利用il－1拮抗剂治疗自身炎症性疾病的方法

专利名称：利用il－1拮抗剂治疗自身炎症性疾病的方法
背景发明领域本发明涉及利用白细胞介素-1(IL-1)拮抗剂治疗自身炎症性疾病的方法，所述自身炎症性疾病例如包括家族性地中海热(FMF)、NOMID/CINCA、穆-韦综合征、FCAS以及肿瘤坏死因子受体相关的周期性发热综合征(TRAPS)。
相关领域的描述重要的一组自身炎症性疾病包括与CIAS-1中突变相关的常染色体显性疾病，所述CIAS-1是编码被称为“cryopyrin”的pyrin相关蛋白的基因(Feldmann等人，(2002)Am.J.Hum.Genet.71198-203；Hoffman等人，(2001)Nat.Genet.29301-305)。这些病症包括新生儿期起病的多系统炎性病症(NOMID/CINCA)、穆-韦综合征(MWS)和家族性寒冷型自身炎症性综合征(FCAS)。这些病症呈现出从最轻微的FCAS到严重的残疾疾病NOMID/CINCA的一系列临床表现。荨麻疹样皮疹是整个范围的这些疾病所共有的。在FCAS患者中，这种皮疹由寒冷暴露诱导，而在大部分MWS或NOMID患者中存在一向由各种不同的刺激引起的日常皮疹。结膜炎存在于所有形式的疾病表现中，然而，听力丧失、无菌性脑膜炎和关节炎主要见于MWS和NOMID/CINCA患者。在骨骺和髌骨处的损形性和致残性骨过度生长仅见于NOMID/CINCA患者。
FMF是以发热和浆膜炎或滑膜炎的发作为特征的隐性遗传疾病；某些受试者还发展为全身性淀粉样变性(Balow等人，(1997)Genomics44280-291)。FMF基因编码被称为pyrin的新型蛋白，所述pyrin蛋白是与凋亡(细胞死亡)和炎症调节有关的分子家族的原型。这些蛋白起作用以及突变导致疾病的精确的生物化学机制仍是未知的。
斯蒂尔病(全身性发作的青少年特发性关节炎)表现为峰热、渐失性橙红色皮疹、关节炎、关节痛和肝脾肿大(Masson等人，(1995)Rev.Rhum.Engl.Ed.62748-757；Spiegel等人，(2000)ArthritisRheum.432402-2409)。迄今仍没有与斯蒂尔病的确定遗传联系而且发病机理知之甚少。有趣的是，斯蒂尔病的许多体征和症状与自身炎症性疾病的那些类似。斯蒂尔病一般首先在儿童期发生，但也可以在成人期发作。
类似地，川崎病是侵袭儿童的疾病，它伴随发热、肿胀和关节炎性关节以及皮疹，还有血管炎症，所述血管炎症可在大约15-25％的受侵袭儿童中导致永久性冠状动脉损伤。其他两种类似的疾病是Blau综合征和早发型结节病(Early Onset Sarcoidosis)(EOS)，这两种疾病均由NOD2中的功能突变的获得而引起，并引起皮疹、肉芽肿、关节炎和葡萄膜炎，所述NOD2是与Pyrin类似的蛋白。也已被认为是自身炎症性的其他疾病包括化脓性汗腺炎、贝切特综合征、具有周期性发热综合征(HIDS)的高免疫球蛋白血症D、肿瘤坏死因子受体相关的周期性发热综合征(TRAPS)和脓性无菌性关节炎、坏疽性脓皮症和痤疮(PAPA综合征)。
自身炎症性疾病的发病机理还未完全了解。有一批增长中的证据表明白细胞介素-1(IL-1)在许多这种疾病中起作用并且这种细胞因子的靶向可以提供重大利益(Hoffman等人，(2004)Arthritis.Rheum.50345-349)。显然需要开发这些自身炎症性疾病的改良的治疗处理。
发明概述在第一个方面，本发明以治疗、抑制或改善自身炎症性病症的方法为特征，所述方法包括在需要时对受试者施用白细胞介素-1(IL-1)拮抗剂。IL-1拮抗剂是能够阻断或抑制IL-1的生物作用的化合物，包括IL-1结合性融合蛋白。在一个优选实施方案中，IL-1拮抗剂是包括两个受体组分和多聚化组分的IL-1特异性融合蛋白，例如，2003年7月31日公布的美国专利公开号2003/0143697中描述的IL-1融合蛋白捕获拮抗剂(“IL-1捕获剂”)。在一个具体实施方案中，IL-1拮抗剂是SEQ ID NO4、6、8、10、12、14、16、18、20、22、24、26中显示的融合蛋白。优选的融合蛋白显示于SEQ ID NO10中。本发明包括IL-1结合性融合蛋白的用途，所述IL-1结合性融合蛋白与SEQ ID NO4、6、8、10、12、14、16、18、20、22、24、26的蛋白基本上相同，即，与SEQ ID NO4、6、8、10、12、14、16、18、20、22、24、26的蛋白具有至少95％的同一性、至少97％的同一性、至少98％的同一性，并且能够结合和抑制IL-1的蛋白。进一步地，在具体实施方案中，该IL-1拮抗剂是包括一个或多个免疫球蛋白衍生组分的融合蛋白，所述免疫球蛋白衍生组分代替一个或多个受体组分。在具体实施方案中，该IL-1拮抗剂包括一个或多个对于IL-1和/或IL-1受体特异的免疫球蛋白衍生组分。
被治疗的受试者最优选是被诊断为患自身炎症性病症的人。更具体而言，患者是被诊断有与CIAS-1中突变相关的自身炎症性病症的成人或儿童，所述自身炎症性病症例如为新生儿期起病的多系统炎性病症(NOMID/CINCA)、穆-韦综合征(MWS)、家族性寒冷型自身炎症性综合征(FCAS)；家族性地中海热(FMF)；全身性发作的青少年特发性关节炎(斯蒂尔病)、肿瘤坏死因子受体相关的周期性发热综合征(TRAPS)或川崎病。
本发明的方法包括通过本领域已知的任何方法施用IL-1拮抗剂，所述方法例如皮下、肌内、鼻内、静脉内、经皮肤给药或口服给药。优选皮下或静脉内给药。
在第二个方面，本发明以治疗、抑制或改善疾病或病状的方法为特征，所述疾病或病状选自NOMID/CINCA、MWS、FCAS、FMP、斯蒂尔病、TRAPS和川崎病，所述方法包括在需要时对受试者施用白细胞介素-1(IL-1)拮抗剂。在一个优选实施方案中，该IL-1拮抗剂是能够捕获IL-1的融合蛋白。在一个具体实施方案中，该IL-1拮抗剂是SEQID NO4、6、8、10、12、14、16、18、20、22、24、26中显示的融合蛋白，或能够结合并抑制IL-1的基本上相同的蛋白。优选的IL-1拮抗剂显示于SEQ ID NO10中。优选地，被治疗的受试者是被诊断有该疾病或病状的儿童或成人。
在第三个方面，本发明以治疗、抑制或改善新生儿期起病的多系统炎性病症(NOMID/CINCA)的方法为特征，所述方法包括在需要时对受试者施用白细胞介素-1(IL-1)拮抗剂。在一个优选实施方案中，该IL-1拮抗剂是能够捕获IL-1的融合蛋白。在一个具体实施方案中，该IL-1拮抗剂是SEQ ID NO4、6、8、10、12、14、16、18、20、22、24、26中显示的融合蛋白，或能够结合并抑制IL-1的基本上相同的蛋白。优选的IL-1拮抗剂显示于SEQ ID NO10中。
在第四个方面，本发明以治疗、抑制或改善穆-韦综合征(MWS)的方法为特征，所述方法包括在需要时对受试者施用白细胞介素-1(IL-1)拮抗剂。在一个优选实施方案中，该IL-1拮抗剂是能够捕获IL-1的融合蛋白。在一个具体实施方案中，该IL-1拮抗剂是SEQ ID NO4、6、8、10、12、14、16、18、20、22、24、26中显示的融合蛋白，或能够结合并抑制IL-1的基本上相同的蛋白。优选的IL-1拮抗剂显示于SEQ ID NO10中。
在第五个方面，本发明以治疗、抑制或改善家族性寒冷型自身炎症性综合征(FCAS)的方法为特征，所述方法包括在需要时对受试者施用白细胞介素-1(IL-1)拮抗剂。在一个优选实施方案中，该IL-1拮抗剂是能够捕获IL-1的融合蛋白。在一个具体实施方案中，该IL-1拮抗剂是SEQ ID NO4、6、8、10、12、14、16、18、20、22、24、26中显示的融合蛋白，或能够结合并抑制IL-1的基本上相同的蛋白。优选的IL-1拮抗剂显示于SEQ ID NO10中。
在第六个方面，本发明以治疗、抑制或改善家族性地中海热(FMF)的方法为特征，该方法包括在需要时对受试者施用白细胞介素-1(IL-1)拮抗剂。在一个优选实施方案中，该IL-1拮抗剂是能够捕获IL-1的融合蛋白。在一个具体实施方案中，该IL-1捕获剂是SEQ ID NO4、6、8、10、12、14、16、18、20、22、24、26中显示的融合蛋白，或能够结合并抑制IL-1的基本上相同的蛋白。优选的IL-1捕获剂显示于SEQ ID NO10中。
在第七个方面，本发明以治疗、抑制或改善全身性发作的青少年特发性关节炎(斯蒂尔病)的方法为特征，所述方法包括在需要时对受试者施用白细胞介素-1(IL-1)拮抗剂。在一个优选实施方案中，该IL-1拮抗剂是能够捕获IL-1的融合蛋白。在一个具体实施方案中，该IL-1拮抗剂是SEQ ID NO4、6、8、10、12、14、16、18、20、22、24、26中显示的融合蛋白，或能够结合并抑制IL-1的基本上相同的蛋白。优选的IL-1捕获剂显示于SEQ ID NO10中。
在第八个方面，本发明以治疗、抑制或改善肿瘤坏死因子受体相关的周期性发热综合征(TRAPS)的方法为特征，所述方法包括在需要时对受试者施用IL-1拮抗剂。在一个优选实施方案中，该IL-1拮抗剂是能够捕获IL-1的融合蛋白。在一个具体实施方案中，该IL-1拮抗剂是SEQ ID NO4、6、8、10、12、14、16、18、20、22、24、26中显示的融合蛋白，或能够结合并抑制IL-1的基本上相同的蛋白。优选的IL-1捕获剂显示于SEQ ID NO10中。
在本发明治疗方法的具体实施方案中，用第一种IL-1结合性融合蛋白捕获分子和第二种治疗剂的组合来治疗受试者。第二种治疗剂可以是第二种IL-1拮抗剂，例如，第二种IL-1结合性融合蛋白捕获剂，阿那白滞素(Kineret，Amgen)、重组非糖基化形式的人IL-1受体拮抗剂(IL1Ra)，或抗IL-18药物例如IL-18BP或衍生物、IL-18结合性融合蛋白捕获剂(IL-18捕获剂)、抗IL-18、抗IL-18R1、或抗IL-18Racp抗体或抗体片段。其他协同疗法包括对于FMF的低剂量的秋水仙碱，阿司匹林或其他NSAIDs，类固醇例如泼尼松龙，甲氨蝶呤，低剂量的环孢菌素A，TNF抑制剂例如Enbrel或Humira，其他炎症抑制剂例如胱天蛋白酶-1的抑制剂、p38、IKK1/2、CTLA-4Ig、抗IL-6或抗IL6Ra等。
在第九个方面，本发明以治疗自身炎症性疾病或病状的治疗方法为特征，所述方法包括施用包含IL-1结合性融合蛋白捕获剂和药物学上可接受载体的药物组合物。在一个实施方案中，在1周到1年或更长的治疗时期内在每周一次的基础上以1-20mg/kg的剂量范围施用IL-1结合性融合蛋白捕获剂。在另一实施方案中，总IL-1结合性融合蛋白的施用范围为50-2000mg，它可以以单剂量形式或以连续剂量形式在例如数周或数月的时间段内被提供。
其他目的和优点经参阅随后的详细描述将是显而易见的。
发明详述在描述本方法之前，应当理解本发明不限于所描述的具体方法和实验条件，因为此类方法和条件可以改变。还应当理解本文所使用的术语仅用于描述具体实施方案，并不希望用于限制，因为本发明的范围将仅由所附的权利要求来限定。
如本说明书和所附权利要求中所使用的，除非上下文明确说明否则单数形式的“a”、“an”和“the”包括复数。因此例如提及“一种方法”包括本文所描述的和/或阅读本公开内容等后对于本领域技术人员将是显而易见的类型的一种或多种方法和/或步骤。
除非另外定义，本文所使用的所有技术和科学术语具有与本发明所属领域普通技术人员通常理解相同的含义。尽管与本文所述那些类似或等同的任何方法和材料均可用于本发明的实践或测试中，现在还是描述优选的方法和材料。
一般描述现在认识到基因CIAS1中的突变负责三种罕见的遗传综合征新生儿期起病的多系统炎性病症(NOMID)、穆-韦综合征(MWS)和家族性寒冷型自身炎症性综合征(FCAS)(Hoffman等人，2001 Naure29301-305；Feldmann等人，2002 Am J Hum Genet 71198-203；Aksentijevich等人，2002 Arthritis Rheum 463340-3348)。总的说来，这些病状被称为“CAPS”，“CIAS1相关的周期性综合征”的首字母缩写。CAPS病症非常罕见在美国大约200-300位有FCAS的成人和儿童并且明显更少的有NOMID或MWS的成人已知有这些疾病。这些病状特别是NOMID和MWS的稀少，很可能是由于疾病严重度对生存或生殖适合度的影响。
CAPS是以常染色体显性方式遗传的，具有单个发生或家族模式。CIAS1编码被称为NALP3的蛋白，所述NALP3是“inflammasome”的组分，所述“inflammasome”是调节胱天蛋白酶1活性的亚细胞酶复合体。胱天蛋白酶1是将促炎细胞因子IL-1的无活性前体形式(pro-form)裂解成其生物学活性形式的酶(Agostini等人，2004，同上)。CIAS1中的突变导致IL-1产生增加以及众多的病理学后果(Aksentijevich等人，2002，同上)。IL-1强烈诱导肝脏中产生急性期反应物，例如C-反应性蛋白(CRP)和血清淀粉样A(SAA)。
CAPS的遗传学的有趣之处在于CIAS1中可以有许多不同的点突变与这些综合征相关(Sarrauste de Menthiere等人，2003 NucleicAcids Res 31282-285；Aksentijevich等人，2002，同上)。这些突变中的一些仅与一种综合征相关；其他的与两种综合征相关。例如，某些突变可以与FCAS和MWS相关；其他突变可以与MWS和NOMID相关。大约50％的NOMID患者在CIAS1编码区中没有可识别的突变。在这些患者中，该疾病可以归因于在CIAS1的调节区或蛋白中，或在编码该途径中的紧密相关蛋白的另一基因中迄今仍未识别的突变。FCAS在遗传学上比NOMID更同源几乎所有的FCAS患者分享共同的突变(Sarrauste de Menthiere等人，2003，同上；Hoffman等人，2001，同上)。
CAPS病症分享共同的临床特征并且呈现为一系列的临床严重度。NOMID是最严重的残疾，MWS稍微轻些而FCAS最不严重。CAPS病症具有重叠的特征并且存在具有独特集群的体征和症状的个人和家族。所有这些症状的共同特征包括发热、荨麻疹样皮疹、关节炎或关节痛、肌痛、不舒服和结膜炎。然而，对于任何有CAPS病症的患者，这系列的症状可以不同于有相同病症的另一患者。活跃的CAPS疾病的普遍特征是急性期反应物的实验室检验上升，所述急性期反应物例如为CRP、SAA和/或红细胞沉降率(ESR)。
在NOMID中，慢性无菌性脑膜炎可以导致智力发育迟缓并且这些患者还可能遭受在骨骺和髌骨处的损形性和致残性骨过度生长。这些患者还可能由于视神经萎缩而遭受失明，所述视神经萎缩由颅内压升高引起。MWS和NOMID通常与重度炎症相关，所述重度炎症可以包括听觉系统、脑膜和关节。这些患者可能遭受每日高的峰热以及经常改变分布和强度的慢性皮疹。患者可能遭受听力丧失或耳聋。经常观察到结膜炎和视神经乳头水肿。由于慢性炎症和急性期反应物(特别是SAA)的过度产生，淀粉样变性可以发展并导致肾衰竭。MWS也被称为“淀粉样变性-耳聋综合征”。
FCAS的临床体征和症状通过暴露于适度冷的空气诱导(例如，季节性温度改变、空调)。在寒冷的月份时或在空调盛行的场所患者可以经常(有时是每日)发作疼痛的或痒的皮疹、发热、疲劳、不舒服、头痛、恶心和口渴。在许多场所，这可以包括大多数工作场所。FCAS是患者频繁疼痛的来源并可限制他们的工作、社交和娱乐机会。高达2％的FCAS患者发展出淀粉样变性，这是危及生命的病状。这个频率基本上高于一般公众中淀粉样变性的比率。FCAS的遗传学和自然历史的详细描述见于Hoffman等人，2001 Nature 29301-305和Hoffman等人，2001 J Allergy clin Immunol 108615-620。
定义术语“阻滞剂”、“抑制剂”或“拮抗剂”是指延缓或阻止化学或生理反应或应答的物质。通常的阻滞剂或抑制剂包括但不限于反义分子、抗体、拮抗剂及其衍生物。更具体而言，IL-1的阻滞剂或抑制剂的实例为IL-1拮抗剂，包括但不限于，IL-1融合蛋白捕获拮抗剂，它可以结合并抑制IL-1。
术语“治疗上有效的剂量”是指产生施用预期效应的剂量。确切的剂量将取决于治疗的目的，并且将由本领域技术人员利用已知技术确定(参见，例如Lloyd(1999)The Art，Science and Technologyof Pharmaceutical Compounding)。
术语“基本上相同”是指与氨基酸序列具有至少95％的同一性并且能够结合IL-1并抑制IL-1生物活性的蛋白质序列，所述氨基酸序列选自氨基酸SEQ ID NO4、6、8、10、12、14、16、18、20、22、24和26。
术语“同一性”或“同源性”被解释为指比对序列后，候选序列中与进行比较的对应序列的残基相同的氨基酸残基的百分比，在比对过程中如果需要引入缺口以达到整个序列的最大百分比同一性，并且不考虑任何保守置换作为序列同一性的一部分。N-或C-末端延伸以及插入将均不解释为降低同一性或同源性。关于比对的方法和计算机程序是本领域众所周知的。序列同一性可以利用序列分析软件(例如Sequence Analysis Software Package，Genetics Computer Group，University of Wisconsin Biotechnology Center，1710 UniversityAve.，Madison，Wis.53705)进行测量。这个软件通过将同源度指定为各种置换、删除和其他修饰来匹配相似序列。
IL-1结合性融合蛋白捕获拮抗剂白细胞介素-1(IL-1)捕获剂是包含IL-1受体组分和多聚化组分的融合蛋白的多聚体，所述多聚化组分能够与存在于另一融合蛋白中的多聚化组分相互作用形成高级结构，例如二聚体。本发明方法中有用的IL-1结合性融合蛋白包括结合单个细胞因子的两种不同的受体组分，导致产生的拮抗剂具有显著增加的超过由单组分反应试剂所提供的亲和力。IL-1结合性融合蛋白捕获剂包括人I型(IL-1RI)或II型(IL-1RII)IL-1R的胞外域，随后为人IL-1辅助蛋白(IL-1AcP)的胞外域，随后为多聚化组分。在一个优选实施方案中，该多聚化组分为免疫球蛋白衍生结构域，例如，人IgG的Fc区，包括部分铰链区，CH2和CH3结构域。免疫球蛋白衍生结构域可以选自任何主要种类的免疫球蛋白，包括IgA、IgD、IdE、IgG和IgM，以及任何亚类或亚型，例如，IgG1、IgG2、IgG3和IgG4；IgA-1和IgA-2。可替代地，本发明方法中有用的IL-1结合性融合蛋白包括人IL-1AcP的胞外域，随后为人IL-1RI或IL-1RII的胞外域，随后为多聚化组分。关于IL-1结合性融合蛋白捕获剂的更详细描述参见WO 00/18932。优选的IL-1拮抗剂具有SEQ ID NO2、4、6、8、10、12、14、16、18、20、22、24和26中显示的氨基酸序列，或与SEQ ID NO4、6、8、10、12、14、16、18、20、22、24或26的序列具有至少95％的序列同一性并且能够结合和抑制IL-1的基本上相同的蛋白。
治疗群体本发明的治疗方法可用于治疗受CIAS-1突变病症(NOMID、MWS、FCAS)、FMF、TRAPS或斯蒂尔病侵袭的个体。关于CIAS-1突变相关疾病(NOMID、MWS、FCAS)、家族性地中海热(FMF)或斯蒂尔病(成人或幼年发病)的通常所接受的诊断标准是本领域技术人员已知的。在诊断有FMF的患者的情况下，本发明的治疗方法对于患有用秋水仙碱难以治疗的疾病的那些可以特别有用。
给药方法本发明提供了包括对受试者施用有效量的本发明试剂的治疗方法。在一个优选方面，该试剂是基本上纯化的(例如，基本上不含限制其效果或产生所不希望的副作用的物质)。
各种递药系统是已知的并且可以用于施用本发明试剂，例如封装在脂质体中、微粒、微囊、能够表达该化合物的重组细胞、受体介导的细胞内吞作用(参见，例如Wu和Wu，1987，J.Biol.Chem.2624429-4432)、构建核酸作为逆转录病毒或其他载体的一部分，等等。导入方法可以是经肠的或肠胃外的，包括但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内、硬膜外以及口服。所述化合物可以通过任何方便的途径施用，例如通过输注或推注，通过经上皮的或粘膜与皮肤的衬层(例如口腔粘膜，直肠和肠粘膜等)的吸收，并且可以与其他生物学活性试剂一起施用。施用可以是全身的或局部的。此外，可以希望通过任何适合的途径将本发明的药物组合物导入中枢神经系统，所述途径包括心室内和鞘内注射；通过例如与贮器例如奥马耶贮器(Ommaya reservoir)相连的心室内导管可以促进心室内注射。也可以采用肺给药，例如，通过使用吸入器或雾化器，以及含烟雾剂的制剂。
在一个具体实施方案中，可以希望在需要治疗的区域局部施用本发明的药物组合物；这可以通过下列方法达到，所述方法例如且不限于，通过在手术期间局部输注，局部应用，例如，通过注射，通过导管，或通过植入物，所述植入物是多孔的、非多孔的或凝胶状的材料，包括膜例如sialastic膜、纤维、商品化的皮肤替代品或血管成形术的球囊或支架。
在另一实施方案中，可以在囊泡特别是脂质体中输送活性剂(参见Langer(1990)Science 2491527-1533)。在另一实施方案中，以控释系统输送活性剂。在一个实施方案中，可以利用泵(参见Langer(1990)，同上)。在另一实施方案中，可以使用聚合物材料(参见Howard等人，(1989)J.Neurosurg.71105)。在其中本发明的活性剂是编码蛋白质的核酸的另一实施方案中，通过将其构建为合适的核酸表达载体的一部分并施用之从而使得它变成细胞内的，该核酸可施用于体内以促进其编码的蛋白质的表达，例如通过利用逆转录病毒载体(参见，例如美国专利号4,980,286)，或通过直接注射，或通过利用微粒轰击(例如，基因枪；Biolistic，Dupont)，或用脂质或细胞表面受体或转染剂包裹，或通过将其与已知进入核的同源异型框样肽连接施用(参见例如Joliot等人，，1991，Proc.Natl.Acad.Sci.USA881864-1868)等。可替代地，通过同源重组，核酸可以被导入细胞内并整合到宿主细胞DNA内以便表达。
组合治疗在众多实施方案中，在本发明方法中有用的IL-1拮抗剂可以与一种或多种另外的化合物或疗法组合施用。组合治疗可以是同时的或顺次的。本发明的IL-1结合性融合蛋白可以与下列物质组合，例如，TNF-抑制剂例如依那西普(Enbrel，Amgen)、英夫利昔单抗(Remicade，Centocor)、Humira(Abbott)、沙立度胺、类固醇、阿那白滞素(Kinaret，Amgen)、或秋水仙碱。秋水仙碱是治疗FMF受试者的主要依靠；在本研究中，受试者将不离开用这种药剂的治疗。对于斯蒂尔病(以及经典的自身炎症性疾病)，化合物例如甲氨蝶呤、环胞菌素、苯丁酸氮芥、环磷酰胺(DMARDs)已被用作单一疗法或与非一致性应答(no consistent responce)组合。某些受试者对高剂量的类固醇有反应。DMARDs以及更近来的抗TNF试剂已被使用，并有着可变的成功。本发明的IL-1结合性融合蛋白也可与抗IL-18药物组合，所述抗IL-18药物例如为IL-18BP或衍生物、IL-18结合性融合蛋白、抗IL-18、抗IL-18R1或抗IL-18Racp。其他协同疗法包括对于FMF的低剂量的秋水仙碱，阿司匹林或其他NSAIDs，类固醇例如泼尼松龙，甲氨蝶呤，低剂量的环胞菌素A，TNF抑制剂例如Enbre1或Humira，其他炎症抑制剂例如胱天蛋白酶-1的抑制剂、p38、IKK1/2、CTLA-4Ig、抗IL-6或抗-IL6Ra等。
药物组合物本发明还提供了药物组合物。此类组合物包括治疗上有效剂量的活性剂以及药物学上可接受的载体。术语“药物学上可接受的”指经联邦或州政府管理机构批准的或在美国药典或其他普遍公认的药典中列出的用于动物并且更具体而言用于人的。术语“载体(carrier)”是指稀释剂、佐剂、赋形剂或通过其施用治疗剂的媒介物。此类药物载体可以是无菌的液体，例如水和油，包括石油、动物、植物或合成来源的那些，例如花生油、大豆油、矿物油、芝麻油等。适当的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙稀、甘醇、水、乙醇等。需要时，该组合物还可包含少量湿润剂或乳化剂或pH缓冲剂。这些组合物可采取的形式有溶液、悬浮液、乳状液、片剂、丸剂、胶囊、粉剂、持续释放制剂等。该组合物可以被配制为含常规粘合剂和载体例如甘油三酯的栓剂。口服制剂可以包括标准载体例如药物级别的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适当的药物载体的实例由E.W.Martin描述于″Remington′s Pharmaceutical Sciences″中。
在一个优选实施方案中，该组合物依照常规操作配制为适合于人类静脉内给药的药物组合物。必要时，该组合物也可包括增溶剂和局部麻醉剂例如利多卡因以减轻注射位置处的疼痛。该组合物通过输注施用时，它可以在包含药物级别的无菌水或盐水的输注瓶中分散。该组合物通过注射施用时，可以提供一安瓿的无菌注射用水或盐水，从而使得成分可以在给药前被混合。
本发明的活性剂可以被配制为中性或盐形式。药物学上可接受的盐包括由游离的氨基基团形成的盐，例如从盐酸、磷酸、乙酸、草酸、酒石酸等衍生的盐，以及由游离的羧基基团形成的盐，例如从钠、钾、铵、钙、氢氧化铁、异丙胺、三乙胺、2-乙氨基乙醇、组氨酸、普鲁卡因等衍生的盐。
将在迟发型超敏反应的治疗中有效的本发明活性剂的量可以通过基于本说明书的标准临床技术确定。此外，体外测定法可任选用于帮助鉴定最佳剂量范围。用于制剂中的精确剂量还将取决于给药途径以及病状的严重度，并且应该根据从业医生的判断以及每个受试者的情况来决定。然而，静脉内给药的合适剂量范围一般高达约2克的活性化合物。从由体外或动物模型测试系统得到的剂量-响应曲线可以外推出有效剂量。
对于全身给药，最初可以由体外测定法估计治疗上有效的剂量。例如，可以在动物模型中配制剂量以达到循环浓度范围，所述循环浓度范围包括在细胞培养中所测定的IC50。此类信息可用于更精确地测定在人中的有用剂量。也可利用本领域众所周知的技术由体内数据例如动物模型估计最初剂量。本领域普通的技术人员基于动物数据可以很容易地优化对人的给药。
可以单独调整剂量和间隔以提供足够维持疗效的化合物的血浆水平。在局部给药或选择性摄取的情况下，所述化合物的有效局部浓度可以与血浆浓度无关。无需过度实验，本领域技术人员将能够优化治疗上有效的局部剂量。
当然，所施用的化合物的量将取决于被治疗的受试者，取决于该受试者的体重、痛苦的严重度、给药方式、给药频率以及开处方的医师的判断。当症状可检测时或甚至当它们不可检测时，可以间歇地重复该疗法。该疗法可以被单独提供或与其他药物组合提供。
试剂盒本发明还提供了一种包括包装材料和包含在包装材料内的药物试剂的制品，其中该药物试剂包括至少一种本发明的IL-1特异性融合蛋白，并且其中该包装材料包括标签或药品说明书，所述标签或药品说明书指出该IL-1特异性融合蛋白可以用于治疗自身炎症性疾病或病状。
本发明的其他特征在下列示例性实施例的描述过程中将是显而易见的，所述实施例是为了举例说明本发明而给出的而并不是希望限制本发明。
实施例提出下列实施例是为了给本领域普通技术人员提供如何制造并使用本发明方法和组合物的完整公开内容和描述，而不是希望限制本发明人视为其发明的范围。已付出努力确保关于所使用的数字(例如量、温度等)的精确性，但某些试验误差和偏差应当被说明。除非另有说明，份是重量份，分子量是平均分子量，温度是摄氏度数，和压力为大气压或接近大气压。
实施例1.IL-1捕获剂对人自身炎症性疾病的影响最初的研究在15名患有已知对IL-1的阻断作出反应的疾病(NOMID/MWS/FCAS)的成人受试者以及有成人斯蒂尔病和秋水仙碱抗性FMF的受试者中进行。筛选出合格、临床症状确定、活动性疾病确认的受试者，并且以一周的间隔大约3次抽取基准血样以确定炎症基准水平。进行仔细且完全的标准化病史和体格检查(适合于研究中的疾病)以保证每个受试者的统一的数据收集。在每次就诊时获取生命体征和体重。临床数据基于包括所有被报告的临床表现的详细调查表。下列评价程序特别属于CIAS-1突变相关病症并且如临床说明执行皮肤病学评估；眼科学评估；耳/鼻/喉科学评估；神经学评估；腰椎穿刺；头部MRI；X光照片；关节MRI；以及药物代谢动力学作图。
所有研究受试者接受IL-1结合性融合蛋白(SEQ ID NO10)，给药方案为连续3天每天1次100mg，这是期望提供2-4周的显著的IL-1抑制活性的方案。在用IL-1捕获剂治疗开始后第10天，初步结果在这个期间被测量，包括药物安全性、临床有效性分析以及所选择的炎症生物标记物(例如急性期反应物，例如CRP、血清淀粉样A和ESR)的变化。如果在第10天观察到良好反应，在预定的时间点(没有进一步治疗)监视受试者直到体征和症状回复(发红(flare))。发红后，受试者适合进入延长期，所述延长期需要用负荷方案(连续3天100mg/天的IL-1捕获剂)再治疗，随后为每周1次100mg IL-1捕获剂的定量给药直至一年。
基于研究者的临床判断，如果在延长期以100mg/周定量给药4周后，受试者第1月的急性期反应物水平没有正常化(CRP＞0.5mg/dL和/或SAA＞10mg/L)，或基于疾病的持续体征和/或症状而证明增加剂量具有充分的理由，可以执行IL-1捕获剂剂量增加方案。第一个剂量增加水平可以是每周1次皮下160。受试者将被观察4周，如果仍然适合剂量增加的标准，随后剂量可以上升到每周1次皮下320mg。
初步结果。最初参加的是4名有CAPS的受试者。结果表明用IL-1捕获剂(SEQ ID NO10)治疗后，所有受试者经历了炎症体征和症状的快速而广泛的改善，包括患者和医师报告的疾病表现的改善。还观察到炎症生物标记物例如CRP和SAA的大大下降。体征和症状在初始给药的21天这一中值(范围9-26)内回复，并随后对再治疗反应迅速。表1提供了每日日志评分、急性期反应物和临床评估的总结(对3名受试者执行；*与以前时间点有统计学上显著的差异，p＜0.1水平；**与以前时间点有统计学上显著的差异，p＜0.05水平)。医师和受试者总体评价VAS评分反映出在基线处、在发红时以及在指定为反映最大有效性的时间点上的急性期反应物(SAA、CRP和ESR)的变化。
表1
序列表<110>Regeneron Pharmaceuticals，Inc.
<120>利用IL-1拮抗剂治疗自身炎症性疾病的方法<130>REG 2090A-WO<140>to be assigned<141>2005-06-03<150>60/577,023<151>2004-06-04<160>26<170>FastSEQ for Windows Version 3.0<210>1<211>2733<212>DNA<213>智人<400>1atg gtg ctt ctg tgg tgt gta gtg agt ctc tac ttt tat gga atc ctg 48caa agt gat gcc tca gaa cgc tgc gat gac tgg gga cta gac acc atg 96agg caa atc caa gtg ttt gaa gat gag cca gct cgc atc aag tgc cca144ctc ttt gaa cac ttc ttg aaa ttc aac tac agc aca gcc cat tca gct192ggc ctt act ctg atc tgg tat tgg act agg cag gac cgg gac ctt gag240gag cca att aac ttc cgc ctc ccc gag aac cgc att agt aag gag aaa288gat gtg ctg tgg ttc cgg ccc act ctc ctc aat gac act ggc aac tat336acc tgc atg tta agg aac act aca tat tgc agc aaa gtt gca ttt ccc384ttg gaa gtt gtt caa aaa gac agc tgt ttc aat tcc ccc atg aaa ctc432cca gtg cat aaa ctg tat ata gaa tat ggc att cag agg atc act tgt480cca aat gta gat gga tat ttt cct tcc agt gtc aaa ccg act atc act528tgg tat atg ggc tgt tat aaa ata cag aat ttt aat aat gta ata ccc576gaa ggt atg aac ttg agt ttc ctc att gcc tta att tca aat aat gga624aat tac aca tgt gtt gtt aca tat cca gaa aat gga cgt acg ttt cat672ctc acc agg act ctg act gta aag gta gta ggc tct cca aaa aat gca720gtg ccc cct gtg atc cat tca cct aat gat cat gtg gtc tat gag aaa768
gaa cca gga gag gag cta ctc att ccc tgt acg gtc tat ttt agt ttt 816ctg atg gat tct cgc aat gag gtt tgg tgg acc att gat gga aaa aaa 864cct gat gac atc act att gat gtc acc att aac gaa agt ata agt cat 912agt aga aca gaa gat gaa aca aga act cag att ttg agc atc aag aaa 960gtt acc tct gag gat ctc aag cgc agc tat gtc tgt cat gct aga agt1008gcc aaa ggc gaa gtt gcc aaa gca gcc aag gtg aag cag aaa gtg cca1056gct cca aga tac aca gtg tcc ggt ggc gcg cct atg ctg agc gag gct1104gat aaa tgc aag gaa cgt gaa gaa aaa ata att tta gtg tca tct gca1152aat gaa att gat gtt cgt ccc tgt cct ctt aac cca aat gaa cac aaa1200ggc act ata act tgg tat aag gat gac agc aag aca cct gta tct aca1248gaa caa gcc tcc agg att cat caa cac aaa gag aaa ctt tgg ttt gtt1296cct gct aag gtg gag gat tca gga cat tac tat tgc gtg gta aga aat1344tca tct tac tgc ctc aga att aaa ata agt gca aaa ttt gtg gag aat1392gag cct aac tta tgt tat aat gca caa gcc ata ttt aag cag aaa cta1440ccc gtt gca gga gac gga gga ctt gtg tgc cct tat atg gag ttt ttt1488aaa aat gaa aat aat gag tta cct aaa tta cag tgg tat aag gat tgc1536aaa cct cta ctt ctt gac aat ata cac ttt agt gga gtc aaa gat agg1584ctc atc gtg atg aat gtg gct gaa aag cat aga ggg aac tat act tgt1632cat gca tcc tac aca tac ttg ggc aag caa tat cct att acc cgg gta1680ata gaa ttt att act cta gag gaa aac aaa ccc aca agg cct gtg att1728gtg agc cca gct aat gag aca atg gaa gta gac ttg gga tcc cag ata1776caa ttg atc tgt aat gtc acc ggc cag ttg agt gac att gct tac tgg1824aag tgg aat ggg tca gta att gat gaa gat gac cca gtg cta ggg gaa1872gac tat tac agt gtg gaa aat cct gca aac aaa aga agg agt acc ctc1920atc aca gtg ctt aat ata tcg gaa att gag agt aga ttt tat aaa cat1968cca ttt acc tgt ttt gcc aag aat aca cat ggt ata gat gca gca tat2016atc cag tta ata tat cca gtc act aat tcc gga gac aaa act cac aca2064tgc cca ccg tgc cca gca cct gaa ctc ctg ggg gga ccg tca gtc ttc2112ctc ttc ccc cca aaa ccc aag gac acc ctc atg atc tcc cgg acc cct2160gag gtc aca tgc gtg gtg gtg gac gtg agc cac gaa gac cct gag gtc2208aag ttc aac tgg tac gtg gac ggc gtg gag gtg cat aat gcc aag aca2256aag ccg cgg gag gag cag tac aac agc acg tac cgt gtg gtc agc gtc2304ctc acc gtc ctg cac cag gac tgg ctg aat ggc aag gag tac aag tgc2352aag gtc tcc aac aaa gcc ctc cca gcc ccc atc gag aaa acc atc tcc2400aaa gcc aaa ggg cag ccc cga gaa cca cag gtg tac acc ctg ccc cca2448tcc cgg gag gag atg acc aag aac cag gtc agc ctg acc tgc ctg gtc2496aaa ggc ttc tat ccc agc gac atc gcc gtg gag tgg gag agc aat ggg2544cag ccg gag aac aac tac aag acc acg cct ccc gtg ctg gac tcc gac2592ggc tcc ttc ttc ctc tat agc aag ctc acc gtg gac aag agc agg tgg2640cag cag ggg aac gtc ttc tca tgc tcc gtg atg cat gag gct ctg cac2688aac cac tac acg cag aag agc ctc tcc ctg tct ccg ggt aaa2730tga2733
<210>2<211>910<212>PRT<213>智人<400>2Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Ash Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Ash Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val Ser Gly Gly Ala Pro Met Leu Ser Glu Ala355 360 365Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val Ser Ser Ala370 375 380Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn Glu His Lys385 390 395 400Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro Val Ser Thr405 410 415Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu Trp Phe Val420 425 430Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val Val Arg Asn435 440 445Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe Val Glu Asn450 455 460Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys Gln Lys Leu465 470 475 480Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met Glu Phe Phe485 490 495Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr Lys Asp Cys500 505 510Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val Lys Asp Arg515 520 525Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn Tyr Thr Cys530 535 540His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile Thr Arg Val545 550 555 560Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg Pro Val Ile565 570 575Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly Ser Gln Ile580 585 590Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile Ala Tyr Trp595 600 605Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val Leu Gly Glu610 615 620Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg Ser Thr Leu625 630 635 640Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe Tyr Lys His645 650 655
Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp Ala Ala Tyr660 665 670Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Gly Asp Lys Thr His Thr675 680 685Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe690 695 700Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro705 710 715 720Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val725 730 735Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr740 745 750Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val755 760 765Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys770 775 780Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser785 790 795 800Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro805 810 815Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val820 825 830Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly835 840 845Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp850 855 860Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp865 870 875 880Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His885 890 895Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys900 905 910<210>3<211>2703<212>DNA<213>智人<400>3atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300
tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga1020ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca1080ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg1140atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc1200gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac1260actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc1320ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa1380ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct1440tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat1500aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga1560aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact1620ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct1680aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc1740tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa1800cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa1860gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc1920agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag1980cagaaagtgc cagctccaag atacacagtg gaatccggag acaaaactca cacatgccca2040ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc2100aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc2160cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc2220aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc2280gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc2340ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag2400gtgtacaccc tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc2460ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg2520gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctat2580agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg2640atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa2700tga 2703<210>4
<211>900<212>PRT<213>智人<400>4Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser1 5 10 15Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val20 25 30Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn35 40 45Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro50 55 60Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu65 70 75 80Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val85 90 95Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe100 105 110Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys115 120 125Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met130 135 140Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr145 150 155 160Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val165 170 175Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn180 185 190Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile195 200 205Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg210 215 220Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly225 230 235 240Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile245 250 255Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val260 265 270Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg275 280 285Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe290 295 300Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp
305 310 315 320Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys325 330 335Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp340 345 350Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe355 360 365Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp370 375 380Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro385 390 395 400Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr405 410 415Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr420 425 430Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser435 440 445Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu450 455 460Tyr Gly Ile Gln Arg Ile Thr Cys Pr0 Asn Val Asp Gly Tyr Phe Pro465 470 475 480Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile485 490 495Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu500 505 510Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr515 520 525Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys530 535 540Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro545 550 555 560Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile565 570 575Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val580 585 590Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val595 600 605Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg610 615 620Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg625 630 635 640Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala645 650 655Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser
660 665 670Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu675 680 685Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu690 695 700Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser705 710 715 720His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu725 730 735Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr740 745 750Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn755 760 765Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro770 775 780Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln785 790 795 800Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val805 810 815Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val820 825 830Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro835 840 845Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr850 855 860Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val865 870 875 880Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu885 890 895Ser Pro Gly Lys900<210>5<211>2709<212>DNA<213>智人<400>5atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt120cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac180agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt240tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca300tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt360
tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga1020ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca1080ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg1140atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc1200gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac1260actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc1320ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa1380ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct1440tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat1500aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga1560aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact1620ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct1680aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc1740tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa1800cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa1860gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc1920agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag1980cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca2040tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg2700ggtaaatga2709<210>6<211>902
<21 2>PRI<213>智人<400>6Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser1 5 10 15Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val20 25 30Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn35 40 45Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro50 55 60Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu65 70 75 80Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val85 90 95Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe100 105 110Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys115 120 125Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met130 135 140Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr145 150 155 160Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val165 170 175Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn180 185 190Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile195 200 205Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg210 215 220Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly225 230 235 240Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile245 250 255Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val260 265 270Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg275 280 285Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe290 295 300Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp305 310 315 320
Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys325 330 335Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp340 345 350Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe355 360 365Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp370 375 380Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro385 390 395 400Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr405 410 415Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr420 425 430Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser435440 445Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu450 455 460Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro465 470 475 480Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile485 490 495Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu500 505 510Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr515 520 525Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys530 535 540Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro545 550 555 560Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile565 570 575Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val580 585 590Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val595 600 605Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg610 615 620Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg625 630 635 640Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala645 650 655Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser660 665 670
Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu885 890 895Ser Leu Ser Leu Gly Lys900<210>7<211>2709<212>DNA<213>智人<400>7atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat60aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt120cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac180agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt240tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca300tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt360tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg420
tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca 2040tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700ggtaaatga 2709<210>8<211>902<212>PRT
<213>智人<400>8Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser1 5 10 15Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val20 25 30Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn35 40 45Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro50 55 60Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu65 70 75 80Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val85 90 95Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe100 105 110Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys115 120 125Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met130 135 140Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr145 150 155 160Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val165 170 175Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn180 185 190Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile195 200 205Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg210 215220Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly225 230 235 240Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile245 250 255Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val260 265 270Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg275 280 285Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe290 295 300Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp305 310 315 320Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys
325 330 335Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp340 345 350Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe355 360 365Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp370 375 380Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro385 390 395 400Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr405 410 415Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr420 425 430Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser435 440 445Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu450 455 460Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro465 470 475 480Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile485 490 495Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu500 505 510Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr515 520 525Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys530 535 540Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro545 550 555 560Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile565 570 575Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val580 585 590Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val595 600 605Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg6l0 615 620Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg625 630 635 640Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala645 650 655Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu885 890 895Ser Leu Ser Leu Gly Lys900<210>9<211>2703<212>DNA<213>智人<400>9atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980gcatatatcc agttaatata tccagtcact aattccggag acaaaactca cacatgccca 2040ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 2100aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 2160cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 2220aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 2280gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 2340ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 2400gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 2460ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 2520gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 2580agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 2640atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 2700tga 2703<210>10<211>900<212>PRT<213>智人
<400>10Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile355 360 365Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu370 375 380Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser385 390 395 400Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys405 410 415Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr420 425 430Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser435 440 445Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala450 455 460Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys465 470 475 480Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu485 490 495Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe500 505 510Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His515 520 525Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln530 535 540Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys545 550 555 560Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val565 570 575Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu580 585 590Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp595 600 605Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn610 615 620Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu625 630 635 640Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His645 650 655Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser660 665 670Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu675 680 685
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu690 695 700Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser705 710 715 720His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu725 730 735Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr740 745 750Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn755 760 765Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro770 775 780Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln785 790 795 800Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val805 810 815Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val820 825 830Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro835 840 845Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr850 855 860Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val865 870 875 880Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu885 890 895Ser Pro Gly Lys900<210>11<211>2709<212>DNA<213>智人<400>11atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa1080tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt1140ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc1200aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg1260tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct1320tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat1380aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc1440ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag1500gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc1560gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac1620ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa1680cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc1740cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg1800aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa1860aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag1920agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca1980gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca2040tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg2700ggtaaatga2709<210>12<211>902<212>PRT<213>智人
<400>l2Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile355 360 365Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu370 375 380Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser385 390 395 400Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys405 410 415Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr420 425 430Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser435 440 445Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala450 455 460Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys465 470 475 480Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu485 490 495Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe500 505 510Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His515 520 525Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln530 535 540Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys545 550 555 560Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val565 570 575Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu580 585 590Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp595 600 605Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn610 615 620Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu625 630 635 640Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His645 650 655Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu675 680 685
Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Set Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu885 890 895Ser Leu Ser Leu Gly Lys900<210>13<211>2709<212>DNA<213>智人<400>13atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc540
tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa1080tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt1140ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc1200aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg1260tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct1320tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat1380aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc1440ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag1500gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc1560gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac1620ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa1680cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc1740cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg1800aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa1860aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag1920agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca1980gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca2040tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg2700ggtaaatga2709<210>14<211>902<212>PRT<213>智人<400>14
Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350
Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile355 360 365Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu370 375 380Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser385 390 395 400Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys405 410 415Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr420 425 430Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser435 440 445Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala450 455 460Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys465 470 475 480Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu485 490 495Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe500 505 510Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His515 520 525Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln530 535 540Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys545 550 555 560Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val565 570 575Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu580 585 590Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp595 600 605Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn610 615 620Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu625 630 635 640Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His645 650 655Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp690 695 700
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu885 890 895Ser Leu Ser Leu Gly Lys900<210>15<211>2748<212>DNA<213>智人<400>15atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg120ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct180gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga240gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag300gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc360attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa420attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt480gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat540gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa600gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc660
actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt720tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg780tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac840atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa900aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg960cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040gctccaagat acacagtgtc cggagacaaa actcacacat gcccaccgtg cccagcacct 2100gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 2160atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 2220gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagcegcgg 2280gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 2340tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 2400gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 2460ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 2520tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 2580accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg 2640gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 2700cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga2748<210>16<211>915<212>PRT<213>智人<400>16Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu1 5 10 15
Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly20 25 30Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu35 40 45Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg50 55 60Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly65 70 75 80Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu85 90 95Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn100 105 110Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn115 120 125Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu130 135 140Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg145 150 155 160Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu165 170 175Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu180 185 190Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val195 200 205Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile210 215 220Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile225 230 235 240Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile245 250 255Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu260 265 270Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly275 280 285Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn290 295 300Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu305 310 315 320His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr325 330 335Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys340 345 350Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp355 360 365
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe370 375 380Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp385 390 395 400Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro405 410 415Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr420 425 430Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr435 440 445Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser450 455 460Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu465 470 475 480Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro485 490 495Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile500 505 510Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu515 520 525Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr530 535 540Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys545 550 555 560Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro565 570 575Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile580 585 590Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val595 600 605Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val610 615 620Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg625 630 635 640Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg645 650 655Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala660 665 670Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly675 680 685Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly690 695 700Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met705 710 715 720
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His725 730 735Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val740 745 750His Ash Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr755 760 765Arg VaI Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly770 775 780Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile785 790 795 800Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val805 810 815Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser820 825 830Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu835 840 845Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro850 855 860Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val865 870 875 880Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met885 890 895His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser900 905 910Pro Gly Lys915<210>17<211>2754<212>DNA<213>智人<400>17atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg120ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct180gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga240gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag300gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc360attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa420attttaacct tgtcaacetc tggggtatta gtatgccctg acctgagtga attcaccegt480gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat540gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa600gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc660
actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt720tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg780tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac840atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa900aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg960cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc atcatgccca 2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754<210>18<211>917<212>PRT<213>智人<400>18Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu1 5 10 15
Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly20 25 30Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu35 40 45Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg50 55 60Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly65 70 75 80Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu85 90 95Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn100 105 110Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn115 120 125Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu130 135 140Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg145 150 155 160Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu165 170 175Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu180 185 190Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val195 200 205Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile210 215 220Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile225 230 235 240Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile245 250 255Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu260 265 270Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly275 280 285Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn290 295 300Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu305 310 315 320His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr325 330 335Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys340 345 350Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp355 360 365
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe370 375 380Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp385 390 395 400Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro405 410 415Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr420 425 430Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr435 440 445Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser450 455 460Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu465 470 475 480Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro485 490 495Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile500 505 510Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu515 520 525Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr530 535 540Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys545 550 555 560Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro565 570 575Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile580 585 590Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val595 600 605Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val610 615 620Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg625 630 635 640Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg645 650 655Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala660 665 670Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser900 905 910Leu Ser Leu Gly Lys915<210>19<211>2754<212>DNA<213>智人<400>19atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg120ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct180gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga240gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag300gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc360attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa420attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt480gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat540gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa600atgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660
actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca1020gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg1080aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac1140ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg1200actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt1260agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat1320acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt1380caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa1440tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa1500ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc1560gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt1620gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag1680gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg1740gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt1800ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc1860actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga1920actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt1980catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca2040gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc accatgccca2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754<210>20<211>917<212>PRT<213>智人<400>20Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phc Thr Leu1 5 10 15
Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly20 25 30Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu35 40 45Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg50 55 60Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly65 70 75 80Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu85 90 95Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn100 105 110Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn115 120 125Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu130 135 140Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg145 150 155 160Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu165 170 175Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu180 185 190Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val195 200 205Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile210 215 220Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile225 230 235 240Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile245 250 255Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu260 265 270Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly275 280 285Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn290 295 300Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu305 310 315 320His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr325 330 335Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys340 345 350Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp355 360 365
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe370 375380Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp385 390 395 400Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro405 410 415Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr420 425 430Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr435 440 445Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser450 455 460Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu465 470 475 480Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro485 490 495Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile500 505 510Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu515 520 525Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr530 535 540Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys545 550 555 560Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro565 570 575Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile580 585 590Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val595 600 605Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val610 615 620Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg625 630 635 640Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg645 650 655Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala660 665 670Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser900 905 910Leu Ser Leu Gly Lys915<210>21<211>2748<212>DNA<213>智人<400>21atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca1080ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa1140ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc1200ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa1260gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac1320tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag1380ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta1440accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa1500actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa1560tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct1620ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg1680agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc1740ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg1800ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag1860agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat1920gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg1980gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag2040gaagcctcct ccacgttctc cggagacaaa actcacacat gcccaccgtg cccagcacct2100gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg2160atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag2220gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg2280gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac2340tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc2400gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc2460ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc2520tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag2580accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg2640gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg2700cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 2748<210>22<211>915<212>PRT<213>智人<400>22Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe355 360 365
Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val370 375 380Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser385 390 395 400Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val405 410 415Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp420 425 430Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr435 440 445Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe450 455 460Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu465 470 475 480Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe485 490 495Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu500 505 510Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr515 520 525His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg530 535 540Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg545 550 555 560Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val565 570 575Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu580 585 590Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr595 600 605Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro610 615 620Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn625 630 635 640Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu645 650 655Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe660 665 670Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly675 680 685Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly690 695 700Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met705 710 715 720
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His725 730 735Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val740 745 750His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr755 760 765Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly770 775 780Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile785 790 795 800Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val805 810 815Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser820 825 830Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu835 840 845Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro850 855 860Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val865 870 875 880Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met885 890 895His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser900 905 910Pro Gly Lys915<210>23<211>2754<212>DNA<213>智人<400>23atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca1080ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa1140ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc1200ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa1260gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac1320tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag1380ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta1440accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa1500actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa1560tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct1620ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg1680agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc1740ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg1800ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag1860agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat1920gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg1980gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag2040gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc atcatgccca2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754<210>24<211>917<212>PRT<213>智人<400>24Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe355 360 365
Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val370 375 380Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser385 390 395 400Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val405 410 415Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp420 425 430Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr435 440 445Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe450 455 460Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu465 470 475 480Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe485 490 495Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu500 505 510Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr515 520 525His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg530 535 540Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg545 550 555 560Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val565 570 575Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu580 585 590Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr595 600 605Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro610 615 620Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn625 630 635 640Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu645 650 655Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe660 665 670Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser900 905 910Leu Ser Leu Gly Lys915<210>25<211>2754<212>DNA<213>智人<400>25atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca1080ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa1140ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc1200ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa1260gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac1320tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag1380ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta1440accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa1500actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa1560tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct1620ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg1680agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc1740ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg1800ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag1860agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat1920gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg1980gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag2040gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc accatgccca2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754<210>26<211>917<212>PRT<213>智人<400>26Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe355 360 365
Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val370 375 380Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser385 390 395 400Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val405 410 415Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp420 425 430Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr435 440 445Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe450 455 460Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu465 470 475 480Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe485 490 495Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu500 505 510Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr515 520 525His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg530 535 540Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg545 550 555 560Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val565 570 575Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu580 585 590Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr595 600 605Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro610 615 620Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn625 630 635 640Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu645 650 655Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe660 665 670Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser900 905 910Leu Ser Leu Gly Lys91权利要求
1.包括两个IL-1受体组分和多聚化组分的白细胞介素-1(IL-1)融合蛋白拮抗剂在制造用于治疗、抑制或改善自身炎症性病症、疾病或病状的药物中的用途。
2.根据权利要求1的用途，其中所述融合蛋白拮抗剂包括选自SEQ ID NO4、6、8、10、12、14、16、18、20、22、24和26中显示的氨基酸序列的氨基酸序列；或与SEQ ID NO4、6、8、10、12、14、16、18、20、22、24或26的所述序列显示至少95％的序列同一性并且能够结合和抑制IL-1的氨基酸序列。
3.根据权利要求1或2的用途，其中所述融合蛋白拮抗剂包括SEQ ID NO10。
4.如权利要求1、2或3中所定义的白细胞介素-1(IL-1)融合蛋白拮抗剂作为第一种治疗剂，以及一种或多种进一步的治疗剂，所述进一步的治疗剂选自不同于第一种治疗剂的IL-1融合蛋白、依那西普(Enbrel，Amgen)、英夫利昔单抗(Remicade，Centocor)、Humira(Abbott)、沙立度胺、类固醇、阿那白滞素(Kinaret，Amgen)、秋水仙碱、IL-18BP或衍生物、IL-18结合性融合蛋白、抗IL-18、抗IL-18R1、抗IL-18Racp、阿司匹林、泼尼松龙、甲氨蝶呤、环胞菌素A、胱天蛋白酶-1、p38、IKK1/2、CTLA-4Ig、抗IL-6和抗-IL6Ra，在制造用于治疗、抑制或改善自身炎症性病症、疾病或病状的药物中的用途。
5.根据前述权利要求中任何一项的用途，其中所述自身炎症性病症、疾病或病状是新生儿期起病的多系统炎性病症(NOMID/CINCA)、穆-韦综合征(MWS)、家族性寒冷型自身炎症性综合征(FCAS)、家族性地中海热(FMF)、肿瘤坏死因子受体相关的周期性发热综合征(TRAPS)或全身性发作的青少年特发性关节炎(斯蒂尔病)；和/或与CIAS-1中突变相关的自身炎症性病症、疾病或病状。
6.一种药物组合物，其包括如权利要求1、2或3中所定义的白细胞介素-1(IL-1)融合蛋白拮抗剂作为第一种治疗剂；一种或多种进一步的治疗剂，所述进一步的治疗剂选自不同于第一种治疗剂的IL-1融合蛋白、依那西普(Enbrel，Amgen)、英夫利昔单抗(Remicade，Centocor)、Humira(Abbott)、沙立度胺、类固醇、阿那白滞素(Kinaret，Amgen)、秋水仙碱、IL-18BP或衍生物、IL-18结合性融合蛋白、抗IL-18、抗IL-18R1、抗IL-18Racp、阿司匹林、泼尼松龙、甲氨蝶呤、环胞菌素A、胱天蛋白酶-1、p38、IKK1/2、CTLA-4Ig、抗IL-6和抗-IL6Ra；以及药物学上可接受的载体或赋形剂。
7.一种产品，其包括如权利要求1、2或3中所定义的白细胞介素-1(IL-1)融合蛋白拮抗剂作为第一种治疗剂；以及一种或多种进一步的治疗剂用于在治疗人或动物体的自身炎症性病症、疾病或病状中分开、同时或顺次使用。
8.根据权利要求7的产品，其中所述进一步的治疗剂如权利要求4中所定义。
9.根据权利要求7或8的产品，其中所述自身炎症性病症、疾病或病状如权利要求5中所定义。
10.通过与如权利要求4中所定义的进一步的治疗剂共施用，如权利要求1、2或3中所定义的白细胞介素-1(IL-1)融合蛋白拮抗剂在制造用于治疗、抑制或改善自身炎症性病症、疾病或病状的药物中的用途。
11.通过与如权利要求1、2或3中所定义的白细胞介素-1(IL-1)融合蛋白拮抗剂共施用，如权利要求4中所定义的进一步的治疗剂在制造用于治疗、抑制或改善自身炎症性病症、疾病或病状的药物中的用途。
12.根据权利要求1-5、10或11中任何一项中的用途，其中所述药物用于皮下、肌内、静脉内、局部、经皮肤或口服给药。
13.根据权利要求1-5、10-12中任何一项中的用途，其中所述药物用于以1-20mg/kg的剂量施用治疗上有效量的所述融合蛋白拮抗剂。
14.一种治疗、抑制或改善自身炎症性病症、疾病或病状的方法，其包括在其需要时对受试者施用治疗量的如权利要求1、2或3中所定义的白细胞介素-1(IL-1)拮抗剂。
15.根据权利要求14的方法，其中所述自身炎症性病症、疾病或病状如权利要求5中所定义。
16.根据权利要求14或15的方法，其进一步包括对所述受试者施用一种或多种如权利要求4中所定义的进一步的治疗剂。
17.根据权利要求14、15或16的方法，其中所述自身炎症性病症、疾病或病状与CIAS-1中的突变相关，并且所述IL-1拮抗剂包括SEQ ID NO10的氨基酸序列。
18.根据权利要求15、16、17或18的方法，其中所述药物融合蛋白拮抗剂以1-20mg/kg的剂量施用。
全文摘要
在其需要时治疗、抑制或改善受试者的自身炎症性病症、疾病或病状的方法，包括在需要时对受试者施用治疗量的白细胞介素－1(IL－1)拮抗剂，其中该自身炎症性病症、疾病或病状被治疗、抑制或改善。该IL－1拮抗剂是能够结合并抑制IL－1的分子。该治疗方法可用于治疗患新生儿期起病的多系统炎性病症(NOMID/CINCA)、穆－韦综合征(MWS)、家族性寒冷型自身炎症性综合征(FCAS)、家族性地中海热(FMF)、肿瘤坏死因子受体相关的周期性发热综合征(TRAPS)或全身性发作的青少年特发性关节炎(斯蒂尔病)的成人或儿童。
文档编号A61P29/00GK1964737SQ200580018218
公开日2007年5月16日 申请日期2005年6月3日 优先权日2004年6月4日
发明者S·梅利斯, M·卡罗, G·D·扬克普罗斯, J·帕帕佐普洛斯 申请人:瑞泽恩制药公司