CN102803967A - 用于结直肠腺癌的诊断的基于蛋白质的方法和组合物 - Google Patents

Abstract

本发明公开了用于结直肠腺癌的诊断的基于蛋白质的方法和组合物。公开了用于鉴定细胞表面蛋白的方法，所述细胞表面蛋白是跨膜蛋白或具有信号肽的蛋白并且在结直肠癌(CRC)中过表达。公开了用这种方法发现的生物标记，使用它们和用于磁共振成像(MRI)和/或磁光子成像(MPI)的针对它们的造影剂的诊断方法。本方法和生物标记允许将进行性（高风险）CRC（腺癌）与非进行性（低风险）结直肠腺瘤区分开。

Description

用于结直肠腺癌的诊断的基于蛋白质的方法和组合物

发明主题

本发明的涉及用于检测结肠腺癌的造影剂、诊断标记和方法。

发明背景

大多数癌症是上皮来源的并且通过从正常细胞经发育异常逐步进展至恶性细胞而产生，所述恶性细胞侵入外围组织并且具有转移潜能。结直肠癌(CRC；也称为结肠癌或大肠癌) 是经历这样的肿瘤进展的一个突出类型的癌症。

CRC包括结肠、直肠和阑尾中的癌生长。其为最重要的人癌症之一，具有每年全世界约1,000,000例新病例的发病率。因此，CRC是第三大常见癌症和世界上癌相关死亡的第四大原因(西方国家的第二大原因；综述于例如Gryfe, R.等人 (1997) Curr. Probl. Cancer 21, 233-300; Petersen, G. M. 等人(1999) Cancer 86, 2540-2550中。

如果在肿瘤发展的早期（即I期）被诊断，CRC是可治愈的。早期CRC的五年生存率超过90%。在该早期中，大多数患者不具有该疾病的表型症状。早期检测可显著增加长期生存的机会，因为处于肿瘤发展的晚期（即IV期）的CRC的五年生存率仅为低于5%。超过95%的CRC病例表现为腺癌(Muto, T.等人 (1975) Cancer 36, 2251-2270; Fearon, E. R.等人 (1990) Cell 61, 759 767)。

在过去，采取筛查来鉴定牵涉从低风险结直肠腺瘤至高风险腺癌的进展的基因。为此，鉴定其表达在结直肠腺癌中相对于在腺瘤中被上调或下调的基因（参见例如 Carvalho等人 (2009) Gut 58, 79-89)。

目前，结肠镜检查术是在目前应用的技术当中具有最高的检测结直肠肿瘤的灵敏度和特异度的CRC的标准筛查方式。

然而，利用结肠镜检查术的筛查可具有不利方面。此类不利方面是(i) 当为无症状个体提供CRC筛查时，结肠镜检查术是为限制因素的侵入性技术，(ii)作为结肠镜检查术的结果存在小的但严重的肠穿孔的风险以及(iii)结肠镜检查术不能区分非进行性(低风险)与进行性(高风险)结肠肿瘤损伤。

因此，存在对允许CRC的诊断的试剂、组合物、标记和方法的持续需要。

本发明的目的和概述

本发明的一个目的是提供允许诊断CRC的方法。本发明的进一步目的是提供可用于诊断CRC的标记。

本发明的另一个目的涉及可用于检测CRC的造影剂的提供。

这些和其他目的（如根据下文中接下来的描述它们将变得显然）形成了独立权利要求主题。本发明的某些优选实施方案形成了从属权利要求的主题。

因此在一个实施方案中，本发明涉及诊断标记，优选用于CRC的诊断标记，其包含由下列多肽组成的组的至少一种多肽:

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4 的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6 的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16 的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽，和/或;

• SEQ ID No.: 32 的多肽。

本发明在其他实施方案中涉及选自由下列多肽组成的组的至少一种多肽作为诊断标记，优选用于检测CRC的诊断标记的用途:

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽, 和/或

• SEQ ID No.: 32的多肽。

在一个实施方案中，在人或动物体外进行这样的用途。

本发明的另一个方面涉及任选地用于磁共振成像(MRI) 和/或磁光子成像（magnetic photon imaging）(MPI)的造影剂，其包含至少一种能够与选自由下列多肽组成的组的多肽相互作用的化合物：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6 的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或 SEQ ID No.: 32的多肽。

在优选实施方案中，将此类化合物偶联至优选可被MRI 或MPI检测的标记分子。

化合物优选地可以是抗体。

此类造影剂优选地可用于检测CRC。

在其他实施方案中，本发明涉及至少一种能够与选自由下列多肽组成的组的多肽相互作用的抗体作为造影剂（任选地适用于MRI 和/或 MPI）的用途：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3 的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽，

此类造影剂优选可用于检测CRC。

本发明的另一个实施方案涉及诊断CRC的方法，其包括至少下列步骤：

a) 从至少一个怀疑遭受正在进行或迫近的CRC发展的人或动物个体获得至少一个样品;

b) 测试所述至少一个样品中至少一种选自由下列多肽组成的组的多肽的表达：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2 的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19 的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽;

c) 测试获自至少一个未遭受正在进行或迫近的CRC发展的人或动物个体的至少一个对照样品中至少一种选自由下列多肽组成的组的多肽的表达：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13 的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽;

d) 测定步骤b)和d)的表达的差异;

e) 基于步骤d)中获得的结果确定结直肠癌发展的存在或迫近.

在一个实施方案中，在人或动物体外进行该诊断方法的步骤b)、c)、d) 和/或 e)。

本发明的另一个方面涉及诊断结直肠癌的方法，其包括至少下列步骤：

a) 测试怀疑遭受正在进行或迫近的CRC发展的至少一个人或动物个体中选自由下列多肽组成的组的至少一种多肽的表达：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9 的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24 的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽;

b) 将如步骤a)中测定的表达与如对于未遭受正在进行或迫近的CRC发展的人或动物个体所测定的选自由下列多肽组成的组的至少一种多肽的表达相比较：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽;

c) 基于步骤b)中获得的结果确定CRC发展的存在或迫近。

本发明的另 一个方面涉及数据获取的方法，其包括至少下列步骤：

a) 测试至少一个怀疑遭受正进行或迫近的CRC发展的人或动物个体中选自由下列多肽组成的组的至少一种多肽的表达:

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7 的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽;

b) 将步骤a)中测定的表达与如对于未遭受正在进行或迫近的CRC发展的人或动物个体测定的选自由下列多肽组成的组的至少一种多肽的表达相比较：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29 的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽;

此外，本发明的实施方案涉及鉴定至少一个适合作为结直肠癌的诊断标记的靶分子的方法，其中所述方法包括至少下列步骤：

a) 从全都患有结直肠癌的不同人个体获得细胞和/或获得结直肠癌细胞系;

b) 标记所述细胞表面上的多肽;

c) 将标记的多肽与非标记的多肽分离;

d) 鉴定步骤c)的来自细胞表面多肽-级分的分离的标记的多肽,

e) 在步骤d)的多肽中，选择对于其基因组表达数据显示与从健康个体获得的细胞相比较增加的表达的那些分离的标记的多肽;

f) 在于步骤e)中选择的多肽中，进一步选择包含至少一个跨膜结构域和/或至少一个信号肽的那些分离的标记的多肽;

g) 在于步骤f)中选择的多肽中，进一步选择具有阳性RSC的那些多肽;

h) 在于步骤g)中选择的多肽中，进一步选择在至少70%的来自不同人个体的测试细胞内发现的那些多肽;

i) 在于步骤h)中选择的多肽中，进一步选择组织学分析确认其至质膜的定位的那些多肽。

上述诊断标记、造影剂、用途和方法适合用于区分进行性(高风险)CRC(腺癌)与非进行性(低风险)结直肠腺瘤。

此外，本发明的诊断标记、造影剂、用途和方法可以特别适合用于非侵入性分子成像，例如利用MRI的成像，用于CRC的诊断。

根据下文中的详细描述，本发明的其他实施方案将变得显而易见。

附图图例

图1 描述了结直肠癌细胞系Colo 205、HT-29、Caco2、RKO和HCT116的Neuravidine-纯化的生物素-标记的细胞表面或细胞内级分的SDS-PAGE分析。细胞内级分的两个泳道对应于获自CRC细胞系Colo 205、HT29和Caco2(左泳道)以及RKO和HCT116(右泳道)的级分。

图 2描述了PRNP (SEQ ID NO: 6)的组织学分析。

图3描述了获自结直肠癌患者的组织培养物中的BCAM (SEQ ID NO: 5)的组织学检测。

发明详述

在根据其优选实施方案中的一些详细描述本发明之前，提供了下列一般定义。

可适当地在未在本文中明确地公开的任何要素、限制不存在的情况下实施如在下文中举例说明性描述的本发明。

通过具体的实施方案和参考某些图描述本发明，但本发明不限定于其但只受权利要求要求的限制。

在术语“包含”用于本说明书和权利要求中的情况下，其不排除其他要素。为了本发明的目的，术语“由……组成”被认为是术语“包括（comprising of）”的优选实施方案。如果在下文中，组被定义为包括至少一定数目的实施方案，那么这也可被理解为公开优选只由这些实施方案组成的组。

在使用不定冠词或定冠词（当指单数名词时）例如“一”或“该”的情况下，除非明确地作出其他声明，否则这包括该名词的复数。在本发明的情境中，术语“约”或“大致”表示本领域技术人员将理解仍然确保所述特征的技术效果的精确性的区间。该术语通常表示为±10%的，优选为±5%的与指示的数值的偏差。

在下文中在术语所使用的情境中提供了所述术语的进一步定义。

如背景部分中提及的，用于诊断CRC的分子标记（模式）的鉴定已集中在其表达在CRC发展过程被上调或下调的基因的鉴定。虽然该数据提供了有价值的信息，但诊断标记即基因和它们的产物（例如多肽）可能不全都适合于非侵入性分子成像诊断法。

本发明的发明者已成功地鉴定了一组多肽，所述多肽可能相对于健康个体在大部分遭受结直肠癌发展的患者中过表达并且对于非侵入性分子成像诊断方法是可使用的。

为此，本发明者已设计了筛查策略，其包括至少下列步骤：

a) 从全都患有结直肠癌的不同人个体获得细胞和/或获得结直肠癌细胞系;

b) 标记所述细胞的表面上的多肽;

c) 将标记的多肽与非标记的多肽分离;

d) 鉴定步骤c)的来自细胞表面多肽-级分的分离的标记的多肽,

e) 在步骤d)的多肽中，选择基因组表达数据对于其显示与从健康个体获得的细胞相比较增加的表达的那些分离的标记的多肽；

f) 在于步骤e)中选择的多肽中，进一步选择包含至少一个跨膜结构域和/或至少一个信号肽的那些分离的标记的多肽；

g) 在于步骤f)中选择的多肽中，进一步选择具有阳性RSC的那些多肽;

h) 在于步骤g)中选择的多肽中，进一步选择在至少70% 的来自不同人个体的测试细胞内发现的那些多肽;

i) 在于步骤h)中选择的多肽中，进一步选择组织学分析确认其至质膜的定位的那些多肽。

从患CRC的人个体获得的步骤a)的细胞通常是已知参与CRC的发展的细胞类型。通常，所述细胞包括胚胎干细胞、胎儿干细胞或成人干细胞；祖细胞；血细胞例如B和T-淋巴细胞、单核细胞和巨噬细胞；上皮细胞；成纤维细胞；和神经元细胞。上皮细胞可以是优选的。

步骤a)中使用的细胞还可以是已建立的CRC细胞系。此类细胞系可商购获得并且包括特别是Colo205、HT-29、Caco-2、RKO、HCT116、SW1398、LS513、SW480、SW620和COLO 320。

进行标记步骤b)以允许定位至细胞的表面的优先多肽的有效纯化、富集和分离。 因此，将使用允许例如利用亲和层析进行有效纯化的标记。此类标记可包括例如生物素、麦芽糖结合蛋白(MBP)、谷胱苷肽S-转移酶(GST)、组氨酸-标签、Flag-标签、抗体等。

可将标记共价或非共价地连接至优先定位在细胞表面上的蛋白质。

1. 为了进行共价键改性（covalent modification），可使用通常用于此类目的的偶联化学。因此，可使用同和/或异-双和/或多功能交联剂。典型的交联剂包括但不限于双(硫代琥珀酰亚胺)双(重氮基-联苯胺)、己二酰亚胺二甲酯、Dimethyl Pimelimidate, 辛二酰亚胺二甲酯、Disuccininnclyl Suberate、戊二醛、in-Maleimidobenzoyl-N-Hydroxysuccinimide、4-(N-马来酰亚胺基甲基)环己烷-1-羧酸硫代琥珀酰亚胺酯等。

优选标记可以是硫代-NHS-SS-生物素.

随后，通常裂解细胞。这可通过低渗、酶促、超声或机械细胞破碎来实现。

随后，可利用标记分离标记的多肽。本领域技术人员了解如何选择适当的分离方法。

如果例如使用生物-标记标记多肽，那么可使用如它们可商购获得的基于链霉抗生物素蛋白的层析系统例如链霉抗生物素蛋白标记的或neuravidine-标记的珠粒。对His-标签，可使用可从Qiagen获得的Ni-NTA琼脂糖。对于谷胱苷肽-S-转移酶标记，可使用GST-sepharose等。

通过将来自例如裂解的细胞的标记的多肽经历这样的层析介质，可实现标记的多肽的纯化。由于标记方法通常优先标记细胞表面多肽，因此保留在层析介质上并且从层析介质洗脱的级分可被称为标记的细胞表面多肽级分。在穿流液中发现的多肽可被称为细胞内多肽级分。此外，可使用如它们是公知的特定制备方案来从裂解的细胞获得主要包含细胞表面结合多肽和细胞内多肽的级分。将此类级分经历如上所述的层析介质可改善标记的细胞表面多肽至层析介质的附着。

如果例如已用生物素标记细胞，那么细胞的多肽可优先于细胞质多肽被标记，以便标记的细胞表面多肽将被优先保留在例如链霉抗生物素-珠粒上而细胞质多肽将主要发现于穿流液或洗涤级分中。

本领域技术人员了解如何正确地进行此类分离/纯化方法，例如如何选择适当的洗涤缓冲液、洗脱缓冲液、pH值等。

从而通过将标记的多肽从各自层析介质洗脱来将它们与细胞表面多肽-级分分离。随后，鉴定此类分离的标记的多肽。为此，可使用例如质谱(MS)分析。

随后使利用该方法获得的数据与关于基因的基因组表达数据关联，所述基因的表达在CRC中被上调或下调。基因组表达数据可从例如Carvalho等人 (2009) Gut 58 (1), 79-89（就其提供其表达在CRC中被上调的基因的信息将其通过引用合并入本文）获得。

本发明的情境中的关联意指只选择已鉴定的标记的多肽，对于所述多肽，基因组表达数据显示与获自健康个体的细胞相比较增加的表达。

为了增加标记的、分离的和已鉴定的多肽确实定位至细胞的质膜的可能性，应用进一步的选择标准，所述选择标准只选择对于其基于算法的分析显示跨膜(TM)结构域和/或至少一个信号肽的存在的多肽。术语“信号肽”是指指导蛋白质至细胞的质膜的定位的序列特征。此类信号肽序列在本领域内是已知的。

可使用通常用于此类方法的程序和算法例如由Stockholm Bioinformatics Center (Käll等人 (2004) Journal of Molecular Biology, 338(5):1027-1036)开发的Phobias进行该分析。

在选择具有至少一个跨膜结构域或至少一个信号肽的多肽后，应用进一步选择来减少假阳性的数目。为此，只选择具有阳性相对计数(RSC)值的这类蛋白质。

在这样的分析中，确定当与细胞内多肽级分相比较时哪种标记的多肽富集在细胞表面多肽级分中（即优先保留在层析介质上）。随后进行从谱图计数(RSC)分析测量的log2比率。原则上，该分析依赖于基于图谱计数的非标记定量法并且适合于计算样品之间的相对蛋白质丰度。详细描述可见于Old 等人(2005) Molecular & Cellular Proteomics 4(10): 1487-1502，就关于RSC值的测定而言将其通过引用并入本文。

通过使用该分析，随后只选择具有阳性RSC值的蛋白质。

随后通过鉴定在至少70%的步骤a)中测试的细胞内发现的那些多肽来进一步分析通过该系列不同步骤鉴定的多肽。如上文中所指出的，细胞可获自不同的人个体或可以是已建立的CRC细胞系。通常，将分析至少5种不同的细胞，这意味着分析例如至少来自全都患有CRC的5个不同人个体的细胞或至少5种不同CRC细胞系。

在最后的选择步骤中，选择组织学分析确认其至少定位至质膜的多肽。这样的组织学分析可利用例如特异于所选择的多肽的抗体来进行。.

通常，组织学分析包括获自患CRC的个体或已建立的CRC细胞系的细胞的免疫荧光分析。用于这样的组织学分析的具体方案通常视分析的具体多肽而定。然而，本领域技术人员能够依靠通常可获得的知识进行例如多肽的免疫荧光检测和定位。

基本上，此类方法将包括细胞在固体载体例如透明显微盖玻片上的固定。随后，在用例如抗体标记之前裂解和固定细胞。

此类方法尤其是描述于Carvalho等人 (2009) Gut 58 (1), 79-89中。

本发明的发明者依靠于步骤a)至步骤h)已成功地鉴定了一组32种蛋白质，所述蛋白质满足上述标准。此外， PRNP (SEQ ID NO: 6)和BCAM (SEQ ID NO: 5)的组织学分析确认这两种蛋白质确实至少定位至质膜（分别地，参见图2和图3）。

这32种蛋白质的性质的概述可获自表1。

通过应用甚至更严格的选择标准（即使用至少2.5的RSC），显现一组11种蛋白质，所述蛋白质可特别适合用作诊断标记或造影剂的靶。该11种多肽的列表示于表2中。

因此，本发明的一个实施方案涉及诊断标记，优选用于检测CRC的诊断标记，其包括由下列多肽组成的组的至少一种多肽:

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4 的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽。

术语“诊断标记”是指SEQ ID No. 1至32的多肽适合作为用于检测癌症例如CRC发展的标记的性质。因此，SEQ ID No. 1至SEQ ID No. 32的至少一种多肽的检测原则上允许确定对于其已显示与适当的对照相比较这样的多肽过表达的人个体是否患有例如CRC。

本领域技术人员将了解超过至少一种SEQ ID No. 1至32的多肽的同时检测将增加例如CRC的发生的预测的正确性。

因此本发明还在优选实施方案中涉及包括由SEQ ID Nos. 1至32组成的组的至少2种、至少3种、至少4种、至少5种、至少6种、至少7种、至少8种、至少9种、至少10种、至少11种、至少12种、至少13种、至少14种、至少15种、至少16种、至少17种、至少18种、至少19种、至少20种、至少21种、至少22种、至少23种、至少24种、至少25种、至少26种、至少27种、至少28种、至少29种、至少30种或31种多肽的诊断标记或一组诊断标记。

根据本发明的优选诊断标记涉及包括由SEQ ID No. 1至10和SEQ ID No. 32组成的组的至少10种多肽的诊断标记或一组诊断标记。

其他优选诊断标记涉及包括至少SEQ ID Nos. 1、2和3的多肽的诊断标记或一组诊断标记。

本发明的另一个优选诊断标记涉及包括至少SEQ ID No. 1、2、3和4的多肽的诊断标记或一组诊断标记。

本发明还涉及选自由下列多肽组成的组的至少一种多肽作为用于检测CRC的诊断标记的用途：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9 的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽。

本发明还涉及由SEQ ID Nos. 1至32组成的组的至少2种、至少3种、至少4种、至少5种、至少6种、至少7种、至少8种、至少9种、至少10种、至少11种、至少12种、至少13种、至少14种、至少15种、至少16种、至少17种、至少18种、至少19种、至少20种、至少21种、至少22种、至少23种、至少24种、至少25种、至少26种、至少27种、至少28种、至少29种、至少30种或31种多肽作为用于检测CRC的诊断标记的用途。

优选，本发明涉及由SEQ ID No. 1至10和SEQ ID No.: 32组成的组的至少10种多肽作为用于检测CRC的诊断标记的用途。

另一个优选实施方案涉及SEQ ID Nos. 1、2和3的多肽作为用于检测CRC的诊断标记的用途。

另一个优选实施方案涉及SEQ ID Nos. 1、2、3和4的多肽作为用于检测CRC的诊断标记的用途。

在优选实施方案中，选自SEQ ID No. 1至SEQ ID No. 32的多肽和上述多肽的优选组合例如具有SEQ ID Nos. 1至10和SEQ ID No.: 32的多肽、SEQ ID Nos. 1、2和3的多肽或SEQ ID Nos. 1、2、3和4的多肽可用于人或动物的体外诊断方法。

本发明的另一个实施方案在允许在线检测人个体内的诊断标记的诊断方法中使用选自SEQ ID Nos: 1至32的至少一种多肽或至少上述优选组合。这样的诊断方法可依赖于磁共振成像(MRI) 和/或磁光子共振成像(MPI)。然而，也可应用允许选自SEQ ID Nos. 1至32的至少一种多肽的存在的成像以检测CRC的其他方法。

因此，在一个实施方案中 ，本发明涉及能够特异性检测至少选自SEQ ID Nos. 1至32的多肽的造影剂。

术语“造影剂”和其语法变型是指能够与SEQ ID Nos. 1至32的多肽特异性相互作用并且可通过放置在人或动物体外的装置检测的分子化合物。优选，此类造影剂适合用于磁共振成像 (MRI)或磁光子成像(MPI)。

术语“特异性相互作用”和其语法变型是指分子化合物优先于由存在于人或动物体内的细胞表达的其他蛋白与此类细胞的细胞表面上的SEQ ID Nos. 1至32的多肽相互作用的性质。

也被称为造影剂组合物的优选造影剂能够特异性检测由SEQ ID Nos. 1至32组成的组的至少2种、至少3种、至少4种、至少5种、至少6种、至少7种、至少8种、至少9种、至少10种、至少11种、至少12种、至少13种、至少14种、至少15种、至少16种、至少17种、至少18种、至少19种、至少20种、至少21种、至少22种、至少23种、至少24种、至少25种、至少26种、至少27种、至少28种、至少29种、至少30种或31种多肽。其他优选造影剂/组合物能够检测由SEQ ID No.: 1至10和SEQ ID No.: 32组成的多肽的组、SEQ ID Nos. 1、2和3的组或SEQ ID Nos. 1、2、3和4的组。

由于MRI和MPI原则上允许非侵入性分子成像，因此包含能够与SEQ ID Nos. 1至32的至少一种多肽和优选与上述组特异性相互作用并且可利用MRI 和/或 MPI检测的化合物的造影剂是优选的。

可以特别适合作为用于本发明的目的的造影剂的一类分子是抗体。

特异于SEQ ID Nos. 1至32的多肽，优选特异于上述多肽的组的抗体已可商购获得，例如来自Sigma-Aldrich (St. Louis,MO,USA)第一抗-朊病毒、小鼠克隆8H4抗体(对于SEQ ID No.6)、来自abD serotech (Oxford,UK)的小鼠抗人CD239(对于SEQ ID No. 5)。

如果特异性识别SEQ ID Nos. 1至32的多肽的抗体还不可获得，那么可利用本领域技术人员已知的方法产生它们。此类抗体可以是多克隆或单克隆抗体。单克隆抗体可以利用经典杂交瘤融合技术或例如噬菌体展示系统来产生。

术语“抗体”以其通常的意义用于本发明的上下文中。然而，此外该术语还包括抗体变体和衍生物例如单链抗体、Fab-片段、Fab2-片段、多特异性抗体、双链抗体（diabody）、三链抗体（triabody）、四链抗体（tetrabody）、微抗体（minibody）、线性抗体、螯合重组抗体（chelating recombinant antibody）、tribody、bibody, 细胞内抗体、nanobody、小模块免疫药物（small modular immunopharmaceutical）(SMIP), 结合-结构域免疫球蛋白融合蛋白、骆驼化抗体、包含V_HH的抗体等。

本发明的优选实施方案涉及造影剂，所述造影剂包含至少与SEQ ID Nos. 1至10和SEQ ID No.: 32的多肽、与SEQ ID Nos. 1、2和3的多肽或与SEQ ID Nos. 1、2、3和4的多肽相互作用的抗体的造影剂。

可以以其中所述造影剂是包含不同组的抗体（每一种抗体识别特定SEQ ID 的多肽）的组合物的形式提供包含此类抗体的造影剂。因此，造影剂可包含分别识别SEQ ID Nos. 1、2和3的多肽的3种抗体。

然而，根据本发明的造影剂还可包含为多特异性的抗体。因此，造影剂可包含同时识别例如SEQ ID No. 1、2和3的多肽的单一抗体。此外，根据本发明的造影剂可包含其全部识别相同SEQ ID的多肽的抗体。因此，根据本发明的造影剂可包含例如其全部特异于SEQ ID No. 1 的3种抗体和例如其全部特异于SEQ ID No. 2的四种抗体等。

造影剂，除了它们能够特异性识别SEQ ID Nos. 1至32的多肽的性质外，另外通常包含可利用所使用的特定检测技术检测的标记分子。

例如，如果将荧光光谱学用作检测方法，此类标记分子可包括荧光基团作为可在特定波长下被激发的可检测标记分子。

关于根据本发明的适合用于MRI的优选造影剂，所述造影剂例如上述抗体可包含可利用MRI检测的标记分子。此类可检测的标记包括例如USPIOS和19Fluor。

本发明的另一个实施方案涉及至少一种能够与选自由下列多肽组成的组的多肽相互作用的抗体作为适合用于MRI的造影剂的用途:

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6 的多肽;

• SEQ ID No.: 7 的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15 的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽。

本发明还涉及与由SEQ ID Nos. 1至32组成的组的至少2种、至少3种、至少4种、至少5种、至少6种、至少7种、至少8种、至少9种、至少10种、至少11种、至少12种、至少13种、至少14种、至少15种、至少16种、至少17种、至少18种、至少19种、至少20种、至少21种、至少22种、至少23种、至少24种、至少25种、至少26种、至少27种、至少28种、至少29种、至少30种或31种多肽相互作用的抗体作为造影剂的用途。

优选地，本发明涉及与由SEQ ID No. 1至10和SEQ ID No.: 32组成的组的至少10种多肽相互作用的抗体作为造影剂的用途。

另一个优选实施方案涉及与SEQ ID Nos. 1、2和3的多肽相互作用的抗体用作造影剂的用途。

另一个优选实施方案涉及与SEQ ID Nos. 1、2、3和4的多肽相互作用的抗体作为造影剂的用途。

如上文中所指出的，本发明的诊断标记和造影剂可用于检测和诊断结直肠癌。此类方法可用于人或动物体外或体内。因此，可以在组织学分析中例如使用被标记至荧光基团的抗体以检测已从怀疑患有CRC的个体获得的细胞组织和样品中的SEQ ID Nos. 1 至32的多肽 。

此外或备选地，可使用例如抗体以用于进行非侵入性分子成像技术例如MRI。

由于如上所述的诊断标记和造影剂主要用于CRC的检测和诊断，因此本发明的一个实施方案涉及诊断CRC的方法，其包括至少下列步骤：

a) 从怀疑遭受正在进行或迫近的CRC发展的至少一个人或动物个体获自至少一个样品；

b) 测试所述至少一个样品中选自由下列多肽组成的组的至少一种多肽的表达

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25 的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽;

c) 测试获自未遭受正在进行或迫近的CRC发展的至少一个人或动物个体的至少一个对照样品中选自由下列多肽组成的组的至少一种多肽的表达:

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3 的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽

• SEQ ID No.: 32 的多肽;

d) 测定步骤b)和d)的表达的差异;

e) 基于步骤d)中获得的结果确定CRC发展的存在或迫近。

在一个实施方案中，在人或动物体外进行该诊断方法的步骤b)、c)、d) 和/或 e)。

本发明的另一个实施方案涉及诊断CRC的方法，其包括至少下列步骤:

a) 测试怀疑遭受正在进行或迫近的CRC发展的至少一个人或动物个体中选自由下列多肽组成的组的至少一种多肽的表达：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23 的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽

• SEQ ID No.: 32的多肽;

b) 将步骤a)中测定的表达与如对于未遭受正在进行或迫近的结直肠癌发展的人或动物个体测定的选自由下列多肽组成的组的至少一种多肽的表达相比较:

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽。

c) 基于步骤b)中获得的结果确定结直肠癌发展的存在或迫近。

此外，本发明可涉及数据获取的方法，其包括至少下列步骤：

a) 测试怀疑遭受正在进行或迫近的CRC发展的至少一个人或动物个体中选自由下列多肽组成的组的至少一种多肽的表达:

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽;

b) 将步骤a)中测定的表达与如对于未遭受正在进行或迫近的CRC发展的人或动物个体所测定的选自由下列多肽组成的组的至少一种多肽的表达相比较：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8 的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10 的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32 的多肽。

上述方法具有共同之处：它们确定SEQ ID Nos. 1至32的至少一种多肽在获自怀疑遭受CRC发展的人或动物个体的测试样品中或直接在怀疑遭受CRC发展的人或动物个体中的存在。

此外，随后将对于此类分子获得的数据与从对照样品或对照个体获得的数据相比较。与对照样品或对照个体的比较用于鉴定从怀疑患有CRC的人个体获得的此类测试样品或鉴定怀疑患有CRC的这些人个体，在所述个体中SEQ ID Nos. 1至32 的至少一种多肽与各自的对照样品或对照个体相比较过表达。

因而术语“对照样品”或“对照个体”是指获自例如人个体的样品或指例如未患CRC癌症的人个体。此类个体可通过进行经典CRC诊断来鉴定。本领域技术人员了解为了进行测试样品与对照样品之间以及测试个体与对照个体之间的比较，必须对所获得的表达数据进行恰当的标准化。然而，此类标准化在本领域内是常用的并且通常包括确定相对于例如未参与结直肠癌的多肽，SEQ ID Nos. 1至32的多肽的表达 。因此，在一个方面中，可就化合物例如肌动蛋白（actine）的表达标准化从测试样品和对照样品获得的数据。

在上述诊断或数据获得的方法的优选实施方案中，监测SEQ ID No.1至10和SEQ ID No.: 32的至少十种多肽、SEQ ID No. 1、2、3和4的多肽或SEQ ID No. 1、2和3的多肽的表达。

在下文中，根据某些特定实施例描述本发明。然而这些实施例不被解释为是限制性的。

实施例

实验 1: 潜在地参与结直肠癌的细胞表面蛋白的鉴定

结直肠癌(CRC)细胞系COLO 205、HT-29、Caco-2、RKO和HCT116获自美国典型培养物保藏中心(ATCC)。这些细胞系全都是用作CRC的模型系统的细胞系(Lengauer. 等人(1997) PNAS 94(6):2545-2550)。

除了CACO2外将所有细胞于37℃、5%的CO_2­大气浓度下培养在包含10% 胎牛血清(FCS)和1% 青霉素/链霉素 (青霉素50个单位/ml, Astellas Pharma B.V., Leiderdorp, Netherlands; 链霉素50ug/ml, Fisiopharma, Palomonta (SA), Italy)的完全培养基(Dulbecco’s Modified Eagle’s Medium, DMEM; Lonza Biowhittaker, Verviers, Belgium)中。将CACO2细胞系于37℃、5%的CO_2­大气浓度下培养在含有20%的FCS和1% 青霉素/链霉素 (青霉素50个单位/ml, Astellas Pharma B.V., Leiderdorp, Netherlands; 链霉素50ug/ml, Fisiopharma, Palomonta (SA), Italy)的RPMI1640 (Lonza Biowhittaker, Verviers, Belgium)中。

培养细胞直至获得70/80%的汇合。

随后，通过将细胞在4℃下与412μM溶解在PBS中的硫代-NHS-SS-生物素(Pierce, Rockford, USA)一起温育30分钟来用生物素标记细胞。

在该温育后，用PBS洗涤细胞，然后在补充有蛋白酶抑制剂混合物 (pic) (完全蛋白酶抑制剂混合物, 1x, Roche, Mannheim, Germany)的裂解缓冲液(Pierce) 中裂解细胞。

将细胞裂解物在4℃下与NeutrAvidin蛋白珠粒(Pierce)在旋转器中一起温育120分钟以实现生物素标记的蛋白质至珠粒的结合。随后在两种洗涤缓冲液中洗涤珠粒。首先在含有1% w/v nonidet P-40和0.1 % w/v SDS（于PBS中）的洗涤缓冲液A中清洗3次，然后在含有0.1% w/v nonidet P-40和0.5 M NaCl（于PBS中）的洗涤缓冲液B中洗涤3次。

随后使用含有50 mM DTT和62.5 mM Tris HCl的PBS从珠粒洗脱蛋白质。该级分被称为细胞表面多肽级分。

接着，利用SDS-PAGE分析纯化的级分。生物标记的细胞表面和细胞内级分的实例示于图1中。

随后通过质谱法鉴定细胞表面级分的链霉抗生物素纯化的生物素标记的蛋白质。

在电泳后，将凝胶于50%含有3%磷酸的乙醇中固定，然后用考马斯R-250染色。染色后，将凝胶在MilliQ水中进行洗涤，然后于4 ℃下贮存直至处理以进行凝胶内降解。

将对应于5个不同细胞系的细胞表面蛋白和细胞内级分的混合物的凝胶泳道切割于10个条带中。处理每一个条带以便进行凝胶内降解。简而言之，将条带在50 mM ABC(碳酸氢铵pH 7.9)/50 mM ABC + 50% ACN (乙腈)中洗涤脱水3次。

随后，用10mM二硫苏糖醇在56℃下还原半胱氨酸键，进行1小时，然后在黑暗中于室温下用50 mM碘乙酰胺烷基化，进行45分钟。在两个随后的洗涤/脱水循环后，在真空离心机中干燥条带10分钟，将其与0.06 μg/μl胰蛋白酶于25 ℃下一起温育过夜。在1%甲酸中提取肽一次以及

随后在50%的5%甲酸中的ACN 中进行2次。在LC-MS/MS分析之前在真空离心机中使体积减少至50 μl。

利用配备有20 cm×75 μm ID熔融石英柱（利用3 μm 100 Å ReproSil Pur C18 aqua (Dr Maisch GMBH, Ammerbuch-Entringen, Germany)定制填充的）的Ultimate 3000 nanoLC系统(Dionex LC-Packings, Amsterdam, The Netherlands)分离肽。在注射后，以2%缓冲液B (缓冲液A:MQ中 0.05%的甲酸; 缓冲液B: MQ中80%的ACN+0.05%的甲酸）以30 μl/分钟将肽捕获在5 mm×300 μm ID Pepmap C18 筒（cartridge） (Dionex LC-Packings, Amsterdam, The Netherlands)上并且在60分钟内在10–40% 缓冲液B梯度中以300 nl/分钟分离。

在基于Nanomate Triversa芯片的nanospray 源中在1.7 kV下利用Triversa LC连接器(Advion, Ithaca, NJ)离子化洗脱肽。在LTQ-FT组合质谱仪（ hybrid mass spectrometer ）(Thermo Fisher, Bremen, Germany)上获得完整肽质谱图和片段化谱图。利用1×10⁶ 个电荷的靶值在ICR 室中以分辨率50.000测量完整质量。平行地，在FT预扫描后，将前5个肽信号（电荷状态2+和更高)在线性离子阱(3 amu分离宽度（isolation width）、30 ms活化、35%标准化活化能、0.25的Q值和5000个计数的阈值)中经历MS/MS。应用动态排除（Dynamic exclusion），利用为1的重复计数和30秒的排除时间（exclusion time）。

利用Sequest (版本27, rev 12)针对人IPI数据库3.31(67511个条目)搜索MS/MS谱，所述Sequest为BioWorks 3.3数据分析包(Thermo Fisher, San Jose, CA)的部分。用10 ppm（对于前体质量）和1 amu（对于片段质量）的最大允许偏差搜索MS/MS谱。甲硫氨酸氧化和半胱氨酸羧酰胺甲基化（carboxamidomethylation）被允许作为可变修饰。允许两个缺失的切割并且胰蛋白酶末端的最小数目为1。在数据库搜索后，将DTA和OUT文件输入Scaffold 1.07 (蛋白质组软件, Portland, OR)中。Scaffold用于组织凝胶条带数据（gelband data）并且利用Peptide Prophet算法[14]验证肽的鉴定，只有具有N95%的概率的鉴定得到保留。随后，应用Protein Prophet算法[15]，在至少一个样品中对于2种或更多种肽具有N99%的概率的蛋白质鉴定得到保留。将包含相似肽并且不能仅基于MS/MS分析区分的蛋白质分组。 对于每一个鉴定的蛋白质，将独特肽的数目输出至Excel。(Piersma等人 (2009) J. Proteomics 72(1): 91-109)。

该分析显示约2986种蛋白质。

平行地，分析牵涉腺瘤至结直肠腺癌的越亲现象（transgression）的基因。该分析显示约2478个其表达被上调或下调的基因。该方法详细地描述于Carvalho等人 in Gut (2009), 58(1):79-89中。

基于该分析，只选择对于其基因分析数据显示过表达的纯化的细胞表面级分的蛋白质。这导致约1305种蛋白质的鉴定。在这些基因中，355个基因过表达，具有根据Wilcox秩检验(参见Carvalho 等人Gut (2009), 58(1):79-89)显著性P值(>0.05)。

在下一步骤中，选择包含至少一个跨膜(TM) 结构域的蛋白质。

为此，使用由Stockholm Bioinformatics开发的软件程序Phobias。(Käll等人 (2004) Journal of Molecular Biology, 338(5):1027-1036)。该程序显示蛋白质是否包含跨膜区和/或信号肽。选择包含这两者之一或两者的蛋白质。

为了减少假阳性的数目，我们确定当与非生物化级分相比较时在细胞表面级分中富集的蛋白质。从谱图计数（RSC）分析测量log2比率。该分析依赖于基于谱图计数的无标记定量法。这样的方法特别适合于计算样品之间的相对蛋白质丰度，并且按照Old等人 (Old 等人(2005) Molecular & Cellular Proteomics 4(10): 1487-1502)的方法来进行。

通过使用该分析，只有具有阳性RSC值的蛋白质才可被检测到。

最后，选择在至少70%的被测试的CRC细胞系中被发现的蛋白质。

这揭示了具有SEQ ID Nos.: 1至32的一组31种蛋白质。

鉴定了对于其RSC值增加至至少2.5倍的另一组11种蛋白质。此类蛋白质具有SEQ ID Nos. 1至10和SEQ ID No.: 32。

在此类蛋白质中，在获自CRC患者的肿瘤材料上进行PRNP (SEQ ID No.: 6)和BCAM (SEQ ID No.: 5)的组织学分析。

将福尔马林固定的石蜡包埋的(FFPE)组织的4 mm切片用于免疫组织化学。在于二甲苯中脱蜡，以及通过梯度酒精至水的再水化后，用过氧化氢(0.3% H₂O₂/甲醇)封闭内源过氧化物酶进行30分钟。通过在1.5mM HCL（对于PRNP）和TRIS/EDTA ph 9缓冲液（对于BCAM）中高压灭菌来进行抗原恢复 。将来自sigma-aldrich (St. Louis,MO,USA)的第一抗朊病毒小鼠克隆8H4抗体以1:100的稀释度温育过夜并且也将来自abD serotech (Oxford,UK)的小鼠抗人CD239以1:100的稀释度温育过夜。在充分洗涤后，将载玻片与聚-HRP-山羊抗-小鼠/兔/大鼠IgG (Powervision, Immunologic, Duiven)一起温育30分钟。随后洗涤所有切片，将其与DAB底物-色原体(Dako, Glostrup, Denmark)一起温育。利用Mayer’s苏木精进行复染。将不使用第一抗体的温育用作阴性对照。

结果可见于图2（对于PRNP）和图3（对于BCAM）中。

序列表

<110> Vereniging voor Christelijk Hoger Onderwijs,

Wetenschappelijk Onderzoek en Patientenzorg

<120> 用于结直肠腺癌的诊断的基于蛋白质的方法和组合物

<130> PH012911WO1

<150> EP 09157464.0

<151> 2009-04-07

<160> 32

<170> PatentIn version 3.5

<210> 1

<211> 1896

<212> PRT

<213> 智人

<400> 1

Met Pro Leu Pro Pro Arg Ser Leu Gln Val Leu Leu Leu Leu Leu Leu

1 5 10 15

Leu Leu Leu Leu Leu Pro Gly Met Trp Ala Glu Ala Gly Leu Pro Arg

20 25 30

Ala Gly Gly Gly Ser Gln Pro Pro Phe Arg Thr Phe Ser Ala Ser Asp

35 40 45

Trp Gly Leu Thr His Leu Val Val His Glu Gln Thr Gly Glu Val Tyr

50 55 60

Val Gly Ala Val Asn Arg Ile Tyr Lys Leu Ser Gly Asn Leu Thr Leu

65 70 75 80

Leu Arg Ala His Val Thr Gly Pro Val Glu Asp Asn Glu Lys Cys Tyr

85 90 95

Pro Pro Pro Ser Val Gln Ser Cys Pro His Gly Leu Gly Ser Thr Asp

100 105 110

Asn Val Asn Lys Leu Leu Leu Leu Asp Tyr Ala Ala Asn Arg Leu Leu

115 120 125

Ala Cys Gly Ser Ala Ser Gln Gly Ile Cys Gln Phe Leu Arg Leu Asp

130 135 140

Asp Leu Phe Lys Leu Gly Glu Pro His His Arg Lys Glu His Tyr Leu

145 150 155 160

Ser Ser Val Gln Glu Ala Gly Ser Met Ala Gly Val Leu Ile Ala Gly

165 170 175

Pro Pro Gly Gln Gly Gln Ala Lys Leu Phe Val Gly Thr Pro Ile Asp

180 185 190

Gly Lys Ser Glu Tyr Phe Pro Thr Leu Ser Ser Arg Arg Leu Met Ala

195 200 205

Asn Glu Glu Asp Ala Asp Met Phe Gly Phe Val Tyr Gln Asp Glu Phe

210 215 220

Val Ser Ser Gln Leu Lys Ile Pro Ser Asp Thr Leu Ser Lys Phe Pro

225 230 235 240

Ala Phe Asp Ile Tyr Tyr Val Tyr Ser Phe Arg Ser Glu Gln Phe Val

245 250 255

Tyr Tyr Leu Thr Leu Gln Leu Asp Thr Gln Leu Thr Ser Pro Asp Ala

260 265 270

Ala Gly Glu His Phe Phe Thr Ser Lys Ile Val Arg Leu Cys Val Asp

275 280 285

Asp Pro Lys Phe Tyr Ser Tyr Val Glu Phe Pro Ile Gly Cys Glu Gln

290 295 300

Ala Gly Val Glu Tyr Arg Leu Val Gln Asp Ala Tyr Leu Ser Arg Pro

305 310 315 320

Gly Arg Ala Leu Ala His Gln Leu Gly Leu Ala Glu Asp Glu Asp Val

325 330 335

Leu Phe Thr Val Phe Ala Gln Gly Gln Lys Asn Arg Val Lys Pro Pro

340 345 350

Lys Glu Ser Ala Leu Cys Leu Phe Thr Leu Arg Ala Ile Lys Glu Lys

355 360 365

Ile Lys Glu Arg Ile Gln Ser Cys Tyr Arg Gly Glu Gly Lys Leu Ser

370 375 380

Leu Pro Trp Leu Leu Asn Lys Glu Leu Gly Cys Ile Asn Ser Pro Leu

385 390 395 400

Gln Ile Asp Asp Asp Phe Cys Gly Gln Asp Phe Asn Gln Pro Leu Gly

405 410 415

Gly Thr Val Thr Ile Glu Gly Thr Pro Leu Phe Val Asp Lys Asp Asp

420 425 430

Gly Leu Thr Ala Val Ala Ala Tyr Asp Tyr Arg Gly Arg Thr Val Val

435 440 445

Phe Ala Gly Thr Arg Ser Gly Arg Ile Arg Lys Ile Leu Val Asp Leu

450 455 460

Ser Asn Pro Gly Gly Arg Pro Ala Leu Ala Tyr Glu Ser Val Val Ala

465 470 475 480

Gln Glu Gly Ser Pro Ile Leu Arg Asp Leu Val Leu Ser Pro Asn His

485 490 495

Gln Tyr Leu Tyr Ala Met Thr Glu Lys Gln Val Thr Arg Val Pro Val

500 505 510

Glu Ser Cys Val Gln Tyr Thr Ser Cys Glu Leu Cys Leu Gly Ser Arg

515 520 525

Asp Pro His Cys Gly Trp Cys Val Leu His Ser Ile Cys Ser Arg Arg

530 535 540

Asp Ala Cys Glu Arg Ala Asp Glu Pro Gln Arg Phe Ala Ala Asp Leu

545 550 555 560

Leu Gln Cys Val Gln Leu Thr Val Gln Pro Arg Asn Val Ser Val Thr

565 570 575

Met Ser Gln Val Pro Leu Val Leu Gln Ala Trp Asn Val Pro Asp Leu

580 585 590

Ser Ala Gly Val Asn Cys Ser Phe Glu Asp Phe Thr Glu Ser Glu Ser

595 600 605

Val Leu Glu Asp Gly Arg Ile His Cys Arg Ser Pro Ser Ala Arg Glu

610 615 620

Val Ala Pro Ile Thr Arg Gly Gln Gly Asp Gln Arg Val Val Lys Leu

625 630 635 640

Tyr Leu Lys Ser Lys Glu Thr Gly Lys Lys Phe Ala Ser Val Asp Phe

645 650 655

Val Phe Tyr Asn Cys Ser Val His Gln Ser Cys Leu Ser Cys Val Asn

660 665 670

Gly Ser Phe Pro Cys His Trp Cys Lys Tyr Arg His Val Cys Thr His

675 680 685

Asn Val Ala Asp Cys Ala Phe Leu Glu Gly Arg Val Asn Val Ser Glu

690 695 700

Asp Cys Pro Gln Ile Leu Pro Ser Thr Gln Ile Tyr Val Pro Val Gly

705 710 715 720

Val Val Lys Pro Ile Thr Leu Ala Ala Arg Asn Leu Pro Gln Pro Gln

725 730 735

Ser Gly Gln Arg Gly Tyr Glu Cys Leu Phe His Ile Pro Gly Ser Pro

740 745 750

Ala Arg Val Thr Ala Leu Arg Phe Asn Ser Ser Ser Leu Gln Cys Gln

755 760 765

Asn Ser Ser Tyr Ser Tyr Glu Gly Asn Asp Val Ser Asp Leu Pro Val

770 775 780

Asn Leu Ser Val Val Trp Asn Gly Asn Phe Val Ile Asp Asn Pro Gln

785 790 795 800

Asn Ile Gln Ala His Leu Tyr Lys Cys Pro Ala Leu Arg Glu Ser Cys

805 810 815

Gly Leu Cys Leu Lys Ala Asp Pro Arg Phe Glu Cys Gly Trp Cys Val

820 825 830

Ala Glu Arg Arg Cys Ser Leu Arg His His Cys Ala Ala Asp Thr Pro

835 840 845

Ala Ser Trp Met His Ala Arg His Gly Ser Ser Arg Cys Thr Asp Pro

850 855 860

Lys Ile Leu Lys Leu Ser Pro Glu Thr Gly Pro Arg Gln Gly Gly Thr

865 870 875 880

Arg Leu Thr Ile Thr Gly Glu Asn Leu Gly Leu Arg Phe Glu Asp Val

885 890 895

Arg Leu Gly Val Arg Val Gly Lys Val Leu Cys Ser Pro Val Glu Ser

900 905 910

Glu Tyr Ile Ser Ala Glu Gln Ile Val Cys Glu Ile Gly Asp Ala Ser

915 920 925

Ser Val Arg Ala His Asp Ala Leu Val Glu Val Cys Val Arg Asp Cys

930 935 940

Ser Pro His Tyr Arg Ala Leu Ser Pro Lys Arg Phe Thr Phe Val Thr

945 950 955 960

Pro Thr Phe Tyr Arg Val Ser Pro Ser Arg Gly Pro Leu Ser Gly Gly

965 970 975

Thr Trp Ile Gly Ile Glu Gly Ser His Leu Asn Ala Gly Ser Asp Val

980 985 990

Ala Val Ser Val Gly Gly Arg Pro Cys Ser Phe Ser Trp Arg Asn Ser

995 1000 1005

Arg Glu Ile Arg Cys Leu Thr Pro Pro Gly Gln Ser Pro Gly Ser

1010 1015 1020

Ala Pro Ile Ile Ile Asn Ile Asn Arg Ala Gln Leu Thr Asn Pro

1025 1030 1035

Glu Val Lys Tyr Asn Tyr Thr Glu Asp Pro Thr Ile Leu Arg Ile

1040 1045 1050

Asp Pro Glu Trp Ser Ile Asn Ser Gly Gly Thr Leu Leu Thr Val

1055 1060 1065

Thr Gly Thr Asn Leu Ala Thr Val Arg Glu Pro Arg Ile Arg Ala

1070 1075 1080

Lys Tyr Gly Gly Ile Glu Arg Glu Asn Gly Cys Leu Val Tyr Asn

1085 1090 1095

Asp Thr Thr Met Val Cys Arg Ala Pro Ser Val Ala Asn Pro Val

1100 1105 1110

Arg Ser Pro Pro Glu Leu Gly Glu Arg Pro Asp Glu Leu Gly Phe

1115 1120 1125

Val Met Asp Asn Val Arg Ser Leu Leu Val Leu Asn Ser Thr Ser

1130 1135 1140

Phe Leu Tyr Tyr Pro Asp Pro Val Leu Glu Pro Leu Ser Pro Thr

1145 1150 1155

Gly Leu Leu Glu Leu Lys Pro Ser Ser Pro Leu Ile Leu Lys Gly

1160 1165 1170

Arg Asn Leu Leu Pro Pro Ala Pro Gly Asn Ser Arg Leu Asn Tyr

1175 1180 1185

Thr Val Leu Ile Gly Ser Thr Pro Cys Thr Leu Thr Val Ser Glu

1190 1195 1200

Thr Gln Leu Leu Cys Glu Ala Pro Asn Leu Thr Gly Gln His Lys

1205 1210 1215

Val Thr Val Arg Ala Gly Gly Phe Glu Phe Ser Pro Gly Thr Leu

1220 1225 1230

Gln Val Tyr Ser Asp Ser Leu Leu Thr Leu Pro Ala Ile Val Gly

1235 1240 1245

Ile Gly Gly Gly Gly Gly Leu Leu Leu Leu Val Ile Val Ala Val

1250 1255 1260

Leu Ile Ala Tyr Lys Arg Lys Ser Arg Asp Ala Asp Arg Thr Leu

1265 1270 1275

Lys Arg Leu Gln Leu Gln Met Asp Asn Leu Glu Ser Arg Val Ala

1280 1285 1290

Leu Glu Cys Lys Glu Ala Phe Ala Glu Leu Gln Thr Asp Ile His

1295 1300 1305

Glu Leu Thr Asn Asp Leu Asp Gly Ala Gly Ile Pro Phe Leu Asp

1310 1315 1320

Tyr Arg Thr Tyr Ala Met Arg Val Leu Phe Pro Gly Ile Glu Asp

1325 1330 1335

His Pro Val Leu Lys Glu Met Glu Val Gln Ala Asn Val Glu Lys

1340 1345 1350

Ser Leu Thr Leu Phe Gly Gln Leu Leu Thr Lys Lys His Phe Leu

1355 1360 1365

Leu Thr Phe Ile Arg Thr Leu Glu Ala Gln Arg Ser Phe Ser Met

1370 1375 1380

Arg Asp Arg Gly Asn Val Ala Ser Leu Ile Met Thr Ala Leu Gln

1385 1390 1395

Gly Glu Met Glu Tyr Ala Thr Gly Val Leu Lys Gln Leu Leu Ser

1400 1405 1410

Asp Leu Ile Glu Lys Asn Leu Glu Ser Lys Asn His Pro Lys Leu

1415 1420 1425

Leu Leu Arg Arg Thr Glu Ser Val Ala Glu Lys Met Leu Thr Asn

1430 1435 1440

Trp Phe Thr Phe Leu Leu Tyr Lys Phe Leu Lys Glu Cys Ala Gly

1445 1450 1455

Glu Pro Leu Phe Met Leu Tyr Cys Ala Ile Lys Gln Gln Met Glu

1460 1465 1470

Lys Gly Pro Ile Asp Ala Ile Thr Gly Glu Ala Arg Tyr Ser Leu

1475 1480 1485

Ser Glu Asp Lys Leu Ile Arg Gln Gln Ile Asp Tyr Lys Thr Leu

1490 1495 1500

Thr Leu Asn Cys Val Asn Pro Glu Asn Glu Asn Ala Pro Glu Val

1505 1510 1515

Pro Val Lys Gly Leu Asp Cys Asp Thr Val Thr Gln Ala Lys Glu

1520 1525 1530

Lys Leu Leu Asp Ala Ala Tyr Lys Gly Val Pro Tyr Ser Gln Arg

1535 1540 1545

Pro Lys Ala Ala Asp Met Asp Leu Glu Trp Arg Gln Gly Arg Met

1550 1555 1560

Ala Arg Ile Ile Leu Gln Asp Glu Asp Val Thr Thr Lys Ile Asp

1565 1570 1575

Asn Asp Trp Lys Arg Leu Asn Thr Leu Ala His Tyr Gln Val Thr

1580 1585 1590

Asp Gly Ser Ser Val Ala Leu Val Pro Lys Gln Thr Ser Ala Tyr

1595 1600 1605

Asn Ile Ser Asn Ser Ser Thr Phe Thr Lys Ser Leu Ser Arg Tyr

1610 1615 1620

Glu Ser Met Leu Arg Thr Ala Ser Ser Pro Asp Ser Leu Arg Ser

1625 1630 1635

Arg Thr Pro Met Ile Thr Pro Asp Leu Glu Ser Gly Thr Lys Leu

1640 1645 1650

Trp His Leu Val Lys Asn His Asp His Leu Asp Gln Arg Glu Gly

1655 1660 1665

Asp Arg Gly Ser Lys Met Val Ser Glu Ile Tyr Leu Thr Arg Leu

1670 1675 1680

Leu Ala Thr Lys Gly Thr Leu Gln Lys Phe Val Asp Asp Leu Phe

1685 1690 1695

Glu Thr Ile Phe Ser Thr Ala His Arg Gly Ser Ala Leu Pro Leu

1700 1705 1710

Ala Ile Lys Tyr Met Phe Asp Phe Leu Asp Glu Gln Ala Asp Lys

1715 1720 1725

His Gln Ile His Asp Ala Asp Val Arg His Thr Trp Lys Ser Asn

1730 1735 1740

Cys Leu Pro Leu Arg Phe Trp Val Asn Val Ile Lys Asn Pro Gln

1745 1750 1755

Phe Val Phe Asp Ile His Lys Asn Ser Ile Thr Asp Ala Cys Leu

1760 1765 1770

Ser Val Val Ala Gln Thr Phe Met Asp Ser Cys Ser Thr Ser Glu

1775 1780 1785

His Lys Leu Gly Lys Asp Ser Pro Ser Asn Lys Leu Leu Tyr Ala

1790 1795 1800

Lys Asp Ile Pro Asn Tyr Lys Ser Trp Val Glu Arg Tyr Tyr Ala

1805 1810 1815

Asp Ile Ala Lys Met Pro Ala Ile Ser Asp Gln Asp Met Ser Ala

1820 1825 1830

Tyr Leu Ala Glu Gln Ser Arg Leu His Leu Ser Gln Phe Asn Ser

1835 1840 1845

Met Ser Ala Leu His Glu Ile Tyr Ser Tyr Ile Thr Lys Tyr Lys

1850 1855 1860

Asp Glu Ile Leu Ala Ala Leu Glu Lys Asp Glu Gln Ala Arg Arg

1865 1870 1875

Gln Arg Leu Arg Ser Lys Leu Glu Gln Val Val Asp Thr Met Ala

1880 1885 1890

Leu Ser Ser

1895

<210> 2

<211> 541

<212> PRT

<213> 智人

<400> 2

Met Val Ala Asp Pro Pro Arg Asp Ser Lys Gly Leu Ala Ala Ala Glu

1 5 10 15

Pro Thr Ala Asn Gly Gly Leu Ala Leu Ala Ser Ile Glu Asp Gln Gly

20 25 30

Ala Ala Ala Gly Gly Tyr Cys Gly Ser Arg Asp Gln Val Arg Arg Cys

35 40 45

Leu Arg Ala Asn Leu Leu Val Leu Leu Thr Val Val Ala Val Val Ala

50 55 60

Gly Val Ala Leu Gly Leu Gly Val Ser Gly Ala Gly Gly Ala Leu Ala

65 70 75 80

Leu Gly Pro Glu Arg Leu Ser Ala Phe Val Phe Pro Gly Glu Leu Leu

85 90 95

Leu Arg Leu Leu Arg Met Ile Ile Leu Pro Leu Val Val Cys Ser Leu

100 105 110

Ile Gly Gly Ala Ala Ser Leu Asp Pro Gly Ala Leu Gly Arg Leu Gly

115 120 125

Ala Trp Ala Leu Leu Phe Phe Leu Val Thr Thr Leu Leu Ala Ser Ala

130 135 140

Leu Gly Val Gly Leu Ala Leu Ala Leu Gln Pro Gly Ala Ala Ser Ala

145 150 155 160

Ala Ile Asn Ala Ser Val Gly Ala Ala Gly Ser Ala Glu Asn Ala Pro

165 170 175

Ser Lys Glu Val Leu Asp Ser Phe Leu Asp Leu Ala Arg Asn Ile Phe

180 185 190

Pro Ser Asn Leu Val Ser Ala Ala Phe Arg Ser Tyr Ser Thr Thr Tyr

195 200 205

Glu Glu Arg Asn Ile Thr Gly Thr Arg Val Lys Val Pro Val Gly Gln

210 215 220

Glu Val Glu Gly Met Asn Ile Leu Gly Leu Val Val Phe Ala Ile Val

225 230 235 240

Phe Gly Val Ala Leu Arg Lys Leu Gly Pro Glu Gly Glu Leu Leu Ile

245 250 255

Arg Phe Phe Asn Ser Phe Asn Glu Ala Thr Met Val Leu Val Ser Trp

260 265 270

Ile Met Trp Tyr Ala Pro Val Gly Ile Met Phe Leu Val Ala Gly Lys

275 280 285

Ile Val Glu Met Glu Asp Val Gly Leu Leu Phe Ala Arg Leu Gly Lys

290 295 300

Tyr Ile Leu Cys Cys Leu Leu Gly His Ala Ile His Gly Leu Leu Val

305 310 315 320

Leu Pro Leu Ile Tyr Phe Leu Phe Thr Arg Lys Asn Pro Tyr Arg Phe

325 330 335

Leu Trp Gly Ile Val Thr Pro Leu Ala Thr Ala Phe Gly Thr Ser Ser

340 345 350

Ser Ser Ala Thr Leu Pro Leu Met Met Lys Cys Val Glu Glu Asn Asn

355 360 365

Gly Val Ala Lys His Ile Ser Arg Phe Ile Leu Pro Ile Gly Ala Thr

370 375 380

Val Asn Met Asp Gly Ala Ala Leu Phe Gln Cys Val Ala Ala Val Phe

385 390 395 400

Ile Ala Gln Leu Ser Gln Gln Ser Leu Asp Phe Val Lys Ile Ile Thr

405 410 415

Ile Leu Val Thr Ala Thr Ala Ser Ser Val Gly Ala Ala Gly Ile Pro

420 425 430

Ala Gly Gly Val Leu Thr Leu Ala Ile Ile Leu Glu Ala Val Asn Leu

435 440 445

Pro Val Asp His Ile Ser Leu Ile Leu Ala Val Asp Trp Leu Val Asp

450 455 460

Arg Ser Cys Thr Val Leu Asn Val Glu Gly Asp Ala Leu Gly Ala Gly

465 470 475 480

Leu Leu Gln Asn Tyr Val Asp Arg Thr Glu Ser Arg Ser Thr Glu Pro

485 490 495

Glu Leu Ile Gln Val Lys Ser Glu Leu Pro Leu Asp Pro Leu Pro Val

500 505 510

Pro Thr Glu Glu Gly Asn Pro Leu Leu Lys His Tyr Arg Gly Pro Ala

515 520 525

Gly Asp Ala Thr Val Ala Ser Glu Lys Glu Ser Val Met

530 535 540

<210> 3

<211> 509

<212> PRT

<213> 智人

<400> 3

Met Gly Cys Ser Ala Lys Ala Arg Trp Ala Ala Gly Ala Leu Gly Val

1 5 10 15

Ala Gly Leu Leu Cys Ala Val Leu Gly Ala Val Met Ile Val Met Val

20 25 30

Pro Ser Leu Ile Lys Gln Gln Val Leu Lys Asn Val Arg Ile Asp Pro

35 40 45

Ser Ser Leu Ser Phe Asn Met Trp Lys Glu Ile Pro Ile Pro Phe Tyr

50 55 60

Leu Ser Val Tyr Phe Phe Asp Val Met Asn Pro Ser Glu Ile Leu Lys

65 70 75 80

Gly Glu Lys Pro Gln Val Arg Glu Arg Gly Pro Tyr Val Tyr Arg Glu

85 90 95

Phe Arg His Lys Ser Asn Ile Thr Phe Asn Asn Asn Asp Thr Val Ser

100 105 110

Phe Leu Glu Tyr Arg Thr Phe Gln Phe Gln Pro Ser Lys Ser His Gly

115 120 125

Ser Glu Ser Asp Tyr Ile Val Met Pro Asn Ile Leu Val Leu Gly Ala

130 135 140

Ala Val Met Met Glu Asn Lys Pro Met Thr Leu Lys Leu Ile Met Thr

145 150 155 160

Leu Ala Phe Thr Thr Leu Gly Glu Arg Ala Phe Met Asn Arg Thr Val

165 170 175

Gly Glu Ile Met Trp Gly Tyr Lys Asp Pro Leu Val Asn Leu Ile Asn

180 185 190

Lys Tyr Phe Pro Gly Met Phe Pro Phe Lys Asp Lys Phe Gly Leu Phe

195 200 205

Ala Glu Leu Asn Asn Ser Asp Ser Gly Leu Phe Thr Val Phe Thr Gly

210 215 220

Val Gln Asn Ile Ser Arg Ile His Leu Val Asp Lys Trp Asn Gly Leu

225 230 235 240

Ser Lys Val Asp Phe Trp His Ser Asp Gln Cys Asn Met Ile Asn Gly

245 250 255

Thr Ser Gly Gln Met Trp Pro Pro Phe Met Thr Pro Glu Ser Ser Leu

260 265 270

Glu Phe Tyr Ser Pro Glu Ala Cys Arg Ser Met Lys Leu Met Tyr Lys

275 280 285

Glu Ser Gly Val Phe Glu Gly Ile Pro Thr Tyr Arg Phe Val Ala Pro

290 295 300

Lys Thr Leu Phe Ala Asn Gly Ser Ile Tyr Pro Pro Asn Glu Gly Phe

305 310 315 320

Cys Pro Cys Leu Glu Ser Gly Ile Gln Asn Val Ser Thr Cys Arg Phe

325 330 335

Ser Ala Pro Leu Phe Leu Ser His Pro His Phe Leu Asn Ala Asp Pro

340 345 350

Val Leu Ala Glu Ala Val Thr Gly Leu His Pro Asn Gln Glu Ala His

355 360 365

Ser Leu Phe Leu Asp Ile His Pro Val Thr Gly Ile Pro Met Asn Cys

370 375 380

Ser Val Lys Leu Gln Leu Ser Leu Tyr Met Lys Ser Val Ala Gly Ile

385 390 395 400

Gly Gln Thr Gly Lys Ile Glu Pro Val Val Leu Pro Leu Leu Trp Phe

405 410 415

Ala Glu Ser Gly Ala Met Glu Gly Glu Thr Leu His Thr Phe Tyr Thr

420 425 430

Gln Leu Val Leu Met Pro Lys Val Met His Tyr Ala Gln Tyr Val Leu

435 440 445

Leu Ala Leu Gly Cys Val Leu Leu Leu Val Pro Val Ile Cys Gln Ile

450 455 460

Arg Ser Gln Glu Lys Cys Tyr Leu Phe Trp Ser Ser Ser Lys Lys Gly

465 470 475 480

Ser Lys Asp Lys Glu Ala Ile Gln Ala Tyr Ser Glu Ser Leu Met Thr

485 490 495

Ser Ala Pro Lys Gly Ser Val Leu Gln Glu Ala Lys Leu

500 505

<210> 4

<211> 532

<212> PRT

<213> 智人

<400> 4

Met Ala Pro Ser Ser Pro Arg Pro Ala Leu Pro Ala Leu Leu Val Leu

1 5 10 15

Leu Gly Ala Leu Phe Pro Gly Pro Gly Asn Ala Gln Thr Ser Val Ser

20 25 30

Pro Ser Lys Val Ile Leu Pro Arg Gly Gly Ser Val Leu Val Thr Cys

35 40 45

Ser Thr Ser Cys Asp Gln Pro Lys Leu Leu Gly Ile Glu Thr Pro Leu

50 55 60

Pro Lys Lys Glu Leu Leu Leu Pro Gly Asn Asn Arg Lys Val Tyr Glu

65 70 75 80

Leu Ser Asn Val Gln Glu Asp Ser Gln Pro Met Cys Tyr Ser Asn Cys

85 90 95

Pro Asp Gly Gln Ser Thr Ala Lys Thr Phe Leu Thr Val Tyr Trp Thr

100 105 110

Pro Glu Arg Val Glu Leu Ala Pro Leu Pro Ser Trp Gln Pro Val Gly

115 120 125

Lys Asn Leu Thr Leu Arg Cys Gln Val Glu Gly Gly Ala Pro Arg Ala

130 135 140

Asn Leu Thr Val Val Leu Leu Arg Gly Glu Lys Glu Leu Lys Arg Glu

145 150 155 160

Pro Ala Val Gly Glu Pro Ala Glu Val Thr Thr Thr Val Leu Val Arg

165 170 175

Arg Asp His His Gly Ala Asn Phe Ser Cys Arg Thr Glu Leu Asp Leu

180 185 190

Arg Pro Gln Gly Leu Glu Leu Phe Glu Asn Thr Ser Ala Pro Tyr Gln

195 200 205

Leu Gln Thr Phe Val Leu Pro Ala Thr Pro Pro Gln Leu Val Ser Pro

210 215 220

Arg Val Leu Glu Val Asp Thr Gln Gly Thr Val Val Cys Ser Leu Asp

225 230 235 240

Gly Leu Phe Pro Val Ser Glu Ala Gln Val His Leu Ala Leu Gly Asp

245 250 255

Gln Arg Leu Asn Pro Thr Val Thr Tyr Gly Asn Asp Ser Phe Ser Ala

260 265 270

Lys Ala Ser Val Ser Val Thr Ala Glu Asp Glu Gly Thr Gln Arg Leu

275 280 285

Thr Cys Ala Val Ile Leu Gly Asn Gln Ser Gln Glu Thr Leu Gln Thr

290 295 300

Val Thr Ile Tyr Ser Phe Pro Ala Pro Asn Val Ile Leu Thr Lys Pro

305 310 315 320

Glu Val Ser Glu Gly Thr Glu Val Thr Val Lys Cys Glu Ala His Pro

325 330 335

Arg Ala Lys Val Thr Leu Asn Gly Val Pro Ala Gln Pro Leu Gly Pro

340 345 350

Arg Ala Gln Leu Leu Leu Lys Ala Thr Pro Glu Asp Asn Gly Arg Ser

355 360 365

Phe Ser Cys Ser Ala Thr Leu Glu Val Ala Gly Gln Leu Ile His Lys

370 375 380

Asn Gln Thr Arg Glu Leu Arg Val Leu Tyr Gly Pro Arg Leu Asp Glu

385 390 395 400

Arg Asp Cys Pro Gly Asn Trp Thr Trp Pro Glu Asn Ser Gln Gln Thr

405 410 415

Pro Met Cys Gln Ala Trp Gly Asn Pro Leu Pro Glu Leu Lys Cys Leu

420 425 430

Lys Asp Gly Thr Phe Pro Leu Pro Ile Gly Glu Ser Val Thr Val Thr

435 440 445

Arg Asp Leu Glu Gly Thr Tyr Leu Cys Arg Ala Arg Ser Thr Gln Gly

450 455 460

Glu Val Thr Arg Lys Val Thr Val Asn Val Leu Ser Pro Arg Tyr Glu

465 470 475 480

Ile Val Ile Ile Thr Val Val Ala Ala Ala Val Ile Met Gly Thr Ala

485 490 495

Gly Leu Ser Thr Tyr Leu Tyr Asn Arg Gln Arg Lys Ile Lys Lys Tyr

500 505 510

Arg Leu Gln Gln Ala Gln Lys Gly Thr Pro Met Lys Pro Asn Thr Gln

515 520 525

Ala Thr Pro Pro

530

<210> 5

<211> 628

<212> PRT

<213> 智人

<400> 5

Met Glu Pro Pro Asp Ala Pro Ala Gln Ala Arg Gly Ala Pro Arg Leu

1 5 10 15

Leu Leu Leu Ala Val Leu Leu Ala Ala His Pro Asp Ala Gln Ala Glu

20 25 30

Val Arg Leu Ser Val Pro Pro Leu Val Glu Val Met Arg Gly Lys Ser

35 40 45

Val Ile Leu Asp Cys Thr Pro Thr Gly Thr His Asp His Tyr Met Leu

50 55 60

Glu Trp Phe Leu Thr Asp Arg Ser Gly Ala Arg Pro Arg Leu Ala Ser

65 70 75 80

Ala Glu Met Gln Gly Ser Glu Leu Gln Val Thr Met His Asp Thr Arg

85 90 95

Gly Arg Ser Pro Pro Tyr Gln Leu Asp Ser Gln Gly Arg Leu Val Leu

100 105 110

Ala Glu Ala Gln Val Gly Asp Glu Arg Asp Tyr Val Cys Val Val Arg

115 120 125

Ala Gly Ala Ala Gly Thr Ala Glu Ala Thr Ala Arg Leu Asn Val Phe

130 135 140

Ala Lys Pro Glu Ala Thr Glu Val Ser Pro Asn Lys Gly Thr Leu Ser

145 150 155 160

Val Met Glu Asp Ser Ala Gln Glu Ile Ala Thr Cys Asn Ser Arg Asn

165 170 175

Gly Asn Pro Ala Pro Lys Ile Thr Trp Tyr Arg Asn Gly Gln Arg Leu

180 185 190

Glu Val Pro Val Glu Met Asn Pro Glu Gly Tyr Met Thr Ser Arg Thr

195 200 205

Val Arg Glu Ala Ser Gly Leu Leu Ser Leu Thr Ser Thr Leu Tyr Leu

210 215 220

Arg Leu Arg Lys Asp Asp Arg Asp Ala Ser Phe His Cys Ala Ala His

225 230 235 240

Tyr Ser Leu Pro Glu Gly Arg His Gly Arg Leu Asp Ser Pro Thr Phe

245 250 255

His Leu Thr Leu His Tyr Pro Thr Glu His Val Gln Phe Trp Val Gly

260 265 270

Ser Pro Ser Thr Pro Ala Gly Trp Val Arg Glu Gly Asp Thr Val Gln

275 280 285

Leu Leu Cys Arg Gly Asp Gly Ser Pro Ser Pro Glu Tyr Thr Leu Phe

290 295 300

Arg Leu Gln Asp Glu Gln Glu Glu Val Leu Asn Val Asn Leu Glu Gly

305 310 315 320

Asn Leu Thr Leu Glu Gly Val Thr Arg Gly Gln Ser Gly Thr Tyr Gly

325 330 335

Cys Arg Val Glu Asp Tyr Asp Ala Ala Asp Asp Val Gln Leu Ser Lys

340 345 350

Thr Leu Glu Leu Arg Val Ala Tyr Leu Asp Pro Leu Glu Leu Ser Glu

355 360 365

Gly Lys Val Leu Ser Leu Pro Leu Asn Ser Ser Ala Val Val Asn Cys

370 375 380

Ser Val His Gly Leu Pro Thr Pro Ala Leu Arg Trp Thr Lys Asp Ser

385 390 395 400

Thr Pro Leu Gly Asp Gly Pro Met Leu Ser Leu Ser Ser Ile Thr Phe

405 410 415

Asp Ser Asn Gly Thr Tyr Val Cys Glu Ala Ser Leu Pro Thr Val Pro

420 425 430

Val Leu Ser Arg Thr Gln Asn Phe Thr Leu Leu Val Gln Gly Ser Pro

435 440 445

Glu Leu Lys Thr Ala Glu Ile Glu Pro Lys Ala Asp Gly Ser Trp Arg

450 455 460

Glu Gly Asp Glu Val Thr Leu Ile Cys Ser Ala Arg Gly His Pro Asp

465 470 475 480

Pro Lys Leu Ser Trp Ser Gln Leu Gly Gly Ser Pro Ala Glu Pro Ile

485 490 495

Pro Gly Arg Gln Gly Trp Val Ser Ser Ser Leu Thr Leu Lys Val Thr

500 505 510

Ser Ala Leu Ser Arg Asp Gly Ile Ser Cys Glu Ala Ser Asn Pro His

515 520 525

Gly Asn Lys Arg His Val Phe His Phe Gly Thr Val Ser Pro Gln Thr

530 535 540

Ser Gln Ala Gly Val Ala Val Met Ala Val Ala Val Ser Val Gly Leu

545 550 555 560

Leu Leu Leu Val Val Ala Val Phe Tyr Cys Val Arg Arg Lys Gly Gly

565 570 575

Pro Cys Cys Arg Gln Arg Arg Glu Lys Gly Ala Pro Pro Pro Gly Glu

580 585 590

Pro Gly Leu Ser His Ser Gly Ser Glu Gln Pro Glu Gln Thr Gly Leu

595 600 605

Leu Met Gly Gly Ala Ser Gly Gly Ala Arg Gly Gly Ser Gly Gly Phe

610 615 620

Gly Asp Glu Cys

625

<210> 6

<211> 253

<212> PRT

<213> 智人

<400> 6

Met Ala Asn Leu Gly Cys Trp Met Leu Val Leu Phe Val Ala Thr Trp

1 5 10 15

Ser Asp Leu Gly Leu Cys Lys Lys Arg Pro Lys Pro Gly Gly Trp Asn

20 25 30

Thr Gly Gly Ser Arg Tyr Pro Gly Gln Gly Ser Pro Gly Gly Asn Arg

35 40 45

Tyr Pro Pro Gln Gly Gly Gly Gly Trp Gly Gln Pro His Gly Gly Gly

50 55 60

Trp Gly Gln Pro His Gly Gly Gly Trp Gly Gln Pro His Gly Gly Gly

65 70 75 80

Trp Gly Gln Pro His Gly Gly Gly Trp Gly Gln Gly Gly Gly Thr His

85 90 95

Ser Gln Trp Asn Lys Pro Ser Lys Pro Lys Thr Asn Met Lys His Met

100 105 110

Ala Gly Ala Ala Ala Ala Gly Ala Val Val Gly Gly Leu Gly Gly Tyr

115 120 125

Met Leu Gly Ser Ala Met Ser Arg Pro Ile Ile His Phe Gly Ser Asp

130 135 140

Tyr Glu Asp Arg Tyr Tyr Arg Glu Asn Met His Arg Tyr Pro Asn Gln

145 150 155 160

Val Tyr Tyr Arg Pro Met Asp Glu Tyr Ser Asn Gln Asn Asn Phe Val

165 170 175

His Asp Cys Val Asn Ile Thr Ile Lys Gln His Thr Val Thr Thr Thr

180 185 190

Thr Lys Gly Glu Asn Phe Thr Glu Thr Asp Val Lys Met Met Glu Arg

195 200 205

Val Val Glu Gln Met Cys Ile Thr Gln Tyr Glu Arg Glu Ser Gln Ala

210 215 220

Tyr Tyr Gln Arg Gly Ser Ser Met Val Leu Phe Ser Ser Pro Pro Val

225 230 235 240

Ile Leu Leu Ile Ser Phe Leu Ile Phe Leu Ile Val Gly

245 250

<210> 7

<211> 895

<212> PRT

<213> 智人

<400> 7

Met Arg Met Ser Val Gly Leu Ser Leu Leu Leu Pro Leu Ser Gly Arg

1 5 10 15

Thr Phe Leu Leu Leu Leu Ser Val Val Met Ala Gln Ser His Trp Pro

20 25 30

Ser Glu Pro Ser Glu Ala Val Arg Asp Trp Glu Asn Gln Leu Glu Ala

35 40 45

Ser Met His Ser Val Leu Ser Asp Leu His Glu Ala Val Pro Thr Val

50 55 60

Val Gly Ile Pro Asp Gly Thr Ala Val Val Gly Arg Ser Phe Arg Val

65 70 75 80

Thr Ile Pro Thr Asp Leu Ile Ala Ser Ser Gly Asp Ile Ile Lys Val

85 90 95

Ser Ala Ala Gly Lys Glu Ala Leu Pro Ser Trp Leu His Trp Asp Ser

100 105 110

Gln Ser His Thr Leu Glu Gly Leu Pro Leu Asp Thr Asp Lys Gly Val

115 120 125

His Tyr Ile Ser Val Ser Ala Thr Arg Leu Gly Ala Asn Gly Ser His

130 135 140

Ile Pro Gln Thr Ser Ser Val Phe Ser Ile Glu Val Tyr Pro Glu Asp

145 150 155 160

His Ser Glu Leu Gln Ser Val Arg Thr Ala Ser Pro Asp Pro Gly Glu

165 170 175

Val Val Ser Ser Ala Cys Ala Ala Asp Glu Pro Val Thr Val Leu Thr

180 185 190

Val Ile Leu Asp Ala Asp Leu Thr Lys Met Thr Pro Lys Gln Arg Ile

195 200 205

Asp Leu Leu His Arg Met Arg Ser Phe Ser Glu Val Glu Leu His Asn

210 215 220

Met Lys Leu Val Pro Val Val Asn Asn Arg Leu Phe Asp Met Ser Ala

225 230 235 240

Phe Met Ala Gly Pro Gly Asn Ala Lys Lys Val Val Glu Asn Gly Ala

245 250 255

Leu Leu Ser Trp Lys Leu Gly Cys Ser Leu Asn Gln Asn Ser Val Pro

260 265 270

Asp Ile His Gly Val Glu Ala Pro Ala Arg Glu Gly Ala Met Ser Ala

275 280 285

Gln Leu Gly Tyr Pro Val Val Gly Trp His Ile Ala Asn Lys Lys Pro

290 295 300

Pro Leu Pro Lys Arg Val Arg Arg Gln Ile His Ala Thr Pro Thr Pro

305 310 315 320

Val Thr Ala Ile Gly Pro Pro Thr Thr Ala Ile Gln Glu Pro Pro Ser

325 330 335

Arg Ile Val Pro Thr Pro Thr Ser Pro Ala Ile Ala Pro Pro Thr Glu

340 345 350

Thr Met Ala Pro Pro Val Arg Asp Pro Val Pro Gly Lys Pro Thr Val

355 360 365

Thr Ile Arg Thr Arg Gly Ala Ile Ile Gln Thr Pro Thr Leu Gly Pro

370 375 380

Ile Gln Pro Thr Arg Val Ser Glu Ala Gly Thr Thr Val Pro Gly Gln

385 390 395 400

Ile Arg Pro Thr Met Thr Ile Pro Gly Tyr Val Glu Pro Thr Ala Val

405 410 415

Ala Thr Pro Pro Thr Thr Thr Thr Lys Lys Pro Arg Val Ser Thr Pro

420 425 430

Lys Pro Ala Thr Pro Ser Thr Asp Ser Thr Thr Thr Thr Thr Arg Arg

435 440 445

Pro Thr Lys Lys Pro Arg Thr Pro Arg Pro Val Pro Arg Val Thr Thr

450 455 460

Lys Val Ser Ile Thr Arg Leu Glu Thr Ala Ser Pro Pro Thr Arg Ile

465 470 475 480

Arg Thr Thr Thr Ser Gly Val Pro Arg Gly Gly Glu Pro Asn Gln Arg

485 490 495

Pro Glu Leu Lys Asn His Ile Asp Arg Val Asp Ala Trp Val Gly Thr

500 505 510

Tyr Phe Glu Val Lys Ile Pro Ser Asp Thr Phe Tyr Asp His Glu Asp

515 520 525

Thr Thr Thr Asp Lys Leu Lys Leu Thr Leu Lys Leu Arg Glu Gln Gln

530 535 540

Leu Val Gly Glu Lys Ser Trp Val Gln Phe Asn Ser Asn Ser Gln Leu

545 550 555 560

Met Tyr Gly Leu Pro Asp Ser Ser His Val Gly Lys His Glu Tyr Phe

565 570 575

Met His Ala Thr Asp Lys Gly Gly Leu Ser Ala Val Asp Ala Phe Glu

580 585 590

Ile His Val His Arg Arg Pro Gln Gly Asp Arg Ala Pro Ala Arg Phe

595 600 605

Lys Ala Lys Phe Val Gly Asp Pro Ala Leu Val Leu Asn Asp Ile His

610 615 620

Lys Lys Ile Ala Leu Val Lys Lys Leu Ala Phe Ala Phe Gly Asp Arg

625 630 635 640

Asn Cys Ser Thr Ile Thr Leu Gln Asn Ile Thr Arg Gly Ser Ile Val

645 650 655

Val Glu Trp Thr Asn Asn Thr Leu Pro Leu Glu Pro Cys Pro Lys Glu

660 665 670

Gln Ile Ala Gly Leu Ser Arg Arg Ile Ala Glu Asp Asp Gly Lys Pro

675 680 685

Arg Pro Ala Phe Ser Asn Ala Leu Glu Pro Asp Phe Lys Ala Thr Ser

690 695 700

Ile Thr Val Thr Gly Ser Gly Ser Cys Arg His Leu Gln Phe Ile Pro

705 710 715 720

Val Val Pro Pro Arg Arg Val Pro Ser Glu Ala Pro Pro Thr Glu Val

725 730 735

Pro Asp Arg Asp Pro Glu Lys Ser Ser Glu Asp Asp Val Tyr Leu His

740 745 750

Thr Val Ile Pro Ala Val Val Val Ala Ala Ile Leu Leu Ile Ala Gly

755 760 765

Ile Ile Ala Met Ile Cys Tyr Arg Lys Lys Arg Lys Gly Lys Leu Thr

770 775 780

Leu Glu Asp Gln Ala Thr Phe Ile Lys Lys Gly Val Pro Ile Ile Phe

785 790 795 800

Ala Asp Glu Leu Asp Asp Ser Lys Pro Pro Pro Ser Ser Ser Met Pro

805 810 815

Leu Ile Leu Gln Glu Glu Lys Ala Pro Leu Pro Pro Pro Glu Tyr Pro

820 825 830

Asn Gln Ser Val Pro Glu Thr Thr Pro Leu Asn Gln Asp Thr Met Gly

835 840 845

Glu Tyr Thr Pro Leu Arg Asp Glu Asp Pro Asn Ala Pro Pro Tyr Gln

850 855 860

Pro Pro Pro Pro Phe Thr Ala Pro Met Glu Gly Lys Gly Ser Arg Pro

865 870 875 880

Lys Asn Met Thr Pro Tyr Arg Ser Pro Pro Pro Tyr Val Pro Pro

885 890 895

<210> 8

<211> 926

<212> PRT

<213> 智人

<400> 8

Ser Ala Arg Glu Glu Ser Gly Ala Gly Ala Arg Pro Arg Arg Arg Ser

1 5 10 15

Ala Asp Ser Gly Ala Ala Gly Ala Gly Arg Gly Gly Gly Gly Glu Ala

20 25 30

Ala Gly Lys Glu Glu Glu Gly Glu Ser Arg Ser Arg Arg Ala Ser Met

35 40 45

Gly Arg Leu Ala Ser Arg Pro Leu Leu Leu Ala Leu Leu Ser Leu Ala

50 55 60

Leu Cys Arg Gly Arg Val Val Arg Val Pro Thr Ala Thr Leu Val Arg

65 70 75 80

Val Val Gly Thr Glu Leu Val Ile Pro Cys Asn Val Ser Asp Tyr Asp

85 90 95

Gly Pro Ser Glu Gln Asn Phe Asp Trp Ser Phe Ser Ser Leu Gly Ser

100 105 110

Ser Phe Val Glu Leu Ala Ser Thr Trp Glu Val Gly Phe Pro Ala Gln

115 120 125

Leu Tyr Gln Glu Arg Leu Gln Arg Gly Glu Ile Leu Leu Arg Arg Thr

130 135 140

Ala Asn Asp Ala Val Glu Leu His Ile Lys Asn Val Gln Pro Ser Asp

145 150 155 160

Gln Gly His Tyr Lys Cys Ser Thr Pro Ser Thr Asp Ala Thr Val Gln

165 170 175

Gly Asn Tyr Glu Asp Thr Val Gln Val Lys Val Leu Ala Asp Ser Leu

180 185 190

His Val Gly Pro Ser Ala Arg Pro Pro Pro Ser Leu Ser Leu Arg Glu

195 200 205

Gly Glu Pro Phe Glu Leu Arg Cys Thr Ala Ala Ser Ala Ser Pro Leu

210 215 220

His Thr His Leu Ala Leu Leu Trp Glu Val His Arg Gly Pro Ala Arg

225 230 235 240

Arg Ser Val Leu Ala Leu Thr His Glu Gly Arg Phe His Pro Gly Leu

245 250 255

Gly Tyr Glu Gln Arg Tyr His Ser Gly Asp Val Arg Leu Asp Thr Val

260 265 270

Gly Ser Asp Ala Tyr Arg Leu Ser Val Ser Arg Ala Leu Ser Ala Asp

275 280 285

Gln Gly Ser Tyr Arg Cys Ile Val Ser Glu Trp Ile Ala Glu Gln Gly

290 295 300

Asn Trp Gln Glu Ile Gln Glu Lys Ala Val Glu Val Ala Thr Val Val

305 310 315 320

Ile Gln Pro Ser Val Leu Arg Ala Ala Val Pro Lys Asn Val Ser Val

325 330 335

Ala Glu Gly Lys Glu Leu Asp Leu Thr Cys Asn Ile Thr Thr Asp Arg

340 345 350

Ala Asp Asp Val Arg Pro Glu Val Thr Trp Ser Phe Ser Arg Met Pro

355 360 365

Asp Ser Thr Leu Pro Gly Ser Arg Val Leu Ala Arg Leu Asp Arg Asp

370 375 380

Ser Leu Val His Ser Ser Pro His Val Ala Leu Ser His Val Asp Ala

385 390 395 400

Arg Ser Tyr His Leu Leu Val Arg Asp Val Ser Lys Glu Asn Ser Gly

405 410 415

Tyr Tyr Tyr Cys His Val Ser Leu Trp Ala Pro Gly His Asn Arg Ser

420 425 430

Trp His Lys Val Ala Glu Ala Val Ser Ser Pro Ala Gly Val Gly Val

435 440 445

Thr Trp Leu Glu Pro Asp Tyr Gln Val Tyr Leu Asn Ala Ser Lys Val

450 455 460

Pro Gly Phe Ala Asp Asp Pro Thr Glu Leu Ala Cys Arg Val Val Asp

465 470 475 480

Thr Lys Ser Gly Glu Ala Asn Val Arg Phe Thr Val Ser Trp Tyr Tyr

485 490 495

Arg Met Asn Arg Arg Ser Asp Asn Val Val Thr Ser Glu Leu Leu Ala

500 505 510

Val Met Asp Gly Asp Trp Thr Leu Lys Tyr Gly Glu Arg Ser Lys Gln

515 520 525

Arg Ala Gln Asp Gly Asp Phe Ile Phe Ser Lys Glu His Thr Asp Thr

530 535 540

Phe Asn Phe Arg Ile Gln Arg Thr Thr Glu Glu Asp Arg Gly Asn Tyr

545 550 555 560

Tyr Cys Val Val Ser Ala Trp Thr Lys Gln Arg Asn Asn Ser Trp Val

565 570 575

Lys Ser Lys Asp Val Phe Ser Lys Pro Val Asn Ile Phe Trp Ala Leu

580 585 590

Glu Asp Ser Val Leu Val Val Lys Ala Arg Gln Pro Lys Pro Phe Phe

595 600 605

Ala Ala Gly Asn Thr Phe Glu Met Thr Cys Lys Val Ser Ser Lys Asn

610 615 620

Ile Lys Ser Pro Arg Tyr Ser Val Leu Ile Met Ala Glu Lys Pro Val

625 630 635 640

Gly Asp Leu Ser Ser Pro Asn Glu Thr Lys Tyr Ile Ile Ser Leu Asp

645 650 655

Gln Asp Ser Val Val Lys Leu Glu Asn Trp Thr Asp Ala Ser Arg Val

660 665 670

Asp Gly Val Val Leu Glu Lys Val Gln Glu Asp Glu Phe Arg Tyr Arg

675 680 685

Met Tyr Gln Thr Gln Val Ser Asp Ala Gly Leu Tyr Arg Cys Met Val

690 695 700

Thr Ala Trp Ser Pro Val Arg Gly Ser Leu Trp Arg Glu Ala Ala Thr

705 710 715 720

Ser Leu Ser Asn Pro Ile Glu Ile Asp Phe Gln Thr Ser Gly Pro Ile

725 730 735

Phe Asn Ala Ser Val His Ser Asp Thr Pro Ser Val Ile Arg Gly Asp

740 745 750

Leu Ile Lys Leu Phe Cys Ile Ile Thr Val Glu Gly Ala Ala Leu Asp

755 760 765

Pro Asp Asp Met Ala Phe Asp Val Ser Trp Phe Ala Val His Ser Phe

770 775 780

Gly Leu Asp Lys Ala Pro Val Leu Leu Ser Ser Leu Asp Arg Lys Gly

785 790 795 800

Ile Val Thr Thr Ser Arg Arg Asp Trp Lys Ser Asp Leu Ser Leu Glu

805 810 815

Arg Val Ser Val Leu Glu Phe Leu Leu Gln Val His Gly Ser Glu Asp

820 825 830

Gln Asp Phe Gly Asn Tyr Tyr Cys Ser Val Thr Pro Trp Val Lys Ser

835 840 845

Pro Thr Gly Ser Trp Gln Lys Glu Ala Glu Ile His Ser Lys Pro Val

850 855 860

Phe Ile Thr Val Lys Met Asp Val Leu Asn Ala Phe Lys Tyr Pro Leu

865 870 875 880

Leu Ile Gly Val Gly Leu Ser Thr Val Ile Gly Leu Leu Ser Cys Leu

885 890 895

Ile Gly Tyr Cys Ser Ser His Trp Cys Cys Lys Lys Glu Val Gln Glu

900 905 910

Thr Arg Arg Glu Arg Arg Arg Leu Met Ser Met Glu Met Asp

915 920 925

<210> 9

<211> 613

<212> PRT

<213> 智人

<400> 9

Met Gly Ala Leu Arg Pro Thr Leu Leu Pro Pro Ser Leu Pro Leu Leu

1 5 10 15

Leu Leu Leu Met Leu Gly Met Gly Cys Trp Ala Arg Glu Val Leu Val

20 25 30

Pro Glu Gly Pro Leu Tyr Arg Val Ala Gly Thr Ala Val Ser Ile Ser

35 40 45

Cys Asn Val Thr Gly Tyr Glu Gly Pro Ala Gln Gln Asn Phe Glu Trp

50 55 60

Phe Leu Tyr Arg Pro Glu Ala Pro Asp Thr Ala Leu Gly Ile Val Ser

65 70 75 80

Thr Lys Asp Thr Gln Phe Ser Tyr Ala Val Phe Lys Ser Arg Val Val

85 90 95

Ala Gly Glu Val Gln Val Gln Arg Leu Gln Gly Asp Ala Val Val Leu

100 105 110

Lys Ile Ala Arg Leu Gln Ala Gln Asp Ala Gly Ile Tyr Glu Cys His

115 120 125

Thr Pro Ser Thr Asp Thr Arg Tyr Leu Gly Ser Tyr Ser Gly Lys Val

130 135 140

Glu Leu Arg Val Leu Pro Asp Val Leu Gln Val Ser Ala Ala Pro Pro

145 150 155 160

Gly Pro Arg Gly Arg Gln Ala Pro Thr Ser Pro Pro Arg Met Thr Val

165 170 175

His Glu Gly Gln Glu Leu Ala Leu Gly Cys Leu Ala Arg Thr Ser Thr

180 185 190

Gln Lys His Thr His Leu Ala Val Ser Phe Gly Arg Ser Val Pro Glu

195 200 205

Ala Pro Val Gly Arg Ser Thr Leu Gln Glu Val Val Gly Ile Arg Ser

210 215 220

Asp Leu Ala Val Glu Ala Gly Ala Pro Tyr Ala Glu Arg Leu Ala Ala

225 230 235 240

Gly Glu Leu Arg Leu Gly Lys Glu Gly Thr Asp Arg Tyr Arg Met Val

245 250 255

Val Gly Gly Ala Gln Ala Gly Asp Ala Gly Thr Tyr His Cys Thr Ala

260 265 270

Ala Glu Trp Ile Gln Asp Pro Asp Gly Ser Trp Ala Gln Ile Ala Glu

275 280 285

Lys Arg Ala Val Leu Ala His Val Asp Val Gln Thr Leu Ser Ser Gln

290 295 300

Leu Ala Val Thr Val Gly Pro Gly Glu Arg Arg Ile Gly Pro Gly Glu

305 310 315 320

Pro Leu Glu Leu Leu Cys Asn Val Ser Gly Ala Leu Pro Pro Ala Gly

325 330 335

Arg His Ala Ala Tyr Ser Val Gly Trp Glu Met Ala Pro Ala Gly Ala

340 345 350

Pro Gly Pro Gly Arg Leu Val Ala Gln Leu Asp Thr Glu Gly Val Gly

355 360 365

Ser Leu Gly Pro Gly Tyr Glu Gly Arg His Ile Ala Met Glu Lys Val

370 375 380

Ala Ser Arg Thr Tyr Arg Leu Arg Leu Glu Ala Ala Arg Pro Gly Asp

385 390 395 400

Ala Gly Thr Tyr Arg Cys Leu Ala Lys Ala Tyr Val Arg Gly Ser Gly

405 410 415

Thr Arg Leu Arg Glu Ala Ala Ser Ala Arg Ser Arg Pro Leu Pro Val

420 425 430

His Val Arg Glu Glu Gly Val Val Leu Glu Ala Val Ala Trp Leu Ala

435 440 445

Gly Gly Thr Val Tyr Arg Gly Glu Thr Ala Ser Leu Leu Cys Asn Ile

450 455 460

Ser Val Arg Gly Gly Pro Pro Gly Leu Arg Leu Ala Ala Ser Trp Trp

465 470 475 480

Val Glu Arg Pro Glu Asp Gly Glu Leu Ser Ser Val Pro Ala Gln Leu

485 490 495

Val Gly Gly Val Gly Gln Asp Gly Val Ala Glu Leu Gly Val Arg Pro

500 505 510

Gly Gly Gly Pro Val Ser Val Glu Leu Val Gly Pro Arg Ser His Arg

515 520 525

Leu Arg Leu His Ser Leu Gly Pro Glu Asp Glu Gly Val Tyr His Cys

530 535 540

Ala Pro Ser Ala Trp Val Gln His Ala Asp Tyr Ser Trp Tyr Gln Ala

545 550 555 560

Gly Ser Ala Arg Ser Gly Pro Val Thr Val Tyr Pro Tyr Met His Ala

565 570 575

Leu Asp Thr Leu Phe Val Pro Leu Leu Val Gly Thr Gly Val Ala Leu

580 585 590

Val Thr Gly Ala Thr Val Leu Gly Thr Ile Thr Cys Cys Phe Met Lys

595 600 605

Arg Leu Arg Lys Arg

610

<210> 10

<211> 860

<212> PRT

<213> 智人

<400> 10

Met Gly Pro Trp Gly Trp Lys Leu Arg Trp Thr Val Ala Leu Leu Leu

1 5 10 15

Ala Ala Ala Gly Thr Ala Val Gly Asp Arg Cys Glu Arg Asn Glu Phe

20 25 30

Gln Cys Gln Asp Gly Lys Cys Ile Ser Tyr Lys Trp Val Cys Asp Gly

35 40 45

Ser Ala Glu Cys Gln Asp Gly Ser Asp Glu Ser Gln Glu Thr Cys Leu

50 55 60

Ser Val Thr Cys Lys Ser Gly Asp Phe Ser Cys Gly Gly Arg Val Asn

65 70 75 80

Arg Cys Ile Pro Gln Phe Trp Arg Cys Asp Gly Gln Val Asp Cys Asp

85 90 95

Asn Gly Ser Asp Glu Gln Gly Cys Pro Pro Lys Thr Cys Ser Gln Asp

100 105 110

Glu Phe Arg Cys His Asp Gly Lys Cys Ile Ser Arg Gln Phe Val Cys

115 120 125

Asp Ser Asp Arg Asp Cys Leu Asp Gly Ser Asp Glu Ala Ser Cys Pro

130 135 140

Val Leu Thr Cys Gly Pro Ala Ser Phe Gln Cys Asn Ser Ser Thr Cys

145 150 155 160

Ile Pro Gln Leu Trp Ala Cys Asp Asn Asp Pro Asp Cys Glu Asp Gly

165 170 175

Ser Asp Glu Trp Pro Gln Arg Cys Arg Gly Leu Tyr Val Phe Gln Gly

180 185 190

Asp Ser Ser Pro Cys Ser Ala Phe Glu Phe His Cys Leu Ser Gly Glu

195 200 205

Cys Ile His Ser Ser Trp Arg Cys Asp Gly Gly Pro Asp Cys Lys Asp

210 215 220

Lys Ser Asp Glu Glu Asn Cys Ala Val Ala Thr Cys Arg Pro Asp Glu

225 230 235 240

Phe Gln Cys Ser Asp Gly Asn Cys Ile His Gly Ser Arg Gln Cys Asp

245 250 255

Arg Glu Tyr Asp Cys Lys Asp Met Ser Asp Glu Val Gly Cys Val Asn

260 265 270

Val Thr Leu Cys Glu Gly Pro Asn Lys Phe Lys Cys His Ser Gly Glu

275 280 285

Cys Ile Thr Leu Asp Lys Val Cys Asn Met Ala Arg Asp Cys Arg Asp

290 295 300

Trp Ser Asp Glu Pro Ile Lys Glu Cys Gly Thr Asn Glu Cys Leu Asp

305 310 315 320

Asn Asn Gly Gly Cys Ser His Val Cys Asn Asp Leu Lys Ile Gly Tyr

325 330 335

Glu Cys Leu Cys Pro Asp Gly Phe Gln Leu Val Ala Gln Arg Arg Cys

340 345 350

Glu Asp Ile Asp Glu Cys Gln Asp Pro Asp Thr Cys Ser Gln Leu Cys

355 360 365

Val Asn Leu Glu Gly Gly Tyr Lys Cys Gln Cys Glu Glu Gly Phe Gln

370 375 380

Leu Asp Pro His Thr Lys Ala Cys Lys Ala Val Gly Ser Ile Ala Tyr

385 390 395 400

Leu Phe Phe Thr Asn Arg His Glu Val Arg Lys Met Thr Leu Asp Arg

405 410 415

Ser Glu Tyr Thr Ser Leu Ile Pro Asn Leu Arg Asn Val Val Ala Leu

420 425 430

Asp Thr Glu Val Ala Ser Asn Arg Ile Tyr Trp Ser Asp Leu Ser Gln

435 440 445

Arg Met Ile Cys Ser Thr Gln Leu Asp Arg Ala His Gly Val Ser Ser

450 455 460

Tyr Asp Thr Val Ile Ser Arg Asp Ile Gln Ala Pro Asp Gly Leu Ala

465 470 475 480

Val Asp Trp Ile His Ser Asn Ile Tyr Trp Thr Asp Ser Val Leu Gly

485 490 495

Thr Val Ser Val Ala Asp Thr Lys Gly Val Lys Arg Lys Thr Leu Phe

500 505 510

Arg Glu Asn Gly Ser Lys Pro Arg Ala Ile Val Val Asp Pro Val His

515 520 525

Gly Phe Met Tyr Trp Thr Asp Trp Gly Thr Pro Ala Lys Ile Lys Lys

530 535 540

Gly Gly Leu Asn Gly Val Asp Ile Tyr Ser Leu Val Thr Glu Asn Ile

545 550 555 560

Gln Trp Pro Asn Gly Ile Thr Leu Asp Leu Leu Ser Gly Arg Leu Tyr

565 570 575

Trp Val Asp Ser Lys Leu His Ser Ile Ser Ser Ile Asp Val Asn Gly

580 585 590

Gly Asn Arg Lys Thr Ile Leu Glu Asp Glu Lys Arg Leu Ala His Pro

595 600 605

Phe Ser Leu Ala Val Phe Glu Asp Lys Val Phe Trp Thr Asp Ile Ile

610 615 620

Asn Glu Ala Ile Phe Ser Ala Asn Arg Leu Thr Gly Ser Asp Val Asn

625 630 635 640

Leu Leu Ala Glu Asn Leu Leu Ser Pro Glu Asp Met Val Leu Phe His

645 650 655

Asn Leu Thr Gln Pro Arg Gly Val Asn Trp Cys Glu Arg Thr Thr Leu

660 665 670

Ser Asn Gly Gly Cys Gln Tyr Leu Cys Leu Pro Ala Pro Gln Ile Asn

675 680 685

Pro His Ser Pro Lys Phe Thr Cys Ala Cys Pro Asp Gly Met Leu Leu

690 695 700

Ala Arg Asp Met Arg Ser Cys Leu Thr Glu Ala Glu Ala Ala Val Ala

705 710 715 720

Thr Gln Glu Thr Ser Thr Val Arg Leu Lys Val Ser Ser Thr Ala Val

725 730 735

Arg Thr Gln His Thr Thr Thr Arg Pro Val Pro Asp Thr Ser Arg Leu

740 745 750

Pro Gly Ala Thr Pro Gly Leu Thr Thr Val Glu Ile Val Thr Met Ser

755 760 765

His Gln Ala Leu Gly Asp Val Ala Gly Arg Gly Asn Glu Lys Lys Pro

770 775 780

Ser Ser Val Arg Ala Leu Ser Ile Val Leu Pro Ile Val Leu Leu Val

785 790 795 800

Phe Leu Cys Leu Gly Val Phe Leu Leu Trp Lys Asn Trp Arg Leu Lys

805 810 815

Asn Ile Asn Ser Ile Asn Phe Asp Asn Pro Val Tyr Gln Lys Thr Thr

820 825 830

Glu Asp Glu Val His Ile Cys His Asn Gln Asp Gly Tyr Ser Tyr Pro

835 840 845

Ser Arg Gln Met Val Ser Leu Glu Asp Asp Val Ala

850 855 860

<210> 11

<211> 542

<212> PRT

<213> 智人

<400> 11

Met Thr Lys Ser Asn Gly Glu Glu Pro Lys Met Gly Gly Arg Met Glu

1 5 10 15

Arg Phe Gln Gln Gly Val Arg Lys Arg Thr Leu Leu Ala Lys Lys Lys

20 25 30

Val Gln Asn Ile Thr Lys Glu Asp Val Lys Ser Tyr Leu Phe Arg Asn

35 40 45

Ala Phe Val Leu Leu Thr Val Thr Ala Val Ile Val Gly Thr Ile Leu

50 55 60

Gly Phe Thr Leu Arg Pro Tyr Arg Met Ser Tyr Arg Glu Val Lys Tyr

65 70 75 80

Phe Ser Phe Pro Gly Glu Leu Leu Met Arg Met Leu Gln Met Leu Val

85 90 95

Leu Pro Leu Ile Ile Ser Ser Leu Val Thr Gly Met Ala Ala Leu Asp

100 105 110

Ser Lys Ala Ser Gly Lys Met Gly Met Arg Ala Val Val Tyr Tyr Met

115 120 125

Thr Thr Thr Ile Ile Ala Val Val Ile Gly Ile Ile Ile Val Ile Ile

130 135 140

Ile His Pro Gly Lys Gly Thr Lys Glu Asn Met His Arg Glu Gly Lys

145 150 155 160

Ile Val Arg Val Thr Ala Ala Asp Ala Phe Leu Asp Leu Ile Arg Asn

165 170 175

Met Phe Pro Pro Asn Leu Val Glu Ala Cys Phe Lys Gln Phe Lys Thr

180 185 190

Asn Tyr Glu Lys Arg Ser Phe Lys Val Pro Ile Gln Ala Asn Glu Thr

195 200 205

Leu Val Gly Ala Val Ile Asn Asn Val Ser Glu Ala Met Glu Thr Leu

210 215 220

Thr Arg Ile Thr Glu Glu Leu Val Pro Val Pro Gly Ser Val Asn Gly

225 230 235 240

Val Asn Ala Leu Gly Leu Val Val Phe Ser Met Cys Phe Gly Phe Val

245 250 255

Ile Gly Asn Met Lys Glu Gln Gly Gln Ala Leu Arg Glu Phe Phe Asp

260 265 270

Ser Leu Asn Glu Ala Ile Met Arg Leu Val Ala Val Ile Met Trp Tyr

275 280 285

Ala Pro Val Gly Ile Leu Phe Leu Ile Ala Gly Lys Ile Val Glu Met

290 295 300

Glu Asp Met Gly Val Ile Gly Gly Gln Leu Ala Met Tyr Thr Val Thr

305 310 315 320

Val Ile Val Gly Leu Leu Ile His Ala Val Ile Val Leu Pro Leu Leu

325 330 335

Tyr Phe Leu Val Thr Arg Lys Asn Pro Trp Val Phe Ile Gly Gly Leu

340 345 350

Leu Gln Ala Leu Ile Thr Ala Leu Gly Thr Ser Ser Ser Ser Ala Thr

355 360 365

Leu Pro Ile Thr Phe Lys Cys Leu Glu Glu Asn Asn Gly Val Asp Lys

370 375 380

Arg Val Thr Arg Phe Val Leu Pro Val Gly Ala Thr Ile Asn Met Asp

385 390 395 400

Gly Thr Ala Leu Tyr Glu Ala Leu Ala Ala Ile Phe Ile Ala Gln Val

405 410 415

Asn Asn Phe Glu Leu Asn Phe Gly Gln Ile Ile Thr Ile Ser Ile Thr

420 425 430

Ala Thr Ala Ala Ser Ile Gly Ala Ala Gly Ile Pro Gln Ala Gly Leu

435 440 445

Val Thr Met Val Ile Val Leu Thr Ser Val Gly Leu Pro Thr Asp Asp

450 455 460

Ile Thr Leu Ile Ile Ala Val Asp Trp Phe Leu Asp Arg Leu Arg Thr

465 470 475 480

Thr Thr Asn Val Leu Gly Asp Ser Leu Gly Ala Gly Ile Val Glu His

485 490 495

Leu Ser Arg His Glu Leu Lys Asn Arg Asp Val Glu Met Gly Asn Ser

500 505 510

Val Ile Glu Glu Asn Glu Met Lys Lys Pro Tyr Gln Leu Ile Ala Gln

515 520 525

Asp Asn Glu Thr Glu Lys Pro Ile Asp Ser Glu Thr Lys Met

530 535 540

<210> 12

<211> 698

<212> PRT

<213> 智人

<400> 12

Met Gln Ala His Glu Leu Phe Arg Tyr Phe Arg Met Pro Glu Leu Val

1 5 10 15

Asp Phe Arg Gln Tyr Val Arg Thr Leu Pro Thr Asn Thr Leu Met Gly

20 25 30

Phe Gly Ala Phe Ala Ala Leu Thr Thr Phe Trp Tyr Ala Thr Arg Pro

35 40 45

Lys Pro Leu Lys Pro Pro Cys Asp Leu Ser Met Gln Ser Val Glu Val

50 55 60

Ala Gly Ser Gly Gly Ala Arg Arg Ser Ala Leu Leu Asp Ser Asp Glu

65 70 75 80

Pro Leu Val Tyr Phe Tyr Asp Asp Val Thr Thr Leu Tyr Glu Gly Phe

85 90 95

Gln Arg Gly Ile Gln Val Ser Asn Asn Gly Pro Cys Leu Gly Ser Arg

100 105 110

Lys Pro Asp Gln Pro Tyr Glu Trp Leu Ser Tyr Lys Gln Val Ala Glu

115 120 125

Leu Ser Glu Cys Ile Gly Ser Ala Leu Ile Gln Lys Gly Phe Lys Thr

130 135 140

Ala Pro Asp Gln Phe Ile Gly Ile Phe Ala Gln Asn Arg Pro Glu Trp

145 150 155 160

Val Ile Ile Glu Gln Gly Cys Phe Ala Tyr Ser Met Val Ile Val Pro

165 170 175

Leu Tyr Asp Thr Leu Gly Asn Glu Ala Ile Thr Tyr Ile Val Asn Lys

180 185 190

Ala Glu Leu Ser Leu Val Phe Val Asp Lys Pro Glu Lys Ala Lys Leu

195 200 205

Leu Leu Glu Gly Val Glu Asn Lys Leu Ile Pro Gly Leu Lys Ile Ile

210 215 220

Val Val Met Asp Ala Tyr Gly Ser Glu Leu Val Glu Arg Gly Gln Arg

225 230 235 240

Cys Gly Val Glu Val Thr Ser Met Lys Ala Met Glu Asp Leu Gly Arg

245 250 255

Ala Asn Arg Arg Lys Pro Lys Pro Pro Ala Pro Glu Asp Leu Ala Val

260 265 270

Ile Cys Phe Thr Ser Gly Thr Thr Gly Asn Pro Lys Gly Ala Met Val

275 280 285

Thr His Arg Asn Ile Val Ser Asp Cys Ser Ala Phe Val Lys Ala Thr

290 295 300

Glu Asn Thr Val Asn Pro Cys Pro Asp Asp Thr Leu Ile Ser Phe Leu

305 310 315 320

Pro Leu Ala His Met Phe Glu Arg Val Val Glu Cys Val Met Leu Cys

325 330 335

His Gly Ala Lys Ile Gly Phe Phe Gln Gly Asp Ile Arg Leu Leu Met

340 345 350

Asp Asp Leu Lys Val Leu Gln Pro Thr Val Phe Pro Val Val Pro Arg

355 360 365

Leu Leu Asn Arg Met Phe Asp Arg Ile Phe Gly Gln Ala Asn Thr Thr

370 375 380

Leu Lys Arg Trp Leu Leu Asp Phe Ala Ser Lys Arg Lys Glu Ala Glu

385 390 395 400

Leu Arg Ser Gly Ile Ile Arg Asn Asn Ser Leu Trp Asp Arg Leu Ile

405 410 415

Phe His Lys Val Gln Ser Ser Leu Gly Gly Arg Val Arg Leu Met Val

420 425 430

Thr Gly Ala Ala Pro Val Ser Ala Thr Val Leu Thr Phe Leu Arg Ala

435 440 445

Ala Leu Gly Cys Gln Phe Tyr Glu Gly Tyr Gly Gln Thr Glu Cys Thr

450 455 460

Ala Gly Cys Cys Leu Thr Met Pro Gly Asp Trp Thr Ala Gly His Val

465 470 475 480

Gly Ala Pro Met Pro Cys Asn Leu Ile Lys Leu Val Asp Val Glu Glu

485 490 495

Met Asn Tyr Met Ala Ala Glu Gly Glu Gly Glu Val Cys Val Lys Gly

500 505 510

Pro Asn Val Phe Gln Gly Tyr Leu Lys Asp Pro Ala Lys Thr Ala Glu

515 520 525

Ala Leu Asp Lys Asp Gly Trp Leu His Thr Gly Asp Ile Gly Lys Trp

530 535 540

Leu Pro Asn Gly Thr Leu Lys Ile Ile Asp Arg Lys Lys His Ile Phe

545 550 555 560

Lys Leu Ala Gln Gly Glu Tyr Ile Ala Pro Glu Lys Ile Glu Asn Ile

565 570 575

Tyr Met Arg Ser Glu Pro Val Ala Gln Val Phe Val His Gly Glu Ser

580 585 590

Leu Gln Ala Phe Leu Ile Ala Ile Val Val Pro Asp Val Glu Thr Leu

595 600 605

Cys Ser Trp Ala Gln Lys Arg Gly Phe Glu Gly Ser Phe Glu Glu Leu

610 615 620

Cys Arg Asn Lys Asp Val Lys Lys Ala Ile Leu Glu Asp Met Val Arg

625 630 635 640

Leu Gly Lys Asp Ser Gly Leu Lys Pro Phe Glu Gln Val Lys Gly Ile

645 650 655

Thr Leu His Pro Glu Leu Phe Ser Ile Asp Asn Gly Leu Leu Thr Pro

660 665 670

Thr Met Lys Ala Lys Arg Pro Glu Leu Arg Asn Tyr Phe Arg Ser Gln

675 680 685

Ile Asp Asp Leu Tyr Ser Thr Ile Lys Val

690 695

<210> 13

<211> 552

<212> PRT

<213> 智人

<400> 13

Met Leu Asp His Lys Asp Leu Glu Ala Glu Ile His Pro Leu Lys Asn

1 5 10 15

Glu Glu Arg Lys Ser Gln Glu Asn Leu Gly Asn Pro Ser Lys Asn Glu

20 25 30

Asp Asn Val Lys Ser Ala Pro Pro Gln Ser Arg Leu Ser Arg Cys Arg

35 40 45

Ala Ala Ala Phe Phe Leu Ser Leu Phe Leu Cys Leu Phe Val Val Phe

50 55 60

Val Val Ser Phe Val Ile Pro Cys Pro Asp Arg Pro Ala Ser Gln Arg

65 70 75 80

Met Trp Arg Ile Asp Tyr Ser Ala Ala Val Ile Tyr Asp Phe Leu Ala

85 90 95

Val Asp Asp Ile Asn Gly Asp Arg Ile Gln Asp Val Leu Phe Leu Tyr

100 105 110

Lys Asn Thr Asn Ser Ser Asn Asn Phe Ser Arg Ser Cys Val Asp Glu

115 120 125

Gly Phe Ser Ser Pro Cys Thr Phe Ala Ala Ala Val Ser Gly Ala Asn

130 135 140

Gly Ser Thr Leu Trp Glu Arg Pro Val Ala Gln Asp Val Ala Leu Val

145 150 155 160

Glu Cys Ala Val Pro Gln Pro Arg Gly Ser Glu Ala Pro Ser Ala Cys

165 170 175

Ile Leu Val Gly Arg Pro Ser Ser Phe Ile Ala Val Asn Leu Phe Thr

180 185 190

Gly Glu Thr Leu Trp Asn His Ser Ser Ser Phe Ser Gly Asn Ala Ser

195 200 205

Ile Leu Ser Pro Leu Leu Gln Val Pro Asp Val Asp Gly Asp Gly Ala

210 215 220

Pro Asp Leu Leu Val Leu Thr Gln Glu Arg Glu Glu Val Ser Gly His

225 230 235 240

Leu Tyr Ser Gly Ser Thr Gly His Gln Ile Gly Leu Arg Gly Ser Leu

245 250 255

Gly Val Asp Gly Glu Ser Gly Phe Leu Leu His Val Thr Arg Thr Gly

260 265 270

Ala His Tyr Ile Leu Phe Pro Cys Ala Ser Ser Leu Cys Gly Cys Ser

275 280 285

Val Lys Gly Leu Tyr Glu Lys Val Thr Gly Ser Gly Gly Pro Phe Lys

290 295 300

Ser Asp Pro His Trp Glu Ser Met Leu Asn Ala Thr Thr Arg Arg Met

305 310 315 320

Leu Ser His Ser Ser Gly Ala Val Arg Tyr Leu Met His Val Pro Gly

325 330 335

Asn Ala Gly Ala Asp Val Leu Leu Val Gly Ser Glu Ala Phe Val Leu

340 345 350

Leu Asp Gly Gln Glu Leu Thr Pro Arg Trp Thr Pro Lys Ala Ala His

355 360 365

Val Leu Arg Lys Pro Ile Phe Gly Arg Tyr Lys Pro Asp Thr Leu Ala

370 375 380

Val Ala Val Glu Asn Gly Thr Gly Thr Asp Arg Gln Ile Leu Phe Leu

385 390 395 400

Asp Leu Gly Thr Gly Ala Val Leu Cys Ser Leu Ala Leu Pro Ser Leu

405 410 415

Pro Gly Gly Pro Leu Ser Ala Ser Leu Pro Thr Ala Asp His Arg Ser

420 425 430

Ala Phe Phe Phe Trp Gly Leu His Glu Leu Gly Ser Thr Ser Glu Thr

435 440 445

Glu Thr Gly Glu Ala Arg His Ser Leu Tyr Met Phe His Pro Thr Leu

450 455 460

Pro Arg Val Leu Leu Glu Leu Ala Asn Val Ser Thr His Ile Val Ala

465 470 475 480

Phe Asp Ala Val Leu Phe Glu Pro Ser Arg His Ala Ala Tyr Ile Leu

485 490 495

Leu Thr Gly Pro Ala Asp Ser Glu Ala Pro Gly Leu Val Ser Val Ile

500 505 510

Lys His Lys Val Arg Asp Leu Val Pro Ser Ser Arg Val Val Arg Leu

515 520 525

Gly Glu Gly Gly Pro Asp Ser Asp Gln Ala Ile Arg Asp Arg Phe Ser

530 535 540

Arg Leu Arg Tyr Gln Ser Glu Ala

545 550

<210> 14

<211> 963

<212> PRT

<213> 智人

<400> 14

Met Gly Leu Pro Glu Pro Gly Pro Leu Arg Leu Leu Ala Leu Leu Leu

1 5 10 15

Leu Leu Leu Leu Leu Leu Leu Leu Gln Leu Gln His Leu Ala Ala Ala

20 25 30

Ala Ala Asp Pro Leu Leu Gly Gly Gln Gly Pro Ala Lys Asp Cys Glu

35 40 45

Lys Asp Gln Phe Gln Cys Arg Asn Glu Arg Cys Ile Pro Ser Val Trp

50 55 60

Arg Cys Asp Glu Asp Asp Asp Cys Leu Asp His Ser Asp Glu Asp Asp

65 70 75 80

Cys Pro Lys Lys Thr Cys Ala Asp Ser Asp Phe Thr Cys Asp Asn Gly

85 90 95

His Cys Ile His Glu Arg Trp Lys Cys Asp Gly Glu Glu Glu Cys Pro

100 105 110

Asp Gly Ser Asp Glu Ser Glu Ala Thr Cys Thr Lys Gln Val Cys Pro

115 120 125

Ala Glu Lys Leu Ser Cys Gly Pro Thr Ser His Lys Cys Val Pro Ala

130 135 140

Ser Trp Arg Cys Asp Gly Glu Lys Asp Cys Glu Gly Gly Ala Asp Glu

145 150 155 160

Ala Gly Cys Ala Thr Leu Cys Ala Pro His Glu Phe Gln Cys Gly Asn

165 170 175

Arg Ser Cys Leu Ala Ala Val Phe Val Cys Asp Gly Asp Asp Asp Cys

180 185 190

Gly Asp Gly Ser Asp Glu Arg Gly Cys Ala Asp Pro Ala Cys Gly Pro

195 200 205

Arg Glu Phe Arg Cys Gly Gly Asp Gly Gly Gly Ala Cys Ile Pro Glu

210 215 220

Arg Trp Val Cys Asp Arg Gln Phe Asp Cys Glu Asp Arg Ser Asp Glu

225 230 235 240

Ala Ala Glu Leu Cys Gly Arg Pro Gly Pro Gly Ala Thr Ser Ala Pro

245 250 255

Ala Ala Cys Ala Thr Ala Ser Gln Phe Ala Cys Arg Ser Gly Glu Cys

260 265 270

Val His Leu Gly Trp Arg Cys Asp Gly Asp Arg Asp Cys Lys Asp Lys

275 280 285

Ser Asp Glu Ala Asp Cys Pro Leu Gly Thr Cys Arg Gly Asp Glu Phe

290 295 300

Gln Cys Gly Asp Gly Thr Cys Val Leu Ala Ile Lys His Cys Asn Gln

305 310 315 320

Glu Gln Asp Cys Pro Asp Gly Ser Asp Glu Ala Gly Cys Leu Gln Gly

325 330 335

Leu Asn Glu Cys Leu His Asn Asn Gly Gly Cys Ser His Ile Cys Thr

340 345 350

Asp Leu Lys Ile Gly Phe Glu Cys Thr Cys Pro Ala Gly Phe Gln Leu

355 360 365

Leu Asp Gln Lys Thr Cys Gly Asp Ile Asp Glu Cys Lys Asp Pro Asp

370 375 380

Ala Cys Ser Gln Ile Cys Val Asn Tyr Lys Gly Tyr Phe Lys Cys Glu

385 390 395 400

Cys Tyr Pro Gly Tyr Glu Met Asp Leu Leu Thr Lys Asn Cys Lys Ala

405 410 415

Ala Ala Gly Lys Ser Pro Ser Leu Ile Phe Thr Asn Arg His Glu Val

420 425 430

Arg Arg Ile Asp Leu Val Lys Arg Asn Tyr Ser Arg Leu Ile Pro Met

435 440 445

Leu Lys Asn Val Val Ala Leu Asp Val Glu Val Ala Thr Asn Arg Ile

450 455 460

Tyr Trp Cys Asp Leu Ser Tyr Arg Lys Ile Tyr Ser Ala Tyr Met Asp

465 470 475 480

Lys Ala Ser Asp Pro Lys Glu Gln Glu Val Leu Ile Asp Glu Gln Leu

485 490 495

His Ser Pro Glu Gly Leu Ala Val Asp Trp Val His Lys His Ile Tyr

500 505 510

Trp Thr Asp Ser Gly Asn Lys Thr Ile Ser Val Ala Thr Val Asp Gly

515 520 525

Gly Arg Arg Arg Thr Leu Phe Ser Arg Asn Leu Ser Glu Pro Arg Ala

530 535 540

Ile Ala Val Asp Pro Leu Arg Gly Phe Met Tyr Trp Ser Asp Trp Gly

545 550 555 560

Asp Gln Ala Lys Ile Glu Lys Ser Gly Leu Asn Gly Val Asp Arg Gln

565 570 575

Thr Leu Val Ser Asp Asn Ile Glu Trp Pro Asn Gly Ile Thr Leu Asp

580 585 590

Leu Leu Ser Gln Arg Leu Tyr Trp Val Asp Ser Lys Leu His Gln Leu

595 600 605

Ser Ser Ile Asp Phe Ser Gly Gly Asn Arg Lys Thr Leu Ile Ser Ser

610 615 620

Thr Asp Phe Leu Ser His Pro Phe Gly Ile Ala Val Phe Glu Asp Lys

625 630 635 640

Val Phe Trp Thr Asp Leu Glu Asn Glu Ala Ile Phe Ser Ala Asn Arg

645 650 655

Leu Asn Gly Leu Glu Ile Ser Ile Leu Ala Glu Asn Leu Asn Asn Pro

660 665 670

His Asp Ile Val Ile Phe His Glu Leu Lys Gln Pro Arg Ala Pro Asp

675 680 685

Ala Cys Glu Leu Ser Val Gln Pro Asn Gly Gly Cys Glu Tyr Leu Cys

690 695 700

Leu Pro Ala Pro Gln Ile Ser Ser His Ser Pro Lys Tyr Thr Cys Ala

705 710 715 720

Cys Pro Asp Thr Met Trp Leu Gly Pro Asp Met Lys Arg Cys Tyr Arg

725 730 735

Ala Pro Gln Ser Thr Ser Thr Thr Thr Leu Ala Ser Thr Met Thr Arg

740 745 750

Thr Val Pro Ala Thr Thr Arg Ala Pro Gly Thr Thr Val His Arg Ser

755 760 765

Thr Tyr Gln Asn His Ser Thr Glu Thr Pro Ser Leu Thr Ala Ala Val

770 775 780

Pro Ser Ser Val Ser Val Pro Arg Ala Pro Ser Ile Ser Pro Ser Thr

785 790 795 800

Leu Ser Pro Ala Thr Ser Asn His Ser Gln His Tyr Ala Asn Glu Asp

805 810 815

Ser Lys Met Gly Ser Thr Val Thr Ala Ala Val Ile Gly Ile Ile Val

820 825 830

Pro Ile Val Val Ile Ala Leu Leu Cys Met Ser Gly Tyr Leu Ile Trp

835 840 845

Arg Asn Trp Lys Arg Lys Asn Thr Lys Ser Met Asn Phe Asp Asn Pro

850 855 860

Val Tyr Arg Lys Thr Thr Glu Glu Glu Asp Glu Asp Glu Leu His Ile

865 870 875 880

Gly Arg Thr Ala Gln Ile Gly His Val Tyr Pro Ala Ala Ile Ser Ser

885 890 895

Phe Asp Arg Pro Leu Trp Ala Glu Pro Cys Leu Gly Glu Thr Arg Glu

900 905 910

Pro Glu Asp Pro Ala Pro Ala Leu Lys Glu Leu Phe Val Leu Pro Gly

915 920 925

Glu Pro Arg Ser Gln Leu His Gln Leu Pro Lys Asn Pro Leu Ser Glu

930 935 940

Leu Pro Val Val Lys Ser Lys Arg Val Ala Leu Ser Leu Glu Asp Asp

945 950 955 960

Gly Leu Pro

<210> 15

<211> 150

<212> PRT

<213> 智人

<400> 15

Met Ser Gly Ser Met Ala Thr Ala Glu Ala Ser Gly Ser Asp Gly Lys

1 5 10 15

Gly Gln Glu Val Glu Thr Ser Val Thr Tyr Tyr Arg Leu Glu Glu Val

20 25 30

Ala Lys Arg Asn Ser Leu Lys Glu Leu Trp Leu Val Ile His Gly Arg

35 40 45

Val Tyr Asp Val Thr Arg Phe Leu Asn Glu His Pro Gly Gly Glu Glu

50 55 60

Val Leu Leu Glu Gln Ala Gly Val Asp Ala Ser Glu Ser Phe Glu Asp

65 70 75 80

Val Gly His Ser Ser Asp Ala Arg Glu Met Leu Lys Gln Tyr Tyr Ile

85 90 95

Gly Asp Ile His Pro Ser Asp Leu Lys Pro Glu Ser Gly Ser Lys Asp

100 105 110

Pro Ser Lys Asn Asp Thr Cys Lys Ser Cys Trp Ala Tyr Trp Ile Leu

115 120 125

Pro Ile Ile Gly Ala Val Leu Leu Gly Phe Leu Tyr Arg Tyr Tyr Thr

130 135 140

Ser Glu Ser Lys Ser Ser

145 150

<210> 16

<211> 327

<212> PRT

<213> 智人

<400> 16

Met Ala Ala Ala Ala Ala Ala Ala Ala Ala Thr Asn Gly Thr Gly Gly

1 5 10 15

Ser Ser Gly Met Glu Val Asp Ala Ala Val Val Pro Ser Val Met Ala

20 25 30

Cys Gly Val Thr Gly Ser Val Ser Val Ala Leu His Pro Leu Val Ile

35 40 45

Leu Asn Ile Ser Asp His Trp Ile Arg Met Arg Ser Gln Glu Gly Arg

50 55 60

Pro Val Gln Val Ile Gly Ala Leu Ile Gly Lys Gln Glu Gly Arg Asn

65 70 75 80

Ile Glu Val Met Asn Ser Phe Glu Leu Leu Ser His Thr Val Glu Glu

85 90 95

Lys Ile Ile Ile Asp Lys Glu Tyr Tyr Tyr Thr Lys Glu Glu Gln Phe

100 105 110

Lys Gln Val Phe Lys Glu Leu Glu Phe Leu Gly Trp Tyr Thr Thr Gly

115 120 125

Gly Pro Pro Asp Pro Ser Asp Ile His Val His Lys Gln Val Cys Glu

130 135 140

Ile Ile Glu Ser Pro Leu Phe Leu Lys Leu Asn Pro Met Thr Lys His

145 150 155 160

Thr Asp Leu Pro Val Ser Val Phe Glu Ser Val Ile Asp Ile Ile Asn

165 170 175

Gly Glu Ala Thr Met Leu Phe Ala Glu Leu Thr Tyr Thr Leu Ala Thr

180 185 190

Glu Glu Ala Glu Arg Ile Gly Val Asp His Val Ala Arg Met Thr Ala

195 200 205

Thr Gly Ser Gly Glu Asn Ser Thr Val Ala Glu His Leu Ile Ala Gln

210 215 220

His Ser Ala Ile Lys Met Leu His Ser Arg Val Lys Leu Ile Leu Glu

225 230 235 240

Tyr Val Lys Ala Ser Glu Ala Gly Glu Val Pro Phe Asn His Glu Ile

245 250 255

Leu Arg Glu Ala Tyr Ala Leu Cys His Cys Leu Pro Val Leu Ser Thr

260 265 270

Asp Lys Phe Lys Thr Asp Phe Tyr Asp Gln Cys Asn Asp Val Gly Leu

275 280 285

Met Ala Tyr Leu Gly Thr Ile Thr Lys Thr Cys Asn Thr Met Asn Gln

290 295 300

Phe Val Asn Lys Phe Asn Val Leu Tyr Asp Arg Gln Gly Ile Gly Arg

305 310 315 320

Arg Met Arg Gly Leu Phe Phe

325

<210> 17

<211> 343

<212> PRT

<213> 智人

<400> 17

Met Ala Gln Lys Gly Val Leu Gly Pro Gly Gln Leu Gly Ala Val Ala

1 5 10 15

Ile Leu Leu Tyr Leu Gly Leu Leu Arg Ser Gly Thr Gly Lys Glu Gly

20 25 30

Ala Ala Ala Pro Cys Gly Val Ala Pro Gln Ala Arg Ile Thr Gly Gly

35 40 45

Ser Ser Ala Val Ala Gly Gln Trp Pro Trp Gln Val Ser Ile Thr Tyr

50 55 60

Glu Gly Val His Val Cys Gly Gly Ser Leu Val Ser Glu Gln Trp Val

65 70 75 80

Leu Ser Ala Ala His Cys Phe Pro Ser Glu His His Lys Glu Ala Tyr

85 90 95

Glu Val Lys Leu Gly Ala His Gln Leu Asp Ser Tyr Ser Glu Asp Ala

100 105 110

Lys Val Ser Thr Leu Lys Asp Ile Ile Pro His Pro Ser Tyr Leu Gln

115 120 125

Glu Gly Ser Gln Gly Asp Ile Ala Leu Leu Gln Leu Ser Arg Pro Ile

130 135 140

Thr Phe Ser Arg Tyr Ile Arg Pro Ile Cys Leu Pro Ala Ala Asn Ala

145 150 155 160

Ser Phe Pro Asn Gly Leu His Cys Thr Val Thr Gly Trp Gly His Val

165 170 175

Ala Pro Ser Val Ser Leu Leu Thr Pro Lys Pro Leu Gln Gln Leu Glu

180 185 190

Val Pro Leu Ile Ser Arg Glu Thr Cys Asn Cys Leu Tyr Asn Ile Asp

195 200 205

Ala Lys Pro Glu Glu Pro His Phe Val Gln Glu Asp Met Val Cys Ala

210 215 220

Gly Tyr Val Glu Gly Gly Lys Asp Ala Cys Gln Gly Asp Ser Gly Gly

225 230 235 240

Pro Leu Ser Cys Pro Val Glu Gly Leu Trp Tyr Leu Thr Gly Ile Val

245 250 255

Ser Trp Gly Asp Ala Cys Gly Ala Arg Asn Arg Pro Gly Val Tyr Thr

260 265 270

Leu Ala Ser Ser Tyr Ala Ser Trp Ile Gln Ser Lys Val Thr Glu Leu

275 280 285

Gln Pro Arg Val Val Pro Gln Thr Gln Glu Ser Gln Pro Asp Ser Asn

290 295 300

Leu Cys Gly Ser His Leu Ala Phe Ser Ser Ala Pro Ala Gln Gly Leu

305 310 315 320

Leu Arg Pro Ile Leu Phe Leu Pro Leu Gly Leu Ala Leu Gly Leu Leu

325 330 335

Ser Pro Trp Leu Ser Glu His

340

<210> 18

<211> 198

<212> PRT

<213> 智人

<400> 18

Met Ala Pro Ala Arg Leu Phe Ala Leu Leu Leu Phe Phe Val Gly Gly

1 5 10 15

Val Ala Glu Ser Ile Arg Glu Thr Glu Val Ile Asp Pro Gln Asp Leu

20 25 30

Leu Glu Gly Arg Tyr Phe Ser Gly Ala Leu Pro Asp Asp Glu Asp Val

35 40 45

Val Gly Pro Gly Gln Glu Ser Asp Asp Phe Glu Leu Ser Gly Ser Gly

50 55 60

Asp Leu Asp Asp Leu Glu Asp Ser Met Ile Gly Pro Glu Val Val His

65 70 75 80

Pro Leu Val Pro Leu Asp Asn His Ile Pro Glu Arg Ala Gly Ser Gly

85 90 95

Ser Gln Val Pro Thr Glu Pro Lys Lys Leu Glu Glu Asn Glu Val Ile

100 105 110

Pro Lys Arg Ile Ser Pro Val Glu Glu Ser Glu Asp Val Ser Asn Lys

115 120 125

Val Ser Met Ser Ser Thr Val Gln Gly Ser Asn Ile Phe Glu Arg Thr

130 135 140

Glu Val Leu Ala Ala Leu Ile Val Gly Gly Ile Val Gly Ile Leu Phe

145 150 155 160

Ala Val Phe Leu Ile Leu Leu Leu Met Tyr Arg Met Lys Lys Lys Asp

165 170 175

Glu Gly Ser Tyr Asp Leu Gly Lys Lys Pro Ile Tyr Lys Lys Ala Pro

180 185 190

Thr Asn Glu Phe Tyr Ala

195

<210> 19

<211> 492

<212> PRT

<213> 智人

<400> 19

Met Glu Pro Ser Ser Lys Lys Leu Thr Gly Arg Leu Met Leu Ala Val

1 5 10 15

Gly Gly Ala Val Leu Gly Ser Leu Gln Phe Gly Tyr Asn Thr Gly Val

20 25 30

Ile Asn Ala Pro Gln Lys Val Ile Glu Glu Phe Tyr Asn Gln Thr Trp

35 40 45

Val His Arg Tyr Gly Glu Ser Ile Leu Pro Thr Thr Leu Thr Thr Leu

50 55 60

Trp Ser Leu Ser Val Ala Ile Phe Ser Val Gly Gly Met Ile Gly Ser

65 70 75 80

Phe Ser Val Gly Leu Phe Val Asn Arg Phe Gly Arg Arg Asn Ser Met

85 90 95

Leu Met Met Asn Leu Leu Ala Phe Val Ser Ala Val Leu Met Gly Phe

100 105 110

Ser Lys Leu Gly Lys Ser Phe Glu Met Leu Ile Leu Gly Arg Phe Ile

115 120 125

Ile Gly Val Tyr Cys Gly Leu Thr Thr Gly Phe Val Pro Met Tyr Val

130 135 140

Gly Glu Val Ser Pro Thr Ala Leu Arg Gly Ala Leu Gly Thr Leu His

145 150 155 160

Gln Leu Gly Ile Val Val Gly Ile Leu Ile Ala Gln Val Phe Gly Leu

165 170 175

Asp Ser Ile Met Gly Asn Lys Asp Leu Trp Pro Leu Leu Leu Ser Ile

180 185 190

Ile Phe Ile Pro Ala Leu Leu Gln Cys Ile Val Leu Pro Phe Cys Pro

195 200 205

Glu Ser Pro Arg Phe Leu Leu Ile Asn Arg Asn Glu Glu Asn Arg Ala

210 215 220

Lys Ser Val Leu Lys Lys Leu Arg Gly Thr Ala Asp Val Thr His Asp

225 230 235 240

Leu Gln Glu Met Lys Glu Glu Ser Arg Gln Met Met Arg Glu Lys Lys

245 250 255

Val Thr Ile Leu Glu Leu Phe Arg Ser Pro Ala Tyr Arg Gln Pro Ile

260 265 270

Leu Ile Ala Val Val Leu Gln Leu Ser Gln Gln Leu Ser Gly Ile Asn

275 280 285

Ala Val Phe Tyr Tyr Ser Thr Ser Ile Phe Glu Lys Ala Gly Val Gln

290 295 300

Gln Pro Val Tyr Ala Thr Ile Gly Ser Gly Ile Val Asn Thr Ala Phe

305 310 315 320

Thr Val Val Ser Leu Phe Val Val Glu Arg Ala Gly Arg Arg Thr Leu

325 330 335

His Leu Ile Gly Leu Ala Gly Met Ala Gly Cys Ala Ile Leu Met Thr

340 345 350

Ile Ala Leu Ala Leu Leu Glu Gln Leu Pro Trp Met Ser Tyr Leu Ser

355 360 365

Ile Val Ala Ile Phe Gly Phe Val Ala Phe Phe Glu Val Gly Pro Gly

370 375 380

Pro Ile Pro Trp Phe Ile Val Ala Glu Leu Phe Ser Gln Gly Pro Arg

385 390 395 400

Pro Ala Ala Ile Ala Val Ala Gly Phe Ser Asn Trp Thr Ser Asn Phe

405 410 415

Ile Val Gly Met Cys Phe Gln Tyr Val Glu Gln Leu Cys Gly Pro Tyr

420 425 430

Val Phe Ile Ile Phe Thr Val Leu Leu Val Leu Phe Phe Ile Phe Thr

435 440 445

Tyr Phe Lys Val Pro Glu Thr Lys Gly Arg Thr Phe Asp Glu Ile Ala

450 455 460

Ser Gly Phe Arg Gln Gly Gly Ala Ser Gln Ser Asp Lys Thr Pro Glu

465 470 475 480

Glu Leu Phe His Pro Leu Gly Ala Asp Ser Gln Val

485 490

<210> 20

<211> 180

<212> PRT

<213> 智人

<400> 20

Met Ala Ser Thr Ser Tyr Asp Tyr Cys Arg Val Pro Met Glu Asp Gly

1 5 10 15

Asp Lys Arg Cys Lys Leu Leu Leu Gly Ile Gly Ile Leu Val Leu Leu

20 25 30

Ile Ile Val Ile Leu Gly Val Pro Leu Ile Ile Phe Thr Ile Lys Ala

35 40 45

Asn Ser Glu Ala Cys Arg Asp Gly Leu Arg Ala Val Met Glu Cys Arg

50 55 60

Asn Val Thr His Leu Leu Gln Gln Glu Leu Thr Glu Ala Gln Lys Gly

65 70 75 80

Phe Gln Asp Val Glu Ala Gln Ala Ala Thr Cys Asn His Thr Val Met

85 90 95

Ala Leu Met Ala Ser Leu Asp Ala Glu Lys Ala Gln Gly Gln Lys Lys

100 105 110

Val Glu Glu Leu Glu Gly Glu Ile Thr Thr Leu Asn His Lys Leu Gln

115 120 125

Asp Ala Ser Ala Glu Val Glu Arg Leu Arg Arg Glu Asn Gln Val Leu

130 135 140

Ser Val Arg Ile Ala Asp Lys Lys Tyr Tyr Pro Ser Ser Gln Asp Ser

145 150 155 160

Ser Ser Ala Ala Ala Pro Gln Leu Leu Ile Val Leu Leu Gly Leu Ser

165 170 175

Ala Leu Leu Gln

180

<210> 21

<211> 341

<212> PRT

<213> 智人

<400> 21

Met Arg Lys Val Val Leu Ile Thr Gly Ala Ser Ser Gly Ile Gly Leu

1 5 10 15

Ala Leu Cys Lys Arg Leu Leu Ala Glu Asp Asp Glu Leu His Leu Cys

20 25 30

Leu Ala Cys Arg Asn Met Ser Lys Ala Glu Ala Val Cys Ala Ala Leu

35 40 45

Leu Ala Ser His Pro Thr Ala Glu Val Thr Ile Val Gln Val Asp Val

50 55 60

Ser Asn Leu Gln Ser Val Phe Arg Ala Ser Lys Glu Leu Lys Gln Arg

65 70 75 80

Phe Gln Arg Leu Asp Cys Ile Tyr Leu Asn Ala Gly Ile Met Pro Asn

85 90 95

Pro Gln Leu Asn Ile Lys Ala Leu Phe Phe Gly Leu Phe Ser Arg Lys

100 105 110

Val Ile His Met Phe Ser Thr Ala Glu Gly Leu Leu Thr Gln Gly Asp

115 120 125

Lys Ile Thr Ala Asp Gly Leu Gln Glu Val Phe Glu Thr Asn Val Phe

130 135 140

Gly His Phe Ile Leu Ile Arg Glu Leu Glu Pro Leu Leu Cys His Ser

145 150 155 160

Asp Asn Pro Ser Gln Leu Ile Trp Thr Ser Ser Arg Ser Ala Arg Lys

165 170 175

Ser Asn Phe Ser Leu Glu Asp Phe Gln His Ser Lys Gly Lys Glu Pro

180 185 190

Tyr Ser Ser Ser Lys Tyr Ala Thr Asp Leu Leu Ser Val Ala Leu Asn

195 200 205

Arg Asn Phe Asn Gln Gln Gly Leu Tyr Ser Asn Val Ala Cys Pro Gly

210 215 220

Thr Ala Leu Thr Asn Leu Thr Tyr Gly Ile Leu Pro Pro Phe Ile Trp

225 230 235 240

Thr Leu Leu Met Pro Ala Ile Leu Leu Leu Arg Phe Phe Ala Asn Ala

245 250 255

Phe Thr Leu Thr Pro Tyr Asn Gly Thr Glu Ala Leu Val Trp Leu Phe

260 265 270

His Gln Lys Pro Glu Ser Leu Asn Pro Leu Ile Lys Tyr Leu Ser Ala

275 280 285

Thr Thr Gly Phe Gly Arg Asn Tyr Ile Met Thr Gln Lys Met Asp Leu

290 295 300

Asp Glu Asp Thr Ala Glu Lys Phe Tyr Gln Lys Leu Leu Glu Leu Glu

305 310 315 320

Lys His Ile Arg Val Thr Ile Gln Lys Thr Asp Asn Gln Ala Arg Leu

325 330 335

Ser Gly Ser Cys Leu

340

<210> 22

<211> 454

<212> PRT

<213> 智人

<400> 22

Met Ala Leu Gln Leu Gly Arg Leu Ser Ser Gly Pro Cys Trp Leu Val

1 5 10 15

Ala Arg Gly Gly Cys Gly Gly Pro Arg Ala Trp Ser Gln Cys Gly Gly

20 25 30

Gly Gly Leu Arg Ala Trp Ser Gln Arg Ser Ala Ala Gly Arg Val Cys

35 40 45

Arg Pro Pro Gly Pro Ala Gly Thr Glu Gln Ser Arg Gly Leu Gly His

50 55 60

Gly Ser Thr Ser Arg Gly Gly Pro Trp Val Gly Thr Gly Leu Ala Ala

65 70 75 80

Ala Leu Ala Gly Leu Val Gly Leu Ala Thr Ala Ala Phe Gly His Val

85 90 95

Gln Arg Ala Glu Met Leu Pro Lys Thr Ser Gly Thr Arg Ala Thr Ser

100 105 110

Leu Gly Arg Pro Glu Glu Glu Glu Asp Glu Leu Ala His Arg Cys Ser

115 120 125

Ser Phe Met Ala Pro Pro Val Thr Asp Leu Gly Glu Leu Arg Arg Arg

130 135 140

Pro Gly Asp Met Lys Thr Lys Met Glu Leu Leu Ile Leu Glu Thr Gln

145 150 155 160

Ala Gln Val Cys Gln Ala Leu Ala Gln Val Asp Gly Gly Ala Asn Phe

165 170 175

Ser Val Asp Arg Trp Glu Arg Lys Glu Gly Gly Gly Gly Ile Ser Cys

180 185 190

Val Leu Gln Asp Gly Cys Val Phe Glu Lys Ala Gly Val Ser Ile Ser

195 200 205

Val Val His Gly Asn Leu Ser Glu Glu Ala Ala Lys Gln Met Arg Ser

210 215 220

Arg Gly Lys Val Leu Lys Thr Lys Asp Gly Lys Leu Pro Phe Cys Ala

225 230 235 240

Met Gly Val Ser Ser Val Ile His Pro Lys Asn Pro His Ala Pro Thr

245 250 255

Ile His Phe Asn Tyr Arg Tyr Phe Glu Val Glu Glu Ala Asp Gly Asn

260 265 270

Lys Gln Trp Trp Phe Gly Gly Gly Cys Asp Leu Thr Pro Thr Tyr Leu

275 280 285

Asn Gln Glu Asp Ala Val His Phe His Arg Thr Leu Lys Glu Ala Cys

290 295 300

Asp Gln His Gly Pro Asp Leu Tyr Pro Lys Phe Lys Lys Trp Cys Asp

305 310 315 320

Asp Tyr Phe Phe Ile Ala His Arg Gly Glu Arg Arg Gly Ile Gly Gly

325 330 335

Ile Phe Phe Asp Asp Leu Asp Ser Pro Ser Lys Glu Glu Val Phe Arg

340 345 350

Phe Val Gln Ser Cys Ala Arg Ala Val Val Pro Ser Tyr Ile Pro Leu

355 360 365

Val Lys Lys His Cys Asp Asp Ser Phe Thr Pro Gln Glu Lys Leu Trp

370 375 380

Gln Gln Leu Arg Arg Gly Arg Tyr Val Glu Phe Asn Leu Leu Tyr Asp

385 390 395 400

Arg Gly Thr Lys Phe Gly Leu Phe Thr Pro Gly Ser Arg Ile Glu Ser

405 410 415

Ile Leu Met Ser Leu Pro Leu Thr Ala Arg Trp Glu Tyr Met His Ser

420 425 430

Pro Ser Glu Asn Ser Lys Glu Ala Glu Ile Leu Glu Val Leu Arg His

435 440 445

Pro Arg Asp Trp Val Arg

450

<210> 23

<211> 528

<212> PRT

<213> 智人

<400> 23

Met Arg Cys Ala Leu Ala Leu Ser Ala Leu Leu Leu Leu Leu Ser Thr

1 5 10 15

Pro Pro Leu Leu Pro Ser Ser Pro Ser Pro Ser Pro Ser Pro Ser Gln

20 25 30

Asn Glu Thr Ala Thr Gln Thr Thr Thr Asp Ser Ser Asn Lys Thr Ala

35 40 45

Pro Thr Pro Ala Ser Ser Val Thr Ile Met Ala Thr Asp Thr Ala Gln

50 55 60

Gln Ser Thr Val Pro Thr Ser Lys Ala Asn Glu Ile Leu Ala Ser Val

65 70 75 80

Lys Ala Thr Thr Leu Gly Val Ser Ser Asp Ser Pro Gly Thr Thr Thr

85 90 95

Leu Ala Gln Gln Val Ser Gly Pro Val Asn Thr Thr Val Ala Arg Gly

100 105 110

Gly Gly Ser Gly Asn Pro Thr Thr Thr Ile Glu Ser Pro Lys Ser Thr

115 120 125

Lys Ser Ala Asp Thr Thr Thr Val Ala Thr Ser Thr Ala Thr Ala Lys

130 135 140

Pro Asn Thr Thr Ser Ser Gln Asn Gly Ala Glu Asp Thr Thr Asn Ser

145 150 155 160

Gly Gly Lys Ser Ser His Ser Val Thr Thr Asp Leu Thr Ser Thr Lys

165 170 175

Ala Glu His Leu Thr Thr Pro His Pro Thr Ser Pro Leu Ser Pro Arg

180 185 190

Gln Pro Thr Ser Thr His Pro Val Ala Thr Pro Thr Ser Ser Gly His

195 200 205

Asp His Leu Met Lys Ile Ser Ser Ser Ser Ser Thr Val Ala Ile Pro

210 215 220

Gly Tyr Thr Phe Thr Ser Pro Gly Met Thr Thr Thr Leu Pro Ser Ser

225 230 235 240

Val Ile Ser Gln Arg Thr Gln Gln Thr Ser Ser Gln Met Pro Ala Ser

245 250 255

Ser Thr Ala Pro Ser Ser Gln Glu Thr Val Gln Pro Thr Ser Pro Ala

260 265 270

Thr Ala Leu Arg Thr Pro Thr Leu Pro Glu Thr Met Ser Ser Ser Pro

275 280 285

Thr Ala Ala Ser Thr Thr His Arg Tyr Pro Lys Thr Pro Ser Pro Thr

290 295 300

Val Ala His Glu Ser Asn Trp Val Thr Pro Ala Gly Val Gly Thr Gln

305 310 315 320

Thr Arg Val Glu Glu Ala Leu Arg Gln Ala Leu Thr His Ser Leu Leu

325 330 335

Pro Ala Gly Gly Ala Ser Asp Glu Lys Leu Ile Ser Leu Ile Cys Arg

340 345 350

Ala Val Lys Ala Thr Phe Asn Pro Ala Gln Asp Lys Cys Gly Ile Arg

355 360 365

Leu Ala Ser Val Pro Gly Ser Gln Thr Val Val Val Lys Glu Ile Thr

370 375 380

Ile His Thr Lys Leu Pro Ala Lys Asp Val Tyr Glu Arg Leu Lys Asp

385 390 395 400

Lys Trp Asp Glu Leu Lys Glu Ala Gly Val Ser Asp Met Lys Leu Gly

405 410 415

Asp Gln Gly Pro Pro Glu Glu Ala Glu Asp Arg Phe Ser Met Pro Leu

420 425 430

Ile Ile Thr Ile Val Cys Met Ala Ser Phe Leu Leu Leu Val Ala Ala

435 440 445

Leu Tyr Gly Cys Cys His Gln Arg Leu Ser Gln Arg Lys Asp Gln Gln

450 455 460

Arg Leu Thr Glu Glu Leu Gln Thr Val Glu Asn Gly Tyr His Asp Asn

465 470 475 480

Pro Thr Leu Glu Val Met Glu Thr Ser Ser Glu Met Gln Glu Lys Lys

485 490 495

Val Val Ser Leu Asn Gly Glu Leu Gly Asp Ser Trp Ile Val Pro Leu

500 505 510

Asp Asn Leu Thr Lys Asp Asp Leu Asp Glu Glu Glu Asp Thr His Leu

515 520 525

<210> 24

<211> 475

<212> PRT

<213> 智人

<400> 24

Met Ala Ala Lys Ser Gln Pro Asn Ile Pro Lys Ala Lys Ser Leu Asp

1 5 10 15

Gly Val Thr Asn Asp Arg Thr Ala Ser Gln Gly Gln Trp Gly Arg Ala

20 25 30

Trp Glu Val Asp Trp Phe Ser Leu Ala Ser Val Ile Phe Leu Leu Leu

35 40 45

Phe Ala Pro Phe Ile Val Tyr Tyr Phe Ile Met Ala Cys Asp Gln Tyr

50 55 60

Ser Cys Ala Leu Thr Gly Pro Val Val Asp Ile Val Thr Gly His Ala

65 70 75 80

Arg Leu Ser Asp Ile Trp Ala Lys Thr Pro Pro Ile Thr Arg Lys Ala

85 90 95

Ala Gln Leu Tyr Thr Leu Trp Val Thr Phe Gln Val Leu Leu Tyr Thr

100 105 110

Ser Leu Pro Asp Phe Cys His Lys Phe Leu Pro Gly Tyr Val Gly Gly

115 120 125

Ile Gln Glu Gly Ala Val Thr Pro Ala Gly Val Val Asn Lys Tyr Gln

130 135 140

Ile Asn Gly Leu Gln Ala Trp Leu Leu Thr His Leu Leu Trp Phe Ala

145 150 155 160

Asn Ala His Leu Leu Ser Trp Phe Ser Pro Thr Ile Ile Phe Asp Asn

165 170 175

Trp Ile Pro Leu Leu Trp Cys Ala Asn Ile Leu Gly Tyr Ala Val Ser

180 185 190

Thr Phe Ala Met Val Lys Gly Tyr Phe Phe Pro Thr Ser Ala Arg Asp

195 200 205

Cys Lys Phe Thr Gly Asn Phe Phe Tyr Asn Tyr Met Met Gly Ile Glu

210 215 220

Phe Asn Pro Arg Ile Gly Lys Trp Phe Asp Phe Lys Leu Phe Phe Asn

225 230 235 240

Gly Arg Pro Gly Ile Val Ala Trp Thr Leu Ile Asn Leu Ser Phe Ala

245 250 255

Ala Lys Gln Arg Glu Leu His Ser His Val Thr Asn Ala Met Val Leu

260 265 270

Val Asn Val Leu Gln Ala Ile Tyr Val Ile Asp Phe Phe Trp Asn Glu

275 280 285

Thr Trp Tyr Leu Lys Thr Ile Asp Ile Cys His Asp His Phe Gly Trp

290 295 300

Tyr Leu Gly Trp Gly Asp Cys Val Trp Leu Pro Tyr Leu Tyr Thr Leu

305 310 315 320

Gln Gly Leu Tyr Leu Val Tyr His Pro Val Gln Leu Ser Thr Pro His

325 330 335

Ala Val Gly Val Leu Leu Leu Gly Leu Val Gly Tyr Tyr Ile Phe Arg

340 345 350

Val Ala Asn His Gln Lys Asp Leu Phe Arg Arg Thr Asp Gly Arg Cys

355 360 365

Leu Ile Trp Gly Arg Lys Pro Lys Val Ile Glu Cys Ser Tyr Thr Ser

370 375 380

Ala Asp Gly Gln Arg His His Ser Lys Leu Leu Val Ser Gly Phe Trp

385 390 395 400

Gly Val Ala Arg His Phe Asn Tyr Val Gly Asp Leu Met Gly Ser Leu

405 410 415

Ala Tyr Cys Leu Ala Cys Gly Gly Gly His Leu Leu Pro Tyr Phe Tyr

420 425 430

Ile Ile Tyr Met Ala Ile Leu Leu Thr His Arg Cys Leu Arg Asp Glu

435 440 445

His Arg Cys Ala Ser Lys Tyr Gly Arg Asp Trp Glu Arg Tyr Thr Ala

450 455 460

Ala Val Pro Tyr Arg Leu Leu Pro Gly Ile Phe

465 470 475

<210> 25

<211> 1241

<212> PRT

<213> 智人

<400> 25

Met Ser Ser Ala Pro Arg Arg Pro Ala Lys Gly Ala Asp Ser Phe Cys

1 5 10 15

Thr Pro Glu Pro Glu Ser Leu Gly Pro Gly Thr Pro Gly Phe Pro Glu

20 25 30

Gln Glu Glu Asp Glu Leu His Arg Thr Leu Gly Val Glu Arg Phe Glu

35 40 45

Glu Ile Leu Gln Glu Ala Gly Ser Arg Gly Gly Glu Glu Pro Gly Arg

50 55 60

Ser Tyr Gly Glu Glu Asp Phe Glu Tyr His Arg Gln Ser Ser His His

65 70 75 80

Ile His His Pro Leu Ser Thr His Leu Pro Pro Asp Ala Arg Arg Arg

85 90 95

Lys Thr Pro Gln Gly Pro Gly Arg Lys Pro Arg Arg Arg Pro Gly Ala

100 105 110

Ser Pro Thr Gly Glu Thr Pro Thr Ile Glu Glu Gly Glu Glu Asp Glu

115 120 125

Asp Glu Ala Ser Glu Ala Glu Gly Ala Arg Ala Leu Thr Gln Pro Ser

130 135 140

Pro Val Ser Thr Pro Ser Ser Val Gln Phe Phe Leu Gln Glu Asp Asp

145 150 155 160

Ser Ala Asp Arg Lys Ala Glu Arg Thr Ser Pro Ser Ser Pro Ala Pro

165 170 175

Leu Pro His Gln Glu Ala Thr Pro Arg Ala Ser Lys Gly Ala Gln Ala

180 185 190

Gly Thr Gln Val Glu Glu Ala Glu Ala Glu Ala Val Ala Val Ala Ser

195 200 205

Gly Thr Ala Gly Gly Asp Asp Gly Gly Ala Ser Gly Arg Pro Leu Pro

210 215 220

Lys Ala Gln Pro Gly His Arg Ser Tyr Asn Leu Gln Glu Arg Arg Arg

225 230 235 240

Ile Gly Ser Met Thr Gly Ala Glu Gln Ala Leu Leu Pro Arg Val Pro

245 250 255

Thr Asp Glu Ile Glu Ala Gln Thr Leu Ala Thr Ala Asp Leu Asp Leu

260 265 270

Met Lys Ser His Arg Phe Glu Asp Val Pro Gly Val Arg Arg His Leu

275 280 285

Val Arg Lys Asn Ala Lys Gly Ser Thr Gln Ser Gly Arg Glu Gly Arg

290 295 300

Glu Pro Gly Pro Thr Pro Arg Ala Arg Pro Arg Ala Pro His Lys Pro

305 310 315 320

His Glu Val Phe Val Glu Leu Asn Glu Leu Leu Leu Asp Lys Asn Gln

325 330 335

Glu Pro Gln Trp Arg Glu Thr Ala Arg Trp Ile Lys Phe Glu Glu Asp

340 345 350

Val Glu Glu Glu Thr Glu Arg Trp Gly Lys Pro His Val Ala Ser Leu

355 360 365

Ser Phe Arg Ser Leu Leu Glu Leu Arg Arg Thr Leu Ala His Gly Ala

370 375 380

Val Leu Leu Asp Leu Asp Gln Gln Thr Leu Pro Gly Val Ala His Gln

385 390 395 400

Val Val Glu Gln Met Val Ile Ser Asp Gln Ile Lys Ala Glu Asp Arg

405 410 415

Ala Asn Val Leu Arg Ala Leu Leu Leu Lys His Ser His Pro Ser Asp

420 425 430

Glu Lys Asp Phe Ser Phe Pro Arg Asn Ile Ser Ala Gly Ser Leu Gly

435 440 445

Ser Leu Leu Gly His His His Gly Gln Gly Ala Glu Ser Asp Pro His

450 455 460

Val Thr Glu Pro Leu Met Gly Gly Val Pro Glu Thr Arg Leu Glu Val

465 470 475 480

Glu Arg Glu Arg Glu Leu Pro Pro Pro Ala Pro Pro Ala Gly Ile Thr

485 490 495

Arg Ser Lys Ser Lys His Glu Leu Lys Leu Leu Glu Lys Ile Pro Glu

500 505 510

Asn Ala Glu Ala Thr Val Val Leu Val Gly Cys Val Glu Phe Leu Ser

515 520 525

Arg Pro Thr Met Ala Phe Val Arg Leu Arg Glu Ala Val Glu Leu Asp

530 535 540

Ala Val Leu Glu Val Pro Val Pro Val Arg Phe Leu Phe Leu Leu Leu

545 550 555 560

Gly Pro Ser Ser Ala Asn Met Asp Tyr His Glu Ile Gly Arg Ser Ile

565 570 575

Ser Thr Leu Met Ser Asp Lys Gln Phe His Glu Ala Ala Tyr Leu Ala

580 585 590

Asp Glu Arg Glu Asp Leu Leu Thr Ala Ile Asn Ala Phe Leu Asp Cys

595 600 605

Ser Val Val Leu Pro Pro Ser Glu Val Gln Gly Glu Glu Leu Leu Arg

610 615 620

Ser Val Ala His Phe Gln Arg Gln Met Leu Lys Lys Arg Glu Glu Gln

625 630 635 640

Gly Arg Leu Leu Pro Thr Gly Ala Gly Leu Glu Pro Lys Ser Ala Gln

645 650 655

Asp Lys Ala Leu Leu Gln Met Val Glu Ala Ala Gly Ala Ala Glu Asp

660 665 670

Asp Pro Leu Arg Arg Thr Gly Arg Pro Phe Gly Gly Leu Ile Arg Asp

675 680 685

Val Arg Arg Arg Tyr Pro His Tyr Leu Ser Asp Phe Arg Asp Ala Leu

690 695 700

Asp Pro Gln Cys Leu Ala Ala Val Ile Phe Ile Tyr Phe Ala Ala Leu

705 710 715 720

Ser Pro Ala Ile Thr Phe Gly Gly Leu Leu Gly Glu Lys Thr Gln Asp

725 730 735

Leu Ile Gly Val Ser Glu Leu Ile Met Ser Thr Ala Leu Gln Gly Val

740 745 750

Val Phe Cys Leu Leu Gly Ala Gln Pro Leu Leu Val Ile Gly Phe Ser

755 760 765

Gly Pro Leu Leu Val Phe Glu Glu Ala Phe Phe Ser Phe Cys Ser Ser

770 775 780

Asn His Leu Glu Tyr Leu Val Gly Arg Val Trp Ile Gly Phe Trp Leu

785 790 795 800

Val Phe Leu Ala Leu Leu Met Val Ala Leu Glu Gly Ser Phe Leu Val

805 810 815

Arg Phe Val Ser Arg Phe Thr Gln Glu Ile Phe Ala Phe Leu Ile Ser

820 825 830

Leu Ile Phe Ile Tyr Glu Thr Phe Tyr Lys Leu Val Lys Ile Phe Gln

835 840 845

Glu His Pro Leu His Gly Cys Ser Ala Ser Asn Ser Ser Glu Val Asp

850 855 860

Gly Gly Glu Asn Met Thr Trp Ala Gly Ala Arg Pro Thr Leu Gly Pro

865 870 875 880

Gly Asn Arg Ser Leu Ala Gly Gln Ser Gly Gln Gly Lys Pro Arg Gly

885 890 895

Gln Pro Asn Thr Ala Leu Leu Ser Leu Val Leu Met Ala Gly Thr Phe

900 905 910

Phe Ile Ala Phe Phe Leu Arg Lys Phe Lys Asn Ser Arg Phe Phe Pro

915 920 925

Gly Arg Ile Arg Arg Val Ile Gly Asp Phe Gly Val Pro Ile Ala Ile

930 935 940

Leu Ile Met Val Leu Val Asp Tyr Ser Ile Glu Asp Thr Tyr Thr Gln

945 950 955 960

Lys Leu Ser Val Pro Ser Gly Phe Ser Val Thr Ala Pro Glu Lys Arg

965 970 975

Gly Trp Val Ile Asn Pro Leu Gly Glu Lys Ser Pro Phe Pro Val Trp

980 985 990

Met Met Val Ala Ser Leu Leu Pro Ala Ile Leu Val Phe Ile Leu Ile

995 1000 1005

Phe Met Glu Thr Gln Ile Thr Thr Leu Ile Ile Ser Lys Lys Glu

1010 1015 1020

Arg Met Leu Gln Lys Gly Ser Gly Phe His Leu Asp Leu Leu Leu

1025 1030 1035

Ile Val Ala Met Gly Gly Ile Cys Ala Leu Phe Gly Leu Pro Trp

1040 1045 1050

Leu Ala Ala Ala Thr Val Arg Ser Val Thr His Ala Asn Ala Leu

1055 1060 1065

Thr Val Met Ser Lys Ala Val Ala Pro Gly Asp Lys Pro Lys Ile

1070 1075 1080

Gln Glu Val Lys Glu Gln Arg Val Thr Gly Leu Leu Val Ala Leu

1085 1090 1095

Leu Val Gly Leu Ser Ile Val Ile Gly Asp Leu Leu Arg Gln Ile

1100 1105 1110

Pro Leu Ala Val Leu Phe Gly Ile Phe Leu Tyr Met Gly Val Thr

1115 1120 1125

Ser Leu Asn Gly Ile Gln Phe Tyr Glu Arg Leu His Leu Leu Leu

1130 1135 1140

Met Pro Pro Lys His His Pro Asp Val Thr Tyr Val Lys Lys Val

1145 1150 1155

Arg Thr Leu Arg Met His Leu Phe Thr Ala Leu Gln Leu Leu Cys

1160 1165 1170

Leu Ala Leu Leu Trp Ala Val Met Ser Thr Ala Ala Ser Leu Ala

1175 1180 1185

Phe Pro Phe Ile Leu Ile Leu Thr Val Pro Leu Arg Met Val Val

1190 1195 1200

Leu Thr Arg Ile Phe Thr Asp Arg Glu Met Lys Cys Leu Asp Ala

1205 1210 1215

Asn Glu Ala Glu Pro Val Phe Asp Glu Arg Glu Gly Val Asp Glu

1220 1225 1230

Tyr Asn Glu Met Pro Met Pro Val

1235 1240

<210> 26

<211> 707

<212> PRT

<213> 智人

<400> 26

Met Ala Ala Ala Val Ala Ala Ala Gly Arg Leu Gly Trp Leu Phe Ala

1 5 10 15

Ala Leu Cys Leu Gly Asn Ala Ala Gly Glu Ala Ala Pro Gly Pro Arg

20 25 30

Val Leu Gly Phe Cys Leu Glu Glu Asp Gly Ala Ala Gly Ala Gly Trp

35 40 45

Val Arg Gly Gly Ala Ala Arg Asp Thr Pro Asp Ala Thr Phe Leu Leu

50 55 60

Arg Leu Phe Gly Pro Gly Phe Ala Asn Ser Ser Trp Ser Trp Val Ala

65 70 75 80

Pro Glu Gly Ala Gly Cys Arg Glu Glu Ala Ala Ser Pro Ala Gly Glu

85 90 95

Trp Arg Ala Leu Leu Arg Leu Arg Leu Arg Ala Glu Ala Val Arg Pro

100 105 110

His Ser Ala Leu Leu Ala Val Arg Val Glu Pro Gly Gly Gly Ala Ala

115 120 125

Glu Glu Ala Ala Pro Pro Trp Ala Leu Gly Leu Gly Ala Ala Gly Leu

130 135 140

Leu Ala Leu Ala Ala Leu Ala Arg Gly Leu Gln Leu Ser Ala Leu Ala

145 150 155 160

Leu Ala Pro Ala Glu Val Gln Val Leu Arg Glu Ser Gly Ser Glu Ala

165 170 175

Glu Arg Ala Ala Ala Arg Arg Leu Glu Pro Ala Arg Arg Trp Ala Gly

180 185 190

Cys Ala Leu Gly Ala Leu Leu Leu Leu Ala Ser Leu Ala Gln Ala Ala

195 200 205

Leu Ala Val Leu Leu Tyr Arg Ala Ala Gly Gln Arg Ala Val Pro Ala

210 215 220

Val Leu Gly Ser Ala Gly Leu Val Phe Leu Val Gly Glu Val Val Pro

225 230 235 240

Ala Ala Val Ser Gly Arg Trp Thr Leu Ala Leu Ala Pro Arg Ala Leu

245 250 255

Gly Leu Ser Arg Leu Ala Val Leu Leu Thr Leu Pro Val Ala Leu Pro

260 265 270

Val Gly Gln Leu Leu Glu Leu Ala Ala Arg Pro Gly Arg Leu Arg Glu

275 280 285

Arg Val Leu Glu Leu Ala Arg Gly Gly Gly Asp Pro Tyr Ser Asp Leu

290 295 300

Ser Lys Gly Val Leu Arg Cys Arg Thr Val Glu Asp Val Leu Thr Pro

305 310 315 320

Leu Glu Asp Cys Phe Met Leu Asp Ala Ser Thr Val Leu Asp Phe Gly

325 330 335

Val Leu Ala Ser Ile Met Gln Ser Gly His Thr Arg Ile Pro Val Tyr

340 345 350

Glu Glu Glu Arg Ser Asn Ile Val Asp Met Leu Tyr Leu Lys Asp Leu

355 360 365

Ala Phe Val Asp Pro Glu Asp Cys Thr Pro Leu Ser Thr Ile Thr Arg

370 375 380

Phe Tyr Asn His Pro Leu His Phe Val Phe Asn Asp Thr Lys Leu Asp

385 390 395 400

Ala Val Leu Glu Glu Phe Lys Arg Gly Lys Ser His Leu Ala Ile Val

405 410 415

Gln Lys Val Asn Asn Glu Gly Glu Gly Asp Pro Phe Tyr Glu Val Leu

420 425 430

Gly Leu Val Thr Leu Glu Asp Val Ile Glu Glu Ile Ile Arg Ser Glu

435 440 445

Ile Leu Asp Glu Ser Glu Asp Tyr Arg Asp Thr Val Val Lys Arg Lys

450 455 460

Pro Ala Ser Leu Met Ala Pro Leu Lys Arg Lys Glu Glu Phe Ser Leu

465 470 475 480

Phe Lys Val Ser Asp Asp Glu Tyr Lys Val Thr Ile Ser Pro Gln Leu

485 490 495

Leu Leu Ala Thr Gln Arg Phe Leu Ser Arg Glu Val Asp Val Phe Ser

500 505 510

Pro Leu Arg Ile Ser Glu Lys Val Leu Leu His Leu Leu Lys His Pro

515 520 525

Ser Val Asn Gln Glu Val Arg Phe Asp Glu Ser Asn Arg Leu Ala Thr

530 535 540

His His Tyr Leu Tyr Gln Arg Ser Gln Pro Val Asp Tyr Phe Ile Leu

545 550 555 560

Ile Leu Gln Gly Arg Val Glu Val Glu Ile Gly Lys Glu Gly Leu Lys

565 570 575

Phe Glu Asn Gly Ala Phe Thr Tyr Tyr Gly Val Ser Ala Leu Thr Val

580 585 590

Pro Ser Ser Val His Gln Ser Pro Val Ser Ser Leu Gln Pro Ile Arg

595 600 605

His Asp Leu Gln Pro Asp Pro Gly Asp Gly Thr His Ser Ser Ala Tyr

610 615 620

Cys Pro Asp Tyr Thr Val Arg Ala Leu Ser Asp Leu Gln Leu Ile Lys

625 630 635 640

Val Thr Arg Leu Gln Tyr Leu Asn Ala Leu Leu Ala Thr Arg Ala Gln

645 650 655

Asn Leu Pro Gln Ser Pro Glu Asn Thr Asp Leu Gln Val Ile Pro Gly

660 665 670

Ser Gln Thr Arg Leu Leu Gly Glu Lys Thr Thr Thr Ala Ala Gly Ser

675 680 685

Ser His Ser Arg Pro Gly Val Pro Val Glu Gly Ser Pro Gly Arg Asn

690 695 700

Pro Gly Val

705

<210> 27

<211> 501

<212> PRT

<213> 智人

<400> 27

Met Val Arg Lys Pro Val Val Ser Thr Ile Ser Lys Gly Gly Tyr Leu

1 5 10 15

Gln Gly Asn Val Asn Gly Arg Leu Pro Ser Leu Gly Asn Lys Glu Pro

20 25 30

Pro Gly Gln Glu Lys Val Gln Leu Lys Arg Lys Val Thr Leu Leu Arg

35 40 45

Gly Val Ser Ile Ile Ile Gly Thr Ile Ile Gly Ala Gly Ile Phe Ile

50 55 60

Ser Pro Lys Gly Val Leu Gln Asn Thr Gly Ser Val Gly Met Ser Leu

65 70 75 80

Thr Ile Trp Thr Val Cys Gly Val Leu Ser Leu Phe Gly Ala Leu Ser

85 90 95

Tyr Ala Glu Leu Gly Thr Thr Ile Lys Lys Ser Gly Gly His Tyr Thr

100 105 110

Tyr Ile Leu Glu Val Phe Gly Pro Leu Pro Ala Phe Val Arg Val Trp

115 120 125

Val Glu Leu Leu Ile Ile Arg Pro Ala Ala Thr Ala Val Ile Ser Leu

130 135 140

Ala Phe Gly Arg Tyr Ile Leu Glu Pro Phe Phe Ile Gln Cys Glu Ile

145 150 155 160

Pro Glu Leu Ala Ile Lys Leu Ile Thr Ala Val Gly Ile Thr Val Val

165 170 175

Met Val Leu Asn Ser Met Ser Val Ser Trp Ser Ala Arg Ile Gln Ile

180 185 190

Phe Leu Thr Phe Cys Lys Leu Thr Ala Ile Leu Ile Ile Ile Val Pro

195 200 205

Gly Val Met Gln Leu Ile Lys Gly Gln Thr Gln Asn Phe Lys Asp Ala

210 215 220

Phe Ser Gly Arg Asp Ser Ser Ile Thr Arg Leu Pro Leu Ala Phe Tyr

225 230 235 240

Tyr Gly Met Tyr Ala Tyr Ala Gly Trp Phe Tyr Leu Asn Phe Val Thr

245 250 255

Glu Glu Val Glu Asn Pro Glu Lys Thr Ile Pro Leu Ala Ile Cys Ile

260 265 270

Ser Met Ala Ile Val Thr Ile Gly Tyr Val Leu Thr Asn Val Ala Tyr

275 280 285

Phe Thr Thr Ile Asn Ala Glu Glu Leu Leu Leu Ser Asn Ala Val Ala

290 295 300

Val Thr Phe Ser Glu Arg Leu Leu Gly Asn Phe Ser Leu Ala Val Pro

305 310 315 320

Ile Phe Val Ala Leu Ser Cys Phe Gly Ser Met Asn Gly Gly Val Phe

325 330 335

Ala Val Ser Arg Leu Phe Tyr Val Ala Ser Arg Glu Gly His Leu Pro

340 345 350

Glu Ile Leu Ser Met Ile His Val Arg Lys His Thr Pro Leu Pro Ala

355 360 365

Val Ile Val Leu His Pro Leu Thr Met Ile Met Leu Phe Ser Gly Asp

370 375 380

Leu Asp Ser Leu Leu Asn Phe Leu Ser Phe Ala Arg Trp Leu Phe Ile

385 390 395 400

Gly Leu Ala Val Ala Gly Leu Ile Tyr Leu Arg Tyr Lys Cys Pro Asp

405 410 415

Met His Arg Pro Phe Lys Val Pro Leu Phe Ile Pro Ala Leu Phe Ser

420 425 430

Phe Thr Cys Leu Phe Met Val Ala Leu Ser Leu Tyr Ser Asp Pro Phe

435 440 445

Ser Thr Gly Ile Gly Phe Val Ile Thr Leu Thr Gly Val Pro Ala Tyr

450 455 460

Tyr Leu Phe Ile Ile Trp Asp Lys Lys Pro Arg Trp Phe Arg Ile Met

465 470 475 480

Ser Glu Lys Ile Thr Arg Thr Leu Gln Ile Ile Leu Glu Val Val Pro

485 490 495

Glu Glu Asp Lys Leu

500

<210> 28

<211> 905

<212> PRT

<213> 智人

<400> 28

Met Asp Ser Thr Ala Cys Leu Lys Ser Leu Leu Leu Thr Val Ser Gln

1 5 10 15

Tyr Lys Ala Val Lys Ser Glu Ala Asn Ala Thr Gln Leu Leu Arg His

20 25 30

Leu Glu Val Ile Ser Gly Gln Lys Leu Thr Arg Leu Phe Thr Ser Asn

35 40 45

Gln Ile Leu Thr Ser Glu Cys Leu Ser Cys Leu Val Glu Leu Leu Glu

50 55 60

Asp Pro Asn Ile Ser Ala Ser Leu Ile Leu Ser Ile Ile Gly Leu Leu

65 70 75 80

Ser Gln Leu Ala Val Asp Ile Glu Thr Arg Asp Cys Leu Gln Asn Thr

85 90 95

Tyr Asn Leu Asn Ser Val Leu Ala Gly Val Val Cys Arg Ser Ser His

100 105 110

Thr Asp Ser Val Phe Leu Gln Cys Ile Gln Leu Leu Gln Lys Leu Thr

115 120 125

Tyr Asn Val Lys Ile Phe Tyr Ser Gly Ala Asn Ile Asp Glu Leu Ile

130 135 140

Thr Phe Leu Ile Asp His Ile Gln Ser Ser Glu Asp Glu Leu Lys Met

145 150 155 160

Pro Cys Leu Gly Leu Leu Ala Asn Leu Cys Arg His Asn Leu Ser Val

165 170 175

Gln Thr His Ile Lys Thr Leu Ser Asn Val Lys Ser Phe Tyr Arg Thr

180 185 190

Leu Ile Thr Leu Leu Ala His Ser Ser Leu Thr Val Val Val Phe Ala

195 200 205

Leu Ser Ile Leu Ser Ser Leu Thr Leu Asn Glu Glu Val Gly Glu Lys

210 215 220

Leu Phe His Ala Arg Asn Ile His Gln Thr Phe Gln Leu Ile Phe Asn

225 230 235 240

Ile Leu Ile Asn Gly Asp Gly Thr Leu Thr Arg Lys Tyr Ser Val Asp

245 250 255

Leu Leu Met Asp Leu Leu Lys Asn Pro Lys Ile Ala Asp Tyr Leu Thr

260 265 270

Arg Tyr Glu His Phe Ser Ser Cys Leu His Gln Val Leu Gly Leu Leu

275 280 285

Asn Gly Lys Asp Pro Asp Ser Ser Ser Lys Val Leu Glu Leu Leu Leu

290 295 300

Ala Phe Cys Ser Val Thr Gln Leu Arg His Met Leu Thr Gln Met Met

305 310 315 320

Phe Glu Gln Ser Pro Pro Gly Ser Ala Thr Leu Gly Ser His Thr Lys

325 330 335

Cys Leu Glu Pro Thr Val Ala Leu Leu Arg Trp Leu Ser Gln Pro Leu

340 345 350

Asp Gly Ser Glu Asn Cys Ser Val Leu Ala Leu Glu Leu Phe Lys Glu

355 360 365

Ile Phe Glu Asp Val Ile Asp Ala Ala Asn Cys Ser Ser Ala Asp Arg

370 375 380

Phe Val Thr Leu Leu Leu Pro Thr Ile Leu Asp Gln Leu Gln Phe Thr

385 390 395 400

Glu Gln Asn Leu Asp Glu Ala Leu Thr Arg Lys Lys Cys Glu Arg Ile

405 410 415

Ala Lys Ala Ile Glu Val Leu Leu Thr Leu Cys Gly Asp Asp Thr Leu

420 425 430

Lys Met His Ile Ala Lys Ile Leu Thr Thr Val Lys Cys Thr Thr Leu

435 440 445

Ile Glu Gln Gln Phe Thr Tyr Gly Lys Ile Asp Leu Gly Phe Gly Thr

450 455 460

Lys Val Ala Asp Ser Glu Leu Cys Lys Leu Ala Ala Asp Val Ile Leu

465 470 475 480

Lys Thr Leu Asp Leu Ile Asn Lys Leu Lys Pro Leu Val Pro Gly Met

485 490 495

Glu Val Ser Phe Tyr Lys Ile Leu Gln Asp Pro Arg Leu Ile Thr Pro

500 505 510

Leu Ala Phe Ala Leu Thr Ser Asp Asn Arg Glu Gln Val Gln Ser Gly

515 520 525

Leu Arg Ile Leu Leu Glu Ala Ala Pro Leu Pro Asp Phe Pro Ala Leu

530 535 540

Val Leu Gly Glu Ser Ile Ala Ala Asn Asn Ala Tyr Arg Gln Gln Glu

545 550 555 560

Thr Glu His Ile Pro Arg Lys Met Pro Trp Gln Ser Ser Asn His Ser

565 570 575

Phe Pro Thr Ser Ile Lys Cys Leu Thr Pro His Leu Lys Asp Gly Val

580 585 590

Pro Gly Leu Asn Ile Glu Glu Leu Ile Glu Lys Leu Gln Ser Gly Met

595 600 605

Val Val Lys Asp Gln Ile Cys Asp Val Arg Ile Ser Asp Ile Met Asp

610 615 620

Val Tyr Glu Met Lys Leu Ser Thr Leu Ala Ser Lys Glu Ser Arg Leu

625 630 635 640

Gln Asp Leu Leu Glu Thr Lys Ala Leu Ala Leu Ala Gln Ala Asp Arg

645 650 655

Leu Ile Ala Gln His Arg Cys Gln Arg Thr Gln Ala Glu Thr Glu Ala

660 665 670

Arg Thr Leu Ala Ser Met Leu Arg Glu Val Glu Arg Lys Asn Glu Glu

675 680 685

Leu Ser Val Leu Leu Lys Ala Gln Gln Val Glu Ser Glu Arg Ala Gln

690 695 700

Ser Asp Ile Glu His Leu Phe Gln His Asn Arg Lys Leu Glu Ser Val

705 710 715 720

Ala Glu Glu His Glu Ile Leu Thr Lys Ser Tyr Met Glu Leu Leu Gln

725 730 735

Arg Asn Glu Ser Thr Glu Lys Lys Asn Lys Asp Leu Gln Ile Thr Cys

740 745 750

Asp Ser Leu Asn Lys Gln Ile Glu Thr Val Lys Lys Leu Asn Glu Ser

755 760 765

Leu Lys Glu Gln Asn Glu Lys Ser Ile Ala Gln Leu Ile Glu Lys Glu

770 775 780

Glu Gln Arg Lys Glu Val Gln Asn Gln Leu Val Asp Arg Glu His Lys

785 790 795 800

Leu Ala Asn Leu His Gln Lys Thr Lys Val Gln Glu Glu Lys Ile Lys

805 810 815

Thr Leu Gln Lys Glu Arg Glu Asp Lys Glu Glu Thr Ile Asp Ile Leu

820 825 830

Arg Lys Glu Leu Ser Arg Thr Glu Gln Ile Arg Lys Glu Leu Ser Ile

835 840 845

Lys Ala Ser Ser Leu Glu Val Gln Lys Ala Gln Leu Glu Gly Arg Leu

850 855 860

Glu Glu Lys Glu Ser Leu Val Lys Leu Gln Gln Glu Glu Leu Asn Lys

865 870 875 880

His Ser His Met Ile Ala Met Ile His Ser Leu Ser Gly Gly Lys Ile

885 890 895

Asn Pro Glu Thr Val Asn Leu Ser Ile

900 905

<210> 29

<211> 474

<212> PRT

<213> 智人

<400> 29

Met Glu Leu Pro Ser Gly Pro Gly Pro Glu Arg Leu Phe Asp Ser His

1 5 10 15

Arg Leu Pro Gly Asp Cys Phe Leu Leu Leu Val Leu Leu Leu Tyr Ala

20 25 30

Pro Val Gly Phe Cys Leu Leu Val Leu Arg Leu Phe Leu Gly Ile His

35 40 45

Val Phe Leu Val Ser Cys Ala Leu Pro Asp Ser Val Leu Arg Arg Phe

50 55 60

Val Val Arg Thr Met Cys Ala Val Leu Gly Leu Val Ala Arg Gln Glu

65 70 75 80

Asp Ser Gly Leu Arg Asp His Ser Val Arg Val Leu Ile Ser Asn His

85 90 95

Val Thr Pro Phe Asp His Asn Ile Val Asn Leu Leu Thr Thr Cys Ser

100 105 110

Thr Val Ser Glu Ser Glu Ala Glu Ser Ala Thr Gly Arg Phe Pro Gly

115 120 125

Ala Gln Leu Lys Ala Pro Leu Ser Pro Leu Ala Phe Pro Met Glu Asp

130 135 140

Thr Glu Leu Pro Leu Thr Pro Ile Leu Tyr Pro Thr Cys Gln Phe Phe

145 150 155 160

Phe Ile Phe Leu Asn Ile Phe Leu Leu Ala Phe Ser Ser Pro Gly Ser

165 170 175

Gln Pro Leu Leu Asn Ser Pro Pro Ser Phe Val Cys Trp Ser Arg Gly

180 185 190

Phe Met Glu Met Asn Gly Arg Gly Glu Leu Val Glu Ser Leu Lys Arg

195 200 205

Phe Cys Ala Ser Thr Arg Leu Pro Pro Thr Pro Leu Leu Leu Phe Pro

210 215 220

Glu Glu Glu Ala Thr Asn Gly Arg Glu Gly Leu Leu Arg Phe Ser Ser

225 230 235 240

Trp Pro Phe Ser Ile Gln Asp Val Val Gln Pro Leu Thr Leu Gln Val

245 250 255

Gln Arg Pro Leu Val Ser Val Thr Val Ser Asp Ala Ser Trp Val Ser

260 265 270

Glu Leu Leu Trp Ser Leu Phe Val Pro Phe Thr Val Tyr Gln Val Arg

275 280 285

Trp Leu Arg Pro Val His Arg Gln Leu Gly Glu Ala Asn Glu Glu Phe

290 295 300

Ala Leu Arg Val Gln Gln Leu Val Ala Lys Glu Leu Gly Gln Thr Gly

305 310 315 320

Thr Arg Leu Thr Pro Ala Asp Lys Ala Glu His Met Lys Arg Gln Arg

325 330 335

His Pro Arg Leu Arg Pro Gln Ser Ala Gln Ser Ser Phe Pro Pro Ser

340 345 350

Pro Gly Pro Ser Pro Asp Val Gln Leu Ala Thr Leu Ala Gln Arg Val

355 360 365

Lys Glu Val Leu Pro His Val Pro Leu Gly Val Ile Gln Arg Asp Leu

370 375 380

Ala Lys Thr Gly Cys Val Asp Leu Thr Ile Thr Asn Leu Leu Glu Gly

385 390 395 400

Ala Val Ala Phe Met Pro Glu Asp Ile Thr Lys Gly Thr Gln Ser Leu

405 410 415

Pro Thr Ala Ser Ala Ser Lys Phe Pro Ser Ser Gly Pro Val Thr Pro

420 425 430

Gln Pro Thr Ala Leu Thr Phe Ala Lys Ser Ser Trp Ala Arg Gln Glu

435 440 445

Ser Leu Gln Glu Arg Lys Gln Ala Leu Tyr Glu Tyr Ala Arg Arg Arg

450 455 460

Phe Thr Glu Arg Arg Ala Gln Glu Ala Asp

465 470

<210> 30

<211> 532

<212> PRT

<213> 智人

<400> 30

Met Glu Lys Ser Asn Glu Thr Asn Gly Tyr Leu Asp Ser Ala Gln Ala

1 5 10 15

Gly Pro Ala Ala Gly Pro Gly Ala Pro Gly Thr Ala Ala Gly Arg Ala

20 25 30

Arg Arg Cys Ala Gly Phe Leu Arg Arg Gln Ala Leu Val Leu Leu Thr

35 40 45

Val Ser Gly Val Leu Ala Gly Ala Gly Leu Gly Ala Ala Leu Arg Gly

50 55 60

Leu Ser Leu Ser Arg Thr Gln Val Thr Tyr Leu Ala Phe Pro Gly Glu

65 70 75 80

Met Leu Leu Arg Met Leu Arg Met Ile Ile Leu Pro Leu Val Val Cys

85 90 95

Ser Leu Val Ser Gly Ala Ala Ser Leu Asp Ala Ser Cys Leu Gly Arg

100 105 110

Leu Gly Gly Ile Ala Val Ala Tyr Phe Gly Leu Thr Thr Leu Ser Ala

115 120 125

Ser Ala Leu Ala Val Ala Leu Ala Phe Ile Ile Lys Pro Gly Ser Gly

130 135 140

Ala Gln Thr Leu Gln Ser Ser Asp Leu Gly Leu Glu Asp Ser Gly Pro

145 150 155 160

Pro Pro Val Pro Lys Glu Thr Val Asp Ser Phe Leu Asp Leu Ala Arg

165 170 175

Asn Leu Phe Pro Ser Asn Leu Val Val Ala Ala Phe Arg Thr Tyr Ala

180 185 190

Thr Asp Tyr Lys Val Val Thr Gln Asn Ser Ser Ser Gly Asn Val Thr

195 200 205

His Glu Lys Ile Pro Ile Gly Thr Glu Ile Glu Gly Met Asn Ile Leu

210 215 220

Gly Leu Val Leu Phe Ala Leu Val Leu Gly Val Ala Leu Lys Lys Leu

225 230 235 240

Gly Ser Glu Gly Glu Asp Leu Ile Arg Phe Phe Asn Ser Leu Asn Glu

245 250 255

Ala Thr Met Val Leu Val Ser Trp Ile Met Trp Tyr Val Pro Val Gly

260 265 270

Ile Met Phe Leu Val Gly Ser Lys Ile Val Glu Met Lys Asp Ile Ile

275 280 285

Val Leu Val Thr Ser Leu Gly Lys Tyr Ile Phe Ala Ser Ile Leu Gly

290 295 300

His Val Ile His Gly Gly Ile Val Leu Pro Leu Ile Tyr Phe Val Phe

305 310 315 320

Thr Arg Lys Asn Pro Phe Arg Phe Leu Leu Gly Leu Leu Ala Pro Phe

325 330 335

Ala Thr Ala Phe Ala Thr Cys Ser Ser Ser Ala Thr Leu Pro Ser Met

340 345 350

Met Lys Cys Ile Glu Glu Asn Asn Gly Val Asp Lys Arg Ile Ser Arg

355 360 365

Phe Ile Leu Pro Ile Gly Ala Thr Val Asn Met Asp Gly Ala Ala Ile

370 375 380

Phe Gln Cys Val Ala Ala Val Phe Ile Ala Gln Leu Asn Asn Val Glu

385 390 395 400

Leu Asn Ala Gly Gln Ile Phe Thr Ile Leu Val Thr Ala Thr Ala Ser

405 410 415

Ser Val Gly Ala Ala Gly Val Pro Ala Gly Gly Val Leu Thr Ile Ala

420 425 430

Ile Ile Leu Glu Ala Ile Gly Leu Pro Thr His Asp Leu Pro Leu Ile

435 440 445

Leu Ala Val Asp Trp Ile Val Asp Arg Thr Thr Thr Val Val Asn Val

450 455 460

Glu Gly Asp Ala Leu Gly Ala Gly Ile Leu His His Leu Asn Gln Lys

465 470 475 480

Ala Thr Lys Lys Gly Glu Gln Glu Leu Ala Glu Val Lys Val Glu Ala

485 490 495

Ile Pro Asn Cys Lys Ser Glu Glu Glu Thr Ser Pro Leu Val Thr His

500 505 510

Gln Asn Pro Ala Gly Pro Val Ala Ser Ala Pro Glu Leu Glu Ser Lys

515 520 525

Glu Ser Val Leu

530

<210> 31

<211> 910

<212> PRT

<213> 智人

<400> 31

Met Lys Lys Met Ser Arg Asn Val Leu Leu Gln Met Glu Glu Glu Glu

1 5 10 15

Asp Asp Asp Asp Gly Asp Ile Val Leu Glu Asn Leu Gly Gln Thr Ile

20 25 30

Val Pro Asp Leu Gly Ser Leu Glu Ser Gln His Asp Phe Arg Thr Pro

35 40 45

Glu Phe Glu Glu Phe Asn Gly Lys Pro Asp Ser Leu Phe Phe Asn Asp

50 55 60

Gly Gln Arg Arg Ile Asp Phe Val Leu Val Tyr Glu Asp Glu Ser Arg

65 70 75 80

Lys Glu Thr Asn Lys Lys Gly Thr Asn Glu Lys Gln Arg Arg Lys Arg

85 90 95

Gln Ala Tyr Glu Ser Asn Leu Ile Cys His Gly Leu Gln Leu Glu Ala

100 105 110

Thr Arg Ser Val Leu Asp Asp Lys Leu Val Phe Val Lys Val His Ala

115 120 125

Pro Trp Glu Val Leu Cys Thr Tyr Ala Glu Ile Met His Ile Lys Leu

130 135 140

Pro Leu Lys Pro Asn Asp Leu Lys Asn Arg Ser Ser Ala Phe Gly Thr

145 150 155 160

Leu Asn Trp Phe Thr Lys Val Leu Ser Val Asp Glu Ser Ile Ile Lys

165 170 175

Pro Glu Gln Glu Phe Phe Thr Ala Pro Phe Glu Lys Asn Arg Met Asn

180 185 190

Asp Phe Tyr Ile Val Asp Arg Asp Ala Phe Phe Asn Pro Ala Thr Arg

195 200 205

Ser Arg Ile Val Tyr Phe Ile Leu Ser Arg Val Lys Tyr Gln Val Ile

210 215 220

Asn Asn Val Ser Lys Phe Gly Ile Asn Arg Leu Val Asn Ser Gly Ile

225 230 235 240

Tyr Lys Ala Ala Phe Pro Leu His Asp Cys Lys Phe Arg Arg Gln Ser

245 250 255

Glu Asp Pro Ser Cys Pro Asn Glu Arg Tyr Leu Leu Tyr Arg Glu Trp

260 265 270

Ala His Pro Arg Ser Ile Tyr Lys Lys Gln Pro Leu Asp Leu Ile Arg

275 280 285

Lys Tyr Tyr Gly Glu Lys Ile Gly Ile Tyr Phe Ala Trp Leu Gly Tyr

290 295 300

Tyr Thr Gln Met Leu Leu Leu Ala Ala Val Val Gly Val Ala Cys Phe

305 310 315 320

Leu Tyr Gly Tyr Leu Asn Gln Asp Asn Cys Thr Trp Ser Lys Glu Val

325 330 335

Cys His Pro Asp Ile Gly Gly Lys Ile Ile Met Cys Pro Gln Cys Asp

340 345 350

Arg Leu Cys Pro Phe Trp Lys Leu Asn Ile Thr Cys Glu Ser Ser Lys

355 360 365

Lys Leu Cys Ile Phe Asp Ser Phe Gly Thr Leu Val Phe Ala Val Phe

370 375 380

Met Gly Val Trp Val Thr Leu Phe Leu Glu Phe Trp Lys Arg Arg Gln

385 390 395 400

Ala Glu Leu Glu Tyr Glu Trp Asp Thr Val Glu Leu Gln Gln Glu Glu

405 410 415

Gln Ala Arg Pro Glu Tyr Glu Ala Arg Cys Thr His Val Val Ile Asn

420 425 430

Glu Ile Thr Gln Glu Glu Glu Arg Ile Pro Phe Thr Ala Trp Gly Lys

435 440 445

Cys Ile Arg Ile Thr Leu Cys Ala Ser Ala Val Phe Phe Trp Ile Leu

450 455 460

Leu Ile Ile Ala Ser Val Ile Gly Ile Ile Val Tyr Arg Leu Ser Val

465 470 475 480

Phe Ile Val Phe Ser Ala Lys Leu Pro Lys Asn Ile Asn Gly Thr Asp

485 490 495

Pro Ile Gln Lys Tyr Leu Thr Pro Gln Thr Ala Thr Ser Ile Thr Ala

500 505 510

Ser Ile Ile Ser Phe Ile Ile Ile Met Ile Leu Asn Thr Ile Tyr Glu

515 520 525

Lys Val Ala Ile Met Ile Thr Asn Phe Glu Leu Pro Arg Thr Gln Thr

530 535 540

Asp Tyr Glu Asn Ser Leu Thr Met Lys Met Phe Leu Phe Gln Phe Val

545 550 555 560

Asn Tyr Tyr Ser Ser Cys Phe Tyr Ile Ala Phe Phe Lys Gly Lys Phe

565 570 575

Val Gly Tyr Pro Gly Asp Pro Val Tyr Trp Leu Gly Lys Tyr Arg Asn

580 585 590

Glu Glu Cys Asp Pro Gly Gly Cys Leu Leu Glu Leu Thr Thr Gln Leu

595 600 605

Thr Ile Ile Met Gly Gly Lys Ala Ile Trp Asn Asn Ile Gln Glu Val

610 615 620

Leu Leu Pro Trp Ile Met Asn Leu Ile Gly Arg Phe His Arg Val Ser

625 630 635 640

Gly Ser Glu Lys Ile Thr Pro Arg Trp Glu Gln Asp Tyr His Leu Gln

645 650 655

Pro Met Gly Lys Leu Gly Leu Phe Tyr Glu Tyr Leu Glu Met Ile Ile

660 665 670

Gln Phe Gly Phe Val Thr Leu Phe Val Ala Ser Phe Pro Leu Ala Pro

675 680 685

Leu Leu Ala Leu Val Asn Asn Ile Leu Glu Ile Arg Val Asp Ala Trp

690 695 700

Lys Leu Thr Thr Gln Phe Arg Arg Leu Val Pro Glu Lys Ala Gln Asp

705 710 715 720

Ile Gly Ala Trp Gln Pro Ile Met Gln Gly Ile Ala Ile Leu Ala Val

725 730 735

Val Thr Asn Ala Met Ile Ile Ala Phe Thr Ser Asp Met Ile Pro Arg

740 745 750

Leu Val Tyr Tyr Trp Ser Phe Ser Val Pro Pro Tyr Gly Asp His Thr

755 760 765

Ser Tyr Thr Met Glu Gly Tyr Ile Asn Asn Thr Leu Ser Ile Phe Lys

770 775 780

Val Ala Asp Phe Lys Asn Lys Ser Lys Gly Asn Pro Tyr Ser Asp Leu

785 790 795 800

Gly Asn His Thr Thr Cys Arg Tyr Arg Asp Phe Arg Tyr Pro Pro Gly

805 810 815

His Pro Gln Glu Tyr Lys His Asn Ile Tyr Tyr Trp His Val Ile Ala

820 825 830

Ala Lys Leu Ala Phe Ile Ile Val Met Glu His Val Ile Tyr Ser Val

835 840 845

Lys Phe Phe Ile Ser Tyr Ala Ile Pro Asp Val Ser Lys Arg Thr Lys

850 855 860

Ser Lys Ile Gln Arg Glu Lys Tyr Leu Thr Gln Lys Leu Leu His Glu

865 870 875 880

Asn His Leu Lys Asp Met Thr Lys Asn Met Gly Val Ile Ala Glu Arg

885 890 895

Met Ile Glu Ala Val Asp Asn Asn Leu Arg Pro Lys Ser Glu

900 905 910

<210> 32

<211> 879

<212> PRT

<213> 智人

<400> 32

Met Gly Arg Leu Ala Ser Arg Pro Leu Leu Leu Ala Leu Leu Ser Leu

1 5 10 15

Ala Leu Cys Arg Gly Arg Val Val Arg Val Pro Thr Ala Thr Leu Val

20 25 30

Arg Val Val Gly Thr Glu Leu Val Ile Pro Cys Asn Val Ser Asp Tyr

35 40 45

Asp Gly Pro Ser Glu Gln Asn Phe Asp Trp Ser Phe Ser Ser Leu Gly

50 55 60

Ser Ser Phe Val Glu Leu Ala Ser Thr Trp Glu Val Gly Phe Pro Ala

65 70 75 80

Gln Leu Tyr Gln Glu Arg Leu Gln Arg Gly Glu Ile Leu Leu Arg Arg

85 90 95

Thr Ala Asn Asp Ala Val Glu Leu His Ile Lys Asn Val Gln Pro Ser

100 105 110

Asp Gln Gly His Tyr Lys Cys Ser Thr Pro Ser Thr Asp Ala Thr Val

115 120 125

Gln Gly Asn Tyr Glu Asp Thr Val Gln Val Lys Val Leu Ala Asp Ser

130 135 140

Leu His Val Gly Pro Ser Ala Arg Pro Pro Pro Ser Leu Ser Leu Arg

145 150 155 160

Glu Gly Glu Pro Phe Glu Leu Arg Cys Thr Ala Ala Ser Ala Ser Pro

165 170 175

Leu His Thr His Leu Ala Leu Leu Trp Glu Val His Arg Gly Pro Ala

180 185 190

Arg Arg Ser Val Leu Ala Leu Thr His Glu Gly Arg Phe His Pro Gly

195 200 205

Leu Gly Tyr Glu Gln Arg Tyr His Ser Gly Asp Val Arg Leu Asp Thr

210 215 220

Val Gly Ser Asp Ala Tyr Arg Leu Ser Val Ser Arg Ala Leu Ser Ala

225 230 235 240

Asp Gln Gly Ser Tyr Arg Cys Ile Val Ser Glu Trp Ile Ala Glu Gln

245 250 255

Gly Asn Trp Gln Glu Ile Gln Glu Lys Ala Val Glu Val Ala Thr Val

260 265 270

Val Ile Gln Pro Ser Val Leu Arg Ala Ala Val Pro Lys Asn Val Ser

275 280 285

Val Ala Glu Gly Lys Glu Leu Asp Leu Thr Cys Asn Ile Thr Thr Asp

290 295 300

Arg Ala Asp Asp Val Arg Pro Glu Val Thr Trp Ser Phe Ser Arg Met

305 310 315 320

Pro Asp Ser Thr Leu Pro Gly Ser Arg Val Leu Ala Arg Leu Asp Arg

325 330 335

Asp Ser Leu Val His Ser Ser Pro His Val Ala Leu Ser His Val Asp

340 345 350

Ala Arg Ser Tyr His Leu Leu Val Arg Asp Val Ser Lys Glu Asn Ser

355 360 365

Gly Tyr Tyr Tyr Cys His Val Ser Leu Trp Ala Pro Gly His Asn Arg

370 375 380

Ser Trp His Lys Val Ala Glu Ala Val Ser Ser Pro Ala Gly Val Gly

385 390 395 400

Val Thr Trp Leu Glu Pro Asp Tyr Gln Val Tyr Leu Asn Ala Ser Lys

405 410 415

Val Pro Gly Phe Ala Asp Asp Pro Thr Glu Leu Ala Cys Arg Val Val

420 425 430

Asp Thr Lys Ser Gly Glu Ala Asn Val Arg Phe Thr Val Ser Trp Tyr

435 440 445

Tyr Arg Met Asn Arg Arg Ser Asp Asn Val Val Thr Ser Glu Leu Leu

450 455 460

Ala Val Met Asp Gly Asp Trp Thr Leu Lys Tyr Gly Glu Arg Ser Lys

465 470 475 480

Gln Arg Ala Gln Asp Gly Asp Phe Ile Phe Ser Lys Glu His Thr Asp

485 490 495

Thr Phe Asn Phe Arg Ile Gln Arg Thr Thr Glu Glu Asp Arg Gly Asn

500 505 510

Tyr Tyr Cys Val Val Ser Ala Trp Thr Lys Gln Arg Asn Asn Ser Trp

515 520 525

Val Lys Ser Lys Asp Val Phe Ser Lys Pro Val Asn Ile Phe Trp Ala

530 535 540

Leu Glu Asp Ser Val Leu Val Val Lys Ala Arg Gln Pro Lys Pro Phe

545 550 555 560

Phe Ala Ala Gly Asn Thr Phe Glu Met Thr Cys Lys Val Ser Ser Lys

565 570 575

Asn Ile Lys Ser Pro Arg Tyr Ser Val Leu Ile Met Ala Glu Lys Pro

580 585 590

Val Gly Asp Leu Ser Ser Pro Asn Glu Thr Lys Tyr Ile Ile Ser Leu

595 600 605

Asp Gln Asp Ser Val Val Lys Leu Glu Asn Trp Thr Asp Ala Ser Arg

610 615 620

Val Asp Gly Val Val Leu Glu Lys Val Gln Glu Asp Glu Phe Arg Tyr

625 630 635 640

Arg Met Tyr Gln Thr Gln Val Ser Asp Ala Gly Leu Tyr Arg Cys Met

645 650 655

Val Thr Ala Trp Ser Pro Val Arg Gly Ser Leu Trp Arg Glu Ala Ala

660 665 670

Thr Ser Leu Ser Asn Pro Ile Glu Ile Asp Phe Gln Thr Ser Gly Pro

675 680 685

Ile Phe Asn Ala Ser Val His Ser Asp Thr Pro Ser Val Ile Arg Gly

690 695 700

Asp Leu Ile Lys Leu Phe Cys Ile Ile Thr Val Glu Gly Ala Ala Leu

705 710 715 720

Asp Pro Asp Asp Met Ala Phe Asp Val Ser Trp Phe Ala Val His Ser

725 730 735

Phe Gly Leu Asp Lys Ala Pro Val Leu Leu Ser Ser Leu Asp Arg Lys

740 745 750

Gly Ile Val Thr Thr Ser Arg Arg Asp Trp Lys Ser Asp Leu Ser Leu

755 760 765

Glu Arg Val Ser Val Leu Glu Phe Leu Leu Gln Val His Gly Ser Glu

770 775 780

Asp Gln Asp Phe Gly Asn Tyr Tyr Cys Ser Val Thr Pro Trp Val Lys

785 790 795 800

Ser Pro Thr Gly Ser Trp Gln Lys Glu Ala Glu Ile His Ser Lys Pro

805 810 815

Val Phe Ile Thr Val Lys Met Asp Val Leu Asn Ala Phe Lys Tyr Pro

820 825 830

Leu Leu Ile Gly Val Gly Leu Ser Thr Val Ile Gly Leu Leu Ser Cys

835 840 845

Leu Ile Gly Tyr Cys Ser Ser His Trp Cys Cys Lys Lys Glu Val Gln

850 855 860

Glu Thr Arg Arg Glu Arg Arg Arg Leu Met Ser Met Glu Met Asp

865 870 875

Claims (15)

1.包含由下列多肽组成的组的至少一种多肽的诊断标记:

• SEQ ID No.: 1 的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13 的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25 的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽。

2.权利要求1的诊断标记，其包含至少下列多肽：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;和/或

• SEQ ID No.: 3的多肽。

3.选自由下列多肽组成的组的至少一种多肽作为诊断标记的用途：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽。

4.权利要求3的用途，其中使用至少下列多肽:

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽; 和

• SEQ ID No.: 3的多肽。

5.任选地用于MRI 和/或 MPI的造影剂，其包括至少一种能够与选自由下列多肽组成的组的多肽相互作用的化合物：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽。

6.权利要求5的造影剂，其中所述造影剂包含至少与下列多肽相互作用的单种或复数种化合物：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽; 和

• SEQ ID No.: 3的多肽。

7.权利要求5或6的造影剂，其中所述化合物选自与SEQ ID No. 1至32的至少一种多肽特异性相互作用的抗体。

8.权利要求5至7的任一项的造影剂，其中所述化合物被偶联至可检测的标记分子。

9.至少一种能够与选自由下列多肽组成的组的多肽相互作用的抗体作为任选用于MRI 和/或 MPI的造影剂的用途：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3 的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22 的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28 的多肽;

• SEQ ID No.: 29 的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽。

10.权利要求9的用途，其中所述抗体选自与所述多肽相互作用的商购可得的抗体。

11.权利要求9或10的用途，其中所述抗体被偶联至可检测的标记分子。

12.诊断结直肠癌(CRC) 的方法，其包括至少下列步骤：

a) 从怀疑遭受正在进行或迫近的CRC发展的至少一个人或动物个体获得至少一个样品;

b) 测试所述至少一个样品中选自由下列多肽组成的组的至少一种多肽的表达

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9 的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25 的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽;

c) 测试获自未遭受正在进行或迫近的CRC发展的至少一个人或动物个体的至少一个对照样品中选自由下列多肽组成的组的至少一种多肽的表达:

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽;

d) 测定步骤b)和d)的表达的差异;

e) 基于步骤d)中获得的结果确定CRC发展的存在或迫近。

13.诊断CRC的方法，其包括至少下列步骤：

a) 测试怀疑遭受正在进行或迫近的CRC发展的至少一个人或动物个体中选自由下列多肽组成的组的至少一种多肽的表达:

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2 的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽;

b) 将步骤a)中测定的表达与如对于未遭受正在进行或迫近的结直肠癌发展的人或动物个体测定的选自由下列多肽组成的组的至少一种多肽的表达相比较:

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28 的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽;

c) 基于步骤b)中获得的结果确定CRC发展的存在或迫近。

14.数据获取的方法，其包括至少下列步骤：

a) 测试怀疑遭受正在进行或迫近的CRC发展的至少一个人或动物个体中选自由下列多肽组成的组的至少一种多肽的表达：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3 的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5的多肽;

• SEQ ID No.: 6的多肽;

• SEQ ID No.: 7 的多肽;

• SEQ ID No.: 8 的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19 的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24 的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽;

b) 将步骤a)中测定的表达与如对于未遭受正在进行或迫近的CRC发展的人或动物个体所测定的选自由下列多肽组成的组的至少一种多肽的表达相比较：

• SEQ ID No.: 1的多肽;

• SEQ ID No.: 2的多肽;

• SEQ ID No.: 3的多肽;

• SEQ ID No.: 4的多肽;

• SEQ ID No.: 5 的多肽;

• SEQ ID No.: 6 的多肽;

• SEQ ID No.: 7的多肽;

• SEQ ID No.: 8的多肽;

• SEQ ID No.: 9的多肽;

• SEQ ID No.: 10的多肽;

• SEQ ID No.: 11的多肽;

• SEQ ID No.: 12的多肽;

• SEQ ID No.: 13的多肽;

• SEQ ID No.: 14的多肽;

• SEQ ID No.: 15的多肽;

• SEQ ID No.: 16的多肽;

• SEQ ID No.: 17的多肽;

• SEQ ID No.: 18的多肽;

• SEQ ID No.: 19的多肽;

• SEQ ID No.: 20的多肽;

• SEQ ID No.: 21的多肽;

• SEQ ID No.: 22的多肽;

• SEQ ID No.: 23的多肽;

• SEQ ID No.: 24的多肽;

• SEQ ID No.: 25的多肽;

• SEQ ID No.: 26的多肽;

• SEQ ID No.: 27 的多肽;

• SEQ ID No.: 28的多肽;

• SEQ ID No.: 29的多肽;

• SEQ ID No.: 30的多肽;

• SEQ ID No.: 31的多肽; 和/或

• SEQ ID No.: 32的多肽。

15.权利要求1或2的任一项的诊断标记和/或权利要求5至8的任一项的造影剂用于区分进行性(高风险)CRC(腺癌)与非进行性(低风险)结直肠腺瘤的用途。

Images