CN110582515A - 包含cd47抗体和细胞因子的融合蛋白 - Google Patents

包含cd47抗体和细胞因子的融合蛋白 Download PDF

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CN110582515A
CN110582515A CN201980001915.5A CN201980001915A CN110582515A CN 110582515 A CN110582515 A CN 110582515A CN 201980001915 A CN201980001915 A CN 201980001915A CN 110582515 A CN110582515 A CN 110582515A
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王正毅
曹巍
方磊
郭炳诗
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Tianjing Biotechnology Shanghai Co ltd
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Abstract

本发明提供含有细胞因子和新的CD 47抗体或其免疫活性片段的融合蛋白，以及含有这种融合蛋白的药物组合物，可用于治疗由CD 47介导的疾病或抑制吞噬或血小板聚集。这些融合蛋白在人体中具有低的免疫原性，并引起低水平的或不引起红血细胞清除或血细胞凝聚。

Description

包含CD47抗体和细胞因子的融合蛋白
参考相关申请
本申请要求2018年11月12日提交的国际申请号为PCT/CN2018/114975的国际申请作为优先权，并将其全部内容并入此文本以参考。
背景技术
CD47(分化群47)在20世纪80年代首次被确定为人类卵巢癌的肿瘤抗原。此后，CD47被发现在多种人类肿瘤类型上表达，包括急性髓系白血病(AML)，慢性粒细胞白血病、急性淋巴细胞白血病(ALL)，非霍奇金淋巴瘤(NHL)，多发性骨髓瘤(MM)、膀胱癌，和其它实体肿瘤。高水平的CD47让癌细胞避免吞噬作用，尽管癌细胞表面具有更高水平的钙网蛋白-显性促吞噬信号。
CD47也称为整联蛋白相关蛋白(IAP)、卵巢癌抗原OA3、Rh-相关抗原和MER6，是一种属于免疫球蛋白超家族的多跨的跨膜受体。它的表达和活性已经与许多疾病和失调相关联。它是一种广泛表达的跨膜糖蛋白，并带有一个免疫球蛋白样结构域和五个跨膜区，其作为SIRPα的细胞配体，通过信号调节蛋白α(SIRPα)的NH2末端的V样结构域与SIRPα结合。SIRPα主要表达于骨髓细胞，包括巨噬细胞，粒细胞，树突状细胞(DCs)，肥大细胞，和它们的前体细胞，包括造血干细胞。
巨噬细胞通过吞噬作用清除来自血流中的病原体和受损或老化的细胞。细胞表面的CD47与巨噬细胞上的它的受体SIRPα结合，从而抑制巨噬细胞对正常，健康的细胞的吞噬作用。SIRPα通过巨噬细胞抑制宿主细胞的吞噬作用，其中，巨噬细胞上的SIRPα与宿主靶细胞上表达的CD47结合，产生SHP-1介导的抑制信号，该抑制信号负调节吞噬作用。
与CD47抑制正常细胞的吞噬作用一致的是，有证据表明，CD47在造血干细胞(HSC)和祖细胞在迁移期之前和期间有短暂的上调，且这些细胞上的CD47的水平决定了这些细胞被体内吞噬的概率。
CD47也在许多癌症上组成性上调，包括骨髓白血病。CD47在骨髓白血病系上的过表达通过允许它逃避吞噬作用而增加了其致病性。已经得出结论，在炎症介导的动员过程中，CD47的上调是为正常HSC提供保护的重要机制，并且白血病祖细胞选择这种能力以逃避巨噬细胞的杀伤。
某些CD47抗体已显示出可以恢复吞噬作用和防止动脉粥样硬化。请参考，例如，Kojima等，自然，卷36，86-90(2016年8月4日)。本发明提供了一种新的CD47抗体或其免疫活性片段，其在人体中具有低免疫原性，且导致低水平红细胞消耗或无红细胞清除。本领域技术人员知道，这种抗体也可以被称为“抗CD47抗体”。
细胞因子是一类广泛而松散的小蛋白质(～5-20kDa)，在细胞信号传递中起着重要的作用。它们的释放对周围细胞的行为有影响。可以说，细胞因子作为免疫调节剂参与自分泌信号、旁分泌信号和内分泌信号。他们与激素的明确区别仍然是正在进行的研究的一部分。细胞因子包括趋化因子、干扰素、白细胞介素、淋巴因子和肿瘤坏死因子，但一般不包括激素或生长因子(尽管术语上有些重叠)。细胞因子由多种细胞产生，包括巨噬细胞、B淋巴细胞、T淋巴细胞和肥大细胞等免疫细胞，以及内皮细胞、成纤维细胞和各种基质细胞；一种特定的细胞因子可能由多种细胞产生。它们通过受体发挥作用，在免疫系统中尤为重要；细胞因子调节体液和细胞免疫反应之间的平衡，并调节特定细胞群体的成熟、生长和反应性。一些细胞因子以复杂的方式增强或抑制其他细胞因子的作用。它们在健康和疾病中非常重要，特别是在宿主对感染、免疫反应、炎症、创伤、脓毒症、癌症和生殖的反应中。
粒细胞-巨噬细胞集落刺激因子(GM-CSF)是一种细胞因子，是一种公知的促进天然免疫和适应性免疫反应的免疫刺激因子，临床上用于髓系重建。它能特异性激活巨噬细胞，并能将巨噬细胞表型从M2转移到M1。
到目前为止，还没有关于CD 47抗体和细胞因子的融合蛋白的报道，甚至没有任何建议。
发明内容
一方面，本发明提供了能结合人CD47的分离的单克隆抗体及其免疫活性片段。为简洁起见，这些能结合CD47的分离的单克隆抗体及其免疫活性片段在下文中称为“CD47抗体”。本发明所述的CD47抗体能够调节，例如阻断、抑制、减少、拮抗、中和或以其它方式干扰CD47的表达、活性和/或信号转导，或CD47和SIRPα之间的相互作用。非常重要的，本发明的CD47抗体通常不引起人红血细胞的显著水平的清除或凝聚，并且令人惊讶地是，在许多情况下，根本不引起人红血细胞的清除或凝聚。另外，本发明的CD47抗体表现出有效的抗肿瘤活性。
在一些实施例中，本发明所述的CD47抗体包括(a)可变重(VH)链序列，该序列与选自包括下述序列的组中的氨基酸序列具有至少90％(例如，至少95％)的一致性：SEQ IDNO:1，SEQ ID NO:3，SEQ ID NO:5，SEQ ID NO:7，SEQ ID NO:9，SEQ ID NO:11，SEQ ID NO:13，SEQ ID NO:15，SEQ ID NO:17，SEQ ID NO:19，SEQ ID NO:21，SEQ ID NO:23，SEQ IDNO:25，SEQ ID NO:27，SEQ ID NO:29，SEQ ID NO:31，SEQ ID NO:33，SEQ ID NO:35，SEQ IDNO:37，SEQ ID NO:39，SEQ ID NO:41，SEQ ID NO:43，SEQ ID NO:45，SEQ ID NO:47，SEQ IDNO:49，SEQ ID NO:51，SEQ ID NO:53，SEQ ID NO:55，SEQ ID NO:57，SEQ ID NO:59，SEQ IDNO:61，SEQ ID NO:63，SEQ ID NO:65，SEQ ID NO:67，SEQ ID NO:69，SEQ ID NO:71，SEQ IDNO:73，SEQ ID NO:75，和SEQ ID NO:77；和(b)可变轻(VL)链序列，该序列与选自包括下述序列的组中的氨基酸序列具有至少90％(例如，至少95％)的一致性：SEQ ID NO:2，SEQ IDNO:4，SEQ ID NO:6，SEQ ID NO:8，SEQ ID NO:10，SEQ ID NO:12，SEQ ID NO:14，SEQ IDNO:16，SEQ ID NO:18，SEQ ID NO:20，SEQ ID NO:22，SEQ ID NO:24，SEQ ID NO:26，SEQ IDNO:28，SEQ ID NO:30，SEQ ID NO:32，SEQ ID NO:34，SEQ ID NO:36，SEQ ID NO:38，SEQ IDNO:40，SEQ ID NO:42，SEQ ID NO:44，SEQ ID NO:46，SEQ ID NO:48，SEQ ID NO:50，SEQ IDNO:52，SEQ ID NO:54，SEQ ID NO:56，SEQ ID NO:58，SEQ ID NO:60，SEQ ID NO:62，SEQ IDNO:64，SEQ ID NO:66，SEQ ID NO:68，SEQ ID NO:70，SEQ ID NO:72，SEQ ID NO:74，SEQ IDNO:76，和SEQ ID NO:78。
在一些其它实施例中，本发明所述的CD47抗体包括成对的VH/VL链序列，该成对序列与选自包括下述成对序列的组中的成对VH和VL氨基酸序列具有至少90％(例如，至少95％，95％，96％，97％，98％，99％，或99.5％)的一致性：SEQ ID NO:1和SEQ ID NO:2(即，1A1)，SEQ ID NO:3和SEQ ID NO:4(即，1F8)，SEQ ID NO:5和SEQ ID NO:6(即，2A11)，SEQID NO:7和SEQ ID NO:8(即，2C2)，SEQ ID NO:9和SEQ ID NO:10(即，2D7)，SEQ ID NO:11和SEQ ID NO:12(即，2G4)，SEQ ID NO:13和SEQ ID NO:14(即，2G11)，SEQ ID NO:15和SEQ IDNO:16(即，6F4)，SEQ ID NO:17和SEQ ID NO:18(即，5H1)，SEQ ID NO:19和SEQ ID NO:20(即，5F6)，SEQ ID NO:21和SEQ ID NO:22(即，1F3)，SEQ ID NO:23和SEQ ID NO:24(即，2A4)，SEQ ID NO:25和SEQ ID NO:26(即，2B12)，SEQ ID NO:27和SEQ ID NO:28(即，13A11)，SEQ ID NO:29和SEQ ID NO:30(即，15E1)，SEQ ID NO:31和SEQ ID NO:32(即，13H3)，SEQ ID NO:33和SEQ ID NO:34(即，14A8)，SEQ ID NO:35和SEQ ID NO:36(即，16H3)，SEQ ID NO:37和SEQ ID NO:38(即，1A1)，SEQ ID NO:39和SEQ ID NO:40(即，1A1-A)，SEQ ID NO:41和SEQ ID NO:42(即，1A1-Q)，SEQ ID NO:43和SEQ ID NO:44(即，1A2)，SEQ ID NO:45和SEQ ID NO:46(即，1A8)，SEQ ID NO:47和SEQ ID NO:48(即，1B1)，SEQ IDNO:49和SEQ ID NO:50(即，1B2)，SEQ ID NO:51和SEQ ID NO:52(即，1H3)，SEQ ID NO:53和SEQ ID NO:54(即，1H3-Q)，SEQ ID NO:55和SEQ ID NO:56(即，1H3-A)，SEQ ID NO:57和SEQID NO:58(即，2A2)，SEQ ID NO:59和SEQ ID NO:60(即，2A3)，SEQ ID NO:61和SEQ ID NO:62(即，2A6)，SEQ ID NO:63和SEQ ID NO:64(即，2A10)，SEQ ID NO:65和SEQ ID NO:66(即，2B1)，SEQ ID NO:67和SEQ ID NO:68(即，2C6)，SEQ ID NO:69和SEQ ID NO:70(即，2E7)，SEQ ID NO:71和SEQ ID NO:72(即，2E9)，SEQ ID NO:73和SEQ ID NO:74(即，2F1)，SEQ IDNO:75和SEQ ID NO:76(即，2F3)，和SEQ ID NO:77和SEQ ID NO:78(即，34C5)。在有些情况下，本发明的CD47抗体包括成对VH和VL链序列，该序列对选自包括下述序列对的组：SEQ IDNO:1和SEQ ID NO:2(即，1A1)，SEQ ID NO:3和SEQ ID NO:4(即，1F8)，SEQ ID NO:5和SEQID NO:6(即，2A11)，SEQ ID NO:7和SEQ ID NO:8(即，2C2)，SEQ ID NO:9和SEQ ID NO:10(即，2D7)，SEQ ID NO:11和SEQ ID NO:12(即，2G4)，SEQ ID NO:13和SEQ ID NO:14(即，2G11)，SEQ ID NO:15和SEQ ID NO:16(即，6F4)，SEQ ID NO:17和SEQ ID NO:18(即，5H1)，SEQ ID NO:19和SEQ ID NO:20(即，5F6)，SEQ ID NO:21和SEQ ID NO:22(即，1F3)，SEQ IDNO:23和SEQ ID NO:24(即，2A4)，SEQ ID NO:25和SEQ ID NO:26(即，2B12)，SEQ ID NO:27和SEQ ID NO:28(即，13A11)，SEQ ID NO:29和SEQ ID NO:30(即，15E1)，SEQ ID NO:31和SEQ ID NO:32(即，13H3)，SEQ ID NO:33和SEQ ID NO:34(即，14A8)，SEQ ID NO:35和SEQID NO:36(即，16H3)，SEQ ID NO:37和SEQ ID NO:38(即，1A1)，SEQ ID NO:39和SEQ ID NO:40(即，1A1-A)，SEQ ID NO:41和SEQ ID NO:42(即，1A1-Q)，SEQ ID NO:43和SEQ ID NO:44(即，1A2)，SEQ ID NO:45和SEQ ID NO:46(即，1A8)，SEQ ID NO:47和SEQ ID NO:48(即，1B1)，SEQ ID NO:49和SEQ ID NO:50(即，1B2)，SEQ ID NO:51和SEQ ID NO:52(即，1H3)，SEQ ID NO:53和SEQ ID NO:54(即，1H3-Q)，SEQ ID NO:55和SEQ ID NO:56(即，1H3-A)，SEQID NO:57和SEQ ID NO:58(即，2A2)，SEQ ID NO:59和SEQ ID NO:60(即，2A3)，SEQ ID NO:61和SEQ ID NO:62(即，2A6)，SEQ ID NO:63和SEQ ID NO:64(即，2A10)，SEQ ID NO:65和SEQ ID NO:66(即，2B1)，SEQ ID NO:67和SEQ ID NO:68(即，2C6)，SEQ ID NO:69和SEQ IDNO:70(即，2E7)，SEQ ID NO:71和SEQ ID NO:72(即，2E9)，SEQ ID NO:73和SEQ ID NO:74(即，2F1)，SEQ ID NO:75和SEQ ID NO:76(即，2F3)，和SEQ ID NO:77和SEQ ID NO:78(即，34C5)。
本发明所述的CD47抗体可以是嵌合的或人化的。它们可以阻止或显著减少人CD47与SIRPα的相互作用，或促进巨噬细胞介导的表达CD47的细胞的吞噬作用。
本发明所述的CD47抗体不引起重要或显著水平的红细胞凝聚或红血细胞的清除，并且在许多情况下根本不引起红细胞凝聚或红血细胞的清除。
在另一个方面，本发明提供一种分离的双特异性单克隆抗体。所述分离的双特异性单克隆抗体包括第一臂和第二臂，其中，所述第一臂包括能与人CD47结合的上述第一单克隆抗体或其免疫活性片段，所述第二臂包括不与人CD47结合的第二单克隆抗体。
在一些实施例中，所述分离的双特异性单克隆抗体中的第二臂能与癌细胞结合。
在其它一些实施例中，所述的双特异性单克隆抗体能抑制人CD47与人SIRPα之间的相互作用。
本发明还提供融合蛋白，每一融合蛋白包括分离的单克隆抗体或其免疫活性片段和细胞因子，其中，单克隆抗体或其免疫活性片段与人CD 47结合，单克隆抗体或其免疫活性片段与细胞因子在N-末端融合，在单克隆抗体或其片段与细胞因子之间有或没有连接物。
在一些实施方式中，所述分离的单克隆抗体或其免疫活性片段包括：
可变重(VH)链序列，该序列与选自包括下述序列的组的氨基酸序列具有至少95％的一致性：SEQ ID NO:1，SEQ ID NO:3，SEQ ID NO:5，SEQ ID NO:7，SEQ ID NO:9，SEQ ID NO:11，SEQ ID NO:13，SEQ ID NO:15，SEQ ID NO:17，SEQ ID NO:19，SEQ ID NO:21，SEQ IDNO:23，SEQ ID NO:25，SEQ ID NO:27，SEQ ID NO:29，SEQ ID NO:31，SEQ ID NO:33，SEQ IDNO:35，SEQ ID NO:37，SEQ ID NO:39，SEQ ID NO:41，SEQ ID NO:43，SEQ ID NO:45，SEQ IDNO:47，SEQ ID NO:49，SEQ ID NO:51，SEQ ID NO:53，SEQ ID NO:55，SEQ ID NO:57，SEQ IDNO:59，SEQ ID NO:61，SEQ ID NO:63，SEQ ID NO:65，SEQ ID NO:67，SEQ ID NO:69，SEQ IDNO:71，SEQ ID NO:73，SEQ ID NO:75，和SEQ ID NO:77，和
可变轻(VL)链序列，该序列与选自包括下述序列的组的氨基酸序列具有至少95％的一致性：SEQ ID NO:2，SEQ ID NO:4，SEQ ID NO:6，SEQ ID NO:8，SEQ ID NO:10，SEQ ID NO:12，SEQ ID NO:14，SEQ ID NO:16，SEQ ID NO:18，SEQ ID NO:20，SEQ ID NO:22，SEQ IDNO:24，SEQ ID NO:26，SEQ ID NO:28，SEQ ID NO:30，SEQ ID NO:32，SEQ ID NO:34，SEQ IDNO:36，SEQ ID NO:38，SEQ ID NO:40，SEQ ID NO:42，SEQ ID NO:44，SEQ ID NO:46，SEQ IDNO:48，SEQ ID NO:50，SEQ ID NO:52，SEQ ID NO:54，SEQ ID NO:56，SEQ ID NO:58，SEQ IDNO:60，SEQ ID NO:62，SEQ ID NO:64，SEQ ID NO:66，SEQ ID NO:68，SEQ ID NO:70，SEQ IDNO:72，SEQ ID NO:74，SEQ ID NO:76，和SEQ ID NO:78。
在一些其它实施例中，所述分离的单克隆抗体或其免疫活性片段包括VH/VL序列对，所述的VH/VL序列对包括VH和VL链序列，该序列对与选自包括下述序列对的组中的VH和VL氨基酸序列对具有至少95％的一致性：SEQ ID NO:1和SEQ ID NO:2(即,1A1),SEQ IDNO:3和SEQ ID NO:4(即，1F8)，SEQ ID NO:5和SEQ ID NO:6(即，2A11)，SEQ ID NO:7和SEQID NO:8(即，2C2)，SEQ ID NO:9和SEQ ID NO:10(即，2D7)，SEQ ID NO:11和SEQ ID NO:12(即，2G4)，SEQ ID NO:13和SEQ ID NO:14(即，2G11)，SEQ ID NO:15和SEQ ID NO:16(即，6F4)，SEQ ID NO:17和SEQ ID NO:18(即，5H1)，SEQ ID NO:19和SEQ ID NO:20(即，5F6)，SEQ ID NO:21和SEQ ID NO:22(即，1F3)，SEQ ID NO:23和SEQ ID NO:24(即，2A4)，SEQ IDNO:25和SEQ ID NO:26(即，2B12)，SEQ ID NO:27和SEQ ID NO:28(即，13A11)，SEQ ID NO:29和SEQ ID NO:30(即，15E1)，SEQ ID NO:31和SEQ ID NO:32(即，13H3)，SEQ ID NO:33和SEQ ID NO:34(即，14A8)，SEQ ID NO:35和SEQ ID NO:36(即，16H3)，SEQ ID NO:37和SEQID NO:38(即，1A1)，SEQ ID NO:39和SEQ ID NO:40(即，1A1-A)，SEQ ID NO:41和SEQ IDNO:42(即，1A1-Q)，SEQ ID NO:43和SEQ ID NO:44(即，1A2)，SEQ ID NO:45和SEQ ID NO:46(即，1A8)，SEQ ID NO:47和SEQ ID NO:48(即，1B1)，SEQ ID NO:49和SEQ ID NO:50(即，1B2)，SEQ ID NO:51和SEQ ID NO:52(即，1H3)，SEQ ID NO:53和SEQ ID NO:54(即，1H3-Q)，SEQ ID NO:55和SEQ ID NO:56(即，1H3-A)，SEQ ID NO:57和SEQ ID NO:58(即，2A2)，SEQID NO:59和SEQ ID NO:60(即，2A3)，SEQ ID NO:61和SEQ ID NO:62(即，2A6)，SEQ ID NO:63和SEQ ID NO:64(即，2A10)，SEQ ID NO:65和SEQ ID NO:66(即，2B1)，SEQ ID NO:67和SEQ ID NO:68(即，2C6)，SEQ ID NO:69和SEQ ID NO:70(即，2E7)，SEQ ID NO:71和SEQ IDNO:72(即，2E9)，SEQ ID NO:73和SEQ ID NO:74(即，2F1)，SEQ ID NO:75和SEQ ID NO:76(即，2F3)，SEQ ID NO:77和SEQ ID NO:78(即，34C5)。
在一些其它实施例中，所述分离的单克隆抗体或其免疫活性片段包括VH/VL序列对，其中，所述的VH/VL序列对包括VH和VL链序列，所述序列对选自包括下述序列对的组：SEQ ID NO:1和SEQ ID NO:2(即,1A1)，SEQ ID NO:3和SEQ ID NO:4(即，1F8)，SEQ ID NO:5和SEQ ID NO:6(即，2A11)，SEQ ID NO:7和SEQ ID NO:8(即，2C2)，SEQ ID NO:9和SEQ IDNO:10(即，2D7)，SEQ ID NO:11和SEQ ID NO:12(即，2G4)，SEQ ID NO:13和SEQ ID NO:14(即，2G11)，SEQ ID NO:15和SEQ ID NO:16(即，6F4)，SEQ ID NO:17和SEQ ID NO:18(即，5H1)，SEQ ID NO:19和SEQ ID NO:20(即，5F6)，SEQ ID NO:21和SEQ ID NO:22(即，1F3)，SEQ ID NO:23和SEQ ID NO:24(即，2A4)，SEQ ID NO:25和SEQ ID NO:26(即，2B12)，SEQ IDNO:27和SEQ ID NO:28(即，13A11)，SEQ ID NO:29和SEQ ID NO:30(即，15E1)，SEQ ID NO:31和SEQ ID NO:32(即，13H3)，SEQ ID NO:33和SEQ ID NO:34(即，14A8)，SEQ ID NO:35和SEQ ID NO:36(即，16H3)，SEQ ID NO:37和SEQ ID NO:38(即，1A1)，SEQ ID NO:39和SEQ IDNO:40(即，1A1-A),SEQ ID NO:41和SEQ ID NO:42(即，1A1-Q)，SEQ ID NO:43和SEQ ID NO:44(即，1A2)，SEQ ID NO:45和SEQ ID NO:46(即，1A8)，SEQ ID NO:47和SEQ ID NO:48(即，1B1)，SEQ ID NO:49和SEQ ID NO:50(即，1B2)，SEQ ID NO:51和SEQ ID NO:52(即，1H3)，SEQ ID NO:53和SEQ ID NO:54(即，1H3-Q)，SEQ ID NO:55和SEQ ID NO:56(即，1H3-A)，SEQID NO:57和SEQ ID NO:58(即，2A2)，SEQ ID NO:59和SEQ ID NO:60(即，2A3)，SEQ ID NO:61和SEQ ID NO:62(即，2A6)，SEQ ID NO:63和SEQ ID NO:64(即，2A10)，SEQ ID NO:65和SEQ ID NO:66(即，2B1)，SEQ ID NO:67和SEQ ID NO:68(即，2C6)，SEQ ID NO:69和SEQ IDNO:70(即，2E7)，SEQ ID NO:71和SEQ ID NO:72(即，2E9)，SEQ ID NO:73和SEQ ID NO:74(即，2F1)，SEQ ID NO:75和SEQ ID NO:76(即，2F3)，或SEQ ID NO:77和SEQ ID NO:78(即，34C5)，或与上述序列对具有至少90％(例如，至少95％)一致性的结合体。
在其它一些实施例中，所述的分离的单克隆抗体或其免疫活性片段是嵌合的或人化的。
在其它一些实施例中，所述的分离的单克隆抗体或其免疫活性片段能阻止人CD47与信号调节蛋白α(SIRPα)的相互作用。
在其它一些实施例中，所述的分离的单克隆抗体或其免疫活性片段不引起显著水平的红细胞凝聚或红血细胞的清除。
在其它一些实施例中，所述的分离的单克隆抗体或其免疫活性片段不引起红细胞凝聚或红血细胞的清除。
在其它一些实施例中，所述细胞因子包括免疫球蛋白(Ig)，造血生长因子，干扰素，肿瘤坏死因子，白细胞介素-17受体，或单聚糖蛋白的野生型或其变体。
在其它一些实施例中，所述细胞因子是单聚糖蛋白的野生型或其变体。进一步的，在一些实施例中，所述细胞因子是粒细胞巨噬细胞集落刺激因子(GM-CSF)的野生型或其变体。
在其它一些实施例中，所述单克隆抗体或其免疫活性片段通过或不通过连接物与细胞因子融合，所述连接物选自包括下述的组：(G4S)3，(G4S)6，(GS)9，IGD(F30)，IGD(F64)，IGD(R30)，IGN(R64)，IGD(R30-Cys)，和IGD(R64-Cys)。
在其它一些实施例中，所述融合蛋白能抑制人CD47和人SIRPα的相互作用。
在其它一些融合蛋白的实施例中，所述的分离的单克隆抗体或其免疫活性片段能促进巨噬细胞介导的CD47表达细胞的吞噬作用。
在其它一些实施例中，所述融合蛋白进一步包含小分子治疗制剂或标记物，且所述小分子治疗制剂或标记物与所述单克隆抗体或其免疫活性片段，或与细胞因子缀合。所述小分子治疗制剂是抗癌或抗炎制剂；所述标记物是生物标记或荧光标记。
在另一些实施方案中，分离的单克隆抗体或其免疫活性片段包含与一对VH和VL氨基酸序列至少90％(例如，至少95％)相同的VH/VL序列对，所述VH和VL氨基酸序列选自由SEQ ID NO：3和SEQ ID NO：4，以及SEQ ID NO：31和SEQ ID NO：32组成的组；所述细胞因子是粒细胞-巨噬细胞集落刺激因子(GM-CSF)的野生型或其变体。
在另一些其他实施方案中，所述融合蛋白包含可变轻(VL)链表达载体，其与选自SEQ ID NO：108和SEQ ID NO：116组成的组的氨基酸序列是至少90％(例如，至少95％)相同；和可变重链(VH)表达载体，其与选自下述组的氨基酸序列是至少90％(例如，至少95％)相同：SEQ ID NO:109，SEQ ID NO:110，SEQ ID NO:111，SEQ ID NO:112，SEQ ID NO:113，SEQ ID NO:114，SEQ ID NO:115，SEQ ID NO:117，SEQ ID NO:118，SEQ ID NO:119，SEQ IDNO:120，SEQ ID NO:121，SEQ ID NO:122，SEQ ID NO:123，SEQ ID NO:SEQ ID NO:125，SEQID NO:126，SEQ ID NO.127，SEQ ID NO.128，SEQ ID NO:129，SEQ ID NO:130，SEQ ID NO:131，SEQ ID NO:132，SEQ ID NO:133，SEQ ID NO:134，SEQ ID NO:135，SEQ ID NO:136，SEQID NO:137，SEQ ID NO:138，SEQ ID NO:139，SEQ ID NO:140，SEQ ID NO:141，SEQ ID NO:142，SEQ ID NO:143，SEQ ID NO:144，SEQ ID NO:145，SEQ ID NO:146，SEQ ID NO:147，SEQID NO:148，SEQ ID NO:149，SEQ ID NO:150，SEQ ID NO:151，SEQ ID NO:152，SEQ ID NO:153，SEQ ID NO:154，SEQ ID NO:155，SEQ ID NO:156，SEQ ID NO:147，和SEQ ID NO:158。
在另一些其他实施方案中，所述融合蛋白包含与选自包括以下的组的一对VH和VL氨基酸序列至少90％(例如，至少95％)相同的VH/VL对：SEQ ID NO:108和SEQ ID NO:109，SEQ ID NO:108和SEQ ID NO:110，SEQ ID NO:108和SEQ ID NO:111，SEQ ID NO:108和SEQID NO:112，SEQ ID NO:108和SEQ ID NO:113，SEQ ID NO:108和SEQ ID NO:114，SEQ IDNO:108和SEQ ID NO:115，SEQ ID NO:108和SEQ ID NO:117，SEQ ID NO:108和SEQ ID NO:118，SEQ ID NO:108和SEQ ID NO:119，SEQ ID NO:108和SEQ ID NO:120，SEQ ID NO:108和SEQ ID NO:121，SEQ ID NO:108和SEQ ID NO:122，SEQ ID NO:108和SEQ ID NO:123，SEQID NO:108和SEQ ID NO:124，SEQ ID NO:108和SEQ ID NO:125，SEQ ID NO:108和SEQ IDNO:126，SEQ ID NO:108和SEQ ID NO:127，SEQ ID NO:108和SEQ ID NO:128，SEQ ID NO:108和SEQ ID NO:129，SEQ ID NO:108和SEQ ID NO:130，SEQ ID NO:108和SEQ ID NO:131，SEQ ID NO:108和SEQ ID NO:132，SEQ ID NO:108和SEQ ID NO:133，SEQ ID NO:108和SEQID NO:134，SEQ ID NO:108和SEQ ID NO:135，SEQ ID NO:108和SEQ ID NO:136，SEQ IDNO:108和SEQ ID NO:137，SEQ ID NO:108和SEQ ID NO:138，SEQ ID NO:108和SEQ ID NO:139，SEQ ID NO:108和SEQ ID NO:140，SEQ ID NO:108和SEQ ID NO:141，SEQ ID NO:108和SEQ ID NO:142，SEQ ID NO:108和SEQ ID NO:143，SEQ ID NO:108和SEQ ID NO:144，SEQID NO:108和SEQ ID NO:145，SEQ ID NO:108和SEQ ID NO:146，和SEQ ID NO:108和SEQ IDNO:147；SEQ ID NO:116和SEQ ID NO:109，SEQ ID NO:116和SEQ ID NO:110，SEQ ID NO:116和SEQ ID NO:111，SEQ ID NO:116和SEQ ID NO:112，SEQ ID NO:116和SEQ ID NO:113，SEQ ID NO:116和SEQ ID NO:114，SEQ ID NO:116和SEQ ID NO:115，SEQ ID NO:116和SEQID NO:117，SEQ ID NO:116和SEQ ID NO:120，SEQ ID NO:116和SEQ ID NO:121，SEQ IDNO:116和SEQ ID NO:122，SEQ ID NO:116和SEQ ID NO:124，SEQ ID NO:116和SEQ ID NO:125，SEQ ID NO:116和SEQ ID NO:126，SEQ ID NO:116和SEQ ID NO:127，SEQ ID NO:116和SEQ ID NO:128，SEQ ID NO:116和SEQ ID NO:129，SEQ ID NO:116和SEQ ID NO:130，SEQID NO:116和SEQ ID NO:131，SEQ ID NO:116和SEQ ID NO:132，SEQ ID NO:116和SEQ IDNO:133，SEQ ID NO:116和SEQ ID NO:134，SEQ ID NO:116和SEQ ID NO:135，SEQ ID NO:116和SEQ ID NO:136，SEQ ID NO:116和SEQ ID NO:137，SEQ ID NO:116和SEQ ID NO:138，SEQ ID NO:116和SEQ ID NO:139，SEQ ID NO:116和SEQ ID NO:140，SEQ ID NO:116和SEQID NO:141，SEQ ID NO:116和SEQ ID NO:142，SEQ ID NO:116和SEQ ID NO:143，SEQ IDNO:116和SEQ ID NO:144，SEQ ID NO:116和SEQ ID NO:145，SEQ ID NO:116和SEQ ID NO:146，SEQ ID NO:116和SEQ ID NO:147，SEQ ID NO:116和SEQ ID NO:148，SEQ ID NO:116和SEQ ID NO:149，SEQ ID NO:116和SEQ ID NO:150，SEQ ID NO:116和SEQ ID NO:151，SEQID NO:116和SEQ ID NO:152，SEQ ID NO:116和SEQ ID NO:153，SEQ ID NO:116和SEQ IDNO:154，SEQ ID NO:116和SEQ ID NO:155，和SEQ ID NO:116和SEQ ID NO:156。
在另一方面，本发明提供一种药物组合物，所述药物组合物包括本发明所述的一种融合蛋白，和药学上可接受的载体或赋形剂。
如本文所述，术语“药学上可接受的载体或赋形剂”是指可用于制备药物组合物或制剂的载体或赋形剂，通常安全、无毒，且既不是生物学上也非其它方面不合需要的。所使用的载体或赋形剂通常是适合施用于人体或其他哺乳动物的载体或赋形剂。在制备组合物时，活性成分通常与载体或赋形剂混合，由载体或赋形剂稀释或封闭。当载体或赋形剂用作稀释剂时，其可以是固体，半固体或液体材料，其充当抗体活性成分的媒介物，载体或介质。
本发明还包括治疗有需要的人受试者的疾病的方法，并且所述方法包括向所述受试者施用治疗有效量的本发明所述的融合蛋白或本发明所述的药物组合物，所述疾病是癌症、纤维变性的疾病、或与吞噬作用受到抑制相关的任何疾病。在一些情况下，所述癌症选自包括下述癌症的组：卵巢癌、结肠癌、乳腺癌、肺癌、头颈部肿瘤、膀胱癌、结肠直肠癌、胰腺癌、非霍奇金氏淋巴瘤、急性淋巴细胞性白血病、慢性淋巴细胞白血病、急性髓细胞样白血病、慢性髓细胞性白血病、多毛细胞白血病(HCL)、T细胞幼淋巴细胞白血病(T-PLL)、大粒淋巴细胞白血病、成人T细胞白血病、多发性骨髓瘤、(恶性)黑色素瘤、平滑肌瘤、平滑肌肉瘤、神经胶质瘤、胶质母细胞瘤、骨髓瘤、单核细胞白血病、B细胞衍生白血病、T细胞衍生白血病、B细胞衍生淋巴瘤、T细胞衍生淋巴瘤、子宫内膜癌、肾癌、(良性)胎记瘤、前列腺癌、甲状腺癌、子宫颈癌、胃癌、肝癌、和实体肿瘤；所述纤维变性疾病可选自包括下述疾病的组：心肌梗死、心绞痛、骨关节炎、肺纤维化、哮喘、囊性纤维化、支气管炎、和气喘。实体瘤的例子包括，例如子宫内膜癌，甲状腺癌，宫颈癌，胃癌，乳房肿瘤，卵巢肿瘤，肺肿瘤，胰腺肿瘤，前列腺肿瘤，(恶性)黑素瘤，(良性)胎记瘤，结肠直肠肿瘤，肺肿瘤，头和颈肿瘤，膀胱肿瘤，食道肿瘤，肝肿瘤和肾肿瘤以及成神经细胞衍生的CNS肿瘤。与吞噬作用受到抑制相关的疾病可以是心血管疾病(例如动脉粥样硬化，中风，高血压性心脏病，风湿性心脏病，心肌病，心律失常，先天性心脏病，心脏瓣膜病，心脏炎，主动脉瘤，周边动脉疾病或静脉血栓)。
如本文所述，术语“有效量”是指当施用于受试者时，如本文所述的CD47抗体的量，是足够的或是影响CD47依赖性信号相关疾病的治疗，预后或诊断所需的。当单独或组合使用时，本文提供的治疗有效量的抗体将根据抗体的相对活性(例如促进巨噬细胞介导的表达CD47的癌细胞的吞噬作用)和所治疗的受试者和疾病状况、受试者的体重和年龄、疾病状况的严重程度、施用方式等而变化，其可以容易地由本领域普通技术人员确定。
如本文所述，本发明所述的抗体(例如，CD47抗体)之前的术语“分离的”是指抗体基本上不含其他细胞物质。在一个实施例中，分离的抗体基本上不含来自相同物种的其他蛋白质。在另一个实施例中，分离的抗体由来自不同物种的细胞表达并且基本上不含来自不同物种的其他蛋白质。使用本领域公知的蛋白质纯化技术，可以通过分离得到实质上不含天然相关组分(或与用于产生抗体的细胞表达系统相关的组分)的蛋白质。在一个实施例中，本发明所述的抗体或抗原结合片段被分离。
本文所使用的术语“生物分子”是指包括合成抗体(单克隆抗体或双特异性抗体)，肽，和仿生分子。术语“仿生分子”一词是指被设计或开发的以具有相似或类似于自然发生的大化合物，如蛋白质或核苷酸的结构或性质的分子，并且其分子量，例如至少为3000，至少为5000，或至少为10000。
本文引用的全部参考内容通过整体参考并入本文。
附图说明
图1显示了CD47抗体与单体CD47-ECD结合的剂量效应。
图2a和图2b显示了CD47抗体与二聚体CD47-ECD结合的剂量效应。
图3a，图3b，和图3c显示了CD47抗体阻断CD47和SIRPα结合的剂量效应。
图4a和图4b显示了CD47抗体与CD47+Raji细胞结合的剂量效应；并且图4c，图4d和图4e显示了通过Biacore分析测量的CD47抗体的结合动力学及其数据。
图5a和图5b显示了人MΦ与CD47抗体对肿瘤细胞的吞噬作用。
图6a-6c显示了CD47抗体引发的对于各种人类血液癌细胞系的巨噬细胞介导的吞噬作用。
图7a和7b显示了CD47抗体在不同剂量下诱导红细胞(RBC)凝聚的活性。
图8a，8b，8c和8d显示了CD47抗体在不同和更高剂量下结合RBC和诱导RBC凝聚的活性。
图9a，9b，9c和9d显示了CD47抗体的RBC结合活性。
图10显示了由CD47抗体对于不同来源的人的诱导红细胞凝聚的结果。
图11显示了CD47抗体和SIRPα-Ig融合体分别与人血小板的结合活性，其中CD61作为血小板的表面标记物被染色。
图12a和12b显示了体外由CD47抗体和SIRPα-Ig融合蛋白分别诱导的Cyno猴红细胞凝聚的测试结果。
图13显示了CD47抗体和对照抗体与AML细胞结合和吞噬作用的测试结果。
图14a和图14b显示了CD47抗体和对照抗体对萤光素酶-Raji异种移植小鼠的治疗效果。
图15显示了CD47抗体和对照抗体诱导的荷瘤小鼠体内巨噬细胞的极化。
图16显示了使用各种人类癌症类型的PDX样品的CD47表达谱。
图17显示了对食蟹猴的安全性药物研究(血液学)的结果。
图18显示了抗体1F8和5F9之间，以及抗体1F8和2A1之间由于它们不同的表位以及5F9/CD47复合物和1F8/CD47复合物的结构而在CD47结合中的竞争。
图19a，19b，19c，19d，19e，19f，19g和19h分别显示了CD47抗体13H3在食蟹猴单次给药及多次给药模型中，红细胞，血红蛋白，血小板及淋巴细胞的变化。
图20显示了34C5与重组CD47-ECD的强结合亲和力。
图21显示了34C5与携带CD47的Raji细胞的强结合亲和力。
图22显示了34C5能够有效地阻断CD47与SIRPα的结合，EC50为0.30nM。
图23显示了抗体34C5促进了人MΦ对肿瘤细胞的吞噬作用。
图24显示了抗体34C5不引起体外RBC凝集。
图25显示了抗体34C5与RBC的结合随着该抗体浓度的降低而降低。
图26显示了1F8-GMCSF融合蛋白与IgG对照组、1F8处理组和GM-CSF处理组相比，在CD14+细胞吞噬细胞百分率上引起更大的相对倍数变化。
图27显示了与重组人GMCSF相比，融合蛋白1F8-GMCSF与人GMCSF受体具有更强结合亲和力。
图28显示1F8-GMCSF在诱导STAT5磷酸化方面具有与GMCSF自身相似的活性。
图29显示了，与GMCSF相比，融合蛋白1F8-GMCSF具有更强的刺激TF-1增殖能力。
图30(a)，图30(b)，图30(c)和图30(d)显示了在IgG、1F8、GMCSF或1F8-GMCSF融合蛋白存在下，M1巨噬细胞活化引起的IL-6、IL-12、TNF-α和CD80的产生。
图31显示1F8-GMCSF融合蛋白在Raji异种移植模型的所有五种治疗方法中均显示出最佳疗效。
图32显示了融合蛋白13H3-GMCSF与CD47+Raji细胞结合的剂量效应。
图33显示了融合蛋白13H3-GMCSF阻断CD47与SIRPα结合的剂量效应。
图34显示了13H3-GMCSF对人MΦ对Raji细胞吞噬作用的影响。
图35显示了融合蛋白13H3-GMCSF在不同剂量下诱导红细胞(RBC)凝聚的活性。
图36显示了融合蛋白13H3-GMCSF与GMCSF受体结合的剂量效应。
图37显示了融合蛋白13H3-GMCSF在刺激STAT5磷酸化的剂量效应。
图38显示了融合蛋白13H3-GMCSF在刺激TF-1增值的剂量效应。
图39显示了融合蛋白13H3-GMCSF和对照组对荧光素酶-Raji异种移植小鼠模型的治疗效果。
图40显示了在食蟹猴单次剂量20mg/kg给药后的13H3-GMCSF血清水平浓度-时间曲线。
图41a和41b显示了13H3-GMCSF或IgG以20mg/kg剂量在食蟹猴多次给药后，红细胞和血小板的水平。
图42a，图42b和图42c显示了13H3-GMCSF或IgG以20mg/kg剂量在食蟹猴多次给药后，白细胞，中性粒细胞和单核细胞的水平。
图43显示了13H3-GMCSF变体在刺激STAT5磷酸化中的剂量依赖性反应。
图44显示了13H3-GMCSF变体在刺激TF-1增殖中的剂量依赖性反应。
图45显示了13H3-GMCSF变体在刺激巨噬细胞产生IL-6时的剂量依赖性反应。
图46显示了融合蛋白13H3-GMCSF变体对人MΦ对Raji细胞吞噬作用的影响。
图47a，47b和47c显示了13H3-GMCSF变体的剂量依赖性反应，该变体阻断了CD47与SIRPα的结合。
图48显示了与红细胞结合的13H3-GMCSF变体的剂量依赖性反应。
图49显示了使用13H3-GMCSF变体进行RBC凝集测定时诱导红细胞(RBC)凝聚的活性。
图50显示了带有IgG1 N297A版本的13H3-GMCSF对人MΦ吞噬Raji细胞的影响。
图51显示了具有IgG1 N297A版本的13H3-GMCSF变体对人MΦ吞噬Raji细胞的作用。
图52显示了去糖基化的13H3-GMCSF在STAT5磷酸化诱导中的剂量依赖性反应。
图53显示了去糖基化的13H3-GMCSF在刺激TF-1增殖中的剂量依赖性反应。
图54显示了去糖基化的13H3-GMCSF对人MΦ吞噬Raji细胞的影响。
图55显示了去糖基化的13H3-GMCSF变体在刺激TF-1增殖中的剂量依赖性反应。
图56显示在食蟹猴单次剂量为10mg/kg后，融合蛋白13H3-GMCSF变体的血清水平的浓度-时间曲线。
图57a，57b和57c显示了融合蛋白13H3-GMCSF变体对嗜中性粒细胞，单核细胞和白细胞的外周水平的影响。
图58a，58b和58c显示了融合蛋白13H3-GMCSF变体对红细胞，血红蛋白和血小板的外周水平的影响。
图59显示了13H3-mGMCSF变体在STAT5磷酸化诱导中的剂量依赖性反应。
图60显示了13H3-mGMCSF变体在刺激FDC-P1增殖中的剂量依赖性反应。
具体实施方式
本发明提供了新的分离的单克隆CD47抗体，其可以阻止人CD47与SIRPα相互作用，或促进巨噬细胞介导的对表达CD47的细胞的吞噬作用。这些CD47抗体不引起重要的或显著水平的红细胞凝聚或红血细胞的清除，并且在许多情况下，根本不引起红细胞凝聚或红血细胞的清除。
做为示例，本发明所述的CD47抗体包括(a)一个可变重(VH)链序列，该序列与选自由下述序列组成的组中的一个氨基酸序列具有至少90％(例如，至少95％)的一致性：SEQID NO:1，SEQ ID NO:3，SEQ ID NO:5，SEQ ID NO:7，SEQ ID NO:9，SEQ ID NO:11，SEQ IDNO:13，SEQ ID NO:15，SEQ ID NO:17，SEQ ID NO:19，SEQ ID NO:21，SEQ ID NO:23，SEQ IDNO:25，SEQ ID NO:27，SEQ ID NO:29，SEQ ID NO:31，SEQ ID NO:33，SEQ ID NO:35，SEQ IDNO:37，SEQ ID NO:39，SEQ ID NO:41，SEQ ID NO:43，SEQ ID NO:45，SEQ ID NO:47，SEQ IDNO:49，SEQ ID NO:51，SEQ ID NO:53，SEQ ID NO:55，SEQ ID NO:57，SEQ ID NO:59，SEQ IDNO:61，SEQ ID NO:63，SEQ ID NO:65，SEQ ID NO:67，SEQ ID NO:69，SEQ ID NO:71，SEQ IDNO:73，SEQ ID NO:75，和SEQ ID NO:77；和(b)一个可变轻(VL)链序列，该序列与选自由下述序列组成的组中的一个氨基酸序列具有至少90％(例如，至少95％)的一致性：SEQ IDNO:2，SEQ ID NO:4，SEQ ID NO:6，SEQ ID NO:8，SEQ ID NO:10，SEQ ID NO:12，SEQ ID NO:14，SEQ ID NO:16，SEQ ID NO:18，SEQ ID NO:20，SEQ ID NO:22，SEQ ID NO:24，SEQ IDNO:26，SEQ ID NO:28，SEQ ID NO:30，SEQ ID NO:32，SEQ ID NO:34，SEQ ID NO:36，SEQ IDNO:38，SEQ ID NO:40，SEQ ID NO:42，SEQ ID NO:44，SEQ ID NO:46，SEQ ID NO:48，SEQ IDNO:50，SEQ ID NO:52，SEQ ID NO:54，SEQ ID NO:56，SEQ ID NO:58，SEQ ID NO:60，SEQ IDNO:62，SEQ ID NO:64，SEQ ID NO:66，SEQ ID NO:68，SEQ ID NO:70，SEQ ID NO:72，SEQ IDNO:74，SEQ ID NO:76，和SEQ ID NO:78。进一步的，在有些情况下，本发明所述的CD47抗体包括结合的VH/VL链序列，所述VH/VL链序列与选自由下述序列组成的组的氨基酸序列具有至少90％(例如，至少95％)的一致性：SEQ ID NO:1和SEQ ID NO:2，SEQ ID NO:3和SEQ IDNO:4，SEQ ID NO:5和SEQ ID NO:6，SEQ ID NO:7和SEQ ID NO:8，SEQ ID NO:9和SEQ IDNO:10，SEQ ID NO:11和SEQ ID NO:12，SEQ ID NO:13和SEQ ID NO:14，SEQ ID NO:15和SEQID NO:16，SEQ ID NO:17和SEQ ID NO:18，SEQ ID NO:19和SEQ ID NO:20，SEQ ID NO:21和SEQ ID NO:22，SEQ ID NO:23和SEQ ID NO:24，SEQ ID NO:25和SEQ ID NO:26，SEQ ID NO:27和SEQ ID NO:28，SEQ ID NO:29和SEQ ID NO:30，SEQ ID NO:31和SEQ ID NO:32，SEQ IDNO:33和SEQ ID NO:34，SEQ ID NO:35和SEQ ID NO:36，SEQ ID NO:37和SEQ ID NO:38，SEQID NO:39和SEQ ID NO:40，SEQ ID NO:41和SEQ ID NO:42，SEQ ID NO:43和SEQ ID NO:44，SEQ ID NO:45和SEQ ID NO:46，SEQ ID NO:47和SEQ ID NO:48，SEQ ID NO:49和SEQ IDNO:50，SEQ ID NO:51和SEQ ID NO:52，SEQ ID NO:53和SEQ ID NO:54，SEQ ID NO:55和SEQID NO:56，SEQ ID NO:57和SEQ ID NO:58，SEQ ID NO:59和SEQ ID NO:60，SEQ ID NO:61和SEQ ID NO:62，SEQ ID NO:63和SEQ ID NO:64，SEQ ID NO:65和SEQ ID NO:66，SEQ ID NO:67和SEQ ID NO:68，SEQ ID NO:69和SEQ ID NO:70，SEQ ID NO:71和SEQ ID NO:72，SEQ IDNO:73和SEQ ID NO:74，SEQ ID NO:75和SEQ ID NO:76,和SEQ ID NO:77和SEQ ID NO:78。
如本文所述，术语“抗体”以最广泛的含义使用并且具体包括单克隆抗体(包括全长单克隆抗体)，多克隆抗体，多特异性抗体(例如双特异性抗体)，和抗体片段，只要它们表现出所需的生物活性。“抗体”(或“Abs”)和“免疫球蛋白”(或“Igs”)是具有相同结构特征的糖蛋白。虽然抗体对特定抗原表现出结合特异性，但免疫球蛋白包括抗体和缺乏抗原特异性的其他抗体样分子。后一种多肽例如由淋巴系统以低水平产生，和由骨髓瘤以高水平产生。
如本文所述，术语“表位”是指与抗体的互补位结合的抗原上的任何抗原决定簇。表位决定簇通常由分子的化学活性表面基团组成，例如氨基酸或糖侧链，并且通常具有特定的三维结构特征以及特定的电荷特征。
如本文所述，术语“天然抗体和免疫球蛋白”通常是指约150,000道尔顿的异四聚体糖蛋白，其由两条相同的轻链(L)和两条相同的重链(H)组成。每条轻链通过一个共价二硫键与重链连接(也称为“VH/VL对”)，而不同免疫球蛋白同种型的重链之间的二硫键数量不同。每条重链和轻链也具有规则排列的链内二硫桥。每条重链在一端具有可变结构域(VH)，随后是多个恒定结构域。每条轻链的一端有一个可变结构域(VL)，另一端有一个恒定结构域；轻链的恒定结构域与重链的第一恒定结构域对齐，并且轻链可变结构域与重链的可变结构域对齐。特定的氨基酸残基被认为在轻链和重链可变结构域之间形成界面。请参见，例如Clothia等，分子生物学期刊，186：651(1985)；Novotny和Haber，美国科学院院报，82：4592(1985)。
如本文所述，术语“可变”是指这样的事实，即抗体的可变结构域的序列的某些部分变化强烈，并用于每种特定抗体对其特定抗原的结合和特异性。然而，变异性不均匀地分布在抗体的整个可变区中。它集中在轻链和重链可变区中的三个区段，被称为互补决定区(CDRs)或高变区。可变域中更高度保守的部分被称为框架(FR)。天然重链和轻链的可变结构域各自包含四个FR区，大部分采用β-折叠构型，通过三个CDRs连接，形成环连接，并且在一些情况下形成β-折叠结构的一部分。每条链中的CDRs通过FR区紧密靠近在一起，并与来自另一条链的CDRs一起促成抗体的抗原结合位点的形成。请参考，例如，Kabat等人，免疫学的蛋白质序列，第五版，美国国立卫生研究院，贝塞斯达，马里兰州(1991)。恒定结构域不直接参与抗体与抗原的结合，但表现出各种效应物功能，例如抗体参与抗体依赖性细胞毒性。可变区序列的研究包括所提供的CD47抗体的人化的可变区序列。例如，1A1包括SEQ ID NO：1(重链)和SEQ ID NO：2(轻链)，1F8包括SEQ ID NO：3(重链)和SEQ ID NO：4(轻链)，2A11包括SEQ ID NO：5(重链)和SEQ ID NO：6(轻链)。
木瓜蛋白酶消化抗体产生两个相同的抗原结合片段，称为“Fab”片段，每个抗原结合片段具有单个抗原结合位点和残余的“Fc”片段，其名称反映了其容易结晶的能力。胃蛋白酶产生具有两个抗原结合位点并仍能够交联抗原的F(ab’)2片段。“Fv”是含有完整的抗原识别和结合位点的最小抗体片段。在双链Fv物种中，该区域由紧密非共价结合的一个重链可变结构域和一个轻链可变结构域的二聚体组成。在单链Fv物种(scFv)中，一个重链可变结构域和一个轻链可变结构域可以通过柔性肽接头共价连接，使得轻链和重链可以以类似于双链Fv物种的“二聚体”结构结合。正是在这种构造中，每个可变结构域的三个CDRs相互作用以在VH-VL二聚体的表面上限定抗原结合位点。六个CDRs共同赋予抗体抗原结合特异性。然而，甚至单个可变结构域(或仅包含三个特异于抗原的CDR的Fv的一半)具有识别和结合抗原的能力，尽管其亲和力低于整个结合位点。请参考，例如Pluckthun，单克隆抗体药理学，卷113，Rosenburg和Moore编，施普林格，纽约，第269-315页(1994)。
Fab片段还含有轻链的恒定结构域和重链的第一恒定结构域(CH1)。Fab'片段与Fab片段的不同之处在于在重链CH1结构域的羧基末端添加了几个残基，包括来自抗体铰链区的一个或多个半胱氨酸。Fab'-SH是本文对Fab'的命名，其中恒定结构域的半胱氨酸残基带有一个游离巯基。F(ab’)2抗体片段最初是作为Fab'片段对产生的，在Fab'片段之间具有铰链半胱氨酸的。抗体片段的其他化学偶联也是已知的。
有五种主要类型的免疫球蛋白：IgA，IgD，IgE，IgG和IgM，其中几种可以进一步分成亚类(同种型)，例如IgG1，IgG2，IgG3，IgG4，IgA1，IgA2。对应于不同种类免疫球蛋白的重链恒定结构域分别称为α，δ，ε，γ和μ。不同种类的免疫球蛋白的亚基结构和三维构型是众所周知的。
如本文所述，术语“抗体片段”及其所有语法变体定义为包含完整抗体的抗原结合位点或可变区的完整抗体的一部分，其中该部分不含完整抗体的Fc区中的恒定重链结构域(即CH 2，CH 3和CH 4，取决于抗体同种型)。抗体片段的实例包括Fab，Fab'，Fab'-SH，F(ab’)2和Fv片段；双体；任何抗体片段，抗体片段为具有由一个连续氨基酸残基的不间断序列组成的一级结构的多肽(在本文中称为“单链抗体片段”或“单链多肽”)，包括但不限于(1)单链抗体(scFv)分子，(2)仅包含一个轻链可变结构域的单链多肽或它的含有轻链可变结构域的三个CDRs的片段，没有相关的重链部分，和(3)仅含有一个重链可变区的单链多肽或它的含有重链可变区的三个CDRs的片段，没有相关的轻链部分；以及由抗体片段形成的多特异性或多价结构。在包含一个或多个重链的抗体片段中，所述重链可含有在完整抗体的非Fc区中发现的任何恒定结构域序列(例如IgG同种型中的CH1)，和/或可含有任何在完整抗体中发现的铰链区序列，和/或可以含有与重链的铰链区序列或重链恒定区序列融合的或位于其中的亮氨酸拉链序列。
除非特别的相反的说明，本文使用的术语“缀合”定义为一个或多个抗体片段通过共价键与一个或多个聚合物分子相结合形成异质分子，其中异质分子为水溶性的，即可溶于生理流体如血液中，并且其中该异质分子不含任何结构化聚集体。常用的缀合物是聚乙二醇(PEG)。在前述定义的上下文中，术语“结构化聚集体”是指(1)水溶液中具有球体或球体壳结构的分子的任何聚集体，使得异质分子不处于胶束或其他乳液结构中，并且不固定于脂质双层，囊泡或脂质体；和(2)固体或不溶形式的分子的任何聚集体，例如层析珠基质，其在与水相接触时不会将异质分子释放到溶液中。因此，如本文所定义的术语“缀合物”涵盖了前述的异质分子，所述异质分子可于沉淀物、沉积物、可生物蚀解基质或其它能够基于固体的水合作用将异质分子释放到水溶液里的固体中。
如本文所述，术语“单克隆抗体”(mAb)是指从一群基本上同质的抗体获得的抗体，即集群中的个别抗体是相同的，除了可能存在的少量的自然突变。单克隆抗体是高度特异性的，针对单个抗原位点。每种mAb针对抗原上的单一决定簇。除了它们的特异性之外，单克隆抗体的优点在于它们可以通过杂交瘤培养合成，不受其他免疫球蛋白污染。修饰语“单克隆”表示从基本上同质的抗体群体获得的抗体的特征，并且不被解释为需要通过任何特定方法产生抗体。例如，根据本发明使用的单克隆抗体可以在永生化B细胞或其杂交瘤中制备，或者可以通过重组DNA方法制备。
本文所述的单克隆抗体包括杂合抗体和重组抗体，所述杂合抗体和重组抗体的产生是通过将CD47抗体的可变(包括高变)结构域与恒定结构域(例如“人化”抗体)拼接，或轻链和重链的拼接，或来自一个物种的链与来自另一物种的链的拼接，或与异源蛋白融合，而不管起源物种或免疫球蛋白类别或亚类名称以及抗体片段(例如Fab，F(ab’)2和Fv)，只要它们表现出所需的生物活性即可。
本文所述的单克隆抗体具体包括“嵌合”抗体(免疫球蛋白)，其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源，而链的其余部分与衍生自另一物种的抗体或属于另一种抗体类别或亚类的抗体、以及这些抗体的片段中的相应序列相同或同源，只要它们表现出期望的生物学活性。
如本文所述，“分离的”抗体是已经从其天然环境的组分中识别和分离和/或恢复的抗体。其天然环境的污染成分是干扰抗体诊断或治疗用途的物质，可能包括酶，激素和其他蛋白质或非蛋白质溶质。在一些实施例中，抗体将被纯化：(1)通过Lowry法测定，纯化后抗体的重量大于75％，并且最优选大于80％，90％或99％，或(2)在还原或非还原条件下使用考马斯蓝，或，优选银染色法，通过SDS-PAGE电泳法将抗体同质性。所述分离的抗体包括重组细胞内的原位抗体，因为抗体天然环境中的至少一种组分不存在。通常，然而，至少通过一个纯化步骤来制备分离的抗体。
如本文所述，术语“表位标签的”是指与“表位标签”融合的CD47抗体。表位标签多肽具有足够的残基，其残基可以提供制备抗体的表位，且它足够短以至于并不干扰CD47抗体的活性。表位标签最好是足够独特的，使得表位的特异性抗体与其他表位没有实质上的交叉反应。合适的标签多肽通常具有至少6个氨基酸残基并且通常约8-50个氨基酸残基(优选约9-30个残基)。实施例包括c-myc标签蛋白和其上的8F9，3C7，6E10，G4，B7和9E10抗体(请参考，例如Evan等，分子和细胞生物学，5(12):3610-3616(1985))；和单纯疱疹病毒糖蛋白D(gD)标签及其抗体(请参考，例如Paborsky等，蛋白质工程，3(6)：547-553(1990))。
如本文所述，术语“标记”是指直接或间接与抗体缀合的可检测化合物或组合物。标记本身可以检测到(例如放射性同位素标记或荧光标记)，或者在酶标记的情况下，可以催化可检测的底物化合物或组合物的化学反应。
如本文所述，术语“固相”是指本发明所述的抗体可以粘附的非水性基质。本文所涵盖的固相的实施例包括部分或完全由玻璃(例如可控多孔玻璃)，多糖(例如琼脂糖)，聚丙烯酰胺，聚苯乙烯，聚乙烯醇和硅树脂形成的固相。在某些实施例中，取决于上下文，固相可以包含测定板的孔；在其他情况下，它是纯化柱(例如，亲和层析柱)。该术语还包括离散颗粒的不连续固相。参见，例如，美国专利号4,275,149。
本发明还提供包括上述CD47抗体的药物组合物，以及用上述CD47抗体或药物组合物治疗受试者疾病的方法。
如本文所述，术语“治疗”(treatment)或“治疗”(treating)是指疾病(例如癌症或纤维化疾病)的治疗性治疗和预防或预防性措施。需要治疗的人包括已经患有该病的人以及预防该疾病的人。
所述癌症选自但不限于卵巢癌、结肠癌、乳腺癌、肺癌、头颈部肿瘤、膀胱癌、结肠直肠癌、胰腺癌、非霍奇金氏淋巴瘤、急性淋巴细胞性白血病、慢性淋巴细胞白血病、急性髓细胞样白血病、慢性髓细胞性白血病、多毛细胞白血病、T细胞幼淋巴细胞白血病、大粒淋巴细胞白血病、成人T细胞白血病、多发性骨髓瘤、(恶性)黑色素瘤、平滑肌瘤、平滑肌肉瘤、神经胶质瘤、胶质母细胞瘤、骨髓瘤、单核细胞白血病、B细胞衍生白血病、T细胞衍生白血病、B细胞衍生淋巴瘤、T细胞衍生淋巴瘤、子宫内膜癌、肾癌、(良性)胎记瘤、前列腺癌、甲状腺癌、子宫颈癌、胃癌、肝癌、和实体肿瘤；所述纤维变性疾病可以是，例如心肌梗死、心绞痛、骨关节炎、肺纤维化、哮喘、囊性纤维化、支气管炎、和气喘。
如本文所述，用作治疗对象的术语“受试者”是指归类为哺乳动物的任何动物，包括人，家养动物和农场动物，以及动物园的动物，运动或宠物动物，例如狗，马，猫，牛等。优选地，哺乳动物是人类。
本发明所述的CD47抗体也可以应用在体外和体内，以监测CD47疾病治疗的过程。因此，例如，通过测量表达CD47的细胞，特别是表达CD47的癌细胞的数量的增加或减少，可以确定旨在改善疾病的特定治疗方案是否有效。
本发明所述的CD47抗体可以在体外用于免疫测定中，其中，它们可以在液相中使用或者结合到固相载体上。另外，这些免疫测定中的CD47抗体可以以各种方式连接上可检测标记。可以利用本发明所述的单克隆抗体的免疫测定类型的例子是流式细胞术，例如，FACS，MACS，免疫组织化学，直接和间接形式的竞争性或非竞争性的免疫测定。使用本发明所述的CD47抗体检测抗原可以利用正向，反向或同时模式运行的免疫测定来完成，所述模式包括对生理样品的免疫组织化学测定。本领域技术人员无需过度的实验，就会知道或者可以容易地辨别出其他免疫测定形式。
本发明所述的CD47抗体可以与多种不同的载体结合并用于检测CD47表达细胞的存在。众所周知的载体的例子包括玻璃，聚苯乙烯，聚丙烯，聚乙烯，葡聚糖，尼龙，淀粉酶，天然和改性纤维素，聚丙烯酰胺，琼脂糖和磁铁矿。出于本发明的目的，载体的性质可以是可溶的或不可溶的。本领域技术人员将知道用于结合单克隆抗体的其他合适的载体，或能够使用常规实验来确定这种载体。
本领域普通技术人员已知许多不同的标记和标记方法，其可用作治疗方法中的示踪剂，用于诊断方法等。为了诊断目的，标记可以共价键或非共价键连接至本发明所述的抗体或其片段，包括由CDR序列组成或包含CDR序列的片段。可用于本发明的标记的例子包括酶，放射性同位素，荧光化合物，胶态金属，化学发光化合物和生物发光化合物。本领域普通技术人员将知道用于结合本发明的单克隆抗体的其他合适的标记，或能够使用常规实验来确定。此外，这些标记与本发明所述的单克隆抗体的结合可以使用本领域普通技术人员通用的标准技术完成。
在一些实施例中，本发明所述的CD47抗体附着于纳米颗粒，例如用于成像。可用的纳米粒子是本领域已知的纳米粒子，例如，包括但不限于，拉曼-二氧化硅-金-纳米粒子(R-Si-Au-NP)。R-Si-Au-NP由拉曼有机分子组成，具有窄带谱特征，吸附在金核上。由于拉曼有机分子可以改变，每个纳米粒子可以携带自己的特征，从而允许通过多通路同时独立检测多个纳米粒子。整个纳米粒子被封装在二氧化硅壳中以将拉曼有机分子保持在金纳米核心上。R-Si-Au-NPs与任选的聚乙二醇(PEG)结合，增加了它们的生物利用度并提供了用于连接靶向部分的功能性“手柄”。请参考，例如Thakor等(2011)，转化医学，3(79):79ra33；Jokerst等(2011)Small，7(5):625-33；Gao等(2011)生物材料，32(8):2141-8。
本发明的目的之一，体内或体外的生物流体内或组织上的CD47可被本发明提供的CD47抗体检测出来。能用于任何含有可检测量的CD47的样品。样品可以是液体如尿、唾液、脑脊髓液、血液、血清及类似物，或者样品可以是固体或半固体如组织、粪便及类似物，或者，可以是如那些常用于组织学诊断的固体组织。
另一种能提高灵敏度的标记技术包括与低分子量半抗原结合的抗体。这些半抗原能特异性地被第二种反应检测到。例如，常用半抗原如生物素，半抗原与抗生素蛋白、或二硝基酚、维生素B、或荧光素反应，半抗原能与特异性抗-半抗原抗体反应。
本发明提供的CD47抗体能方便地用于试剂盒中，试剂盒，即，根据要进行的诊断分析的指示由多种预定量的试剂组成的一套组合试剂。其中，抗体用酶标记，所述试剂盒还包括酶所要求的底物和辅助因子(例如，提供可检测的载色体或荧光团的底物前驱体)。另外，试剂盒可以包括其它添加剂，例如稳定剂、缓冲剂(例出，封闭缓冲液或裂解缓冲液)和类似物。各种试剂的相关数量可以在大范围内变化，以使各种试剂在溶液中的浓度能使分析的灵敏度最优。特别的，试剂可以是干粉，通常是低压冻干粉，包括赋形剂，赋形剂溶解后能使试剂溶液具有合适的浓度。
治疗配制剂包括一种或多种本发明提供的抗体，通过将具有符合要求的纯度的抗体和任意的生理学可接受的载体，赋形齐或稳定剂(参考，例如，Remington'sPharmaceutical Sciences,16th edition,Osol,A.Ed.(1980))混合制备成易于储存的低压冻干制剂或水溶液。所述抗体组合物可以配制、定剂量、并和好的医疗行为一起施用。在本文中需要考虑的因素包括要进行治疗的具体的失调，引起失调的原因、试剂的输送部位、用药方式，用药计划，和治疗医师知晓的其它因素。施用的所述抗体的“治疗有效量”由这些需要考虑的因素控制，且是阻止与CD47相关联的疾病所需要的最小用量。
所述治疗剂量可以是至少大约0.01μg/kg体重，至少大约0.05μg/kg体重，至少大约0.1μg/kg体重，至少大约0.5μg/kg体重，至少大约1μg/kg体重，.2.5μg/kg体重，至少大约5μg/kg体重，且不超过大约100μg/kg体重。本领域技术人员知道，这些指导原则需要根据活性试剂的分子量调节，例如，使用抗体片段，或使用抗体缀合物。所述剂量还根据局部施用变化，例如鼻内，吸入物等等，或根据系统给施用方式变化，例如腹腔注射(I.P.)，静脉注射(I.V.)，皮内注射(I.D.)，肌肉注射(I.M.)及类似方式。
本发明提供的CD47抗体不需要，但是可以随意的与一种或多种试剂配制在一起，所述试剂能提高活性，或提高治疗效果。这些常用于上文所示的相同的给药剂量和施用途径或在此之前使用剂量的大约从1％至99％。
可接受的载体、赋形剂或稳定剂，在使用的剂量或浓度下，对接受者是无毒的，且包括缓冲剂例如磷酸盐，柠檬酸盐，和其它有机酸；抗氧化剂包括抗坏血酸和蛋氨酸；防腐剂(例如十八烷基二甲基苄基氯化铵；氯化六烃季铵；杀藻胺；苄索氯铵；苯酚，丁基或苯甲基乙醇；烷基对羟基苯甲酸酯例如甲基或丙基对羟基苯甲酸酯；邻苯二酚；间苯二酚；环已醇；3-戊醇；和间甲酚)；低分子量(小于大约10个残基)多肽；蛋白质，例如血清白蛋白，凝胶，或免疫球蛋白；亲水聚合物例如聚乙烯吡咯烷酮；氨基酸例如甘氨酸，谷氨酰胺，天冬酰胺酸，组氨酸，精氨酸，或赖氨酸；单糖，双糖，和其它碳水化合物包括葡萄糖，甘露糖，或糊精；螯合剂例如EDTA；糖例如蔗糖，甘露醇，海藻糖或山梨(糖)醇；盐形成的反离子例如钠；金属复合物(例如锌-蛋白质复合物)；和/或非离子表面活性剂例如TWEENTM，PLURONICSTM或聚乙二醇(PEG)。用于体内施用的配制剂必须是无菌制剂。这可以通过无菌过滤薄膜过滤方便地完成。
含有CD47抗体的活性组份也可以被包覆在微胶囊中，所述微胶囊，例如，通过反乳化技术或界面聚合制备，例如，羟甲基纤维素或凝胶-微胶囊和聚异丁烯酸甲酯微胶囊，分别地，在胶体型药物传输系统(例如，脂质体，白蛋白微球，乳浊液，纳米颗粒和纳米胶囊)或在乳状液中。Remington's Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980)中公布了这些技术。
本发明提供的CD47抗体或药物组合物可以通过任何合适的方式施用，包括肠胃外，皮下、腹腔、肺内和鼻内施用方式。非经胃肠道注射包括肌肉、静脉、动脉、腹腔或皮下施用。另外，所述抗-CD47抗体适合通过脉冲输液施用，特别是低剂量抗体。
为了预防或治疗疾病，抗体的合适的剂量依据所治疗疾病的类型，如上面说明的，疾病的严重程度和病程，抗体是否用于预防目的，早期治疗，病人的临床史和对抗体的反应，和主治医师的酌处权。所述抗体适于一次或经过一系列治疗施用于病人。
在本发明的另一个实施方式中，提供了含有用于治疗上述失调的材料的制品。所述制品包括容器和标签。合适的容器包括，例如，瓶子，小玻璃瓶，吸管，和试管。所述容器可以由各种材料例如玻璃或塑料制成。所述容器装有能有效治疗症状的组合物，且可具有无菌接口(例如，所述容器可以是静脉注射溶液袋或具有皮下注射针能刺穿的瓶塞的小玻璃瓶)。所述组合物中的活性剂是所述抗-CD47抗体。容器上或与容器相随在一起的标签说明组合物用于治疗选择的症状。所述制品还进一步包括第二容器，第二容器装有药学上可接受的缓冲液，例如磷酸盐缓冲盐水，复方氯化钠溶液和葡萄糖溶液。它可以进一步包括商业上和使用者要求的其它材料，包括其它缓冲液，稀释液，过滤器，针，注射器，和装入使用说明的包装盒。
下面的实施例用于向本领域技术人员完整的公开和说明如何制备和使用本发明，并不用于限制本发明的范围，也不表示下面的实施方式是全部或仅有的实施方式。通过努力获得了精确的关于使用的数值(例如，用量，温度等等)，但是某些实验错误和偏离应该被考虑。除非特别说明，份数是重量份，分子量是重均分子量，温度是摄氏度，压力是大气压或接近大气压。
本说明书引用的全部公布文件和专利申请在此通过参考而并入本文，就如各个单独的公布或专利申请被特别的和独立地说明通过参考而并入本文。
本发明已经描述了本发明的发明人发现或提出的特别的实施方式，包括本发明的优选实施方式。在本发明公开的内容的指引下，本领域技术人员能够不背离本发明的范围而对具体实施方式进行各种修饰和变更。例如，由于密码子过多，能够变更下面DNA序列而不影响蛋白质序列。而且，由于生物功能的等价考虑，能够改变蛋白质结构而不影响生物功能的种类或效果。所有这些修饰都包括在本发明的权利要求的范围内。
建立噬菌体文库
CD47是50kDa的膜受体，具有细胞外N-末端IgV区，五个跨膜区，和短的C-末端细胞内尾部。与人Fc缀合的人CD47-IgV区蛋白或生物素化的人CD47-IgV区蛋白(ACROBiosystems)用作噬菌体文库筛选的抗原。
使用噬菌粒载体构建噬菌体文库，包括来自多于50个健康人体的脾或骨髓细胞扩增的抗体基因片段。所述抗体是单链可变片段(VH+连接物+VL)。所述文库的库容是1.1×1010，所述序列的多样性进行分析如下。对于从文库中提取的62个克隆进一步测序，16个序列具有截短，框移或琥珀密码子；46个序列具有全长scFv，其中所有HCDR3序列是一样的。在46个全长scFv中，13个序列具有λ轻链和33个序列具有k轻链。
噬菌体淘选和克隆筛选
为了获得特异性结合人CD47-IgV区的噬菌体克隆，使用两种噬菌体淘选的方法。1、基于人CD47-IgV的噬菌体文库免疫试管淘选
在该方法中，上述发展的噬菌体文库首先在涂覆有酪蛋白的免疫试管中孵育2小时。人CD47-IgV-Fc融合蛋白用于第一轮淘选。未结合的噬菌体通过用PBST洗涤5-20次洗去。结合的噬菌体用新鲜制备的100mM三乙胺溶液洗脱，并加入三羟甲基氨基甲烷盐酸盐缓冲液中和，成为第一个输出噬菌体池。第一个输出噬菌体池通过大肠杆菌的TG-1细胞感染扩增进行救援，之后，用生物素化的人CD47-IgV作为抗原进行第二轮淘选。结合的噬菌体用相同的步骤洗脱，成为第二输出噬菌体池，第二输出噬菌体池接着进行救援，且接着，用人CD47-IgV-Fc融合蛋白作为抗原进行第三轮淘选。之后，结合的噬菌体成为第三输出噬菌体池，且用生物素化的人CD47-IgV进行第四轮淘选。
2、基于人CD47-IgV的噬菌体文库液相淘选
在该第二种方法中，所述噬菌体文库首先在酪蛋白封闭的100μL链酶素磁珠内孵育以消耗链酶素磁珠结合位点。所述链酶素磁珠和AG0084-huIgG1/k用于富集。对所述富集的文库进行援救，之后，用生物素化的人CD47-IgV作为抗原进行第二轮淘选，且进一步用酪蛋白封闭的链酶素磁珠富集。用PBST洗涤5-20次将未结合的噬菌体洗去。结合的噬菌体用新鲜制备的100mM三乙胺溶液洗脱，并加入三羟甲基氨基甲烷盐酸盐缓冲液中和，之后，进行援救，之后，用人CD47-IgV-Fc融合蛋白进行第三轮淘选，且用AG0084-huIgG1/k富集。之后，结合的噬菌体成为第三输出噬菌体池，并用生物素化的人CD47-IgV进行第四轮淘选，及用酪蛋白封闭的链酶素磁珠富集。
这步骤之后，特异性结合人CD47-IgV区的多个噬菌体克隆被获得和富集。所述噬菌体克隆接着被稀释，并涂板以在37℃成长8小时，并用抗-kappa抗体涂覆的过滤器反应过夜。生物素化的人CD47-IgV(50nM)和亲合素-AP缀合物(1:1000稀释)被用于过滤器以检测阳性结合的噬菌体克隆。阳性噬菌体板被摘下并洗脱到100μL噬菌体洗脱液中。大约10-15μL洗脱的噬菌体用于感染1mL XL1 Blue细胞以制备用于噬菌体单点ELISA(SPE)的高滴度噬菌体(HT)。所述由过滤器摘下的阳性单克隆与人CD47-IgV-Fc融合蛋白和酶化的人CD47-IgV域蛋白结合。针对这些阳性单克隆的VH和VL基因进行了测序。独特的VH和VL基因的全部阳性位点被克隆到表达载体pFUSE2ss-CLIg-hk(轻链，InvivoGen,Cat No.pfuse2ss-hclk)和pFUSEss-CHIg-hG1(重链,InvivoGen,Cat No.pfusess-hchg1)上。这些抗体在HEK293细胞中表达并由蛋白A和琼脂糖纯化。
CD47抗体的亲和力成熟
本发明提供的CD47抗体的结合亲和力能够通过体外亲和力成熟提高，例如，通过特别位点的随机变异，这导致了变异序列，该变异序列也属于本发明的保护范围。
例如，本发明提供的一种CD47抗体，1F8的BiaCore分析，显示2.8nM的结合亲和力(KD)具有高的离解速率1.04E-03 1/s，其可通过体外亲和力成熟提高。1F8的重链和轻链的CDR序列外延分析证明HCDR1和LCDR1区的几个残基能够随机变异。从而，随机变异文库可以构建并导入特定残基以产生各种各样的新序列。所述CDR变异文库用液相中的生物素化的可溶CD47 ECD在平衡条件下淘选。经过多轮伴随着降低抗原浓度的淘选，选出富集的输出结合物，用于结合ELISA实验，并随后转换成完整的IgG，该IgG是BiaCore分析的对象，以特别地选择离解速率改进的序列。通过这个筛选程序，本发明提供的抗体分子可以构建成具有全面的最优性能的临床应用的抗体。
实施例1、与重组CD47-ECD蛋白结合的噬菌体克隆的ELISA筛选
溶于磷酸盐缓冲液(PBS)中的浓度2ug/mL的重组人CD47-Fc融合蛋白(Acrobiosystems)，包被于微孔板上，在室温(RT)下反应2小时。包被抗原之后，将微孔用含1％BSA的PBS/0.05％吐温(PBST)，在室温(RT)下封闭1小时。用PBST洗涤这些孔之后，向孔中加入纯化的单克隆噬菌体，在室温下孵育1小时。为了检测结合的噬菌体克隆，加入结合(against)M13的HRP缀合的第二抗体(Jackson免疫研究)，之后，加入荧光底物(Roche)。在所有孵育步骤之间，板上的孔用PBST洗涤三次。荧光用TECAN荧光平板阅读器测量。选出阳性噬菌体克隆，用于重链和轻链基因的测序。
本发明提供的CD47抗体，经检测，全部显示出与重组人CD47-Fc融合蛋白有好的结合活性。
实施例2、抗体阻断CD47与SIRPα的相互作用的ELISA分析
浓度为1ug/mL的重组人CD47/小鼠Fc融合蛋白或生物素标记的CD47蛋白(Acrobiosystems)的PBS溶液，包被到微量滴定板上，在室温反应2小时。在包被抗原之后，这些微孔用含1％BSA的PBS/0.05％Tween(PBST)在室温封闭1小时。用PBST洗涤微孔之后，将用PBS稀释的抗体(5ug/mL)加入微孔中并在室温下孵育1小时。为了检测结合的抗体，加入HRP缀合的结合(against)人Fc的二抗(Jackson免疫研究)，之后，加入荧光底物(Roche)。在所有孵育步骤之间，板上的孔用PBST洗涤三次。荧光用TECAN荧光平板阅读器测量。
本发明提供的CD47抗体，经检测，全部显示出与重组人CD47-Fc融合蛋白和生物素标记的CD47蛋白有好的结合活性。
实施例3、抗体阻断CD47与SIRPα的相互作用的ELISA分析
重组CD47-Fc融合蛋白(Acrobiosystems)以浓度1ug/mL的PBS溶液包被在微孔板上，于4℃反应16个小时。用含1％BSA的PBST于室温封闭1小时后，将1ug/ml浓度的SIRPα-His蛋白加入到有或没有CD47抗体(10ug/mL)的微孔中，在室温下反应1小时。连续洗涤微孔板3次并加入HRP缀合的抗His二抗在室温孵育1小时。洗涤后，向每个微孔加入TMB溶液反应30分钟，并用2.0M H2SO4终止反应，并在490nm处测量OD值。
本发明提供的CD47抗体，经检测，全部能有效阻断CD47蛋白与SIRPα的结合。
实施例4、CD47抗体与单体CD47-ECD结合的剂量效应
直接的结合和竞争筛选之后，选择本发明的CD47抗体1F8用于本实验，与两种现有的参考抗体相比较。浓度为1ug/mL的酶化的CD47蛋白(Acrobiosystems)的PBS溶液，包被到微孔板上，在室温反应2小时。在包被抗原之后，这些微孔用含1％BSA的PBS/0.05％Tween(PBST)在室温封闭1小时。用PBST洗涤微孔之后，不同浓度的CD47抗体加入到微孔中并在室温下孵育1小时。为了检测结合的抗体，加入HRP缀合的结合(against)人Fc的二抗(Jackson免疫研究)，之后，加入荧光底物(Roche)。在所有孵育步骤之间，板上的孔用PBST洗涤三次。荧光用TECAN荧光平板阅读器测量。
参考抗体5F9和2A1依据Stanford University,Inhibrx LLC,和Celgene Corp.的研究者公布的Hu5F9和CC-90002序列制备(请参考，例如，美国专利号9,017,675B2，美国专利号9,382,320，美国专利号9,221,908，美国专利申请公布号2014/0140989和WO 2016/109415)，并用于相同的研究。
如图1所示，三种抗体(1F8,5F9,和2A1)显示了与单体CD47-ECD的相近的结合活性。
实施例5、CD47抗体与二聚CD47-ECD结合的剂量效应
在实施例4中使用的三种抗体(即,1F8,5F9,和2A1)也用于本研究中
浓度为1ug/mL的CD47/鼠Fc融合蛋白(Acrobiosystems)的PBS溶液，包被到微孔板上，在室温反应2小时。在包被抗原之后，这些微孔用含1％BSA的PBS/0.05％Tween(PBST)在室温封闭1小时。用PBST洗涤微孔之后，不同浓度的抗-CD47抗体加入微孔中并在室温下孵育1小时。为了检测结合的抗体，加入HRP标记的结合(against)人Fc的二抗(Jackson免疫研究)，之后，加入荧光底物(Roche)。在所有孵育步骤之间，板上的孔用PBST洗涤三次。荧光用TECAN荧光平板阅读器测量。
同样的，如图2a所示，检测的三种抗体1F8,5F9,和2A1中，三种抗体显示了相近的与二聚CD47-ECD结合的活性。
另一方面的关于结合活性的研究是比较本发明的两种抗体的结合亲合力，即1F8和13H3与重组CD47-ECD的结合亲和力。如图2b所示，在剂量依赖性方式下，这两种抗体也显示了相近的结合活性，1F8的EC50是0.038nM，13H3的EC50是0.045nM。
实施例6、CD47抗体阻断CD47与SIRPα的结合的剂量效应
所述三种抗体(即,1F8,5F9,和2A1)也用于本研究中。
浓度为1ug/mL的重组CD47-Fc融合蛋白(Acrobiosystems)的PBS溶液，包被到微孔板上，在4℃反应16小时。用含1％BSA的PBST于室温封闭1小时，将1ug/ml浓度的SIRPa-His蛋白加入到没有或有不同浓度的抗-CD47抗体的微孔中，在室温下反应1小时。微孔板连续洗涤3次并加入HRP标记的抗His二抗在室温孵育1小时。洗涤后，向每个微孔加入TMB溶液反应30分钟，并用2M H2SO4终止反应，并在490nm处测量OD值。
再次，如图3a所示，所有三种抗体显示了相近的阻断CD47与SIRPα的结合的活性。
另一方面的研究是比较本发明的两种CD47抗体，即1F8和13H3阻断CD47与SIRPα的结合的性能。如图3b和图3c所示，在剂量依赖性方式下，这两种抗体也显示了相近的阻断活性，1F8的EC50是0.78nM，13H3的EC50是0.20nM。
实施例7、CD47抗体与CD47+Raji细胞结合的剂量效应
三种抗体(即,1F8,5F9,和2A1)也用于本研究中。
Raji细胞表面内源性表达人CD47，用不同浓度的1F8,5F9和2A1抗体在4℃反应30分钟。接着，所述细胞用PBS洗涤3次，之后，与APC标记的抗人Fc特异性抗体(Invitrogen公司)一起在4℃孵育30分钟。用FACSCanto流式细胞分析仪(Becton-Dickinson公司)测量其结合。
如图4a所示，在相同的剂量依赖模式下，这三种抗体显示了相近的与CD47+Raji细胞结合的活性。
另一方面的研究是比较本发明的两种CD47抗体，即1F8和13H3与携带CD47的Raji细胞结合的性能。如图4b所示，在与携带CD47的Raji细胞结合方面，13H3显示了比1F8更强的亲和力，1F8的EC50是2.95nM，13H3的EC50是1.06nM。
图4c和图4d分别显示了1F8和13H3的结合动力学，由Biocore分析测量，图4e显示了数据。
实施例8、人巨噬细胞(MΦ)对瘤细胞的吞噬作用的研究
三种CD47抗体(即,1F8,5F9,和2A1)也用于本研究中。
由人血中分离出PBMCs，单核细胞经6天分化为巨噬细胞。将所述单核细胞衍生的巨噬细胞(MDMs)刮下来，并重置在24孔板上，附着24小时。选择内源性表达CD47的人瘤细胞系Raji作为靶细胞，并用1uM CFSE标记10分钟，之后，按照5：1的比例加入MDMs，每个巨噬细胞5个瘤细胞，并加入不同剂量的CD47抗体。孵育3小时，用PBS洗去未被吞噬的靶细胞，刮下剩下的吞噬细胞，用巨噬细胞标记物CD14抗体染色，用流式细胞仪分析。测量CD14+细胞，分析在CD14+细胞中的CFSE+细胞的百分含量，据此测量吞噬作用。
如图5a所示，这三种被测抗体(即1F8,5F9,和2A1)显示了相近的激发人MΦ吞噬瘤细胞的活性。图6a、图6b、和图6c显示了三种CD47抗体激发的巨噬细胞介导的三种不同的人血癌细胞系的吞噬作用。
另一方面的研究在于比较本发明的两种CD47抗体1F8和13H3激活人MΦ对瘤细胞的吞噬作用的能力。如图5b所示，13H3和1F8显示了相近的能力，其中，13H3在某些浓度下轻微地更加强了吞噬作用。
实施例9、CD47抗体对于红细胞凝集的影响
人红细胞在PBS中稀释到10％，与滴入的CD47抗体在圆底96孔板内在37℃孵育2小时。未沉淀的红细胞的存在是证明血细胞凝聚的证据，与未凝聚的红细胞沉淀形成的间断的红点相比，未沉淀的红细胞呈网状(见图7a和图8a)。图7b和图8b中的曲线表示血细胞凝集的定量分析，指出“凝聚指数”由在抗体存在下，测量红细胞颗粒的面积来确定，IgG对照的测量结果作为正常标准。
如图7a、图7b、图8a、和图8b所示，虽然CD47抗体5F9已经显示在等于或高于0.1ug/uL的浓度下，红细胞会显著凝聚，但是，CD47抗体1F8和2A1在浓度达到30ug/uL(图7a和图7b)或甚至达到150ug/mL(图8a和图8b)的实验中，未引起实质上的红细胞凝聚。
而且，图8c和图8d显示了本发明的CD47抗体(即，1F8和13H3)在浓度高达150ug/mL的实验里，未引起实质上的红细胞凝集，反之，CD47抗体5F9已经显示在等于或高于0.1ug/uL的浓度下，红细胞会显著凝集。
实施例10、红细胞结合分析
CD47抗体与人红细胞的结合用流式细胞仪检测。人红细胞和CD47抗体(10ug/mL)在4℃孵育1小时，之后加入APC标记的二抗在4℃反应30分钟。
如图9a和图9b所示，出人意料地，本发明的CD47抗体1F8不与红细胞结合，但是参考CD47抗体5F9和2A1在实验的浓度下与红细胞结合。
而且，图9c和图9d显示了，虽然1F8在实验的浓度不引起红细胞凝集，但是13H3在实验的浓度仅与红细胞有很低水平的结合。
实施例11、不同人来源的红细胞凝集分析
从6个健康男性和6个健康女性采集红细胞用于加入CD47抗体后红细胞的凝集分析。图10a和图10b显示了红细胞凝聚分析的滴定结果，指出“凝聚指数”通过测量抗体存在下红细胞沉淀的颗粒的面积来确定，以IgG对照或参考抗体为正常标准。
实施例12、血小板结合分析
本发明的CD47抗体与人血小板的结合用流式细胞计检测。人外周血全血与本发明的实验CD47抗体(10ug/mL)或SIRPα-Ig融合蛋白一起孵育，且CD61作为血小板的表面标识物被染色。通过测量CD61阳性群体(血小板)来测量血小板与CD47或SIRPα-Ig融合蛋白的结合，并进一步检验CD47或SIRPα-Ig融合蛋白与血小板的结合的百分量。
如图11所示，本发明的实验CD47抗体并不明显的与人血小板结合，但是SIRPα蛋白与人血小板结合。
实施例13、食蟹猴红细胞凝集实验
来源于雄性或雌性Cyno猴的红细胞在PBS中稀释到10％，与指示浓度的CD47抗体在圆底96孔板内在37℃孵育2小时。未沉淀的红细胞的存在是证明血细胞凝聚的证据，与未凝聚的红细胞沉淀形成的间断的红点相比，未沉淀的红细胞呈雾状，如图12a和图12b所示，显示了血细胞凝聚实验的滴定结果，指出“凝聚指数”由在抗体存在下，红细胞沉淀形成的颗粒的面积的测量来确定，IgG对照作为正常标准。
数据显示本发明实验的CD47抗体不明显的引起Cyno红细胞在体外的凝集。
实施例14、由CD47抗体激发的原代人AML细胞的吞噬作用
将来源于AML病人(AML-PB003F)的原代PBMCs用1uM CFSE标记10分钟，之后，按照5：1的比例加入到MDMs，每个巨噬细胞5个瘤细胞，并加入不同浓度的特定的CD47抗体。孵育3小时，用PBS洗去未被吞噬的靶细胞，刮下剩下的吞噬细胞，用CD14抗体染色，用流式细胞计分析。测量CD14+细胞，分析CFSE+细胞在CD14+细胞中的百分含量，以测量吞噬作用。按照前面所提示的内容测量吞噬作用。
如图13a至图13h所示，本发明的实验的CD47抗体显示了显著的与AML结合的能力(大于75％)及吞噬能力(至少36％)。全部这些指标都比用于相同试验中的参考CD47抗体高很多。
实施例15、利用荧光素标记Raji异种移植模型(CDX)检测1F8在体内的效果
通过尾静脉注射，向NSG小鼠注入Raji Luc-EGFP，浓度为1百万细胞每只小鼠。注射5天后，观察鼠的体内影像以确认注入的水平。从那一天开始，用CD47抗体(即，1F8，5F9，和2A1)治疗，给药量为10mg/kg。全部小鼠每隔一天通过腹腔注射方式注射。按照下面的时间点，用IVIS Lumina III成像系统将小鼠的体内成像：抗体治疗的第0天，抗体治疗的第2天，抗体治疗的第6天，抗体治疗的第9天。通过活体体内成像系统分析小鼠体内的荧光来测量小鼠体内肿瘤的生长。
如在图14a中所见，发光强度分析显示，小鼠体内的肿瘤只在用本发明的实验的CD47抗体(即，1F8)治疗后的前三天内生长，且肿瘤自治疗后的第6天开始减小。通过比较，用参考CD47抗体治疗的小鼠体内的肿瘤在相同的治疗期内继续生长。
类似的，图14b显示了CD47抗体13H3，在不同的实验浓度下，对体内的Raji异种移植模型也有效。
在Raji异种移植模型研究的末期，全部小鼠用CO2实施安乐死。来自四组小鼠的脾淋巴细胞被分离出来，并用于分析M1巨噬细胞的百分量(CD80阳性在F4/80阳性巨噬细胞内的百分数)和M2巨噬细胞的百分量(CD206阳性在F4/80阳性巨噬细胞内的百分数)，通过流式细胞计分析。
如图15a-15b所示，所有实验的CD47抗体(包括1F8)能引起荷瘤小鼠体内的巨噬细胞的极化。
实施例16、用各种人类癌症类型的PDX模型样本获得CD47表达图谱
54个PDX样本(7种人癌症类型相交叉)通过免疫组织化学染色分析CD47表达。CD47在各种PDX样本中的染色水平通过几何形状和染色强度来评价，图16a，图16b和图16c显示了用CD47抗体治疗后的不同的CD47的表达水平。
实施例17、安全性药物研究(体内Cyno PK研究)
将药物载体，1F8(n＝3,15mg/kg)和5F9(n＝3,15mg/kg)通过静脉注射注入到食蟹猴(n＝2)体内。采集血液后在24小时内进行血液学(CBC)分析，在注射前取血两次，并在施用抗体后的第3、6、10、14和21天取血。检查的CBC指标包括红细胞(RBC)量，血红蛋白(HGB)，网织红细胞和血小板数量。结果在图17a至图17d中显示，且显示了1F8治疗不影响cyno猴体内的血液学指标。
相似的，cyno猴(n＝2)通过静脉注射方式注射了CD47抗体13H3，给药量为20mg/kg。在不同的时间点通过静脉穿刺采集它们的血液收集到试管里，不加抗凝血剂。用CD47蛋白作为包被试剂，通过ELISA测量CD47抗体13H3的血清水平，之后，用HRP-标记的抗人Kappa二抗检测。在cyno猴体内的药物代谢动力学参数通过Winolin分析，并在图17e及表1中显示。
表1
抗体13H3在食蟹猴体内的安全性药物研究(血液学)
食蟹猴通过静脉注射方式注入了单剂量或重复剂量(每周给药)的抗体13H3(20mg/kg)。在施用抗体后的指定的时间点检查血液学(CBC)参数，CBC参数包括红细胞量(RBC)，血红蛋白(HGB)，血小板数量和淋巴细胞量。
图19a，图19b，图19c，图19d，图19e，图19f，图19g，和图19h显示了CD47抗体13H3对RBC聚集、血红蛋白、血小板和淋巴细胞的影响。
实施例18、抗体1F8的结构
CD47抗体识别的抗原表位区域通过竞争ELISA确定。CD47 ECD蛋白和第一抗-CD47抗体被预孵育并加入酶化的第二抗-CD47抗体，用链霉亲和素-HRP抗体检测。如果所述第一抗-CD47抗体和第二抗体，与CD47-ECD的结合产生竞争，两种抗体置于相同的或重叠的抗原表位区域。如果不是，它们置于不重叠的抗原表位区域。结果显示在图18a和图18b，显示了本发明的CD47抗体1F8与参考抗体5F9和2A1相比，具有不同的抗原表位。
图18c显示了参考抗体5F9(上方部分)与人CD47-ECD(绿色)复合的晶体结构，如在文献中记载的(参见，例如J.Clin.Investigation,126,7:2610-2620)。
图18d显示了1F8-Fab(上方部分)与人CD47-ECD(绿色)复合的晶体结构。CD47-1F8Fab的复合结构采用直的头对头排列，不像CD47-SIRPα和CD47-5F9双特异抗体呈现的倾斜的头对头排列的复合结构。所述1F8在CD47上的表位是不连续的和广范围的，所述表位包括残基L3、V25、T26、N27、M28、E29、A30、Q31、T34、E35、Y37、A53、L54、L74、K75、G76、T99、E100、L101、T102和R103，其中，L3、N27、E29、Q31、T34、E35、Y37、A53、T99、E100、L101、T102和R103也涉及与SIRPα相互作用，这解释了1F8的对抗性。该复杂的结构也揭示1F8的VH区与CD47形成8个氢键和4个盐桥，及1F8的VL区与CD47也形成了8个氢键。
不像已公布的CD47-IgV/抗体或SIRPa的复合结构，所述1F8抗体结合标靶的大部分不同的表位，虽然都是以简单的头对头排列结合。所述1F8在CD47上的表位是构像上不连续的，所述表位包括CD47的TNMEAQ环(残基26-31)、T34、E35、L74、和CD47的LTR铰链(残基101-103)。在抗体残基的侧链和CD47主链的氧原子之间形成了许多氢键相互作用。1F8的R103与CD47的E35之间也形成了盐桥。也发现了一些范德华接触，这些接触对保持合适的排列起了关键作用。所述抗体1F8的VH区主要涉及与CD47的T34，E35和LTR铰链(残基101-103)的结合，而VK区与TNMEAQ环(残基26-31)和L74相互作用。CD47上的这些表位与5F9抗体和SIRPα在CD47上的表位是不同的。结构分析暗示所述1F8抗体的两个长环(残基26-38和52-59)帮助它与CD47以接近垂直排列的方式结合，这可导致抗体分离，邻近细胞上的CD47不能被抗体桥接，从而阻止大部分血细胞的凝集。
图18e显示了5F9和1F8与CD47的结合的比较。
参考抗体5F9/CD47的复合结构与1F8/CD47的复合结构的重合揭示这两种复合物的CD47结合排列非常不同。虽然两种抗体都具有头对头的结合排列，但CD47水平旋转大约180度。1F8/CD47复合物的结构中，CD47的N末端的焦谷氨酸与轻链环残基61-64接近，而5F9的复合物的结构中，CD47的N末端位于3个重链环W52，N32，和W101之间。在抗体1F8中，重链残基Trp33和Arg103分别与CD47的Leu101和Glu35形成了范德华接触和盐桥。在相同的位置，抗体5F9的残基Tyr101通过范德华接触指向CD47的N末端，且Arg102与CD47的Glu104形成氢键。抗体1F8的环残基Asn31,Trp33和铰链残基Arg53和Asp56形成域间氢键网，所以Asn31和Arg53与CD47中的Leu101和Thr34的主链形成氢键。在相同的界面，5F9不显示相互作用，除了残基Tyr 52与CD47中的Leu3形成范德华接触之外。所述铰链(残基52-56)比1F8的铰链(残基52-59)少了3个残基。在轻链中，Fab 1F8和5F9二者均具有几个重要的来自环(1F8中的V29-Y38和5F9中的V152-Y158)的与CD47的氢键连接。1F8中的残基Y97和Y98将环(残基26-38)“推”开，且后者在1F8和CD47之间形成2个氢键，即在1F8的Arg34和CD47上的Leu74主链之间，在1F8的Arg36和CD47上的Thr26主链之间形成氢键。无论如何，5F9的残基Gly218和Ser219(相应于1F8中的Tyr97和Tyr98)导致5F9中的环(残基149-158)与CD47(在Asn157-Lys39，Tyr159-Glu104和Lys177-Thr99)形成了3个氢键。在重链中也像这样，5F9中的环(残基149-158)比1F8中的环(残基26-38)短大约3个残基。1F8中的这些相对较长的环主要决定了与CD47的结合的排列。
实施例19、CD47抗体34C5
为了产生抗人CD47抗体，不同菌株的6-8周的小鼠包括BALB/C,C57/BL6或SJL小鼠，用重组人CD47细胞外域蛋白免疫几个循环。免疫之后，具有足够滴度的抗-CD47 IgG的小鼠用相同的抗原加强，然后融合。通过ELISA筛选，检测杂交瘤上清液直接与人CD47 ECD蛋白的结合，及SIRPα与CD47结合的竞争。进行一系列的筛选分析，依据上述分析，34C5被选为人化抗体并进一步描述体外特性。
图20和图21显示了34C5与重组CD47-ECD(EC50是0.27nM)和带有CD47的Raji细胞(EC50是0.83nM)分别具有强的结合力。
图22显示了34C5能有效阻断CD47与SIRPα的结合，EC50是0.30nM。
图23显示了抗体34C5提高了人MΦ对瘤细胞的吞噬作用。
图24显示了抗体34C5不引起体外的RBC凝集。
图25显示了抗体34C5随着浓度的降低，与RBC的结合也降低了。
实施例20融合蛋白的制备
人GM-CSF细胞因子通过(GGGGS)3,(GGGGS)6,(GGGGS)9,IGD(F30),IGD(F64),IGD(R30),IGN(R64),IGD(R30-Cys),和IGD(R64-Cys)等不同长度的连接物或不通过连接物与抗CD 47抗体(1F8)的重链C末端融合。然后将轻链和重链表达载体共转染CHO细胞。瞬时转染后，用蛋白A亲和层析法从培养基中纯化融合蛋白。
实施例21融合蛋白连接物的筛选
表2显示了本发明的一些不具有连接物或具有几种不同连接物之一的融合蛋白的聚集、主峰、片段和产率。
表2
连接物 聚集 主峰 片段 产率(mg/L)
1F8-GMCSF 0.82％ 92.13％ 7.04％ 2.8
1F8-(G4S)<sub>3</sub>-GMCSF NA NA NA 1.9
1F8-(G4S)<sub>6</sub>-GMCSF 0.27％ 93.68％ 6.04％ 2.5
1F8-(GS)<sub>9</sub>-GMCSF 0.15％ 94.83％ 5.03％ 2.3
1F8-IGD(F30)-GMCSF 0.21％ 90.83％ 8.96％ 1.9
1F8-IGD(F64)-GMCSF - 96.94％ 3.06％ 1.8
1F8-IGD(R30)-GMCSF 0.69％ 92％ 7.31％ 1.1
1F8-IGD(R64)-GMCSF 0.75％ 94.77％ 4.48％ 1.5
1F8-IGD(R30-Cys)-GMCSF 0.87％ 90.79％ 8.34％ 1.4
1F8-IGD(R64-Cys)-GMCSF 0.84％ 91.31％ 7.84％ 1.4
实施例22融合蛋白与重组CD47蛋白的结合
本发明融合蛋白1F8-GMCSF对生物素化人CD 47-ECD蛋白(1ug/ml@100ul)的ELISA结合剂量反应试验。在本试验中，生物素化CD 47蛋白(AcroBiosystems)以1ug/ml的PBS包被在微滴度板上，室温下放置2h。包被抗原后，孔用PBS/0.05％吐温(PBST)和1％BSA在室温下封闭1小时。孔用PBST洗涤后，加入不同浓度的1F8-GMCSF融合分子，在室温下孵育1h。为检测结合抗体，加入抗人Fc(Jackson免疫研究)的HRP结合次级抗体，然后加入荧光底物(Roche)。在所有培养步骤之间，板的孔用PBST冲洗三次。在TECAN光谱平板阅读器中测量荧光。以CD 47抗体1F8为参照。
数据显示，CD47抗体1F8和融合蛋白1F8-GMCSF对重组CD47蛋白具有相似的结合亲和力。
实施例23融合蛋白能够阻断CD47和SIRPα的相互作用
阻断CD 47和SIRPα相互作用是根据制造商的协议(CISBIO)进行的。简单地说，CD47-SIRPα结合试验利用HTRF(均项时间分辨荧光)技术，能够以高通量的形式检测CD 47-SIRPα的相互作用。制备抗体工作液和稀释缓冲液中的Tag1-CD47/Ta-2SIRPα蛋白。将CD 47抗体或抗CD 47-GMCSF融合分子加入到一个384孔板中，然后加入Tag1-CD 47和Tag2-SIRPα。混合物在25℃中孵育15分钟，加入结合预混合物之后，在25℃中进一步孵育1小时。然后移除平板封口，在PerkinElmer Envision平板阅读器上读取荧光数据。
数据表明，1F8-GMCSF比1F8本身具有更强的阻断能力，相比于1F8的IC50为1.6nM，1F8-GMCSF的IC50为1.3nM。
实施例24、融合蛋白诱导红细胞(RBC)凝聚的活性
人红血细胞在PBS中稀释至10％，与滴入的1F8或1F8-GMCSF融合蛋白在圆底96孔板中，在37℃孵育2h。未沉淀的红血细胞的存在是证明血凝的证据，与未血凝的红细胞的间断的红点相比，未沉淀的红血细胞呈网状。本研究结果表明，1F8和1F8-GMCSF在规定浓度下均未诱导红细胞凝集。
实施例25融合蛋白促进吞噬肿瘤细胞功能
将PBMC从人血液分离，将单核细胞分化为巨噬细胞6天。将单核细胞衍生的巨噬细胞(MDMs)刮下并重置在24孔培养皿中，并使其粘附24小时。将内源性表达CD47的人肿瘤细胞系Raji作为靶细胞，用1uM CFSE标记10分钟，然后以5∶1肿瘤细胞每巨噬细胞的比例加入MDMs。以各种剂量加入1F8、GM-CSF蛋白或1F8-GMCSF融合蛋白。孵育3小时后，将未吞噬的靶细胞用PBS洗除，并将剩余的吞噬细胞刮下，用巨噬细胞标记物CD14抗体染色，并通过流式细胞术进行分析。吞噬作用的测定是通过CD14+细胞进行门控，然后评估CFSE+细胞的百分比。
图26显示了，与IgG对照组、1F8处理组和GM-CSF处理组相比，1F8-GMCSF融合蛋白在CD14+细胞吞噬细胞百分率上引起更大的相对倍数变化。
实施例26融合蛋白与人GM-CSF受体的结合
采用ELISA法检测融合蛋白1F8-GMCSF与人GMCSF受体蛋白(2ug/ml@100ul)结合的剂量效应。重组GMCSF Rα蛋白(R&D系统)以2μg/mL的PBS包被在微滴度板上，室温下包被2h。包被抗原后，孔用PBS/0.05％吐温(PBST)和1％BSA在室温下封闭1小时。孔用PBST洗涤后，加入不同浓度的1F8-GMCSF融合蛋白，在室温下孵育1h。为了检测结合抗体，加入抗人Fc(Jackson免疫研究)的HRP结合次级抗体，然后加入荧光底物(Roche)。在所有孵育步骤之间，板上的孔用PBST冲洗三次。在TECAN光谱平板阅读器中测量荧光。以重组人GMCSF蛋白为参考。
图27显示，与重组人GMCSF本身相比，融合蛋白1F8-GMCSF对人GMCSF受体具有更强的结合亲和力。
实施例27融合蛋白对STAT5的诱导活性
通过使用CD14阳性微珠(Miltenyi Biotec)，从人的外周血液中纯化CD14+单核细胞。在37℃下，用不同浓度的融合蛋白1F8-GMCSF刺激纯化的单核细胞30分钟。培养后，收集细胞并用FACS缓冲液(1×PBS+2％FBS)洗涤，并用2％PFA固定，然后用冰冷的甲醇进行细胞渗透。然后在4℃下将PE-结合的抗-pSTAT5抗体添加到细胞中，在4℃下孵育30分钟，并通过流式细胞术进行分析。通过试验样品的MFI/IgG对照处理组的MFI的比值计算MFI的倍数变化。
图28显示了1F8-GMCSF具有与GMCSF本身相似的诱导活性。
实施例28融合蛋白刺激TF-1增殖能力
在GMCSF刺激前，TF-1细胞用RPMI 1640基础培养液冲洗，并饥饿过夜。在第2天，收集这些饥饿的细胞，然后以3×105个细胞/ml的浓度接种到一个平底96孔板中，每孔接种50μl。将不同浓度的1F8-GMCSF融合蛋白加入TF-1细胞培养物中，在37℃孵育72h。根据制备商的协议，用CellTiter-发光细胞活力测定法检测细胞增殖情况。
图29显示了，与GMCSF相比，融合蛋白1F8-GMCSF具有更强的刺激TF-1增殖能力。
实施例29融合蛋白活化M1巨噬细胞
人体外分化巨噬细胞与Raji细胞按瘤细胞每巨噬细胞5：1的比例共培养。加入IgG、1F8、GMCSF或1F8-GMCSF融合蛋白，孵育8h。培养后用Luminex法检测培养上清液中IL-6、IL-12和TNF-α的产生，并用流式细胞仪检测细胞CD 80的表达。这四项参数均为M1巨噬细胞活化的特征标志。
图30(a)，图30(b)，图30(c)和图30(d)显示了在IgG、1F8、GMCSF或1F8-GMCSF融合蛋白存在下，M1巨噬细胞活化引起的IL-6、IL-12、TNF-α和CD80的产生。
实施例30融合蛋白在Raji异种移植模型中的体内疗效
将Raji细胞移植到NSG小鼠皮下，培养至100mm3。然后这些小鼠分别接种IgG、单独的1F8、单独的小鼠GMCSF、1F8和小鼠GMCSF组合，1F8-mGMCSF融合蛋白，70nmol每只小鼠，2次每周。用精密卡尺测量肿瘤的二维大小。
图31显示了五种治疗在降低肿瘤体积方面的功效，在这些治疗中，1F8-GMCSF融合蛋白表现出最佳疗效。
实施例31融合蛋白13H3-GMCSF
为了产生融合蛋白13H3-GMCSF，将人GMCSF细胞因子直接融合到抗CD 47抗体(13H3)的重链C端。然后将轻链和重链表达载体共转染CHO细胞。瞬时转染后，用蛋白A亲和层析法从培养基中纯化融合蛋白。
根据上述分析方法，将高质量融合蛋白13H3-GMCSF用于体外鉴定。
表3显示CD 47抗体13H3与融合蛋白13H3-GMCSF具有相似的结合动力学，由Biacore分析测量。
表3
分子 ka(1/Ms) kd(1/s) KD(M)
13H3 3.61E+05 2.82E-03 7.81E-09
13H3-GMCSF 7.21E+05 4.43E-03 6.14E-09
图32显示了，针对携带CD 47的Raji细胞，CD47抗体13H3和融合蛋白13H3-GMCSF具有相似的结合亲合力。
图33a和图33b显示，13H3-GMCSF在阻断CD 47-SIRPα相互作用方面表现出与13H3自身相当的能力。
图34显示，与13H3本身相比，13H3-GMCSF融合蛋白在促进人MΦ吞噬肿瘤细胞方面表现出更强的活性。
图35显示13H3-GMCSF不引起体外红细胞凝集。
图36显示13H3-GMCSF与人GMCSF受体结合的能力与重组GMCSF蛋白相当。
图37显示13H3-GMCSF与重组GMCSF蛋白诱导STAT 5活化的能力相当。
图38显示，13H3-GMCSF与重组GM-CSF蛋白刺激TF-1增殖的能力相当。
实施例32融合蛋白13H3-GMCSF在Raji异种移植模型的体内效应
将Raji细胞移植到NSG小鼠皮下，培养至100mm3。然后，这些小鼠分别接种IgG、单独13H3、单独GMCSF、13H3和GMCSF复合物、13H3-GMCSF融合蛋白，70nmol每只小鼠，每周2次。用精密卡尺测量肿瘤的二维大小。
图39显示了五种治疗方法减小肿瘤体积的效果，其中，13H3-GMCSF融合蛋白的效果最好。
实施例33 13H3-GMCSF在食蟹猴的体内PK研究
食蟹猴(n＝2)以20mg/kg的剂量静脉注射融合蛋白13H3-GMCSF。在不同的时间点，通过静脉穿刺将其血液收集到没有抗凝剂的管中。用ELISA测定融合蛋白13H3-GMCSF的血清水平，用CD47蛋白作为包被试剂，然后用抗GMCSF二级抗体检测。食蟹猴单次剂量20mg/kg给药后，血清13H3-GMCSF浓度-时间曲线如图40所示。用Winolin分析药代动力学参数，如表4所示。
表4
T<sub>1/2</sub>(h) C<sub>max</sub>(μg/ml) AUC<sub>0-t</sub>(hr*ug/ml) MRTlast(hr)
6.8 191 3849 11.4
实施例34 13H3-GMCSF对食蟹猴的安全性研究(血液学)
将融合蛋白13H3-GMCSF(20mg/kg)的重复剂量(每周剂量)静脉滴注于食蟹猴体内。在注射融合蛋白后的指定时间点检测红细胞(RBC)、血小板和白细胞(WBC)、中性粒细胞和单核细胞的数量等血液学(CBC)参数。
图41a，图41b，图42a，图42b和图42c显示了融合蛋白13H3-GMCSF对红细胞、血小板、白细胞、中性粒细胞和单核细胞的水平的影响。
实施例35融合蛋白1F8-GMCSF变体
为了产生具有减弱的GMCSF活性的融合蛋白1F8-GMCSF，对人GMCSF部分进行位点突变。这些具有不同位点突变的变体的序列列于表5。
表5. 1F8-GMCSF野生型序列和具有位点突变的变体序列
分子 VL抗体链 VH抗体链
1F8-GMCSF SEQ ID NO:108 SEQ ID NO:109
1F8-GMCSF,E21S SEQ ID NO:108 SEQ ID NO:110
1F8-GMCSF,E21A SEQ ID NO:108 SEQ ID NO:111
1F8-GMCSF,E21R SEQ ID NO:108 SEQ ID NO:112
1F8-GMCSF,E21S,D112K SEQ ID NO:108 SEQ ID NO:113
1F8-GMCSF,E21R,D112K SEQ ID NO:108 SEQ ID NO:114
1F8-GMCSF,E45K,D48K,D112K SEQ ID NO:108 SEQ ID NO:115
实施例36融合蛋白13H3-GMCSF变体
为了产生具有减弱的GMCSF活性的融合蛋白13H3-GMCSF，对人GM-CSF部分进行位点突变。这些具有不同位点突变的变体的序列在表6中列出。然后，将13H3-GMCSF变体的轻链和重链表达载体共转染到CHO细胞中。瞬时转染后，通过蛋白A亲和层析法从培养基中纯化融合蛋白变体。
表6. 13H3-GMCSF野生型序列和具有位点突变的变体序列
分子 VL抗体链 VH搞体链
13H3-GMCSF SEQ ID NO:116 SEQ ID NO:109
13H3-GMCSF,E21S SEQ ID NO:116 SEQ ID NO:110
13H3-GMCSF,E21A SEQ ID NO:116 SEQ ID NO:111
13H3-GMCSF,E21R SEQ ID NO:116 SEQ ID NO:112
13H3-GMCSF,E21S,D112K SEQ ID NO:116 SEQ ID NO:113
13H3-GMCSF,E21R,D112K SEQ ID NO:116 SEQ ID NO:114
13H3-GMCSF,E45K,D48K,D112K SEQ ID NO:116 SEQ ID NO:115
根据上述测定方法，将合格的13H3-GMCSF变体应用于体外鉴定。
图43显示，与野生型融合蛋白13H3-GMCSF相比，13H3-GMCSF变体在STAT5激活的诱导中表现出减弱的效力。
图44显示与野生型融合蛋白13H3-GMCSF相比，在刺激TF-1增殖方面，13H3-GMCSF变体表现出分化的效能。
在具有一系列浓度的13H3-GMCSF变体的存在下培养人体外分化的巨噬细胞48小时。通过ELISA分析培养上清液中IL-6的产生水平。图45显示，在活化巨噬细胞介导的IL-6表达中，与野生型13H3-GMCSF融合分子相比，所有13H3-GMCSF变体均表现出不同程度的较低活性。
图46显示13H3-GMCSF变体在促进人MΦ对肿瘤细胞的吞噬作用方面表现出与野生型13H3-GMCSF相当的活性。
表7显示，如通过Biacore分析所测量的，13H3-GMCSF变体与野生型13H3-GMCSF表现出相似的结合动力学。
表7. 13H3-GMCSF变体的Biacore分析
图47a-c显示13H3-GMCSF变体在阻断CD47-SIRPα相互作用中表现出与野生型13H3-GMCSF相当的能力。
将人RBC与不同浓度的13H3-GMCSF变体在4℃下孵育30分钟，以5F9作为参考抗体。然后，将细胞用FACS缓冲液洗涤两次，然后在4℃下用偶联有Alexa Fluor 633的抗人Fc特异性抗体(Invitrogen)染色30分钟。用FACSCelesta流式细胞仪(BD Biosciences)测量结合。图48显示，与参考抗体5F9相比，野生型的13H3-GMCSF及其变体表现出非常低的RBC结合水平。
图49显示13H3-GMCSF变体不引起体外RBC凝集。
实施例37具有IgG1同种型的部分沉默版本的融合蛋白1F8-GMCSF变体
为了产生具有减弱的Fc介导的效应子功能的融合蛋白1F8-GMCSF，将人IgG1的Fc部分中的一个位点突变N297A应用于1F8-GMCSF的野生型和变体。表8列出了带有IgG1N297A的1F8-GMCSF野生型和变体序列。
表8 具有IgG1 N297A同种型的1F8-GMCSF融合蛋白(野生型和变体)
实施例38具有IgG1同种型的部分沉默版本的融合蛋白13H3-GMCSF变体
为了产生具有减弱的Fc介导的效应子功能的融合蛋白13H3-GMCSF，将人IgG1的Fc部分中的一个位点突变N297A应用于13H3-GMCSF的野生型和变体。表9列出了具有IgG1N297A的13H3-GMCSF野生型和变体的序列。将具有IgG1 N297A的13H3-GMCSF变体的轻链和重链表达载体共转染到CHO细胞中。瞬时转染后，通过蛋白A亲和层析法从培养基中纯化融合蛋白变体。
表9具有IgG1 N297A同种型的13H3-GMCSF融合蛋白(野生型和变体)
图50显示，与野生型13H3-GMCSF相比，具有IgG1 N297A同种型的13H3-GMCSF在促进人MΦ吞噬肿瘤细胞方面表现出适度较低的活性。
图51显示，与具有IgG1同种型的13H3-GMCSF变体相比，具有IgG1 N297A同种型的13H3-GMCSF变体在促进人MΦ吞噬肿瘤细胞方面表现出适度较低的活性。
实施例39去糖基化的融合蛋白1F8-GMCSF
人GMCSF在Asn 27和Asn 37处有两个N-糖基化位点，在Ser 7，Ser 9和Thr 10的N端区有三个O-糖基化位点。为了生成去糖基化的融合蛋白1F8-GMCSF，将这些位点突变(N27Q，N37Q/S7A，S9A，T10A/N27Q，N37Q，S7A，S9A，T10A)或N端截短(1-10aa)应用于具有IgG1格式和IgG1 N297A格式的融合蛋白1F8-GMCSF的GMCSF部分。表10-11列出了去糖基化融合蛋白的序列。
表10 具有IgG1格式的去糖基化融合蛋白1F8-GMCSF的序列
表11 具有IgG1 N297A格式的去糖基化融合蛋白1F8-GMCSF的序列
实施例40去糖基化的融合蛋白1F8-GMCSF变体
为了产生去糖基化的融合蛋白1F8-GMCSF变体，将位点突变(N27Q，N37Q/S7A，S9A，T10A/N27Q，N37Q，S7A，S9A，T10A)或N端截短(1-10aa)应用于具有IgG1格式和IgG1 N297A格式的融合蛋白1F8-GMCSF变体的GMCSF部分。表12-13中列出了去糖基化融合蛋白的序列。
表12 具有IgG1格式的去糖基化融合蛋白1F8-GMCSF变体的序列
表13 具有IgG1 N297A格式的去糖基化的1F8-GMCSF变体的序列
实施例41去糖基化的融合蛋白13H3-GMCSF
为产生去糖基化的融合蛋白13H3-GMCSF，将位点突变(N27Q，N37Q/S7A，S9A，T10A/N27Q，N37Q，S7A，S9A，T10A)或N端截短(1-10aa)应用于具有IgG1格式和IgG1 N297A格式的融合蛋白13H3-GMCSF的GMCSF部分。然后，将去糖基化的13H3-GMCSF的轻链和重链表达载体共转染到HEK293细胞中。瞬时转染后，通过蛋白A亲和层析法从培养基中纯化融合蛋白变体。表14-15列出了去糖基化融合蛋白的序列。
表14 具有IgG1格式的去糖基化的13H3-GMCSF的序列
表15 具有IgG1 N297A格式的去糖基化13H3-GMCSF的序列
根据上述测定，将具有IgG1格式的合格的去糖基化的13H3-GMCSF用于体外表征。
图52显示，在诱导STAT5磷酸化中，去糖基化的13H3-GMCSF表现出与野生型13H3-GMCSF相当的活性。
图53显示，去糖基化的13H3-GMCSF在刺激TF-1增殖方面表现出与野生型13H3-GMCSF相当的活性。
图54显示，去糖基化的13H3-GMCSF在促进人MΦ对肿瘤细胞(Raji)的吞噬作用方面表现出与野生型13H3-GMCSF相当的活性。
实施例42去糖基化的融合蛋白13H3-GMCSF变体
为了产生去糖基化的融合蛋白13H3-GMCSF变体，将位点突变(N27Q，N37Q/S7A，S9A，T10A/N27Q，N37Q，S7A，S9A，T10A)或N端截短(1-10aa)应用于具有IgG1格式和IgG1N297A格式的融合蛋白13H3-GMCSF变体的GMCSF部分。然后，将去糖基化的13H3-GMCSF变体的轻链和重链表达载体共转染到HEK293细胞中。瞬时转染后，通过蛋白A亲和层析从培养基中纯化去糖基化的融合蛋白变体。表16-17列出了去糖基化融合蛋白的序列。
表16 具有IgG1格式的去糖基化的13H3-GMCSF变体的序列
表17 具有IgG1 N297A格式的去糖基化的13H3-GMCSF变体的序列
根据上述测定，将具有IgG1格式的合格的去糖基化的13H3-GMCSF变体应用于体外表征。
图55显示，GMCSF部分的去糖基化对13H3-GMCSF变体介导的TF-1增殖的刺激没有影响。
实施例43食蟹猴中13H3-GMCSF变体的体内PK研究
幼稚的食蟹猴(n＝2)以10mg/kg的剂量静脉注射融合蛋白13H3-GMCSF变体(E21S，D112K，IgG 1N297A)。在不同的时间点通过静脉穿刺将他们的血液收集到无抗凝剂的试管中。通过ELISA，使用CD47蛋白作为包被试剂，测量融合蛋白13H3-GMCSF变体的血清水平，然后用抗Fc二抗检测。食蟹猴单次剂量10mg/kg后，13H3-GMCSF变体血清水平的浓度-时间曲线如图56所示。用Winolin分析了药代动力学参数，并如表18中所示。
表18 13H3-GMCSF变体的体内PK研究的药代动力学参数
实施例44食蟹猴中13H3-GMCSF变体的安全药理研究(血液学)
幼食蟹猴在第1天和第4天以重复剂量静脉滴注融合蛋白13H3-GMCSF变体(20mg/kg)。在施用融合蛋白后的指定时间点检查血液学(CBC)参数，包括红细胞(RBC)，血小板和白细胞(WBC)，嗜中性粒细胞和单核细胞的计数。
图57a-c显示了融合蛋白13H3-GMCSF变体对嗜中性粒细胞，单核细胞和白细胞的外周水平的影响。
图58a-c显示了融合蛋白13H3-GMCSF变体对红细胞，血球蛋白和血小板的外周水平的影响。
实施例45 13H3-GMCSF的替代分子
为了产生融合蛋白13H3-GMCSF的替代分子用于概念研究，人类GMCSF部分被全长鼠GMCSF代替。然后，将13H3-mGMCSF的轻链和重链表达载体共转染到HEK293细胞中。瞬时转染后，通过蛋白A亲和层析从培养基中纯化融合蛋白变体。表19列出了替代分子13H3-mGMCSF的序列。
表19 替代分子13H3-mGMCSF的序列
分子 VL抗体链 VH抗体链
13H3-mGMCSF SEQ ID NO:116 SEQ ID NO:148
实施例46 13H3-GMCSF变体的替代分子
为了筛选和产生融合蛋白13H3-GMCSF变体的替代分子以用于概念研究，将位点突变应用于替代分子13H3-mGMCSF的鼠GMCSF部分以减弱GMCSF活性。然后，将13H3-mGMCSF变体的轻链和重链表达载体共转染到HEK293细胞中。瞬时转染后，通过蛋白A亲和层析法从培养基中纯化融合蛋白变体。表20列出了替代分子13H3-mGMCSF变体的序列。
表16 替代分子13H3-mGMCSF变体的序列
分子 VL抗体链 VH抗体链
13H3-mGMCSF,E21S SEQ ID NO:116 SEQ ID NO:149
13H3-mGMCSF,E21A SEQ ID NO:116 SEQ ID NO:150
13H3-mGMCSF,E21R SEQ ID NO:116 SEQ ID NO:151
13H3-mGMCSF,K14A,H15A SEQ ID NO:116 SEQ ID NO:152
13H3-mGMCSF,K14A,K20A SEQ ID NO:116 SEQ ID NO:153
13H3-mGMCSF,K14A,E21A SEQ ID NO:116 SEQ ID NO:154
13H3-mGMCSF,H15A,K20A SEQ ID NO:116 SEQ ID NO:155
13H3-mGMCSF,H15A,E21A SEQ ID NO:116 SEQ ID NO:156
根据上述测定，将合格的替代分子13H3-mGMCSF变体应用于体外表征。
替代分子13H3-mGMCSF变体诱导STAT5激活
通过使用CD11b阳性微珠(MiltenyiBiotec)从小鼠脾脏中纯化CD11b+巨噬细胞。用替代分子13H3-mGMCSF变体以不同浓度在37℃刺激纯化的巨噬细胞30分钟。孵育后，收集细胞并用FACS缓冲液(1×PBS+2％FBS)洗涤并用2％PFA固定，然后使用冰冷的甲醇渗透细胞。然后将PE偶联的抗pSTAT5抗体添加到细胞中，在4℃下再孵育30分钟，并通过流式细胞仪进行分析。MFI的倍数变化通过测试样品的MFI/IgG对照处理的MFI来计算。
图59显示在诱导STAT5磷酸化中，与野生型融合蛋白13H3-mGMCSF相比，13H3-mGMCSF变体表现出减弱的效力。
替代分子13H3-mGMCSF变体刺激FDC-P1增殖
在小鼠GMCSF刺激之前，先收集FDC-P1细胞，然后将其以2×105细胞/ml的浓度接种在平底96孔板的孔中，每孔50μL。将不同浓度的13H3-mGMCSF变体添加到FDC-P1细胞培养物中，并在37℃下孵育72小时。根据制造商的方案，通过CellTiter-发光细胞活力测定法测量细胞增殖。图60显示在刺激FDC-P1增殖中，与野生型融合蛋白13H3-mGMCSF相比，13H3-mGMCSF变体表现出减弱的效力。
序列表
<110> 天境生物科技（上海）有限公司
<120> 包含CD47抗体和细胞因子的融合蛋白
<130> 168782-010137
<150> PCT/CN2018/114975
<151> 2018-11-12
<160> 156
<170> SIPOSequenceListing 1.0
<210> 1
<211> 119
<212> PRT
<213> Homo sapiens
<400> 1
Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Ser Ile Gly Arg His Thr Phe Asp His Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 2
<211> 111
<212> PRT
<213> Homo sapiens
<400> 2
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Gly Ile Ala Ser Asn
20 25 30
Phe Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Val Pro Thr Thr Val
35 40 45
Ile Tyr Arg Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Val Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Lys Thr Asp Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Asp
85 90 95
His Asn His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 3
<211> 118
<212> PRT
<213> Homo sapiens
<400> 3
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 4
<211> 113
<212> PRT
<213> Homo sapiens
<400> 4
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu His Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 5
<211> 118
<212> PRT
<213> Homo sapiens
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Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
20 25 30
Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Ser Thr Gly Gly Arg Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Thr Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Ser Asn Phe Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 6
<211> 112
<212> PRT
<213> Homo sapiens
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Glu Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Asn Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Gln Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Ile Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys
100 105 110
<210> 7
<211> 118
<212> PRT
<213> Homo sapiens
<400> 7
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ile Asp Ala
20 25 30
Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Ala Arg Gly His Pro Gly Gln Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 8
<211> 112
<212> PRT
<213> Homo sapiens
<400> 8
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Thr Ile Ala Ser Asn
20 25 30
Phe Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ser Pro Thr Pro Val
35 40 45
Ile Phe Glu Asn Asp Arg Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Ser
65 70 75 80
Leu Asn Thr Glu Asp Lys Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser
85 90 95
Ser Thr His Gly Trp Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu
100 105 110
<210> 9
<211> 117
<212> PRT
<213> Homo sapiens
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Gln Val Asn Leu Arg Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Gly Gly Leu Glu Trp Val
35 40 45
Ser Tyr Thr Ser Arg Phe Gly Ser Asp Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Gln Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Asp Val His Asn Arg Asp Ala Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 10
<211> 110
<212> PRT
<213> Homo sapiens
<400> 10
Ser Tyr Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Gly Asn
20 25 30
Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Arg Asn His Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Asp Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Phe Ser Leu
85 90 95
Ser Gly Phe Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105 110
<210> 11
<211> 108
<212> PRT
<213> Homo sapiens
<400> 11
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Tyr Tyr
65 70 75 80
Cys Ala Asn Thr Asp Tyr Tyr Asp Ser Ser Ser His Thr Pro Ala Asp
85 90 95
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
100 105
<210> 12
<211> 108
<212> PRT
<213> Homo sapiens
<400> 12
Glu Thr Thr Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Asp
20 25 30
Leu Asp Trp Phe Gln Gln Lys Pro Gly Glu Ala Pro Lys Arg Leu Ile
35 40 45
Ser Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Gly Gly Ser Gly Ser Glu Phe Thr Leu Thr Ile His Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Thr Pro Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 13
<211> 122
<212> PRT
<213> Homo sapiens
<400> 13
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Gly Ser Gly Ser Ser Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Lys Gly Arg Tyr Tyr Tyr Asp Ser Leu Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ala
115 120
<210> 14
<211> 108
<212> PRT
<213> Homo sapiens
<400> 14
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Glu Ile Arg Thr Ala
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Tyr Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Ser Cys Gln Gln Tyr Asp Thr Ser Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 15
<211> 122
<212> PRT
<213> Homo sapiens
<400> 15
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Thr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ala Tyr Tyr Cys
85 90 95
Ala Lys Asp Lys Trp Ser Ser Trp Pro Thr Tyr Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 16
<211> 110
<212> PRT
<213> Homo sapiens
<400> 16
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ser Pro Thr Thr Val
35 40 45
Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser
85 90 95
Ser Asn Val Ile Phe Gly Gly Gly Thr Lys Val Thr Val Leu
100 105 110
<210> 17
<211> 122
<212> PRT
<213> Homo sapiens
<400> 17
Gln Val Gln Leu Gln Val Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Val Ser Asn Ser Gly Val Glu Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Arg Thr Arg Gln Leu Leu Thr Pro Arg Glu Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Leu Ala
115 120
<210> 18
<211> 107
<212> PRT
<213> Homo sapiens
<400> 18
Glu Thr Thr Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Arg Ala Ser Gln Asp Ile Thr Arg Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Ser Ser Val Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 19
<211> 117
<212> PRT
<213> Homo sapiens
<400> 19
Gln Val Asn Leu Arg Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Val Ser Ser Ala Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Val Asn Arg Ala Phe Asp Leu Trp Gly Arg Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 20
<211> 110
<212> PRT
<213> Homo sapiens
<400> 20
Asp Val Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Pro Met Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 21
<211> 121
<212> PRT
<213> Homo sapiens
<400> 21
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Val Trp Val
35 40 45
Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Thr Asp Lys Ser Tyr Gly Tyr Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 22
<211> 110
<212> PRT
<213> Homo sapiens
<400> 22
Ser Tyr Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Gly Ser Asn Ile Gly Ser Asn
20 25 30
Ser Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Thr Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Ile Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Val Tyr Tyr Cys Ala Thr Trp Asp Asp Arg Leu
85 90 95
Ser Gly Pro Val Phe Ala Ala Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 23
<211> 119
<212> PRT
<213> Homo sapiens
<400> 23
Gln Val Asn Leu Arg Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Ala Gly Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ser Leu Ser Phe Gly Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Ser Val Ser Gly
115
<210> 24
<211> 110
<212> PRT
<213> Homo sapiens
<400> 24
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Gly Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Gly Ser Thr
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Pro Pro Thr Thr Val
35 40 45
Ile Tyr Lys Asp Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Gly Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Glu Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Ser Asp Thr
85 90 95
Ser Asn Leu Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu
100 105 110
<210> 25
<211> 121
<212> PRT
<213> Homo sapiens
<400> 25
Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Pro Gly Phe Thr Phe Ser Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gly Asp Gly Ser Gln Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Met Lys Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Lys Gly Ala Ala Tyr His Ile Asn Ser Trp Leu Asp Pro Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 26
<211> 108
<212> PRT
<213> Homo sapiens
<400> 26
Glu Thr Thr Leu Thr Gln Ser Pro Gly Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Gly Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Phe Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr Asn Asn Phe Pro
85 90 95
His Thr Phe Gly Ala Gly Thr Lys Val Asp Ile Lys
100 105
<210> 27
<211> 118
<212> PRT
<213> Homo sapiens
<400> 27
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Phe Lys His Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 28
<211> 113
<212> PRT
<213> Homo sapiens
<400> 28
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Gln
20 25 30
Val Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 29
<211> 118
<212> PRT
<213> Homo sapiens
<400> 29
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 30
<211> 113
<212> PRT
<213> Homo sapiens
<400> 30
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Thr Val Leu Tyr Pro
20 25 30
Leu Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 31
<211> 118
<212> PRT
<213> Homo sapiens
<400> 31
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Glu Arg Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 32
<211> 113
<212> PRT
<213> Homo sapiens
<400> 32
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ala
20 25 30
Gly Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 33
<211> 118
<212> PRT
<213> Homo sapiens
<400> 33
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Pro Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 34
<211> 113
<212> PRT
<213> Homo sapiens
<400> 34
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Pro
20 25 30
Gly Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 35
<211> 118
<212> PRT
<213> Homo sapiens
<400> 35
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Gly Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 36
<211> 113
<212> PRT
<213> Homo sapiens
<400> 36
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Pro
20 25 30
Gly Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 37
<211> 118
<212> PRT
<213> Homo sapiens
<400> 37
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Gly Asn His Ser Ser Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 38
<211> 113
<212> PRT
<213> Homo sapiens
<400> 38
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 39
<211> 118
<212> PRT
<213> Homo sapiens
<400> 39
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Gly Ala His Ser Ser Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 40
<211> 113
<212> PRT
<213> Homo sapiens
<400> 40
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 41
<211> 118
<212> PRT
<213> Homo sapiens
<400> 41
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Gly Gln His Ser Ser Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 42
<211> 113
<212> PRT
<213> Homo sapiens
<400> 42
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 43
<211> 118
<212> PRT
<213> Homo sapiens
<400> 43
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Ala Tyr Ala Phe Asp Ala Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 44
<211> 113
<212> PRT
<213> Homo sapiens
<400> 44
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 45
<211> 118
<212> PRT
<213> Homo sapiens
<400> 45
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Ala Tyr Ala Phe Asp Ser Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 46
<211> 113
<212> PRT
<213> Homo sapiens
<400> 46
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 47
<211> 118
<212> PRT
<213> Homo sapiens
<400> 47
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asp Arg Ala Ser Asp Lys Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 48
<211> 113
<212> PRT
<213> Homo sapiens
<400> 48
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 49
<211> 118
<212> PRT
<213> Homo sapiens
<400> 49
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Ala Tyr Ala Phe Asp Thr Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 50
<211> 113
<212> PRT
<213> Homo sapiens
<400> 50
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 51
<211> 118
<212> PRT
<213> Homo sapiens
<400> 51
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Gly Asn His Ser Gln Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 52
<211> 113
<212> PRT
<213> Homo sapiens
<400> 52
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 53
<211> 118
<212> PRT
<213> Homo sapiens
<400> 53
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Gly Gln His Ser Gln Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 54
<211> 113
<212> PRT
<213> Homo sapiens
<400> 54
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 55
<211> 118
<212> PRT
<213> Homo sapiens
<400> 55
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Gly Ala His Ser Gln Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 56
<211> 113
<212> PRT
<213> Homo sapiens
<400> 56
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 57
<211> 118
<212> PRT
<213> Homo sapiens
<400> 57
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 58
<211> 113
<212> PRT
<213> Homo sapiens
<400> 58
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Leu Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 59
<211> 118
<212> PRT
<213> Homo sapiens
<400> 59
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 60
<211> 113
<212> PRT
<213> Homo sapiens
<400> 60
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Leu Arg Pro Pro Leu Asn Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 61
<211> 118
<212> PRT
<213> Homo sapiens
<400> 61
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 62
<211> 113
<212> PRT
<213> Homo sapiens
<400> 62
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Leu Thr Pro Pro Leu Asn Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 63
<211> 118
<212> PRT
<213> Homo sapiens
<400> 63
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 64
<211> 113
<212> PRT
<213> Homo sapiens
<400> 64
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Asn
85 90 95
Tyr Leu Thr Pro Pro Leu Ser Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 65
<211> 118
<212> PRT
<213> Homo sapiens
<400> 65
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 66
<211> 113
<212> PRT
<213> Homo sapiens
<400> 66
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Leu Lys Ala Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 67
<211> 118
<212> PRT
<213> Homo sapiens
<400> 67
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 68
<211> 113
<212> PRT
<213> Homo sapiens
<400> 68
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Leu Asn Ala Pro Leu His Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 69
<211> 118
<212> PRT
<213> Homo sapiens
<400> 69
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 70
<211> 113
<212> PRT
<213> Homo sapiens
<400> 70
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Leu Glu Ala Pro Leu Val Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 71
<211> 118
<212> PRT
<213> Homo sapiens
<400> 71
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 72
<211> 113
<212> PRT
<213> Homo sapiens
<400> 72
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Leu Lys Ala Pro Leu His Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 73
<211> 118
<212> PRT
<213> Homo sapiens
<400> 73
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 74
<211> 113
<212> PRT
<213> Homo sapiens
<400> 74
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Arg
85 90 95
Leu Ile Ala Pro Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 75
<211> 118
<212> PRT
<213> Homo sapiens
<400> 75
Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ala
115
<210> 76
<211> 113
<212> PRT
<213> Homo sapiens
<400> 76
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Asn
85 90 95
Tyr Leu Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 77
<211> 360
<212> DNA
<213> Homo sapiens
<400> 77
caggtccaac tggtgcagtc tggggctgaa gtgaagaagc ctgggtcttc agtgaaggtg 60
tcctgcaagg cttctggcta caccttcagc agctactata tgcactgggt gaggcaggct 120
cctggacaag gccttgagtg gatgggagag attaatccca acaatgcccg tattaacttc 180
aatgaaaagt tcaagaccag ggtcacactc actgtggaca aatccaccag cacagcatac 240
atggagctca gcagcctgag atctgaggac accgcggtct attactgtac cagaggatac 300
tataggtacg gggcctggtt tggttactgg ggccaaggga ctctggtcac tgtctcttca 360
<210> 78
<211> 321
<212> DNA
<213> Homo sapiens
<400> 78
gatatccaga tgacacagtc tccatcctcc ctgtctgcct ctgtgggaga cagagtcacc 60
atcacttgca gggcaagtca ggacattagc gattatttga actggtatca acagaaacca 120
ggcaaggctc ctaaactcct gatctactac atatcaagat tacactcagg agtcccatca 180
cgcttcagtg gcagtgggtc tggaacagat tatactctca ccattagctc cctgcagcca 240
gaagattttg ccacttacta ttgccaacag ggtcatacac ttccgtggac cttcggtgga 300
ggcaccaagg tggaaatcaa a 321
<210> 79
<211> 357
<212> DNA
<213> Homo sapiens
<400> 79
caggtacagc tgcagcagtc agggggaggc ttggtacagc ctggggggtc cctaagactc 60
tcctgtacag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagca attagtggta gtggtggtag cacatactac 180
gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agtcgaggac acggccgtat attactgtgc gagatatagt 300
attggtagac acacctttga ccactggggc cagggcaccc tggtcaccgt ctcggcc 357
<210> 80
<211> 354
<212> DNA
<213> Homo sapiens
<400> 80
aaggtgcagc tggtggagtc tgggggaggc ttggtaaagc ctggggggtc ccttagactc 60
tcctgtgcag cctctggttt cactttcagt aacgcctgga tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtcggccgt attaaaagga aaactgatgg tgagacaaca 180
gactacgctg cacccgtgaa aggcagattc agcatctcaa gagatgattc aaaaaacacc 240
ctgtatctgc aaatgaacag cttgaaaacc gaggacacag ccgtgtatta ctgcgctggc 300
agtaaccgag cttttgatat ctggggccaa gggacaatgg tcaccgtctc tgcc 354
<210> 81
<211> 354
<212> DNA
<213> Homo sapiens
<400> 81
caggtacagc tgcagcagtc agggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc ggctatgcca tgacttgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagct attacttcta ctggtggtcg cacatactac 180
gcagactccg tgaagggccg gttcaccacc tccagagaca attccaggaa cacgttgtat 240
ctgcaaatga acagcctgag agccgaagac acggccgtat attactgtgc gagagagtca 300
aacttcaggg cttttgatat ctggggccaa gggacaatgg tcaccgtctc tgcc 354
<210> 82
<211> 354
<212> DNA
<213> Homo sapiens
<400> 82
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc ccttagactc 60
tcctgtgcag cctctggatt cactttcatt gacgcctgga tgacctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctg 240
caaatgaaca gcctgagagc cgaggacacg gccgtatatt actgtgcgag aggggctagg 300
ggccatcccg ggcaggacta ctgggggcag ggcaccctgg tcaccgtctc ggcc 354
<210> 83
<211> 351
<212> DNA
<213> Homo sapiens
<400> 83
caggtcaact taagggagtc tgggggaggc ttggtacagc ctggcgggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt gactactaca tgagctggat ccgccaggct 120
ccaggggggg ggctggagtg ggtttcatac actagtcgtt ttggtagtga cacaaactac 180
gcagactctg tgaagggccg attcaccatc tccagagaca acgtccagaa ctcactatat 240
ctgcaaatga acagcctgag ggccgaggac acggctgttt attactgtgt gagagatgta 300
cataacaggg atgcctactg gggccagggc accctggtca ccgtctcggc c 351
<210> 84
<211> 369
<212> DNA
<213> Homo sapiens
<400> 84
caggtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180
gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaacacagat 300
tactatgata gtagtagcca tacccccgct gactactggg gccagggcac cctggtcacc 360
gtctcggcc 369
<210> 85
<211> 366
<212> DNA
<213> Homo sapiens
<400> 85
caggtgcagc tgcaggagtc ggggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agctatggca tgagctgggt ccgccaggct 120
ccagggaaag ggctggagtg ggtctcaact atcagtggca gtggtagtag cacaaactac 180
gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctattt 240
ctgcaaatga acagcctgag agccgaggac acggccgtat atttctgtgc gaaaggccga 300
tattactatg atagtcttga tgcttttgat atctggggcc aagggacaat ggtcaccgtc 360
tctgcc 366
<210> 86
<211> 366
<212> DNA
<213> Homo sapiens
<400> 86
caggtacagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagct attagtggta ctggtggtag cacatactac 180
gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgcat attactgtgc gaaagataaa 300
tggagcagct ggcccactta ctactttgac tactggggcc agggaaccct ggtcaccgtc 360
tcggcc 366
<210> 87
<211> 366
<212> DNA
<213> Homo sapiens
<400> 87
caggtgcagc tgcaggtgtc ggggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatagca tggcctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtcgcggct gttagtaata gtggtgttga gacatactac 180
gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ttgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaacgaact 300
agacaactgc taactccgcg ggagtttgac tactggggcc agggcaccct ggtcaccgtc 360
ttggcc 366
<210> 88
<211> 351
<212> DNA
<213> Homo sapiens
<400> 88
caggtcaact taagggagtc tgggggaggc ttgatacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttacc aattatgcca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcaagt gttagtagtg ctggtggtag tacatactac 180
gcagactccg tgaagggccg gttcaccatc tccagagaca acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgttt attactgtgc gagacgagtc 300
aatcgggcct tcgatctctg gggccgtgga accctggtca ccgtctcggc c 351
<210> 89
<211> 363
<212> DNA
<213> Homo sapiens
<400> 89
caggtgcagc tgcaggagtc ggggggaggc ttggtacagc ctggggggtc ccttagactc 60
tcctgtgcag cctctggatt cactttcagt aacgcctgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggtgtg ggttggccgt attaaaagca aaactgatgg tgggacaaca 180
gactacgctg cacccgtgaa aggcagattc accatctcaa gagatgattc aaaaaacacg 240
ctgtatctgc aaatgaacag cctgaaaacc gaggacacag ccgtgtatta ctgtaccaca 300
gataagagct atggttacac atttgactac tggggccagg gcaccctggt caccgtctcg 360
gcc 363
<210> 90
<211> 357
<212> DNA
<213> Homo sapiens
<400> 90
caggtcaact taagggagtc tgggggaggc ttggtaaagc cgggggggtc ccttagactc 60
tcctgtgcag cctctggatt caccttcagt agctactgga tgcactgggt ccgccaagcc 120
ccagggaagg ggctggagtg ggtctcagct atcagtggta gtggtgccgg cacatactac 180
ccagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gagagatcgg 300
tccttatctt ttggttttga tatttggggc caaggcaccc tggtctccgt ctctggc 357
<210> 91
<211> 363
<212> DNA
<213> Homo sapiens
<400> 91
caggtacagc tgcagcagtc agggggaggc ttggtccagc cgggggggtc actgagactc 60
tcctgtgcag cccctggatt cacctttagt agatattgga tgagttgggt ccgccaggct 120
ccagggaagg gactggagtg ggtggccaac ataaagggag atggaagtca gacatactat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccatgaa aacagtgtat 240
ctgcaaatga acagcctgag agccgaggac acggccatat attactgtgc gaaaggggct 300
gcttatcaca ttaacagctg gctcgacccc tggggccagg gcaccctggt caccgtctcg 360
gcc 363
<210> 92
<211> 333
<212> DNA
<213> Homo sapiens
<400> 92
aattttatgc tgactcagcc ccactctgtg tcggagtctc cggggaagac ggtaaccatc 60
tcctgcaccc gcagcagtgg cggcattgcc agtaactttg tgcagtggta ccagcagcgc 120
ccgggcagtg tccccaccac tgtgatctat agggataacc aaagaccctc tggagtccct 180
gatcggttct ctggctccgt cgacagctcc tccaattctg cctccctcac catctctggg 240
ctgaagactg acgatgaggc tgactattat tgtcagtcct atgatgacca caatcattgg 300
gtgttcggcg gcgggaccaa gctgaccgtc cta 333
<210> 93
<211> 339
<212> DNA
<213> Homo sapiens
<400> 93
gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60
atcaactgca agtccagcca gagtgtttta tacagctcca acaataggaa ctacctagct 120
tggtaccagc agaaaccagg acagcctcct aagctgctca ttaaccaggc atctacccgg 180
gcatccggcg tccctgaccg attcagtggc agcgggtctg ggacagagtt cactctcatc 240
atcagcagcc tgcaggctga agatgtggcg atttattact gtcagcaata ttatactcct 300
cccctcgctt tcggcggagg gaccaagctg gagatcaaa 339
<210> 94
<211> 336
<212> DNA
<213> Homo sapiens
<400> 94
gaaattgtgt tgacgcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
atctcctgca ggtctagtca gagcctcctg cacagtaatg gatacaacta tttggattgg 120
tacctgcaga aaccagggca gtctccacag ctcctgatct atttgaattc taatcgggcc 180
tccggggtcc ctgacaggtt cagtggcagt ggatcaggta cagattttac actgcaaatc 240
agcagagtgg aggctgagga tgttggggtt tactactgta tgcaagctct acaaattcct 300
cccactttcg gcggagggac caaagtggat atcaaa 336
<210> 95
<211> 336
<212> DNA
<213> Homo sapiens
<400> 95
aattttatgc tgactcagcc ccactctgtg tcggagtctc cgggaaagac ggtaaccatc 60
tcctgcaccc gcagcagtgg caccattgcc agcaactttg tgcagtggta tcaacagcgc 120
ccgggcagtt cgcccacccc agtgatcttt gagaatgacc gaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacagctcc tccaattctg cctccctcac catttcgtca 240
ctgaacactg aggacaaggc tgactactac tgtcagtcct atgatagcag cactcatggg 300
tgggtgtttg gcggagggac ccagctcacc gtttta 336
<210> 96
<211> 330
<212> DNA
<213> Homo sapiens
<400> 96
tcctatgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60
tcttgttctg gaagcagctc caacatcggc ggtaattctg tatcctggta ccagcaactc 120
ccaggaacgg cccccaagct cctcatctat aggaatcatc agcggccctc aggggtccct 180
gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccgg 240
tccgacgacg aggctgatta ttattgtgca acatgggatt tcagcctgag tggttttgtc 300
ttcggaactg ggaccaaggt caccgtccta 330
<210> 97
<211> 324
<212> DNA
<213> Homo sapiens
<400> 97
gaaactacac tcacgcagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca ggacatcaga aatgatttag actggtttca acaaaaacca 120
ggcgaagccc ctaaacgcct gatctctgct gcatctaatt tgcagagtgg ggtcccctca 180
cgattcagcg gcggtggctc tggctccgaa ttcactctca caatccacag cctggagtct 240
gaagattttg caacttacta ctgtcaacag agttacatta cccctccttg gacgttcggc 300
caagggacca agctggagat caaa 324
<210> 98
<211> 324
<212> DNA
<213> Homo sapiens
<400> 98
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca ggaaattagg accgcctact tagcctggta ccagcagaaa 120
cctggccagg ctcccaggct cctcatctat tatgcatcca gcagggccac tggcatccca 180
gacaggttca gcggcagtag gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttcctgtcag cagtatgata cctcacctcc caccttcggc 300
caagggacac gactggagat taaa 324
<210> 99
<211> 330
<212> DNA
<213> Homo sapiens
<400> 99
aattttatgc tgactcagcc ccactctgtg tcggagtctc cggggaagac ggtaaccatc 60
tcctgcaccc gcagcagtgg cagcattgcc agcaactatg tgcagtggta ccaacagcgc 120
ccgggcagtt cccccaccac tgtgatctat gaggataacc aaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacagctcc tccaactctg cctccctcac catctctgga 240
ctgaagactg aggacgaggc tgactactac tgtcagtctt atgatagcag caatgtgata 300
ttcggcggag ggaccaaggt caccgtccta 330
<210> 100
<211> 321
<212> DNA
<213> Homo sapiens
<400> 100
gaaactacac tcacgcagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
ctcacttgtc gggcgagtca ggatatcaca aggtggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgat gcatccagtt tgcaaagtgg ggtcccatca 180
agattcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag ggttccagtg ttcctttcac tttcggcgga 300
gggaccaagg tggagatcaa a 321
<210> 101
<211> 330
<212> DNA
<213> Homo sapiens
<400> 101
gatgttgtga tgactcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccaacagaaa 120
cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctcc tatgtacact 300
tttggccagg ggaccaagct ggagatcaaa 330
<210> 102
<211> 330
<212> DNA
<213> Homo sapiens
<400> 102
tcctatgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60
tcttgttctg gaagtggctc caacatcgga agtaattctg ttcactggta ccagcaactc 120
ccaggaacgg cccccaaact cctcatctat actaataatc agcggccctc aggggtccct 180
gaccgattct ctggctccaa gtctggcatt tcagcctccc tggctatcag tgggctccag 240
tctgaggatg aggctgttta ttactgtgca acgtgggatg acagactgag tggtccggtg 300
ttcgccgcag ggaccaagct gaccgtccta 330
<210> 103
<211> 330
<212> DNA
<213> Homo sapiens
<400> 103
aattttatgc tgactcagcc ccactctgtg tcggggtctc cggggaagac ggtaaccatc 60
tcctgcaccc gcagcagtgg cagcattggc agcacctatg tgcagtggta ccaacagcgc 120
ccgggcagtc cccccaccac tgtgatctat aaggatgacc aaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacggctcc tccaactctg cctccctcac catctctgga 240
ctggagactg aggacgaggc tgactactac tgtcagtctt ctgataccag caatctggtc 300
ttcggcggag ggaccaaggt caccgtccta 330
<210> 104
<211> 324
<212> DNA
<213> Homo sapiens
<400> 104
gaaactacac tcacgcagtc tccaggcacc ctgtctgttt ctccggggga aagagttacc 60
ctctcctgca gggccagtca gagtattagc ggtaattact tagcctggta ccagcagaga 120
cctggccagg ctcccaggct cctcatctat ggggcattca ggagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcac cagactggag 240
cctgaagatt ttgcaactta ttactgccaa cactataata atttccccca cactttcggc 300
gcagggacca aagtggatat caaa 324
<210> 105
<211> 120
<212> PRT
<213> Homo sapiens
<400> 105
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Ser Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Asn Pro Asn Asn Ala Arg Ile Asn Phe Asn Glu Lys Phe
50 55 60
Lys Thr Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Gly Tyr Tyr Arg Tyr Gly Ala Trp Phe Gly Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 106
<211> 107
<212> PRT
<213> Homo sapiens
<400> 106
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asp Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ile Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly His Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 107
<211> 123
<212> PRT
<213> Homo sapiens
<400> 107
Gln Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn
1 5 10 15
Asp Thr Val Val Ile Pro Cys Phe Val Thr Asn Met Glu Ala Gln Asn
20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp Ile Tyr
35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser
50 55 60
Ser Ala Lys Ile Glu Val Ser Gln Leu Leu Lys Gly Asp Ala Ser Leu
65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys
85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr Ile Ile Glu Leu Lys
100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu
115 120
<210> 108
<211> 220
<212> PRT
<213> Homo sapiens
<400> 108
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 109
<211> 575
<212> PRT
<213> Homo sapiens
<400> 109
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 110
<211> 575
<212> PRT
<213> Homo sapiens
<400> 110
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Ser Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 111
<211> 575
<212> PRT
<213> Homo sapiens
<400> 111
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Ala Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 112
<211> 575
<212> PRT
<213> Homo sapiens
<400> 112
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Arg Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 113
<211> 575
<212> PRT
<213> Homo sapiens
<400> 113
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Ser Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Lys
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 114
<211> 575
<212> PRT
<213> Homo sapiens
<400> 114
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Arg Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Lys
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 115
<211> 575
<212> PRT
<213> Homo sapiens
<400> 115
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Lys Met Phe Lys
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Lys
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 116
<211> 220
<212> PRT
<213> Homo sapiens
<400> 116
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ala
20 25 30
Gly Asn Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Asn Gln Ala Ser Thr Arg Ala Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Pro Pro Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 117
<211> 575
<212> PRT
<213> Homo sapiens
<400> 117
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 118
<211> 575
<212> PRT
<213> Homo sapiens
<400> 118
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Ser Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 119
<211> 575
<212> PRT
<213> Homo sapiens
<400> 119
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Ala Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 120
<211> 575
<212> PRT
<213> Homo sapiens
<400> 120
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Arg Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 121
<211> 575
<212> PRT
<213> Homo sapiens
<400> 121
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Ser Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Lys
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 122
<211> 575
<212> PRT
<213> Homo sapiens
<400> 122
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Arg Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Lys
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 123
<211> 575
<212> PRT
<213> Homo sapiens
<400> 123
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Lys Met Phe Lys
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Lys
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 124
<211> 575
<212> PRT
<213> Homo sapiens
<400> 124
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Gln Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Gln Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 125
<211> 575
<212> PRT
<213> Homo sapiens
<400> 125
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ala Pro Ala Ala Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 126
<211> 575
<212> PRT
<213> Homo sapiens
<400> 126
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ala Pro Ala Ala Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Gln Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Gln Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 127
<211> 565
<212> PRT
<213> Homo sapiens
<400> 127
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Gln Pro Trp Glu His Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu
450 455 460
Gln Leu Ser Arg Asp Thr Ala Ala Glu Met Gln Glu Thr Val Glu Val
465 470 475 480
Ile Ser Glu Met Phe Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg
485 490 495
Leu Glu Leu Tyr Lys Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys
500 505 510
Gly Pro Leu Thr Met Met Ala Ser His Tyr Lys Gln His Cys Pro Pro
515 520 525
Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe
530 535 540
Lys Glu Asn Leu Lys Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp
545 550 555 560
Glu Pro Val Gln Glu
565
<210> 128
<211> 575
<212> PRT
<213> Homo sapiens
<400> 128
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Gln Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Gln Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 129
<211> 575
<212> PRT
<213> Homo sapiens
<400> 129
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ala Pro Ala Ala Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 130
<211> 575
<212> PRT
<213> Homo sapiens
<400> 130
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ala Pro Ala Ala Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Gln Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Gln Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 131
<211> 565
<212> PRT
<213> Homo sapiens
<400> 131
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Gln Pro Trp Glu His Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu
450 455 460
Gln Leu Ser Arg Asp Thr Ala Ala Glu Met Gln Glu Thr Val Glu Val
465 470 475 480
Ile Ser Glu Met Phe Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg
485 490 495
Leu Glu Leu Tyr Lys Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys
500 505 510
Gly Pro Leu Thr Met Met Ala Ser His Tyr Lys Gln His Cys Pro Pro
515 520 525
Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe
530 535 540
Lys Glu Asn Leu Lys Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp
545 550 555 560
Glu Pro Val Gln Glu
565
<210> 132
<211> 575
<212> PRT
<213> Homo sapiens
<400> 132
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Arg Ala Arg Arg Leu Leu Gln Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Gln Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 133
<211> 575
<212> PRT
<213> Homo sapiens
<400> 133
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ala Pro Ala Ala Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Arg Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 134
<211> 575
<212> PRT
<213> Homo sapiens
<400> 134
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ala Pro Ala Ala Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Arg Ala Arg Arg Leu Leu Gln Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Gln Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 135
<211> 565
<212> PRT
<213> Homo sapiens
<400> 135
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Gln Pro Trp Glu His Val Asn Ala Ile Gln Arg Ala Arg Arg Leu Leu
450 455 460
Gln Leu Ser Arg Asp Thr Ala Ala Glu Met Gln Glu Thr Val Glu Val
465 470 475 480
Ile Ser Glu Met Phe Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg
485 490 495
Leu Glu Leu Tyr Lys Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys
500 505 510
Gly Pro Leu Thr Met Met Ala Ser His Tyr Lys Gln His Cys Pro Pro
515 520 525
Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe
530 535 540
Lys Glu Asn Leu Lys Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp
545 550 555 560
Glu Pro Val Gln Glu
565
<210> 136
<211> 575
<212> PRT
<213> Homo sapiens
<400> 136
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Ser Ala Arg Arg Leu Leu Gln Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Gln Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Lys
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 137
<211> 575
<212> PRT
<213> Homo sapiens
<400> 137
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ala Pro Ala Ala Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Ser Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Lys
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 138
<211> 575
<212> PRT
<213> Homo sapiens
<400> 138
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ala Pro Ala Ala Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Ser Ala Arg Arg Leu Leu Gln Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Gln Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Lys
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 139
<211> 565
<212> PRT
<213> Homo sapiens
<400> 139
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Gln Pro Trp Glu His Val Asn Ala Ile Gln Ser Ala Arg Arg Leu Leu
450 455 460
Gln Leu Ser Arg Asp Thr Ala Ala Glu Met Gln Glu Thr Val Glu Val
465 470 475 480
Ile Ser Glu Met Phe Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg
485 490 495
Leu Glu Leu Tyr Lys Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys
500 505 510
Gly Pro Leu Thr Met Met Ala Ser His Tyr Lys Gln His Cys Pro Pro
515 520 525
Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe
530 535 540
Lys Glu Asn Leu Lys Lys Phe Leu Leu Val Ile Pro Phe Asp Cys Trp
545 550 555 560
Glu Pro Val Gln Glu
565
<210> 140
<211> 575
<212> PRT
<213> Homo sapiens
<400> 140
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Arg Ala Arg Arg Leu Leu Gln Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Gln Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 141
<211> 575
<212> PRT
<213> Homo sapiens
<400> 141
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ala Pro Ala Ala Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Arg Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 142
<211> 575
<212> PRT
<213> Homo sapiens
<400> 142
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ala Pro Ala Ala Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Arg Ala Arg Arg Leu Leu Gln Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Gln Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Asp
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 143
<211> 565
<212> PRT
<213> Homo sapiens
<400> 143
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Gln Pro Trp Glu His Val Asn Ala Ile Gln Arg Ala Arg Arg Leu Leu
450 455 460
Gln Leu Ser Arg Asp Thr Ala Ala Glu Met Gln Glu Thr Val Glu Val
465 470 475 480
Ile Ser Glu Met Phe Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg
485 490 495
Leu Glu Leu Tyr Lys Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys
500 505 510
Gly Pro Leu Thr Met Met Ala Ser His Tyr Lys Gln His Cys Pro Pro
515 520 525
Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe
530 535 540
Lys Glu Asn Leu Lys Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp
545 550 555 560
Glu Pro Val Gln Glu
565
<210> 144
<211> 575
<212> PRT
<213> Homo sapiens
<400> 144
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Ser Ala Arg Arg Leu Leu Gln Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Gln Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Lys
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 145
<211> 575
<212> PRT
<213> Homo sapiens
<400> 145
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ala Pro Ala Ala Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Ser Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Lys
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 146
<211> 575
<212> PRT
<213> Homo sapiens
<400> 146
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Ala Arg Ser Pro Ala Pro Ala Ala Gln Pro Trp Glu His Val
450 455 460
Asn Ala Ile Gln Ser Ala Arg Arg Leu Leu Gln Leu Ser Arg Asp Thr
465 470 475 480
Ala Ala Glu Met Gln Glu Thr Val Glu Val Ile Ser Glu Met Phe Asp
485 490 495
Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys Gln
500 505 510
Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met Met
515 520 525
Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser Cys
530 535 540
Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys Lys
545 550 555 560
Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
565 570 575
<210> 147
<211> 565
<212> PRT
<213> Homo sapiens
<400> 147
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Gln Pro Trp Glu His Val Asn Ala Ile Gln Ser Ala Arg Arg Leu Leu
450 455 460
Gln Leu Ser Arg Asp Thr Ala Ala Glu Met Gln Glu Thr Val Glu Val
465 470 475 480
Ile Ser Glu Met Phe Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg
485 490 495
Leu Glu Leu Tyr Lys Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys
500 505 510
Gly Pro Leu Thr Met Met Ala Ser His Tyr Lys Gln His Cys Pro Pro
515 520 525
Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe
530 535 540
Lys Glu Asn Leu Lys Lys Phe Leu Leu Val Ile Pro Phe Asp Cys Trp
545 550 555 560
Glu Pro Val Gln Glu
565
<210> 148
<211> 572
<212> PRT
<213> Homo sapiens
<400> 148
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Glu Arg Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His Val
450 455 460
Glu Ala Ile Lys Glu Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr
465 470 475 480
Leu Asn Glu Glu Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys Lys
485 490 495
Leu Thr Cys Val Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg
500 505 510
Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr
515 520 525
Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln
530 535 540
Val Thr Thr Tyr Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr
545 550 555 560
Asp Ile Pro Phe Glu Cys Lys Lys Pro Val Gln Lys
565 570
<210> 149
<211> 572
<212> PRT
<213> Homo sapiens
<400> 149
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Glu Arg Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His Val
450 455 460
Glu Ala Ile Lys Ser Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr
465 470 475 480
Leu Asn Glu Glu Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys Lys
485 490 495
Leu Thr Cys Val Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg
500 505 510
Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr
515 520 525
Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln
530 535 540
Val Thr Thr Tyr Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr
545 550 555 560
Asp Ile Pro Phe Glu Cys Lys Lys Pro Val Gln Lys
565 570
<210> 150
<211> 572
<212> PRT
<213> Homo sapiens
<400> 150
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Glu Arg Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His Val
450 455 460
Glu Ala Ile Lys Ala Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr
465 470 475 480
Leu Asn Glu Glu Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys Lys
485 490 495
Leu Thr Cys Val Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg
500 505 510
Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr
515 520 525
Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln
530 535 540
Val Thr Thr Tyr Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr
545 550 555 560
Asp Ile Pro Phe Glu Cys Lys Lys Pro Val Gln Lys
565 570
<210> 151
<211> 572
<212> PRT
<213> Homo sapiens
<400> 151
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Glu Arg Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Lys His Val
450 455 460
Glu Ala Ile Lys Arg Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr
465 470 475 480
Leu Asn Glu Glu Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys Lys
485 490 495
Leu Thr Cys Val Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg
500 505 510
Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr
515 520 525
Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln
530 535 540
Val Thr Thr Tyr Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr
545 550 555 560
Asp Ile Pro Phe Glu Cys Lys Lys Pro Val Gln Lys
565 570
<210> 152
<211> 572
<212> PRT
<213> Homo sapiens
<400> 152
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Glu Arg Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Ala Ala Val
450 455 460
Glu Ala Ile Lys Glu Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr
465 470 475 480
Leu Asn Glu Glu Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys Lys
485 490 495
Leu Thr Cys Val Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg
500 505 510
Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr
515 520 525
Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln
530 535 540
Val Thr Thr Tyr Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr
545 550 555 560
Asp Ile Pro Phe Glu Cys Lys Lys Pro Val Gln Lys
565 570
<210> 153
<211> 572
<212> PRT
<213> Homo sapiens
<400> 153
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Glu Arg Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Ala His Val
450 455 460
Glu Ala Ile Ala Glu Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr
465 470 475 480
Leu Asn Glu Glu Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys Lys
485 490 495
Leu Thr Cys Val Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg
500 505 510
Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr
515 520 525
Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln
530 535 540
Val Thr Thr Tyr Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr
545 550 555 560
Asp Ile Pro Phe Glu Cys Lys Lys Pro Val Gln Lys
565 570
<210> 154
<211> 572
<212> PRT
<213> Homo sapiens
<400> 154
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Glu Arg Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
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Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
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Tyr Cys Ala Gly Ser Asn Arg Ala Phe Asp Ile Trp Gly Gln Gly Thr
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Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
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Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
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Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
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Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
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His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
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Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
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Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
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Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
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Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
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Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
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Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
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Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
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Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Ala His Val
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Glu Ala Ile Lys Ala Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr
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Leu Thr Cys Val Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg
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Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr
515 520 525
Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln
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Val Thr Thr Tyr Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr
545 550 555 560
Asp Ile Pro Phe Glu Cys Lys Lys Pro Val Gln Lys
565 570
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Glu Arg Ala
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Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
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His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
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Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
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Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
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Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
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Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
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Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
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Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
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Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
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Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
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Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
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Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Lys Ala Val
450 455 460
Glu Ala Ile Ala Glu Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr
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500 505 510
Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr
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Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln
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Asp Ile Pro Phe Glu Cys Lys Lys Pro Val Gln Lys
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Glu Arg Ala
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Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Glu Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Ser Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
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130 135 140
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Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
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His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
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Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
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Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
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Ala Pro Thr Arg Ser Pro Ile Thr Val Thr Arg Pro Trp Lys Ala Val
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Glu Ala Ile Lys Ala Ala Leu Asn Leu Leu Asp Asp Met Pro Val Thr
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Leu Asn Glu Glu Val Glu Val Val Ser Asn Glu Phe Ser Phe Lys Lys
485 490 495
Leu Thr Cys Val Gln Thr Arg Leu Lys Ile Phe Glu Gln Gly Leu Arg
500 505 510
Gly Asn Phe Thr Lys Leu Lys Gly Ala Leu Asn Met Thr Ala Ser Tyr
515 520 525
Tyr Gln Thr Tyr Cys Pro Pro Thr Pro Glu Thr Asp Cys Glu Thr Gln
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Val Thr Thr Tyr Ala Asp Phe Ile Asp Ser Leu Lys Thr Phe Leu Thr
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Asp Ile Pro Phe Glu Cys Lys Lys Pro Val Gln Lys
565 570

Claims (23)

1.一种融合蛋白，所述蛋白包含分离的单克隆抗体或其免疫活性片段和细胞因子，其特征在于，所述单克隆抗体或其免疫活性片段能结合人CD47，所述单克隆抗体或其免疫活性片段与细胞因子的N-末端融合，在单克隆抗体或其片段与细胞因子之间具有或不具有连接物。
2.如权利要求1所述的融合蛋白，其特征在于，所述分离的单克隆抗体或其免疫活性片段包括：
可变重(VH)链序列，所述序列与选自包括下述序列的组中的氨基酸序列具有至少95％的一致性：SEQ ID NO:1，SEQ ID NO:3，SEQ ID NO:5，SEQ ID NO:7，SEQ ID NO:9，SEQ IDNO:11，SEQ ID NO:13，SEQ ID NO:15，SEQ ID NO:17，SEQ ID NO:19，SEQ ID NO:21，SEQ IDNO:23，SEQ ID NO:25，SEQ ID NO:27，SEQ ID NO:29，SEQ ID NO:31，SEQ ID NO:33，SEQ IDNO:35，SEQ ID NO:37，SEQ ID NO:39，SEQ ID NO:41，SEQ ID NO:43，SEQ ID NO:45，SEQ IDNO:47，SEQ ID NO:49，SEQ ID NO:51，SEQ ID NO:53，SEQ ID NO:55，SEQ ID NO:57，SEQ IDNO:59，SEQ ID NO:61，SEQ ID NO:63，SEQ ID NO:65，SEQ ID NO:67，SEQ ID NO:69，SEQ IDNO:71，SEQ ID NO:73，SEQ ID NO:75，和SEQ ID NO:77；和
可变轻(VL)链序列，该序列与选自包括下述序列的组中的氨基酸序列具有至少95％的一致性：SEQ ID NO:2，SEQ ID NO:4，SEQ ID NO:6，SEQ ID NO:8，SEQ ID NO:10，SEQ IDNO:12，SEQ ID NO:14，SEQ ID NO:16，SEQ ID NO:18，SEQ ID NO:20，SEQ ID NO:22，SEQ IDNO:24，SEQ ID NO:26，SEQ ID NO:28，SEQ ID NO:30，SEQ ID NO:32，SEQ ID NO:34，SEQ IDNO:36，SEQ ID NO:38，SEQ ID NO:40，SEQ ID NO:42，SEQ ID NO:44，SEQ ID NO:46，SEQ IDNO:48，SEQ ID NO:50，SEQ ID NO:52，SEQ ID NO:54，SEQ ID NO:56，SEQ ID NO:58，SEQ IDNO:60，SEQ ID NO:62，SEQ ID NO:64，SEQ ID NO:66，SEQ ID NO:68，SEQ ID NO:70，SEQ IDNO:72，SEQ ID NO:74，SEQ ID NO:76，和SEQ ID NO:78。
3.如权利要求2所述的融合蛋白，其特征在于，所述分离的单克隆抗体或其免疫活性片段，包括VH/VL序列对，所述的VH/VL序列对包括VH和VL链序列，该序列对与选自包括下述序列对的组中的VH和VL氨基酸序列对具有至少95％的一致性：SEQ ID NO:1和SEQ ID NO:2，SEQ ID NO:3和SEQ ID NO:4，SEQ ID NO:5和SEQ ID NO:6，SEQ ID NO:7和SEQ ID NO:8，SEQ ID NO:9和SEQ ID NO:10，SEQ ID NO:11和SEQ ID NO:12，SEQ ID NO:13和SEQ ID NO:14，SEQ ID NO:15和SEQ ID NO:16，SEQ ID NO:17和SEQ ID NO:18，SEQ ID NO:19和SEQ IDNO:20，SEQ ID NO:21和SEQ ID NO:22，SEQ ID NO:23和SEQ ID NO:24，SEQ ID NO:25和SEQID NO:26，SEQ ID NO:27和SEQ ID NO:28，SEQ ID NO:29和SEQ ID NO:30，SEQ ID NO:31和SEQ ID NO:32，SEQ ID NO:33和SEQ ID NO:34，SEQ ID NO:35和SEQ ID NO:36，SEQ ID NO:37和SEQ ID NO:38，SEQ ID NO:39和SEQ ID NO:40，SEQ ID NO:41和SEQ ID NO:42，SEQ IDNO:43和SEQ ID NO:44，SEQ ID NO:45和SEQ ID NO:46，SEQ ID NO:47和SEQ ID NO:48，SEQID NO:49和SEQ ID NO:50，SEQ ID NO:51和SEQ ID NO:52，SEQ ID NO:53和SEQ ID NO:54，SEQ ID NO:55和SEQ ID NO:56，SEQ ID NO:57和SEQ ID NO:58，SEQ ID NO:59和SEQ IDNO:60，SEQ ID NO:61和SEQ ID NO:62，SEQ ID NO:63和SEQ ID NO:64，SEQ ID NO:65和SEQID NO:66，SEQ ID NO:67和SEQ ID NO:68，SEQ ID NO:69和SEQ ID NO:70，SEQ ID NO:71和SEQ ID NO:72，SEQ ID NO:73和SEQ ID NO:74，SEQ ID NO:75和SEQ ID NO:76，和SEQ IDNO:77和SEQ ID NO:78。
4.如权利要求2所述的融合蛋白，其特征在于，所述分离的单克隆抗体或其免疫活性片段包括VH/VL序列对，其中，所述的VH/VL序列对包括VH和VL链序列，所述序列对选自包括下述序列对的组：SEQ ID NO:1和SEQ ID NO:2，SEQ ID NO:3和SEQ ID NO:4，SEQ ID NO:5和SEQ ID NO:6，SEQ ID NO:7和SEQ ID NO:8，SEQ ID NO:9和SEQ ID NO:10，SEQ ID NO:11和SEQ ID NO:12，SEQ ID NO:13和SEQ ID NO:14，SEQ ID NO:15和SEQ ID NO:16，SEQ ID NO:17和SEQ ID NO:18，SEQ ID NO:19和SEQ ID NO:20，SEQ ID NO:21和SEQ ID NO:22，SEQ IDNO:23和SEQ ID NO:24，SEQ ID NO:25和SEQ ID NO:26，SEQ ID NO:27和SEQ ID NO:28，SEQID NO:29和SEQ ID NO:30，SEQ ID NO:31和SEQ ID NO:32，SEQ ID NO:33和SEQ ID NO:34，SEQ ID NO:35和SEQ ID NO:36，SEQ ID NO:37和SEQ ID NO:38，SEQ ID NO:39和SEQ IDNO:40，SEQ ID NO:41和SEQ ID NO:42，SEQ ID NO:43和SEQ ID NO:44，SEQ ID NO:45和SEQID NO:46，SEQ ID NO:47和SEQ ID NO:48，SEQ ID NO:49和SEQ ID NO:50，SEQ ID NO:51和SEQ ID NO:52，SEQ ID NO:53和SEQ ID NO:54，SEQ ID NO:55和SEQ ID NO:56，SEQ ID NO:57和SEQ ID NO:58，SEQ ID NO:59和SEQ ID NO:60，SEQ ID NO:61和SEQ ID NO:62，SEQ IDNO:63和SEQ ID NO:64，SEQ ID NO:65和SEQ ID NO:66，SEQ ID NO:67和SEQ ID NO:68，SEQID NO:69和SEQ ID NO:70，SEQ ID NO:71和SEQ ID NO:72，SEQ ID NO:73和SEQ ID NO:74，SEQ ID NO:75和SEQ ID NO:76，和SEQ ID NO:77和SEQ ID NO:78。
5.如权利要求2所述的融合蛋白，其特征在于，所述的分离的单克隆抗体或其免疫活性片段是嵌合的或人化的。
6.如权利要求2所述的融合蛋白，其特征在于，所述的分离的单克隆抗体或其免疫活性片段能阻止人CD47与信号调节蛋白α(SIRPα)的相互作用。
7.如权利要求2所述的融合蛋白，其特征在于，所述的分离的单克隆抗体或其免疫活性片段能促进巨噬细胞介导的CD47表达细胞的吞噬作用。
8.如权利要求2所述的融合蛋白，其特征在于，所述的分离的单克隆抗体或其免疫活性片段不引起显著水平的红细胞凝聚或红血细胞的清除。
9.如权利要求2所述的融合蛋白，其特征在于，所述的分离的单克隆抗体或其免疫活性片段不引起红细胞凝聚或红血细胞的清除。
10.如权利要求1-9中任一项所述的融合蛋白，其特征在于，所述细胞因子包括免疫球蛋白(Ig)，造血生长因子，干扰素，肿瘤坏死因子，白细胞介素-17受体，或单聚糖蛋白的野生型或变体。
11.如权利要求10所述的融合蛋白，其特征在于，所述细胞因子是单聚糖蛋白的野生型或变体。
12.如权利要求11所述的融合蛋白，其特征在于，所述细胞因子是粒细胞巨噬细胞集落刺激因子(GM-CSF)的野生型或变体。
13.如权利要求1-12中任一项所述的融合蛋白，其特征在于，所述单克隆抗体或其免疫活性片段通过或不通过连接物与细胞因子融合，所述连接物选自包括下述的组：(G4S)3，(G4S)6，(GS)9，IGD(F30)，IGD(F64)，IGD(R30)，IGN(R64)，IGD(R30-Cys)，和IGD(R64-Cys)。
14.如权利要求1-13中任一项所述的融合蛋白，其特征在于，所述融合蛋白能抑制人CD47和人SIRPα的相互作用。
15.如权利要求1-14中任一项所述的融合蛋白，其特征在于，所述融合蛋白进一步包含小分子治疗制剂或标记物，且所述小分子治疗制剂或标记物与所述单克隆抗体或其免疫活性片段，或与细胞因子缀合。
16.如权利要求15所述的融合蛋白，其特征在于，所述小分子治疗制剂是抗癌或抗炎制剂；所述标记物是生物标记或荧光标记。
17.如权利要求12所述的融合蛋白，其特征在于，分离的单克隆抗体或其免疫活性片段包含与选自包括下述的组的一对VH和VL氨基酸序列至少95％相同的VH/VL序列对：SEQ IDNO:3和SEQ ID NO:4，及SEQ ID NO:31和SEQ ID NO:32；且所述细胞因子是粒细胞巨噬细胞集落刺激因子(GM-CSF)的野生型或变体。
18.如权利要求17所述的融合蛋白，其特征在于，所述融合蛋白包含：
与选自包括以下的组的氨基酸序列至少95％相同的可变轻(VL)链表达载体：SEQ IDNO:108和SEQ ID NO:116；和
与选自包括以下的组的氨基酸序列至少95％相同的可变重(VH)链表达载体：SEQ IDNO:109,SEQ ID NO:110,SEQ ID NO:111,SEQ ID NO:112,SEQ ID NO:113,SEQ ID NO:114,SEQ ID NO:115,SEQ ID NO:117,SEQ ID NO:118,SEQ ID NO:119,SEQ ID NO:120,SEQ IDNO:121,SEQ ID NO:122,SEQ ID NO:123,SEQ ID NO:SEQ ID NO:125,SEQ ID NO:126,SEQID NO.127,SEQ ID NO.128,SEQ ID NO:129,SEQ ID NO:130,SEQ ID NO:131,SEQ ID NO:132,SEQ ID NO:133,SEQ ID NO:134,SEQ ID NO:135,SEQ ID NO:136,SEQ ID NO:137,SEQID NO:138,SEQ ID NO:139,SEQ ID NO:140,SEQ ID NO:141,SEQ ID NO:142,SEQ ID NO:143,SEQ ID NO:144,SEQ ID NO:145,SEQ ID NO:146,SEQ ID NO:147,SEQ ID NO:148,SEQID NO:149,SEQ ID NO:150,SEQ ID NO:151,SEQ ID NO:152,SEQ ID NO:153,SEQ ID NO:154,SEQ ID NO:155,SEQ ID NO:156,SEQ ID NO:147,和SEQ ID NO:158。
19.如权利要求18所述的融合蛋白，其特征在于，所述融合蛋白包含与选自包括以下的组的VH和VL氨基酸序列对至少95％相同的VH/VL对：SEQ ID NO:108和SEQ ID NO:109,SEQID NO:108和SEQ ID NO:110,SEQ ID NO:108和SEQ ID NO:111,SEQ ID NO:108和SEQ IDNO:112,SEQ ID NO:108和SEQ ID NO:113,SEQ ID NO:108和SEQ ID NO:114,SEQ ID NO:108和SEQ ID NO:115,SEQ ID NO:108和SEQ ID NO:117,SEQ ID NO:108和SEQ ID NO:118,SEQ ID NO:108和SEQ ID NO:119,SEQ ID NO:108和SEQ ID NO:120,SEQ ID NO:108和SEQID NO:121,SEQ ID NO:108和SEQ ID NO:122,SEQ ID NO:108和SEQ ID NO:123,SEQ IDNO:108和SEQ ID NO:124,SEQ ID NO:108和SEQ ID NO:125,SEQ ID NO:108和SEQ ID NO:126,SEQ ID NO:108和SEQ ID NO:127,SEQ ID NO:108和SEQ ID NO:128,SEQ ID NO:108和SEQ ID NO:129,SEQ ID NO:108和SEQ ID NO:130,SEQ ID NO:108和SEQ ID NO:131,SEQID NO:108和SEQ ID NO:132,SEQ ID NO:108和SEQ ID NO:133,SEQ ID NO:108和SEQ IDNO:134,SEQ ID NO:108和SEQ ID NO:135,SEQ ID NO:108和SEQ ID NO:136,SEQ ID NO:108和SEQ ID NO:137,SEQ ID NO:108和SEQ ID NO:138,SEQ ID NO:108和SEQ ID NO:139,SEQ ID NO:108和SEQ ID NO:140,SEQ ID NO:108和SEQ ID NO:141,SEQ ID NO:108和SEQID NO:142,SEQ ID NO:108和SEQ ID NO:143,SEQ ID NO:108和SEQ ID NO:144,SEQ IDNO:108和SEQ ID NO:145,SEQ ID NO:108和SEQ ID NO:146,和SEQ ID NO:108和SEQ IDNO:147；SEQ ID NO:116和SEQ ID NO:109,SEQ ID NO:116和SEQ ID NO:110,SEQ ID NO:116和SEQ ID NO:111,SEQ ID NO:116和SEQ ID NO:112,SEQ ID NO:116和SEQ ID NO:113,SEQ ID NO:116和SEQ ID NO:114,SEQ ID NO:116和SEQ ID NO:115,SEQ ID NO:116和SEQID NO:117,SEQ ID NO:116和SEQ ID NO:120,SEQ ID NO:116和SEQ ID NO:121,SEQ IDNO:116和SEQ ID NO:122,SEQ ID NO:116和SEQ ID NO:124,SEQ ID NO:116和SEQ ID NO:125,SEQ ID NO:116和SEQ ID NO:126,SEQ ID NO:116和SEQ ID NO:127,SEQ ID NO:116和SEQ ID NO:128,SEQ ID NO:116和SEQ ID NO:129,SEQ ID NO:116和SEQ ID NO:130,SEQID NO:116和SEQ ID NO:131,SEQ ID NO:116和SEQ ID NO:132,SEQ ID NO:116和SEQ IDNO:133,SEQ ID NO:116和SEQ ID NO:134,SEQ ID NO:116和SEQ ID NO:135,SEQ ID NO:116和SEQ ID NO:136,SEQ ID NO:116和SEQ ID NO:137,SEQ ID NO:116和SEQ ID NO:138,SEQ ID NO:116和SEQ ID NO:139,SEQ ID NO:116和SEQ ID NO:140,SEQ ID NO:116和SEQID NO:141,SEQ ID NO:116和SEQ ID NO:142,SEQ ID NO:116和SEQ ID NO:143,SEQ IDNO:116和SEQ ID NO:144,SEQ ID NO:116和SEQ ID NO:145,SEQ ID NO:116和SEQ ID NO:146,SEQ ID NO:116和SEQ ID NO:147,SEQ ID NO:116和SEQ ID NO:148,SEQ ID NO:116和SEQ ID NO:149,SEQ ID NO:116和SEQ ID NO:150,SEQ ID NO:116和SEQ ID NO:151,SEQID NO:116和SEQ ID NO:152,SEQ ID NO:116和SEQ ID NO:153,SEQ ID NO:116和SEQ IDNO:154,SEQ ID NO:116和SEQ ID NO:155,和SEQ ID NO:116和SEQ ID NO:156。
20.一种药物组合物，包括如权利要求1-19之中任一项所述的融合蛋白，和药学上可接受的载体。
21.一种治疗有需要的人受试者疾病的方法，包括向受试者施用治疗有效量的如权利要求1-16中任一项所述的融合蛋白，或如权利要求17所述的药物组合物；其中，所述疾病是癌症、纤维变性的疾病、与吞噬作用受到抑制相关的疾病、或与血小板凝聚相关的疾病。
22.如权利要求21所述的方法，其特征在于，所述癌症选自包括下述癌症的组：卵巢癌、结肠癌、乳腺癌、肺癌、头颈部肿瘤、膀胱癌、结肠直肠癌、胰腺癌、非霍奇金氏淋巴瘤、急性淋巴细胞性白血病、慢性淋巴细胞白血病、急性髓细胞样白血病、慢性髓细胞性白血病、多毛细胞白血病(HCL)、T细胞幼淋巴细胞白血病(T-PLL)、大粒淋巴细胞白血病、成人T细胞白血病、多发性骨髓瘤、(恶性)黑色素瘤、平滑肌瘤、平滑肌肉瘤、神经胶质瘤、胶质母细胞瘤、骨髓瘤、单核细胞白血病、B细胞衍生白血病、T细胞衍生白血病、B细胞衍生淋巴瘤、T细胞衍生淋巴瘤、子宫内膜癌、肾癌、(良性)胎记瘤、前列腺癌、甲状腺癌、子宫颈癌、胃癌、肝癌、和实体肿瘤；所述纤维变性疾病选自包括下述疾病的组：心肌梗死、心绞痛、骨关节炎、肺纤维化、哮喘、囊性纤维化、支气管炎、和气喘；与吞噬作用受到抑制相关的疾病是心血管疾病；与血小板凝聚相关的疾病是血小板无力症、延长出血时间、免疫性血小板减少症(ITP)、血管性血友病(vWD)。
23.如权利要求22所述的方法，其特征在于，所述心血管疾病选自包括下述疾病的组：动脉粥样硬化、中风、高血压性心脏病、风湿性心脏病、心肌病、心律失常、先天性心脏病、心脏瓣膜病、心肌炎、主动脉瘤、周边动脉疾病、和静脉血栓。
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