQ ID NO：9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 NO：9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 NO：10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 NO：11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 IDNO：11中的核苷酸1078-2013)，之后连接一段氨基酸片段(对应于SEQID NO：11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 NO：7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 NO：12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 NO：1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 NO：1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 NO：1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 NO：2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 NO：3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 NO：3中的核苷酸997-2013)，之后连接一段氨基酸片段(对应于SEQ ID NO：3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 NO：3中的核苷酸2020-2709)构成。核酸序列编码的融合多肽为SEQ ID NO：4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 NO：5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 NO：5中的核苷酸997-2013)，之后连接一段氨基酸片段(对应于SEQ ID NO：5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 NO：7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 NO：6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 NO：13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 NO：13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 NO：13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 NO：14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 NO：15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 IDNO：15中的核苷酸1045-2058)，之后连接一段氨基酸片段(对应于EQID NO：15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 NO：15中的核苷酸2065-2754)构成。核酸序列编码的融合多肽为SEQ ID NO：16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 NO：17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 IDNO：17中的核苷酸1045-2058)，之后连接一段氨基酸片段(对应于SEQID NO：17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 NO：17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 NO：17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 NO：19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 NO：19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 NO：19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 NO：20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 NO：21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 NO：21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 NO：21中的核苷酸2065-2754)构成。核酸序列编码的融合多肽为SEQ ID NO：22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 NO：23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 NO：23中的核苷酸1075-2058)，之后连接一段氨基酸片段(对应于SEQ ID NO：23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 NO：23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 NO：24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.C：AcP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.C：AcP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.C：AcP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-C：AcP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 97：204-211.)。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 Intl1：165-169)。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 5：367-369)。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 95：237-243；Joosten等人(1999)J Immunol 163：5049-5055.；van de Loo等人(1992)J Rheumatol 19：348-356.)，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 97：204-211)，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.
<120>基于IL-1受体的拮抗剂和制造与使用的方法
<130>REG 203C-WO
<140>to be assigned
<141>2003-10-24
<150>10/282,162
<151>2002-10-28
<150>09/787,835
<151>2001-03-22
<150>PCT/US99/22045
<151>1999-09-22
<160>26
<170>FastSEQ for Windows Version 3.0
<210>1
<211>2703
<212>DNA
<213>人
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atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60
aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120
cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180
agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240
tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300
tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360
tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420
tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480
aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540
atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600
tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660
aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720
tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780
tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840
gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900
gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960
gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020
ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080
ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140
atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200
gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260
actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320
ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380
ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440
tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500
aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560
aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620
ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680
aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740
tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800
cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860
gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920
agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980
cagaaagtgc cagctccaag atacacagtg gaatccggag acaaaactca cacatgccca 2040
ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 2100
aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 2160
cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 2220
aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 2280
gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 2340
ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 2400
gtgtacaccc tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc 2460
ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 2520
gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctat 2580
agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 2640
atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 2700
tga 2703
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Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn
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Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro
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Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu
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Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val
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Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe
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Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys
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Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met
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Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr
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Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val
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Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn
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Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile
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Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg
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Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly
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Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile
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Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val
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Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg
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Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe
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Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp
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Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys
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Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp
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Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe
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Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp
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Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro
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Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr
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Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr
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Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser
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Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu
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Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu
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Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr
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Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys
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Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro
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Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile
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Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val
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Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val
595 600 605
Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg
610 615 620
Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg
625 630 635 640
Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala
645 650 655
Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser
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Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
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Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
690 695 700
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
705 710 715 720
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
725 730 735
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
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Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
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Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
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Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
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Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
835 840 845
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
850 855 860
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
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Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
885 890 895
Ser Pro Gly Lys
900
<210>3
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<212>DNA
<213>人
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atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60
aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120
cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180
agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240
tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300
tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360
tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420
tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480
aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540
atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600
tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660
aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720
tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780
tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840
gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900
gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960
gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020
ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080
ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140
atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200
gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260
actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320
ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380
ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440
tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500
aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560
aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620
ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680
aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740
tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800
cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860
gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920
agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980
cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca 2040
tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100
aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160
gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220
aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280
ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340
aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400
ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460
acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580
ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640
tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700
ggtaaatga 2709
<210>4
<211>902
<212>PRT
<213>人
<400>4
Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser
1 5 10 15
Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val
20 25 30
Ser Ser Ala Asn GluIle Asp Val Arg Pro Cys Pro Leu Asn Pro Asn
35 40 45
Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro
50 55 60
Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu
65 70 75 80
Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val
85 90 95
Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe
100 105 110
Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys
115 120 125
Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met
130 135 140
Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr
145 150 155 160
Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val
165 170 175
Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn
180 185 190
Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile
195 200 205
Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg
210 215 220
Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly
225 230 235 240
Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile
245 250 255
Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val
260 265 270
Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg
275 280 285
Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe
290 295 300
Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp
305 310 315 320
Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys
325 330 335
Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp
340 345 350
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe
355 360 365
Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp
370 375 380
Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro
385 390 395 400
Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr
405 410 415
Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr
420 425 430
Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser
435 440 445
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu
450 455 460
Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro
465 470 475 480
Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile
485 490 495
Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu
500 505 510
Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr
515 520 525
Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys
530 535 540
Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro
545 550 555 560
Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile
565 570 575
Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val
580 585 590
Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val
595 600 605
Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg
610 615 620
Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg
625 630 635 640
Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala
645 650 655
Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser
660 665 670
Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu
675 680 685
Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
690 695 700
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
705 710 715 720
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
725 730 735
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
740 745 750
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
755 760 765
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
770 775 780
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
785 790 795 800
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
805 810 815
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
820 825 830
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
835 840 845
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
850 855 860
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
865 870 875 880
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
885 890 895
Ser Leu Ser Leu Gly Lys
900
<210>5
<211>2709
<212>DNA
<213>人
<400>5
atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60
aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120
cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180
agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240
tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300
tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360
tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420
tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480
aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540
atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600
tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660
aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720
tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780
tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840
gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900
gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960
gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020
ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080
ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140
atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200
gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260
actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320
ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380
ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440
tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500
aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560
aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620
ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680
aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740
tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800
cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860
gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920
agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980
cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca 2040
tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100
aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160
gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220
aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280
ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340
aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400
ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460
acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580
ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640
tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700
ggtaaatga 2709
<210>6
<211>902
<212>PRT
<213>人
<400>6
Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser
1 5 10 15
Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val
20 25 30
Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn
35 40 45
Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro
50 55 60
Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu
65 70 75 80
Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val
85 90 95
Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe
100 105 110
Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys
115 120 125
Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met
130 135 140
Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr
145 150 155 160
Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val
165 170 175
Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn
180 185 190
Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile
195 200 205
Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg
210 215 220
Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly
225 230 235 240
Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile
245 250 255
Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val
260 265 270
Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg
275 280 285
Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe
290 295 300
Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp
305 310 315 320
Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys
325 330 335
Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp
340 345 350
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe
355 360 365
Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp
370 375 380
Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro
385 390 395 400
Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr
405 410 415
Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr
420 425 430
Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser
435 440 445
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu
450 455 460
Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro
465 470 475 480
Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile
485 490 495
Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu
500 505 510
Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr
515 520 525
Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys
530 535 540
Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro
545 550 555 560
Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile
565 570 575
Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val
580 585 590
Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val
595 600 605
Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg
610 615 620
Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg
625 630 635 640
Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala
645 650 655
Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser
660 665 670
Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
675 680 685
Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
690 695 700
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
705 710 715 720
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
725 730 735
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
740 745 750
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
755 760 765
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
770 775 780
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
785 790 795 800
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
805 810 815
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
820 825 830
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
835 840 845
Thr Pr0 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
850 855 860
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
865 870 875 880
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
885 890 895
Ser Leu Ser Leu Gly Lys
900
<210>7
<211>2703
<212>DNA
<213>人
<400>7
atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60
tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120
gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180
gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240
gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300
ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360
tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420
cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540
tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600
attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720
gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780
gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840
tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900
agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960
gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020
gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080
tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140
ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200
aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260
tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320
tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 13 8 0
aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440
ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500
gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560
gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620
ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680
cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740
cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800
aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860
aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920
agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980
gcatatatcc agttaatata tccagtcact aattccggag acaaaactca cacatgccca 2040
ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 2100
aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 2160
cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 2220
aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 2280
gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 2340
ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 2400
gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 2460
ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 2520
gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 2580
agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 2640
atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 2700
tga 2703
<210>8
<211>900
<212>PRT
<213>人
<400>8
Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu
1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met
20 25 30
Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro
35 40 45
Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala
50 55 60
Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80
Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125
Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140
Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys
145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr
165 170 175
Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro
180 185 190
Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly
195 200 205
Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His
210 215 220
Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala
225 230 235 240
Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys
245 250 255
Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe
260 265 270
Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys
275 280 285
Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His
290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys
305 310 315 320
Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser
325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350
Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile
355 360 365
Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu
370 375 380
Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser
385 390 395 400
Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys
405 410 415
Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr
420 425 430
Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser
435 440 445
Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala
450 455 460
Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys
465 470 475 480
Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu
485 490 495
Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe
500 505 510
Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His
515 520 525
Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln
530 535 540
Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys
545 550 555 560
Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val
565 570 575
Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu
580 585 590
Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp
595 600 605
Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn
610 615 620
Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu
625 630 635 640
Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His
645 650 655
Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser
660 665 670
Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
675 680 685
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
690 695 700
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
705 710 715 720
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
725 730 735
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
740 745 750
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
755 760 765
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
770 775 780
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
785 790 795 800
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
805 810 815
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
820 825 830
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
835 840 845
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
850 855 860
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
865 870 875 880
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
885 890 895
Ser Pro Gly Lys
900
<210>9
<211>2709
<212>DNA
<213>人
<400>9
atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60
tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120
gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180
gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240
gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300
ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360
tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420
cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540
tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600
attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720
gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780
gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840
tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900
agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960
gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020
gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080
tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140
ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200
aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260
tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320
tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380
aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440
ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500
gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560
gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620
ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680
cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740
cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800
aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860
aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920
agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980
gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca 2040
tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100
aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160
gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220
aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280
ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340
aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400
ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460
acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580
ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640
tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700
ggtaaatga 2709
<210>10
<211>902
<212>PRT
<213>人
<400>10
Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu
1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met
20 25 30
Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro
35 40 45
Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala
50 55 60
Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80
Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125
Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140
Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys
145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr
165 170 175
Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro
180 185 190
Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly
195 200 205
Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His
210 215 220
Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala
225 230 235 240
Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys
245 250 255
Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe
260 265 270
Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys
275 280 285
Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His
290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys
305 310 315 320
Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser
325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350
Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile
355 360 365
Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu
370 375 380
Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser
385 390 395 400
Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys
405 410 415
Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr
420 425 430
Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser
435 440 445
Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala
450 455 460
Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys
465 470 475 480
Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu
485 490 495
Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe
500 505 510
Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His
515 520 525
Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln
530 535 540
Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys
545 550 555 560
Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val
565 570 575
Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu
580 585 590
Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp
595 600 605
Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn
610 615 620
Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu
625 630 635 640
Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His
645 650 655
Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser
660 665 670
Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu
675 680 685
Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
690 695 700
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
705 710 715 720
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
725 730 735
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
740 745 750
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
755 760 765
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
770 775 780
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
785 790 795 800
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
805 810 815
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
820 825 830
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
835 840 845
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
850 855 860
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
865 870 875 880
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
885 890 895
Ser Leu Ser Leu Gly Lys
900
<210>11
<211>2709
<212>DNA
<213>人
<400>11
atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60
tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120
gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180
gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240
gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300
ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360
tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420
cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540
tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600
attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720
gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780
gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840
tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900
agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960
gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020
gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080
tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140
ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200
aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260
tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320
tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380
aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440
ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500
gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560
gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620
ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680
cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740
cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg l800
aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860
aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920
agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980
gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca 2040
tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100
aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160
gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220
aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280
ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340
aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400
ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460
acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580
ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640
tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700
ggtaaatga 2709
<210>12
<211>902
<212>PRT
<213>人
<400>12
Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu
1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met
20 25 30
Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro
35 40 45
Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala
50 55 60
Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80
Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125
Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140
Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys
145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr
165 170 175
Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro
180 185 190
Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly
195 200 205
Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His
210 215 220
Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala
225 230 235 240
Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys
245 250 255
Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe
260 265 270
Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys
275 280 285
Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His
290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys
305 310 315 320
Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser
325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350
Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile
355 360 365
Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu
370 375 380
Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser
385 390 395 400
Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys
405 410 415
Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr
420 425 430
Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser
435 440 445
Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala
450 455 460
Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys
465 470 475 480
Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu
485 490 495
Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe
500 505 510
Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His
515 520 525
Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln
530 535 540
Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys
545 550 555 560
Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val
565 570 575
Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu
580 585 590
Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp
595 600 605
Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn
610 615 620
Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu
625 630 635 640
Ser Arg Phe Tyr Lys Hig Pro Phe Thr Cys Phe Ala Lys Asn Thr His
645 650 655
Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser
660 665 670
Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
675 680 685
Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
690 695 700
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
705 710 715 720
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
725 730 735
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
740 745 750
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
755 760 765
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
770 775 780
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
785 790 795 800
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
805 810 815
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
820 825 830
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
835 840 845
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
850 855 860
Leu Thr val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
865 870 875 880
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
885 890 895
Ser Leu Ser Leu Gly Lys
900
<210>13
<211>2748
<212>DNA
<213>人
<400>13
atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60
cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120
ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180
gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240
gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300
gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360
attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420
attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480
gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540
gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600
gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660
actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720
tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780
tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840
atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900
aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960
cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020
gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080
aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140
ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200
actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260
agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320
acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380
caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440
tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500
ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560
gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620
gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680
gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740
gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800
ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860
actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920
actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980
catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040
gctccaagat acacagtgtc cggagacaaa actcacacat gcccaccgtg cccagcacct 2100
gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 2160
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 2220
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 2280
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 2340
tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 2400
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 2460
ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 2520
tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 2580
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg 2640
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 2700
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 2748
<210>14
<211>915
<212>PRT
<213>人
<400>14
Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu
1 5 10 15
Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly
20 25 30
Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu
35 40 45
Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg
50 55 60
Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly
65 70 75 80
Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu
85 90 95
Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn
100 105 110
Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn
115 120 125
Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu
130 135 140
Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg
145 150 155 160
Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu
165 170 175
Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu
180 185 190
Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Va1
195 200 205
Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile
210 215 220
Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile
225 230 235 240
Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile
245 250 255
Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu
260 265 270
Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly
275 280 285
Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn
290 295 300
Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu
305 310 315 320
His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr
325 330 335
Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys
340 345 350
Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp
355 360 365
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe
370 375 380
Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp
385 390 395 400
Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro
405 410 415
Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr
420 425 430
Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr
435 440 445
Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser
450 455 460
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu
465 470 475 480
Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro
485 490 495
Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile
500 505 510
Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu
515 520 525
Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr
530 535 540
Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys
545 550 555 560
Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro
565 570 575
Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile
580 585 590
Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val
595 600 605
Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val
610 615 620
Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg
625 630 635 640
Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg
645 650 655
Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala
660 665 670
Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly
675 680 685
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
690 695 700
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
705 710 715 720
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
725 730 735
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
740 745 750
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
755 760 765
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
770 775 780
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
785 790 795 800
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
805 810 815
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
820 825 830
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
835 840 845
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
850 855 860
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
865 870 875 880
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
885 890 895
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
900 905 910
Pro Gly Lys
915
<210>15
<211>2754
<212>DNA
<213>人
<400> 15
atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60
cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120
ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180
gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240
gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300
gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360
attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420
attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480
gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540
gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600
gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660
actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720
tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780
tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840
atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900
aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960
cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020
gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080
aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140
ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200
actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260
agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320
acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380
caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440
tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500
ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560
gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620
gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680
gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740
gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800
ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860
actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920
actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980
catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040
gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc atcatgccca 2100
gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160
ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220
cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280
ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340
caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400
tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460
ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520
ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640
accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700
gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754
<210>16
<211>917
<212>PRT
<213>人
<400>16
Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu
1 5 10 15
Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly
20 25 30
Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu
35 40 45
Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg
50 55 60
Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly
65 70 75 80
Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu
85 90 95
Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn
100 105 110
Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn
115 120 125
Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu
130 135 140
Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg
145 150 155 160
Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu
165 170 175
Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu
180 185 190
Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val
195 200 205
Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile
210 215 220
Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile
225 230 235 240
Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile
245 250 255
Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu
260 265 2 70
Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly
275 280 285
Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn
290 295 300
Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu
305 310 315 320
His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr
325 330 335
Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys
340 345 350
Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp
355 360 365
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe
370 375 380
Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp
385 390 395 400
Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro
405 410 415
Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr
420 425 430
Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr
435 440 445
Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser
450 455 460
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu
465 470 475 480
Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro
485 490 495
Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile
500 505 510
Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu
515 520 525
Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr
530 535 540
Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys
545 550 555 560
Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro
565 570 575
Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile
580 585 590
Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val
595 600 605
Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val
610 615 620
Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg
625 630 635 640
Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg
645 650 655
Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala
660 665 670
Ala Lys Val Lys Gln Lys Val Pro Ala pro Arg Tyr Thr Val Ser Gly
675 680 685
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe
690 695 700
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
705 710 715 720
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
725 730 735
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
740 745 750
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
755 760 765
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
770 775 780
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
785 790 795 800
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
805 810 815
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
820 825 830
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
835 840 845
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
850 855 860
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
865 870 875 880
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
885 890 895
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
900 905 910
Leu Ser Leu Gly Lys
915
<210>17
<211>2754
<212>DNA
<213>人
<400>17
atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60
cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120
ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180
gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240
gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300
gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360
attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420
attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480
gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540
gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600
gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660
actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720
tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780
tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840
atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900
aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960
cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020
gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080
aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140
ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200
actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260
agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320
acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380
caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440
tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500
ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560
gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620
gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680
gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740
gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800
ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860
actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920
actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980
catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040
gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc accatgccca 2100
gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160
ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220
cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280
ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340
caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400
tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460
ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520
ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640
accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700
gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754
<210>18
<211>917
<212>PRT
<213>人
<400>18
Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu
1 5 10 15
Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly
20 25 30
Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu
35 40 45
Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg
50 55 60
Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly
65 70 75 80
Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu
85 90 95
Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn
100 105 110
Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn
115 120 125
Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu
130 135 140
Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg
145 150 155 160
Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu
165 170 175
Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu
180 185 190
Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val
195 200 205
Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile
210 215 220
Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile
225 230 235 240
Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile
245 250 255
pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu
260 265 270
Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly
275 280 285
Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn
290 295 300
Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu
305 310 315 320
His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr
325 330 335
Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys
340 345 350
Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp
355 360 365
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe
370 375 380
Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp
385 390 395 400
Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro
405 410 415
Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr
420 425 430
Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr
435 440 445
Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser
450 455 460
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu
465 470 475 480
Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro
485 490 495
Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile
500 505 510
Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu
515 520 525
Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr
530 535 540
Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys
545 550 555 560
Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro
565 570 575
Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile
580 585 590
Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val
595 600 605
Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val
610 615 620
Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg
625 630 635 640
Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg
645 650 655
Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala
660 665 670
Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly
675 680 685
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
690 695 700
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
705 710 715 720
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
725 730 735
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
740 745 750
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
755 760 765
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
770 775 780
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
785 790 795 800
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
805 810 815
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
820 825 830
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
835 840 845
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
850 855 860
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
865 870 875 880
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
885 890 895
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
900 905 910
Leu Ser Leu Gly Lys
915
<210>19
<211>2748
<212>DNA
<213>人
<400>19
atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60
tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120
gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180
gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240
gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300
ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360
tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420
cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540
tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600
attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720
gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780
gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840
tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900
agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960
gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020
gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080
ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140
ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200
ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260
gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320
tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380
ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440
accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500
actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560
tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620
ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680
agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740
ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800
ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860
agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920
gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980
gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040
gaagcctcct ccacgttctc cggagacaaa actcacacat gcccaccgtg cccagcacct 2100
gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 2160
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 2220
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 2280
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 2340
tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 2400
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 2460
ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 2520
tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 2580
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg 2640
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 2700
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 2748
<210>20
<211>915
<212>PRT
<213>人
<400>20
Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu
1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met
20 25 30
Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro
35 40 45
Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala
50 55 60
Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80
Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125
Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140
Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys
145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr
165 170 175
Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro
180 185 190
Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly
195 200 205
Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His
210 215 220
Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala
225 230 235 240
Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys
245 250 255
Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe
260 265 270
Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys
275 280 285
Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His
290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys
305 310 315 320
Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser
325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350
Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe
355 360 365
Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val
370 375 380
Ala Leu Arg Cys Pro Gln val Pro Tyr Trp Leu Trp Ala Ser Val Ser
385 390 395 400
Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val
405 410 415
Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp
420 425 430
Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr
435 440 445
Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe
450 455 460
Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu
465 470 475 480
Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe
485 490 495
Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu
500 505 510
Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr
515 520 525
His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg
530 535 540
Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg
545 550 555 560
Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val
565 570 575
Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu
580 585 590
Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr
595 600 605
Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro
610 615 620
Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn
625 630 635 640
Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu
645 650 655
Asp Leu His Met Asp Phe Lys cys Val Val His Asn Thr Leu Ser Phe
660 665 670
Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly
675 680 685
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
690 695 700
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
705 710 715 720
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
725 730 735
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
740 745 750
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
755 760 765
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
770 775 780
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
785 790 795 800
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
805 810 815
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
820 825 830
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
835 840 845
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
850 855 860
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
865 870 875 880
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
885 890 895
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
900 905 910
Pro Gly Lys
915
<210>21
<211>2754
<212>DNA
<213>人
<400>21
atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60
tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120
gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180
gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240
gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300
ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360
tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420
cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540
tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600
attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720
gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780
gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840
tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900
agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960
gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020
gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080
ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140
ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200
ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260
gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320
tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380
ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440
accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500
actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560
tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620
ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680
agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740
ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800
ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860
agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920
gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980
gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040
gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc atcatgccca 2100
gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160
ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220
cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280
ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340
caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400
tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460
ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520
ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640
accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700
gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754
<210>22
<211>917
<212>PRT
<213>人
<400>22
Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu
1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met
20 25 30
Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro
35 40 45
Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala
50 55 60
Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80
Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125
Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140
Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys
145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr
165 170 175
Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro
180 185 190
Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly
195 200 205
Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His
210 215 220
Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala
225 230 235 240
Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys
245 250 255
Glu Pro Gly Glu Glu Leu LeuIle Pro Cys Thr Val Tyr Phe Ser Phe
260 265 270
Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys
275 280 285
Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His
290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys
305 310 315 320
Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser
325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350
Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe
355 360 365
Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val
370 375 380
Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser
385 390 395 400
Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val
405 4l0 4l5
Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp
420 425 430
Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr
435 440 445
Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe
450 455 460
Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu
465 470 475 480
Thr Leu Ser Thr Ser Gly Val Leu val Cys Pro Asp Leu Ser Glu Phe
485 490 495
Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu
500 505 510
Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr
515 520 525
His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg
530 535 540
Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg
545 550 555 560
Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val
565 570 575
Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu
580 585 590
Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr
595 600 605
Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro
610 615 620
Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn
625 630 635 640
Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu
645 650 655
Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe
660 665 670
Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly
675 680 685
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe
690 695 700
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
705 710 715 720
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
725 730 735
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
740 745 750
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
755 760 765
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
770 775 780
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
785 790 795 800
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
805 810 815
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
820 825 830
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
835 840 845
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
850 855 860
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
865 870 875 880
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
885 890 895
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
900 905 910
Leu Ser Leu Gly Lys
915
<210>23
<211>2754
<212>DNA
<213>人
<400>23
atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60
tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120
gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180
gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240
gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300
ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360
tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420
cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540
tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600
attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720
gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780
gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840
tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900
agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960
gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020
gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080
ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140
ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200
ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260
gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320
tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380
ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440
accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500
actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560
tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620
ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680
agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740
ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800
ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860
agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920
gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980
gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040
gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc accatgccca 2100
gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160
ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220
cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280
ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340
caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400
tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460
ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520
ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640
accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700
gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754
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Claims (19)
1.分离的核酸分子，其包含选自下列的序列：SEQ ID NO：1，3，5，7，9，11，13，15，17，19，21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 NO：2，4，6，8，10，12，14，16，18，20，22，和24。
3.权利要求1的分离的核酸分子，其中该序列为SEQ ID NO：7。
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 NO：8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 NO：1，3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 NO：7，9，或11的核酸包含一或多个如下改变：
(a)SEQ ID NO：7，9，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 NO：13，15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 NO：19，21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 NO：2，4，6，8，10，12，14，16，18，20，22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 NO：8的序列。
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| US10/282,162 US6927044B2 (en) | 1998-09-25 | 2002-10-28 | IL-1 receptor based cytokine traps |
| US10/282,162 | 2002-10-28 | ||
| PCT/US2003/033718 WO2004039951A2 (en) | 2002-10-28 | 2003-10-24 | Il-1 receptor based antagonists and methods of making and using |
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| CN1878871B CN1878871B (zh) | 2011-08-03 |
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| PT (1) | PT1572967E (zh) |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103509100A (zh) * | 2012-06-15 | 2014-01-15 | 上海百迈博制药有限公司 | 一种白细胞介素-1受体拮抗剂突变体 |
Families Citing this family (164)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6927044B2 (en) * | 1998-09-25 | 2005-08-09 | Regeneron Pharmaceuticals, Inc. | IL-1 receptor based cytokine traps |
| US20090137416A1 (en) | 2001-01-16 | 2009-05-28 | Regeneron Pharmaceuticals, Inc. | Isolating Cells Expressing Secreted Proteins |
| US20040224893A1 (en) * | 2003-05-06 | 2004-11-11 | Li-Hsien Wang | Methods of using IL-1 antagonists to treat neointimal hyperplasia |
| TWI353991B (en) | 2003-05-06 | 2011-12-11 | Syntonix Pharmaceuticals Inc | Immunoglobulin chimeric monomer-dimer hybrids |
| EP1648940B1 (en) * | 2003-07-28 | 2016-04-27 | Genentech, Inc. | Reducing protein a leaching during protein a affinity chromatography |
| US20050129685A1 (en) * | 2003-09-18 | 2005-06-16 | Jingtai Cao | Use of IL-1 blockers to prevent corneal inflammation and neovascularization |
| US20050165222A1 (en) * | 2003-10-15 | 2005-07-28 | Applera Corporation | Method of reducing leachate from protein a affinity media |
| WO2005085284A1 (en) * | 2004-02-27 | 2005-09-15 | Regeneron Pharmaceuticals, Inc. | Il-4/il-13 sepecific polypetides and therapeutic uses thereof |
| US7459426B2 (en) | 2004-06-04 | 2008-12-02 | Regeneron Pharmaceuticals, Inc. | Methods of using IL-1 antagonists to treat autoinflammatory disease |
| CN101014617B (zh) * | 2004-08-17 | 2011-03-30 | 瑞泽恩制药公司 | Il-1拮抗剂制剂 |
| US7655758B2 (en) | 2004-08-17 | 2010-02-02 | Regeneron Pharmaceuticals, Inc. | Stable liquid IL-1 antagonist formulations |
| US7572893B2 (en) * | 2004-08-17 | 2009-08-11 | Regeneron Pharmaceuticals, Inc. | IL-1 antagonist formulations |
| WO2006076673A2 (en) * | 2005-01-14 | 2006-07-20 | Regeneron Pharmaceuticals, Inc. | Use of il-i antagonists to treat polymyalgia rheumatica and giant cell arteritis |
| US20060171948A1 (en) * | 2005-02-02 | 2006-08-03 | Weinstein Steven P | Methods of using IL-1 antagonists to reduce C-reactive protein |
| JP2009511545A (ja) * | 2005-10-14 | 2009-03-19 | ノボ・ノルデイスク・エー／エス | Ｉｌ−１インヒビターを使用する糖尿病の治療 |
| US7632490B2 (en) * | 2006-10-20 | 2009-12-15 | Regeneron Pharmaceuticals, Inc. | Use of IL-1 antagonists to treat gout |
| ES2389314T3 (es) * | 2006-10-20 | 2012-10-25 | Regeneron Pharmaceuticals, Inc. | Uso de antagonistas de IL-1 para tratar la gota y la pseudogota |
| WO2008093756A1 (ja) * | 2007-01-30 | 2008-08-07 | Niigata University | 生物学的製剤 |
| SI2187964T1 (sl) | 2007-08-10 | 2015-01-30 | Regeneron Pharmaceuticals, Inc. | Visokoafinitetna humana protitelesa proti humanemu živčnemu rastnemu faktorju |
| US10105441B2 (en) * | 2007-08-16 | 2018-10-23 | The Schepens Eye Research Institute, Inc. | Method for inhibiting or reducing dry eye disease by IL-1Ra |
| EP2259774B1 (en) | 2008-02-27 | 2012-12-12 | Biomet Biologics, LLC | Methods and compositions for delivering interleukin-1 receptor antagonist |
| US8753690B2 (en) | 2008-02-27 | 2014-06-17 | Biomet Biologics, Llc | Methods and compositions for delivering interleukin-1 receptor antagonist |
| US8828354B2 (en) * | 2008-03-27 | 2014-09-09 | Warsaw Orthopedic, Inc. | Pharmaceutical gels and methods for delivering therapeutic agents to a site beneath the skin |
| US9132119B2 (en) | 2008-04-18 | 2015-09-15 | Medtronic, Inc. | Clonidine formulation in a polyorthoester carrier |
| US20090264489A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Method for Treating Acute Pain with a Formulated Drug Depot in Combination with a Liquid Formulation |
| US9132085B2 (en) | 2008-04-18 | 2015-09-15 | Warsaw Orthopedic, Inc. | Compositions and methods for treating post-operative pain using clonidine and bupivacaine |
| US8557273B2 (en) | 2008-04-18 | 2013-10-15 | Medtronic, Inc. | Medical devices and methods including polymers having biologically active agents therein |
| US8956641B2 (en) | 2008-04-18 | 2015-02-17 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of inflammatory diseases |
| US8420114B2 (en) * | 2008-04-18 | 2013-04-16 | Warsaw Orthopedic, Inc. | Alpha and beta adrenergic receptor agonists for treatment of pain and / or inflammation |
| US9289409B2 (en) * | 2008-04-18 | 2016-03-22 | Warsaw Orthopedic, Inc. | Sulindac formulations in a biodegradable material |
| USRE48948E1 (en) | 2008-04-18 | 2022-03-01 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
| US20090264477A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc., An Indiana Corporation | Beta adrenergic receptor agonists for treatment of pain and/or inflammation |
| US8722079B2 (en) | 2008-04-18 | 2014-05-13 | Warsaw Orthopedic, Inc. | Methods for treating conditions such as dystonia and post-stroke spasticity with clonidine |
| US8846068B2 (en) | 2008-04-18 | 2014-09-30 | Warsaw Orthopedic, Inc. | Methods and compositions for treating post-operative pain comprising a local anesthetic |
| US20090263443A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedics, Inc. | Methods for treating post-operative effects such as spasticity and shivering with clondine |
| US8629172B2 (en) | 2008-04-18 | 2014-01-14 | Warsaw Orthopedic, Inc. | Methods and compositions for treating post-operative pain comprising clonidine |
| US8889173B2 (en) | 2008-04-18 | 2014-11-18 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of pain and/or inflammation |
| US20090263451A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Anti-Inflammatory and/or Analgesic Agents for Treatment of Myofascial Pain |
| US8883768B2 (en) * | 2008-04-18 | 2014-11-11 | Warsaw Orthopedic, Inc. | Fluocinolone implants to protect against undesirable bone and cartilage destruction |
| US9125917B2 (en) * | 2008-04-18 | 2015-09-08 | Warsaw Orthopedic, Inc. | Fluocinolone formulations in a biodegradable polymer carrier |
| US8956636B2 (en) | 2008-04-18 | 2015-02-17 | Warsaw Orthopedic, Inc. | Methods and compositions for treating postoperative pain comprosing ketorolac |
| US9072727B2 (en) | 2008-04-18 | 2015-07-07 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of degenerative disc disease |
| US20100015049A1 (en) * | 2008-07-16 | 2010-01-21 | Warsaw Orthopedic, Inc. | Methods and compositions for treating postoperative pain comprising nonsteroidal anti-inflammatory agents |
| US20100016265A1 (en) * | 2008-07-16 | 2010-01-21 | Qaiser Yusuf | Anti-inflammatory composition and method for preparation |
| US9492375B2 (en) * | 2008-07-23 | 2016-11-15 | Warsaw Orthopedic, Inc. | Foam carrier for bone grafting |
| CN102170905B (zh) * | 2008-08-01 | 2016-08-03 | 阿克西斯股份有限公司 | 骨关节炎治疗剂及预防剂 |
| US9161903B2 (en) * | 2008-10-31 | 2015-10-20 | Warsaw Orthopedic, Inc. | Flowable composition that hardens on delivery to a target tissue site beneath the skin |
| US10117906B2 (en) * | 2009-01-09 | 2018-11-06 | The Schepens Eye Research Institute, Inc. | Methods for reducing corneal nerves damage, corneal lymphangiogenesis or immunity to corneal antigens in dry-eye associated ocular surface diseases by IL-1Ra |
| US20100228097A1 (en) * | 2009-03-04 | 2010-09-09 | Warsaw Orthopedic, Inc. | Methods and compositions to diagnose pain |
| US20100226959A1 (en) * | 2009-03-04 | 2010-09-09 | Warsaw Orthopedic, Inc. | Matrix that prolongs growth factor release |
| US20100239632A1 (en) * | 2009-03-23 | 2010-09-23 | Warsaw Orthopedic, Inc. | Drug depots for treatment of pain and inflammation in sinus and nasal cavities or cardiac tissue |
| US8617583B2 (en) | 2009-07-17 | 2013-12-31 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for prevention or treatment of a hematoma, edema, and/or deep vein thrombosis |
| US8231891B2 (en) | 2009-07-31 | 2012-07-31 | Warsaw Orthopedic, Inc. | Implantable drug depot for weight control |
| US20110052561A1 (en) | 2009-08-27 | 2011-03-03 | Biomet Biologics,LLC | Osteolysis treatment |
| US9763875B2 (en) | 2009-08-27 | 2017-09-19 | Biomet Biologics, Llc | Implantable device for production of interleukin-1 receptor antagonist |
| WO2011041584A2 (en) | 2009-09-30 | 2011-04-07 | President And Fellows Of Harvard College | Methods for modulation of autophagy through the modulation of autophagy-enhancing gene products |
| US20110097375A1 (en) | 2009-10-26 | 2011-04-28 | Warsaw Orthopedic, Inc. | Formulation for preventing or reducing bleeding at a surgical site |
| US20110097380A1 (en) * | 2009-10-28 | 2011-04-28 | Warsaw Orthopedic, Inc. | Clonidine formulations having antimicrobial properties |
| US9504698B2 (en) * | 2009-10-29 | 2016-11-29 | Warsaw Orthopedic, Inc. | Flowable composition that sets to a substantially non-flowable state |
| US8597192B2 (en) | 2009-10-30 | 2013-12-03 | Warsaw Orthopedic, Inc. | Ultrasonic devices and methods to diagnose pain generators |
| US8475824B2 (en) | 2010-01-26 | 2013-07-02 | Warsaw Orthopedic, Inc. | Resorbable matrix having elongated particles |
| US8758791B2 (en) | 2010-01-26 | 2014-06-24 | Warsaw Orthopedic, Inc. | Highly compression resistant matrix with porous skeleton |
| US9050274B2 (en) * | 2010-01-28 | 2015-06-09 | Warsaw Orthopedic, Inc. | Compositions and methods for treating an intervertebral disc using bulking agents or sealing agents |
| US9125902B2 (en) * | 2010-01-28 | 2015-09-08 | Warsaw Orthopedic, Inc. | Methods for treating an intervertebral disc using local analgesics |
| US9486500B2 (en) | 2010-01-28 | 2016-11-08 | Warsaw Orthopedic, Inc. | Osteoimplant and methods for making |
| JP2012246222A (ja) * | 2010-01-29 | 2012-12-13 | Axis Inc | 変形性関節症治療剤または予防剤を製造するための使用 |
| JO3183B1 (ar) | 2010-01-29 | 2018-03-08 | Regeneron Pharma | طرق لمعالجة أمراض المناعة الذاتية مضادات dll4 |
| EP3372617B1 (en) | 2010-04-02 | 2024-07-24 | Amunix Pharmaceuticals, Inc. | Binding fusion proteins, binding fusion protein-drug conjugates, xten-drug conjugates and methods of making and using same |
| NZ605400A (en) | 2010-07-09 | 2015-05-29 | Biogen Idec Hemophilia Inc | Chimeric clotting factors |
| KR102080704B1 (ko) | 2010-07-29 | 2020-02-24 | 세센 바이오, 아이엔씨. | 키메라 il-1 수용체 유형 i 항진제 및 길항제들 |
| US8246571B2 (en) | 2010-08-24 | 2012-08-21 | Warsaw Orthopedic, Inc. | Drug storage and delivery device having a retaining member |
| AU2011296356B2 (en) | 2010-09-03 | 2015-07-09 | Biomet Biologics, Llc | Methods and compositions for delivering interleukin-1 receptor antagonist |
| US8740982B2 (en) | 2010-10-26 | 2014-06-03 | Kyphon Sarl | Devices containing a chemonucleolysis agent and methods for treating an intervertebral disc or spinal arachnoiditis |
| US8404268B2 (en) | 2010-10-26 | 2013-03-26 | Kyphon Sarl | Locally targeted anti-fibrotic agents and methods of use |
| US9414930B2 (en) | 2010-10-26 | 2016-08-16 | Kyphon SÀRL | Activatable devices containing a chemonucleolysis agent |
| JO3375B1 (ar) | 2010-11-08 | 2019-03-13 | Regeneron Pharma | أجسام مضادة بشرية للجين a1 الشبيه بعامل النخر الورمي (tl1a) |
| US8623396B2 (en) | 2010-12-03 | 2014-01-07 | Warsaw Orthopedic, Inc. | Compositions and methods for delivering clonidine and bupivacaine to a target tissue site |
| US9301946B2 (en) | 2010-12-03 | 2016-04-05 | Warsaw Orthopedic, Inc. | Clonidine and GABA compounds in a biodegradable polymer carrier |
| US9060978B2 (en) | 2011-01-24 | 2015-06-23 | Warsaw Orthopedic, Inc. | Method for treating an intervertebral disc disorder by administering a dominant negative tumor necrosis factor antagonist |
| US9717779B2 (en) | 2011-01-31 | 2017-08-01 | Warsaw Orthopedic, Inc. | Implantable matrix having optimum ligand concentrations |
| EP2697260A1 (en) | 2011-04-15 | 2014-02-19 | Merck Patent GmbH | Anti- il-1r1 inhibitors for use in cancer |
| US9511077B2 (en) | 2011-04-25 | 2016-12-06 | Warsaw Orthopedic, Inc. | Medical devices and methods comprising an anabolic agent for wound healing |
| US9592243B2 (en) | 2011-04-25 | 2017-03-14 | Warsaw Orthopedic, Inc. | Medical devices and methods comprising an anabolic agent for treatment of an injury |
| US9132194B2 (en) | 2011-07-12 | 2015-09-15 | Warsaw Orthopedic, Inc. | Medical devices and methods comprising an adhesive sheet containing a drug depot |
| US9205241B2 (en) | 2011-07-12 | 2015-12-08 | Warsaw Orthopedic, Inc. | Medical devices and methods comprising an adhesive material |
| US8871209B2 (en) | 2011-11-14 | 2014-10-28 | Regeneron Pharmaceuticals, Inc. | Compositions and methods for increasing muscle mass and muscle strength by specifically antagonizing GDF8 and or Activin A |
| AU2012340107B2 (en) | 2011-11-18 | 2017-06-15 | Regeneron Pharmaceuticals, Inc. | Polymer protein microparticles |
| WO2013106787A1 (en) * | 2012-01-12 | 2013-07-18 | Biogen Idec Ma Inc. | Chimeric factor viii polypeptides and uses thereof |
| US9511018B2 (en) | 2012-04-05 | 2016-12-06 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable matrix |
| US8735504B2 (en) | 2012-05-02 | 2014-05-27 | Warsaw Orthopedic, Inc. | Methods for preparing polymers having low residual monomer content |
| SG11201500889TA (en) | 2012-08-21 | 2015-03-30 | Sanofi Sa | Methods for treating or preventing asthma by administering an il-4r antagonist |
| JO3462B1 (ar) | 2012-08-22 | 2020-07-05 | Regeneron Pharma | أجسام مضادة بشرية تجاه gfr?3 وطرق لاستخدامها |
| WO2014035361A1 (en) * | 2012-08-26 | 2014-03-06 | R-PHARM, CJSC (Closed Joint Stock Company) | IL-1β INHIBITOR COMPOSITION AND USE THEREOF |
| PT3889181T (pt) | 2012-09-07 | 2024-05-29 | Regeneron Pharma | Um anticorpo antagonista de il-4r para utilização no tratamento da dermatite atópica por administração |
| TW202423993A (zh) | 2012-11-14 | 2024-06-16 | 美商再生元醫藥公司 | 重組細胞表面捕捉蛋白質 |
| US9066853B2 (en) | 2013-01-15 | 2015-06-30 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable fiber |
| PL2956471T3 (pl) | 2013-02-15 | 2024-06-24 | R-Pharm International, Llc | Kompozycja inhibitora il-1beta i jej zastosowanie |
| JP6450364B2 (ja) | 2013-03-13 | 2019-01-09 | セセン バイオ， インコーポレイテッド | 眼送達のためのキメラサイトカイン製剤 |
| US10072076B2 (en) | 2013-03-14 | 2018-09-11 | Regeneron Pharmaceuticals, Inc. | Human antibodies to NAv1.7 |
| US9878011B2 (en) | 2013-03-15 | 2018-01-30 | Biomet Biologics, Llc | Treatment of inflammatory respiratory disease using biological solutions |
| US10208095B2 (en) | 2013-03-15 | 2019-02-19 | Biomet Manufacturing, Llc | Methods for making cytokine compositions from tissues using non-centrifugal methods |
| US9895418B2 (en) | 2013-03-15 | 2018-02-20 | Biomet Biologics, Llc | Treatment of peripheral vascular disease using protein solutions |
| US20140271589A1 (en) | 2013-03-15 | 2014-09-18 | Biomet Biologics, Llc | Treatment of collagen defects using protein solutions |
| LT2970422T (lt) | 2013-03-15 | 2018-06-25 | F. Hoffmann-La Roche Ag | Il-22 polipeptidai ir il-22 su fc sulieti baltymai bei panaudojimo būdai |
| US9950035B2 (en) | 2013-03-15 | 2018-04-24 | Biomet Biologics, Llc | Methods and non-immunogenic compositions for treating inflammatory disorders |
| US9758806B2 (en) | 2013-03-15 | 2017-09-12 | Biomet Biologics, Llc | Acellular compositions for treating inflammatory disorders |
| SG11201505926VA (en) | 2013-03-15 | 2015-09-29 | Biogen Ma Inc | Factor ix polypeptide formulations |
| US10143725B2 (en) | 2013-03-15 | 2018-12-04 | Biomet Biologics, Llc | Treatment of pain using protein solutions |
| US20160120941A1 (en) * | 2013-05-31 | 2016-05-05 | Regeneron Pharmaceuticals, Inc. | Methods of using il-1 antagonists to treat alzheimer's disease |
| TWI709411B (zh) | 2013-06-21 | 2020-11-11 | 法商賽諾菲生物技術公司 | Il-4r拮抗劑用於製備治療鼻息肉症的醫藥品之用途 |
| US9833474B2 (en) | 2013-11-26 | 2017-12-05 | Biomet Biologies, LLC | Methods of mediating macrophage phenotypes |
| IL315136A (en) | 2014-02-21 | 2024-10-01 | Sanofi Biotechnology | Methods for treating or preventing asthma by adding an IL-4R antagonist |
| US20210403534A1 (en) * | 2014-03-24 | 2021-12-30 | R-Pharm Overseas, Inc. | IL1-R1 DERIVED INHIBITOR OF IL-1b AND USE THEREOF |
| US11155600B2 (en) * | 2014-03-24 | 2021-10-26 | R-Pharm Overseas, Inc. | Human IL1-R1 derived inhibitor of IL-1β |
| US9775978B2 (en) | 2014-07-25 | 2017-10-03 | Warsaw Orthopedic, Inc. | Drug delivery device and methods having a retaining member |
| US9764122B2 (en) | 2014-07-25 | 2017-09-19 | Warsaw Orthopedic, Inc. | Drug delivery device and methods having an occluding member |
| US10441635B2 (en) | 2014-11-10 | 2019-10-15 | Biomet Biologics, Llc | Methods of treating pain using protein solutions |
| EP3218412A1 (en) | 2014-11-14 | 2017-09-20 | Sanofi Biotechnology | Methods for treating chronic sinusitis with nasal polyps by administering an il-4r antagonist |
| US11761951B2 (en) | 2015-02-04 | 2023-09-19 | Bristol-Myers Squibb Company | Methods of selecting therapeutic molecules |
| TW201641691A (zh) | 2015-02-04 | 2016-12-01 | 必治妥美雅史谷比公司 | Ｔａｕ反義寡聚物及其用途 |
| AU2016227458A1 (en) * | 2015-03-01 | 2018-08-02 | Arjun Jain | Endothelin-1 receptor based endothelin-1 sponge |
| GB201503453D0 (en) | 2015-03-01 | 2015-04-15 | Jain Arjun | Endothelin-1"sponge" |
| US9763800B2 (en) | 2015-03-18 | 2017-09-19 | Biomet C. V. | Implant configured for hammertoe and small bone fixation |
| MA41919A (fr) | 2015-04-06 | 2018-02-13 | Acceleron Pharma Inc | Hétéromultimères alk4:actriib et leurs utilisations |
| AU2016246708B2 (en) | 2015-04-06 | 2020-12-24 | Acceleron Pharma Inc. | ALK7:actRIIB heteromultimers and uses thereof |
| CN107771081A (zh) | 2015-04-15 | 2018-03-06 | 瑞泽恩制药公司 | 用gdf8抑制剂增加力量和功能的方法 |
| US10076650B2 (en) | 2015-11-23 | 2018-09-18 | Warsaw Orthopedic, Inc. | Enhanced stylet for drug depot injector |
| PL3389636T3 (pl) | 2015-12-16 | 2022-11-28 | Regeneron Pharmaceuticals, Inc. | Kompozycje i metody wytwarzania mikrocząstek białkowych |
| USD802755S1 (en) | 2016-06-23 | 2017-11-14 | Warsaw Orthopedic, Inc. | Drug pellet cartridge |
| EP3500856B1 (en) | 2016-08-18 | 2020-10-07 | Regeneron Pharmaceuticals, Inc. | Assay for determining potential to self-association of a protein using concentration-dependent self-interaction nanoparticle spectroscopy |
| WO2018045130A1 (en) | 2016-09-01 | 2018-03-08 | Regeneron Pharmaceuticals, Inc. | Methods for preventing or treating allergy by administering an il-4r antagonist |
| BR112019006993A2 (pt) | 2016-10-05 | 2019-09-03 | Acceleron Pharma Inc | heteromultímeros de alk4:actriib e usos dos mesmos |
| IL310367A (en) | 2016-10-07 | 2024-03-01 | Regeneron Pharma | A stable protein at room temperature that has been lyophilized |
| US10434261B2 (en) | 2016-11-08 | 2019-10-08 | Warsaw Orthopedic, Inc. | Drug pellet delivery system and method |
| MX2019006013A (es) | 2016-11-29 | 2019-10-14 | Regeneron Pharma | Composicion farmaceutica para evitar la adiccion a opioides. |
| TWI784988B (zh) | 2016-12-01 | 2022-12-01 | 美商再生元醫藥公司 | 治療發炎症狀的方法 |
| WO2019018441A1 (en) * | 2017-07-17 | 2019-01-24 | Massachusetts Institute Of Technology | ATLAS OF HEAVY AND ILLUMINATED HEAVY BARRIER TISSUE CELLS |
| PL3703818T3 (pl) | 2017-10-30 | 2024-03-25 | Sanofi Biotechnology | Antagonista IL-4R do zastosowania w sposobie leczenia lub zapobiegania astmie |
| EA202092064A1 (ru) | 2018-03-01 | 2020-12-21 | Ридженерон Фармасьютикалз, Инк. | Способы изменения состава тела |
| JP2021523878A (ja) | 2018-05-18 | 2021-09-09 | バイオベラティブ セラピューティクス インコーポレイテッド | 血友病ａを処置する方法 |
| KR20210043624A (ko) | 2018-08-10 | 2021-04-21 | 리제너론 파아마슈티컬스, 인크. | 무릎 및/또는 고관절 통증의 안전하고 효과적인 치료를 위한 약제학적 조성물 |
| BR112021018627A2 (pt) | 2019-03-21 | 2021-11-23 | Regeneron Pharma | Combinação de inibidores da via de il-4/il-13 e ablação de células plasmáticas para o tratamento de alergia |
| TW202106334A (zh) | 2019-05-01 | 2021-02-16 | 法商賽諾菲生物技術公司 | 藉由投予ｉｌ－３３拮抗劑治療或預防哮喘之方法 |
| US20210032354A1 (en) | 2019-07-16 | 2021-02-04 | Sanofi Biotechnology | Methods for treating or preventing asthma by administering an il-4r antagonist |
| BR112022010934A2 (pt) | 2019-12-06 | 2022-11-29 | Sanofi Biotechnology | Métodos para tratar copd administrando um antagonista de il-33 |
| KR20220119446A (ko) | 2019-12-23 | 2022-08-29 | 사노피 바이오테크놀로지 | Il-33 길항제 및/또는 il-4r 길항제를 투여하여 알레르기성 천식을 치료 또는 예방하는 방법 |
| JP2023515270A (ja) | 2020-04-21 | 2023-04-12 | テンパス・ラボズ・インコーポレイテッド | Ｔｃｒ／ｂｃｒプロファイリング |
| JP2023544406A (ja) | 2020-10-05 | 2023-10-23 | サノフィ・バイオテクノロジー | Ｉｌ－４ｒアンタゴニストを投与することによって小児対象における喘息を治療するための方法 |
| AU2021385363A1 (en) | 2020-11-25 | 2023-06-08 | Regeneron Pharmaceuticals, Inc. | Sustained release formulations using non-aqueous membrane emulsification |
| US12031151B2 (en) | 2021-01-20 | 2024-07-09 | Regeneron Pharmaceuticals, Inc. | Methods of improving protein titer in cell culture |
| AR125585A1 (es) | 2021-03-03 | 2023-08-02 | Regeneron Pharma | Sistemas y métodos para cuantificar y modificar la viscosidad de proteínas |
| WO2022256383A1 (en) | 2021-06-01 | 2022-12-08 | Regeneron Pharmaceuticals, Inc. | Micropchip capillary electrophoresis assays and reagents |
| EP4377345A1 (en) | 2021-07-26 | 2024-06-05 | Sanofi Biotechnology | Methods for treating chronic spontaneous urticaria by administering an il-4r antagonist |
| TW202326138A (zh) | 2021-09-08 | 2023-07-01 | 美商再生元醫藥公司 | 用於定量抗體及其他含Ｆｃ蛋白之高通量及基於質譜之方法 |
| MX2024004762A (es) | 2021-10-20 | 2024-05-08 | Sanofi Biotechnology | Metodos para el tratamiento del prurigo nodular mediante la administracion de un antagonista de il-4r. |
| CA3236367A1 (en) | 2021-10-26 | 2023-05-04 | Michelle Lafond | Systems and methods for generating laboratory water and distributing laboratory water at different temperatures |
| WO2023092052A1 (en) | 2021-11-19 | 2023-05-25 | Regeneron Pharmaceuticals, Inc. | Methods and compositions for reducing centralized pain |
| AU2022445159A1 (en) | 2022-03-10 | 2024-09-26 | Buzzard Pharmaceuticals AB | Inhibitor of interleukin-1 receptor type 1 for use in the treatment of cancer |
| US20240002491A1 (en) | 2022-04-27 | 2024-01-04 | Regeneron Pharmaceuticals, Inc. | Methods for selecting patients for treatment with an ngf antagonist |
| WO2024047021A1 (en) | 2022-08-29 | 2024-03-07 | Sanofi | Methods for treating chronic inducible cold urticaria by administering an il-4r antagonist |
| US20240248097A1 (en) | 2023-01-25 | 2024-07-25 | Regeneron Pharmaceuticals, Inc. | Mass spectrometry-based characterization of antibodies co-expressed in vivo |
| WO2024163708A1 (en) | 2023-02-01 | 2024-08-08 | Regeneron Pharmaceuticals, Inc. | Asymmetrical flow field-flow fractionation with mass spectrometry for biomacromolecule analysis |
| US20240280551A1 (en) | 2023-02-22 | 2024-08-22 | Regeneron Pharmaceuticals, Inc. | System suitability parameters and column aging |
| WO2024197119A1 (en) | 2023-03-22 | 2024-09-26 | Sanofi Biotechnology | Methods for treating chronic obstructive pulmonary disease (copd) by administering an il-4r antagonist |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0835939T3 (da) | 1990-06-28 | 2006-03-13 | Sanofi Aventis Deutschland | Fusionsproteiner med andele af immunglobulin, deres fremstilling og anvendelse |
| EP0533006A1 (en) | 1991-09-18 | 1993-03-24 | F.Hoffmann-La Roche & Co. Aktiengesellschaft | Chimaeric interleukin 5-receptor/immunoglobulin polypeptides |
| WO1993019163A1 (en) | 1992-03-18 | 1993-09-30 | Yeda Research And Development Co, Ltd. | Chimeric receptor genes and cells transformed therewith |
| US8211422B2 (en) | 1992-03-18 | 2012-07-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chimeric receptor genes and cells transformed therewith |
| EP0670730B1 (en) | 1992-03-30 | 2003-06-04 | Immunex Corporation | Fusion protein comprising two tumor necrosis factor receptors |
| WO1994022914A1 (en) | 1993-04-06 | 1994-10-13 | Fred Hutchinson Cancer Research Center | Chimeric cytokine receptors in lymphocytes |
| WO1995006737A1 (en) | 1993-09-03 | 1995-03-09 | Kenneth Francis Prendergast | Glycophorin binding protein (gbp130) fusion compositions |
| US5470952A (en) * | 1993-10-20 | 1995-11-28 | Regeneron Pharmaceuticals, Inc. | CNTF and IL-6 antagonists |
| AU3830895A (en) | 1994-10-07 | 1996-05-02 | Amgen Boulder Inc. | Dimeric il-4 inhibitors |
| US5837544A (en) | 1995-02-02 | 1998-11-17 | Cell Genesys, Inc. | Method of inducing a cell to proliferate using a chimeric receptor comprising janus kinase |
| US5837816A (en) | 1995-05-10 | 1998-11-17 | Chiron Corporation | Interleukin-2 receptor subunit ectodomain fusion protein comprising a leucine zipper domain |
| US5710023A (en) | 1996-03-01 | 1998-01-20 | Genetics Institute, Inc. | IL-13 cytokine receptor chain |
| ES2312179T3 (es) * | 1996-12-06 | 2009-02-16 | Amgen Inc. | Terapia combinada que utiliza un inhibidor del il-1 para el tratamiento de enfermedades mediadas por el il-1. |
| US5945511A (en) * | 1997-02-20 | 1999-08-31 | Zymogenetics, Inc. | Class II cytokine receptor |
| DK1047781T3 (da) | 1998-01-23 | 2004-12-06 | Immunex Corp | IL-18-receptorer |
| US6472179B2 (en) * | 1998-09-25 | 2002-10-29 | Regeneron Pharmaceuticals, Inc. | Receptor based antagonists and methods of making and using |
| US6927044B2 (en) * | 1998-09-25 | 2005-08-09 | Regeneron Pharmaceuticals, Inc. | IL-1 receptor based cytokine traps |
| US6610750B1 (en) * | 2000-09-15 | 2003-08-26 | Laboratoires Negma | Treatment of osteoarthritis |
| US20040224893A1 (en) * | 2003-05-06 | 2004-11-11 | Li-Hsien Wang | Methods of using IL-1 antagonists to treat neointimal hyperplasia |
-
2002
- 2002-10-28 US US10/282,162 patent/US6927044B2/en not_active Expired - Lifetime
-
2003
- 2003-10-24 EP EP03779216A patent/EP1572967B1/en not_active Expired - Lifetime
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- 2003-10-24 WO PCT/US2003/033718 patent/WO2004039951A2/en active Search and Examination
- 2003-10-24 JP JP2004548452A patent/JP4387309B2/ja not_active Expired - Lifetime
- 2003-10-24 SI SI200331505T patent/SI1572967T1/sl unknown
-
2005
- 2005-02-11 US US11/056,730 patent/US7361350B2/en not_active Expired - Lifetime
- 2005-04-14 IL IL168050A patent/IL168050A/en unknown
- 2005-05-20 US US11/134,114 patent/US7417134B2/en not_active Expired - Lifetime
-
2006
- 2006-03-14 HK HK06103232.6A patent/HK1080511A1/xx not_active IP Right Cessation
-
2008
- 2008-07-22 US US12/177,185 patent/US7927583B2/en not_active Expired - Fee Related
-
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- 2009-04-10 CY CY20091100421T patent/CY1110675T1/el unknown
-
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- 2010-04-19 CY CY2010010C patent/CY2010010I1/el unknown
- 2010-04-21 LU LU91680C patent/LU91680I2/fr unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103509100A (zh) * | 2012-06-15 | 2014-01-15 | 上海百迈博制药有限公司 | 一种白细胞介素-1受体拮抗剂突变体 |
| CN103509100B (zh) * | 2012-06-15 | 2017-10-27 | 上海百迈博制药有限公司 | 一种白细胞介素‑1受体拮抗剂突变体 |
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