CN113651888A - Il-11的抗体及其应用 - Google Patents

Il-11的抗体及其应用 Download PDF

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CN113651888A
CN113651888A CN202110923737.0A CN202110923737A CN113651888A CN 113651888 A CN113651888 A CN 113651888A CN 202110923737 A CN202110923737 A CN 202110923737A CN 113651888 A CN113651888 A CN 113651888A
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周加滔
陈苍沙
王淑娟
姚洁
陈小锋
李文佳
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Guangdong HEC Pharmaceutical
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Sunshine Lake Pharma Co Ltd
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Abstract

本发明提出了一种能够特异性识别IL‑11的抗体或其抗原结合片段。该抗体含有选自下列至少之一的CDR序列或与其具有至少95％同一性的氨基酸序列：重链可变区CDR序列：SEQ ID NO:1～33，轻链可变区CDR序列：SEQ IN NO:34～66。该抗体能够特异性的靶向结合IL‑11，阻断IL‑11和IL‑11受体的结合。

Description

IL-11的抗体及其应用
技术领域
本发明涉及生物技术领域，具体地，本发明涉及IL-11的抗体及其应用，更具体地，本发明涉及能够特异性识别IL-11的抗体或其抗原结合片段、核酸分子、表达载体、重组细胞、药物组合物、制药用途以及检测IL-11的试剂盒。
背景技术
纤维化是一个重要的过程，是伤口愈合的关键部分。过度纤维化在许多罕见和常见疾病中很常见，并且在疾病发病机制中很重要。以过度纤维化为特征的疾病包括但不限于：系统性硬化症、硬皮病、肥厚性心肌病、扩张型心肌病(DCM)、心房纤维性颤动、心室纤维性颤动、心肌炎、肝硬化、肾脏疾病、眼部疾病、哮喘、囊性纤维化、关节炎和特发性肺纤维化。尽管对人类健康影响很大，但对纤维化的治疗和诊断方法的医疗需求仍然未得到满足。
白细胞介素11(IL-11)的真正生理作用尚不清楚。IL-11与造血细胞活化和血小板生成的关系最为密切，但也被发现具有促炎和抗炎、促血管生成的作用，并对瘤形成很重要。已知TGFβ1或组织损伤可诱导IL-11的表达。从已发表的文献来看，IL-11在纤维化中的作用尚不清楚。IL-11被认为对肺纤维化和炎症很重要，其表达水平与皮肤和呼吸系统中的胶原水平相关。然而，大多数研究表明IL-11在心脏和肾脏中是抗纤维化的，在几种组织和慢性炎症疾病中的是抗炎的。一般来说，IL-11的分子作用模式被认为是通过STAT3介导的转录调节RNA表达的mRNA水平。
已有研究表明，施用能够抑制白细胞介素11(IL-11)作用的试剂来治疗、预防或缓解需要治疗的受试者中的纤维化。能够抑制IL-11作用的试剂可以阻止或减少IL-11与IL-11受体的结合。
目前上市的针对肺纤维化疾病的药物仅有吡啡尼酮和尼达尼布两款，但这两款药疗效差，需要有全新机制的药物来解决这种困局。
开发具有抑制IL-11作用的试剂已成为开发治疗和预防肺纤维化疾病的药物的方向。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明开发一款具有高中和活性的Anti-IL-11的抗体，以期用于纤维化相关疾病的治疗或预防。
在本发明的的第一方面，本发明提出了一种能够特异性识别IL-11的抗体或其抗原结合片段。根据本发明的实施例，所述抗体含有选自下列至少之一的CDR序列或与其具有至少95％同一性的氨基酸序列：重链可变区CDR序列：SEQ ID NO:1～33，轻链可变区CDR序列：SEQ IN NO:34～66。
GYTFTTNG(SEQ ID NO:1)。
INTNTGEP(SEQ ID NO:2)。
AREGAFGLDY(SEQ ID NO:3)。
DYTFTNYW(SEQ ID NO:4)。
IYPGGGYT(SEQ ID NO:5)。
ARVRSGNDALDF(SEQ ID NO:6)。
GYTFTNYG(SEQ ID NO:7)。
INTNTGEP(SEQ ID NO:8)。
SREGIYGMDS(SEQ ID NO:9)。
GFSLTSYG(SEQ ID NO:10)。
IWAGGRT(SEQ ID NO:11)。
AREGGYDYDGDLWT(SEQ ID NO:12)。
GFSLTSYG(SEQ ID NO:13)。
IWSGGIT(SEQ ID NO:14)。
ARNFDGYYYSIDY(SEQ ID NO:15)。
GFSLTNYG(SEQ ID NO:16)。
IWRGGST(SEQ ID NO:17)。
AKNLYGPAAMDY(SEQ ID NO:18)。
GDTFTNYA(SEQ ID NO:19)。
IDTYTGDP(SEQ ID NO:20)。
AGDTWFAY(SEQ ID NO:21)。
GFSLSSSGMS(SEQ ID NO:22)。
IWWSDDK(SEQ ID NO:23)。
AREGSLGYGLDY(SEQ ID NO:24)。
GFDFRRYW(SEQ ID NO:25)。
INPDSSMI(SEQ ID NO:26)。
ATYGHHATDS(SEQ ID NO:27)。
GYTFTSYW(SEQ ID NO:28)。
IYPGSDST(SEQ ID NO:29)。
ALDSSGYGFAY(SEQ ID NO:30)。
DYEFPSHD(SEQ ID NO:31)。
INSDGGNT(SEQ ID NO:32)。
ARPRPTIGTTATGSSM(SEQ ID NO:33)。
QSVSND(SEQ ID NO:34)。
YGS(SEQ ID NO:35)。
QQDFFSPWT(SEQ ID NO:36)。
ESVDEYGISF(SEQ ID NO:37)。
SAS(SEQ ID NO:38)。
QQSKEVPWT(SEQ ID NO:39)。
QSVSND(SEQ ID NO:40)。
YAS(SEQ ID NO:41)。
QQDYYSPWT(SEQ ID NO:42)。
QSLVHSNGNTY(SEQ ID NO:43)。
KVS(SEQ ID NO:44)。
SQSTHVPPD(SEQ ID NO:45)。
QDISNS(SEQ ID NO:46)。
YTS(SEQ ID NO:47)。
QQGNTLPLT(SEQ ID NO:48)。
QNIYVW(SEQ ID NO:49)。
EAS(SEQ ID NO:50)。
QQGQSYPYT(SEQ ID NO:51)。
QSLLYSRNQKNR(SEQ ID NO:52)。
WAS(SEQ ID NO:53)。
QQYYSYPRT(SEQ ID NO:54)。
QSIVHTDGNTY(SEQ ID NO:55)。
KVS(SEQ ID NO:56)。
FQGSHVPWT(SEQ ID NO:57)。
ESVDSYGNSF(SEQ ID NO:58)。
RAS(SEQ ID NO:59)。
QQSNEDPFT(SEQ ID NO:60)。
QSVSND(SEQ ID NO:61)。
YAS(SEQ ID NO:62)。
QQDYSSPFT(SEQ ID NO:63)。
QSVSTSTYNY(SEQ ID NO:64)。
YAS(SEQ ID NO:65)。
QHSWEIPFT(SEQ ID NO:66)。
根据本发明实施例的上述抗体能够特异性的靶向结合IL-11，阻断IL-11和IL-11受体的结合。
再一方面，本发明提出了一种能够特异性识别IL-11的抗体或其抗原结合片段。根据本发明的实施例，所述抗体含有选自下列至少之一的CDR序列或与其具有至少95％同一性的氨基酸序列：重链可变区CDR序列：SEQ ID NO:1～33，轻链可变区CDR序列：SEQ IN NO:34～66，所述抗体或其抗原结合片段具有人源化修饰。需要说明的是，本申请所述的“人源化修饰”是指能够使得所述抗体或其抗原结合片段的免疫原性降低的氨基酸的改变，包括氨基酸的突变、插入、缺失、化学基团的赘合等等。根据本发明实施例的上述人源化抗体的免疫源性降低，抗体能够特异性的靶向结合IL-11，阻断IL-11和IL-11受体的结合。
根据本发明的实施例，上述抗体或抗原结合片段还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述抗体包括：
分别如SEQ ID NO:1、2和3或者与SEQ ID NO:1、2和3具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:4、5和6或者与SEQ ID NO:4、5和6具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:7、8和9或者与SEQ ID NO:7、8和9具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:10、11和12或者与SEQ ID NO:10、11和12具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:13、14和15或者与SEQ ID NO:13、14和15具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:16、17和18或者与SEQ ID NO:16、17和18具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO19、20和21或者与SEQ ID NO:19、20和21具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:22、23和24或者与SEQ ID NO:22、23和24具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:25、26和27或者与SEQ ID NO:25、26和27具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:28、29和30或者与SEQ ID NO:28、29和30具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:31、32和33或者与SEQ ID NO:31、32和33具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列。
根据本发明的实施例，所述抗体包括：
分别如SEQ ID NO:34、35和36或者与SEQ ID NO:34、35和36具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:37、38和39或者与SEQ ID NO:37、38和39具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:40、41和42或者与SEQ ID NO:40、41和42具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:43、44和45或者与SEQ ID NO:43、44和45具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:46、47和48或者与SEQ ID NO:46、47和48具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:49、50和51或者与SEQ ID NO:49、50和51具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:52、53和54或者与SEQ ID NO:52、53和54具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:55、56和57或者与SEQ ID NO:55、56和57具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:58、59和60或者与SEQ ID NO:58、59和60具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:61、62和63或者与SEQ ID NO:61、62和63具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:64、65和66或者与SEQ ID NO:64、65和66具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列。
根据本发明的实施例，上述抗体或抗原结合片段还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述抗体包括：
分别如SEQ ID NO:1、2和3或者与SEQ ID NO:1、2和3具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；和
分别如SEQ ID NO:34、35和36或者与SEQ ID NO:34、35和36具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；
或，分别如SEQ ID NO:4、5和6或者与SEQ ID NO:4、5和6具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；和
分别如SEQ ID NO:37、38和39或者与SEQ ID NO:37、38和39具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；
或，分别如SEQ ID NO:7、8和9或者与SEQ ID NO:7、8和9具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；和
分别如SEQ ID NO:40、41和42或者与SEQ ID NO:40、41和42具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；
或，分别如SEQ ID NO:10、11和12或者与SEQ ID NO:10、11和12具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；和
分别如SEQ ID NO:43、44和45或者与SEQ ID NO:43、44和45具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；
或，分别如SEQ ID NO:13、14和15或者与SEQ ID NO:13、14和15具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；和
分别如SEQ ID NO:46、47和48或者与SEQ ID NO:46、47和48具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；
或，分别如SEQ ID NO:16、17和18或者与SEQ ID NO:16、17和18具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；和
分别如SEQ ID NO:49、50和51或者与SEQ ID NO:49、50和51具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；
或，分别如SEQ ID NO:19、20和21或者与SEQ ID NO:19、20和21具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；和
分别如SEQ ID NO:52、53和54或者与SEQ ID NO:52、53和54具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；
或，分别如SEQ ID NO:22、23和24或者与SEQ ID NO:22、23和24具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；和
分别如SEQ ID NO:55、56和57或者与SEQ ID NO:55、56和57具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；
或，分别如SEQ ID NO:25、26和27或者与SEQ ID NO:25、26和27具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；和
分别如SEQ ID NO:58、59和60或者与SEQ ID NO:58、59和60具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；
或，分别如SEQ ID NO:28、29和30或者与SEQ ID NO:28、29和30具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；和
分别如SEQ ID NO:61、62和63或者与SEQ ID NO:61、62和63具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；
或，分别如SEQ ID NO:31、32和33或者与SEQ ID NO:31、32和33具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；和
分别如SEQ ID NO:64、65和66或者与SEQ ID NO:64、65和66具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列。
本发明CDR序列参照Kabat命名系统进行限定。
根据本发明的实施例，所述抗体或其抗原结合片段特异性识别IL-11。
根据本发明的实施例，所述抗体含有重链框架区序列和轻链框架区序列的至少之一，所述重链框架区序列和轻链框架区序列的至少之一的至少一部分来自于鼠源抗体、人源抗体、灵长目源抗体或其突变体的至少之一。
根据本发明的实施例，所述重链框架区包括FL1、FL2、FL3和FL4,所述重链框架区FL1、FL2、FL3和FL4分别具有SEQ ID NO:135、136、137和138所示的氨基酸序列，
QVQLVQSGAEVKKPGASVKVSCKAS(SEQ ID NO:135)，
LGWVRQAPGX1GLEWX2GH(SEQ ID NO:136)，
NYNEKFKGRX3TX4TX5DTSTSTVYMELSSLRSEDTAVYX6C(SEQ ID NO:137)，
WGQGTLVTVSS(SEQ ID NO:138)，
其中，X1为Q或H,X2为M或I，X3为V或A，X4为M或L，X5为R或A，X6为Y或F。
根据本发明的实施例，所述轻链框架区包括FL1、FL2、FL3和FL4,所述轻链框架区FL1、FL2、FL3和FL4分别具有SEQ ID NO:139、140、141和142所示的氨基酸序列，
EIVLTQSPATLSLSPGERATLSCRAS(SEQ ID NO:139)，
MNWX7QQKPGQAPRLLIY(SEQ ID NO:140)，
NQGSGIPARFSGSGSGTDFTLTISSLEPEDFAX8YX9C(SEQ ID NO:141)，
FGGGTKLEIK(SEQ ID NO:142)，
其中，X7为Y或F,X8为V或M，X9为Y或F。
根据本发明的实施例，本发明所提出的人源化抗体具有如SEQ ID NO：143～146任一项所示氨基酸序列的重链可变区。
QVQLVQSGAEVKKPGASVKVSCKASDYTFTNYWLGWVRQAPGQGLEWMGHIYPGGGYTNYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARVRSGNDALDFWGQGTLVTVSS(SEQ ID NO：143)。
QVQLVQSGAEVKKPGASVKVSCKASDYTFTNYWLGWVRQAPGQGLEWIGHIYPGGGYTNYNEKFKGRVTMTADTSTSTVYMELSSLRSEDTAVYFCARVRSGNDALDFWGQGTLVTVSS(SEQ ID NO：144)。
QVQLVQSGAEVKKPGASVKVSCKASDYTFTNYWLGWVRQAPGQGLEWIGHIYPGGGYTNYNEKFKGRATLTADTSTSTVYMELSSLRSEDTAVYFCARVRSGNDALDFWGQGTLVTVSS(SEQ ID NO：145)。
QVQLVQSGAEVKKPGASVKVSCKASDYTFTNYWLGWVRQAPGHGLEWIGHIYPGGGYTNYNEKFKGRATLTADTSTSTVYMELSSLRSEDTAVYFCARVRSGNDALDFWGQGTLVTVSS(SEQ ID NO：146)。
根据本发明的实施例，本发明所提出的人源化抗体具有如SEQ ID NO：147～150任一项所示氨基酸序列的轻链可变区。
EIVLTQSPATLSLSPGERATLSCRASESVDEYGISFMNWYQQKPGQAPRLLIYSASNQGSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSKEVPWTFGGGTKLEIK(SEQ ID NO：147)。
EIVLTQSPATLSLSPGERATLSCRASESVDEYGISFMNWYQQKPGQAPRLLIYSASNQGSGIPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSKEVPWTFGGGTKLEIK(SEQ ID NO：148)。
EIVLTQSPATLSLSPGERATLSCRASESVDEYGISFMNWFQQKPGQAPRLLIYSASNQGSGIPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSKEVPWTFGGGTKLEIK(SEQ ID NO：149)。
EIVLTQSPATLSLSPGERATLSCRASESVDEYGISFMNWFQQKPGQAPRLLIYSASNQGSGIPARFSGSGSGTDFTLTISSLEPEDFAMYFCQQSKEVPWTFGGGTKLEIK(SEQ ID NO：150)。
根据本发明的实施例，所述抗体具有如SEQ ID NO：67～77任一项所示氨基酸序列的重链可变区。
QIQLVQSGPELKKPGETVKISCKASGYTFTTNGINWVKQAAGKGLKWMGWINTNTGEPTNAEELKGRFAFSLETSASTAYLQINNLKNEDAAIYFCAREGAFGLDYWGQGTSVTVSS(SEQ ID NO:67)。
QVQLQQSGAELVRPGTSAKISCKASDYTFTNYWLGWLKQRPGHGLEWIGHIYPGGGYTNYNEKFKGKATLTADTSSSTAYMQLSSLTSEDSAVYFCARVRSGNDALDFWGQGTSVTVSS(SEQ ID NO:68)。
QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWINTNTGEPTYAEEIKGRFAFSLETSASTAYLQINNLKNEDTATYFCSREGIYGMDSWGQGTSVTVSS(SEQ ID NO:69)。
QVQLKESGPGLVAPSQSLSITCTVSGFSLTSYGVHWVRQPPGKGLEWLGIIWAGGRTDYNSALVSRLNISKDNSKSQVFLKMHSLQTDDTAMYYCAREGGYDYDGDLWTTGVKEPQSPSPQ(SEQ ID NO:70)。
QVQLKQSGPGLVLPSQSLSITCTVSGFSLTSYGVHWFRQSPGTGLEWLGVIWSGGITDYNATFI.PRLSISKDNSKSQVFFKMNSLQADDTAIYYCARNFDGYYYSIDYWGQGTSVTVSS(SEQ ID NO:71)。
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGAIWRGGSTDYNAAFMSRLSITKDNSKSQVFFKMNSLQPDDTAIYYCAKNLYGPAAMDYWGQGTSVTVSS(SEQ ID NO:72)。
QIQLVQSGPELKKPGETVNISCRASGDTFTNYAVNWVKQAPGKGLKWMGWIDTYTGDPTYADDLKGRFAFSLETSATTAYLQINNLKNEDTATYFCAGDTWFAYWGQGTLVTVSA(SEQ ID NO:73)。
QVTLKESGPGILQPSQTLSLTCSFSGFSLSSSGMSVGWIRQPSGKGLEWLAHIWWSDDKSYNPALKSRLTISKDTSNNQVFLKIASVVTADTATYYCAREGSLGYGLDYWGQGTTLTVSS(SEQ ID NO:74)。
EVKLLESGGGLVQPGGSLKLSCAASGFDFRRYWMSWVRQAPGKGLEWIGQINPDSSMINYTPSLKDKFIISRDNAKNTLYLQMSEVRSEDTALYYCATYGHHATDSWGQGTSVTVSS(SEQ ID NO:75)。
QVQLQQPGAELVRPGTSVKMSCKASGYTFTSYWMHWVKQRPGQGLEWIGDIYPGSDSTNYHEKFKSKATLTVDTSSSTAYMQLSSLTSEDSAVYYCALDSSGYGFAYWGQGTLVTVSA(SEQ ID NO:76)。
EVQLVESGGGLVQPGESLKLSCDSNDYEFPSHDMSWVRKTPEKRLELVAAINSDGGNTYYPDTMERRFIISRDNTKRTLYLQMSSLRSEDTALHYCARPRPTIGTTATGSSMSGAQGPRS(SEQ ID NO:77)。
根据本发明的实施例，所述抗体具有如SEQ ID NO：78～88任一项所示氨基酸序列的轻链可变区。
SIVMTQSPKFLLVSAGDRVIITCKASQSVSNDVVWYQQKPGQSPKLLIYYGSHRNTGVPTRFTGSGYGTDFTFTISTVQAEDLAVYFCQQDFFSPWTFGGGTKLEIK(SEQ ID NO:78)。
DIVLTQSPASLAVSLGQRATISCRASESVDEYGISFMNWFQQKPGQPPRLLIYSASNQGSGVPARFTGSGSGTDFSLNILPMEEDDTAMYFCQQSKEVPWTFGGGTKLEIK(SEQ ID NO:79)。
SIVMTQTPKFLLVSAGDRVTITCKASQSVSNDVVWYRQKPGQSPKLLIYYASNRYIGVPDRFTGSGYGTDFTFTISTVQAEDLAVYFCQQDYYSPWTFGGGTKLEIK(SEQ ID NO:80)。
DVVMTQSPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPDVRWRHQAGNQ(SEQ ID NO:81)。
DIQMTQTTSSLSASLGDRVTISCRASQDISNSLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFTGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPLTFGAGTKLELK(SEQ ID NO:82)。
DIQMNQSPSSLSASLGDTITITCHANQNIYVWLSWYQQKPGNIPKLLIYEASNLHTGVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQGQSYPYTFGGGTKLEIK(SEQ ID NO:83)。
DIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSRNQKNRLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPRTFGGGTNLEIK(SEQ ID NO:84)。
DVLMTQTPLSLPVSLGDQASISCRSSQSIVHTDGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPWTFGGGTKLEIK(SEQ ID NO:85)。
DIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFMHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPFTFGSGTKLEIK(SEQ ID NO:86)。
NIVMTQTPKFLLVSAGDRVTITRKASQSVSNDVVWYQQKPGQSPKLLMYYASYRYTGVPDRFTGSGYGTDFTFTISNVQAEDLAVYFCQQDYSSPFTFGSGTKLEIK(SEQ ID NO:87)。
DIVLTQSPASLAVSLGQRATISCRASQSVSTSTYNYMHWYQQKPGQPPKLLIKYASNLESGVPARFSGSGSGTDFTLNIHPVEEEDTATYYCQHSWEIPFTFGSGTKLEIK(SEQ ID NO:88)。
根据本发明的实施例，所述抗体具有如SEQ ID NO：67所示氨基酸序列的重链可变区，和具有如SEQ ID NO：78所示氨基酸序列的轻链可变区；或者
所述抗体具有如SEQ ID NO：68所示氨基酸序列的重链可变区，和具有如SEQ IDNO：79所示氨基酸序列的轻链可变区；或者
所述抗体具有如SEQ ID NO：69所示氨基酸序列的重链可变区，和具有如SEQ IDNO：80所示氨基酸序列的轻链可变区；或者
所述抗体具有如SEQ ID NO：70所示氨基酸序列的重链可变区，和具有如SEQ IDNO：81所示氨基酸序列的轻链可变区；或者
所述抗体具有如SEQ ID NO：71所示氨基酸序列的重链可变区，和具有如SEQ IDNO：82所示氨基酸序列的轻链可变区；或者
所述抗体具有如SEQ ID NO：72所示氨基酸序列的重链可变区，和具有如SEQ IDNO：83所示氨基酸序列的轻链可变区；或者
所述抗体具有如SEQ ID NO：73所示氨基酸序列的重链可变区，和具有如SEQ IDNO：84所示氨基酸序列的轻链可变区；或者
所述抗体具有如SEQ ID NO：74所示氨基酸序列的重链可变区，和具有如SEQ IDNO：85所示氨基酸序列的轻链可变区；或者
所述抗体具有如SEQ ID NO：75所示氨基酸序列的重链可变区，和具有如SEQ IDNO：86所示氨基酸序列的轻链可变区；或者
所述抗体具有如SEQ ID NO：76所示氨基酸序列的重链可变区，和具有如SEQ IDNO：87所示氨基酸序列的轻链可变区；或者
所述抗体具有如SEQ ID NO：77所示氨基酸序列的重链可变区，和具有如SEQ IDNO：88所示氨基酸序列的轻链可变区。
根据本发明的实施例，本发明所提出的人源化抗体具有如SEQ ID NO：143所示氨基酸序列的重链可变区，和具有如SEQ ID NO：147所示氨基酸序列的轻链可变区；或者
本发明所提出的人源化抗体具有如SEQ ID NO：144所示氨基酸序列的重链可变区，和具有如SEQ ID NO：148所示氨基酸序列的轻链可变区；或者
本发明所提出的人源化抗体具有如SEQ ID NO：145所示氨基酸序列的重链可变区，和具有如SEQ ID NO：149所示氨基酸序列的轻链可变区；或者
本发明所提出的人源化抗体具有如SEQ ID NO：146所示氨基酸序列的重链可变区，和具有如SEQ ID NO：150示氨基酸序列的轻链可变区。
根据本发明的实施例，所述抗体含有重链恒定区和轻链恒定区的至少之一，所述重链恒定区和轻链恒定区的至少之一的至少一部分来自于鼠源抗体、人源抗体、灵长目源抗体或其突变体的至少之一。
根据本发明的实施例，所述抗体的轻链恒定区和重链恒定区均来自于人源IgG抗体或其突变体。进而所述抗体的免疫原性可以得到有效降低。
根据本发明的实施例，所述抗体的轻链恒定区来自于人源的Kappa轻链恒定区；重链恒定区来自于人源IgG1的重链恒定区。
根据本发明的实施例，所述抗体恒定区的全长序列如SEQ ID NO:89或90所示。
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:89)。
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:90)。
其中，上述SEQ ID NO:89所示的抗体恒定区的全长序列包括IgG1重链恒定区和Fc区，其中，IgG1重链恒定区序列为ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV，Fc区序列为EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK；上述SEQ IDNO:90所示的抗体恒定区的全长序列为IgG轻链恒定区。
根据本发明的实施例，所述抗体具有SEQ ID NO:91～101任一项所示氨基酸序列的重链和具有SEQ ID NO:102～112任一项所示氨基酸序列的轻链。
QIQLVQSGPELKKPGETVKISCKASGYTFTTNGINWVKQAAGKGLKWMGWINTNTGEPTNAEELKGRFAFSLETSASTAYLQINNLKNEDAAIYFCAREGAFGLDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:91)。
QVQLQQSGAELVRPGTSAKISCKASDYTFTNYWLGWLKQRPGHGLEWIGHIYPGGGYTNYNEKFKGKATLTADTSSSTAYMQLSSLTSEDSAVYFCARVRSGNDALDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:92)。
QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWINTNTGEPTYAEEIKGRFAFSLETSASTAYLQINNLKNEDTATYFCSREGIYGMDSWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:93)。
QVQLKESGPGLVAPSQSLSITCTVSGFSLTSYGVHWVRQPPGKGLEWLGIIWAGGRTDYNSALVSRLNISKDNSKSQVFLKMHSLQTDDTAMYYCAREGGYDYDGDLWTTGVKEPQSPSPQASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:94)。
QVQLKQSGPGLVLPSQSLSITCTVSGFSLTSYGVHWFRQSPGTGLEWLGVIWSGGITDYNATFI.PRLSISKDNSKSQVFFKMNSLQADDTAIYYCARNFDGYYYSIDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:95)。
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGAIWRGGSTDYNAAFMSRLSITKDNSKSQVFFKMNSLQPDDTAIYYCAKNLYGPAAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:96)。
QIQLVQSGPELKKPGETVNISCRASGDTFTNYAVNWVKQAPGKGLKWMGWIDTYTGDPTYADDLKGRFAFSLETSATTAYLQINNLKNEDTATYFCAGDTWFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQID NO:97)。
QVTLKESGPGILQPSQTLSLTCSFSGFSLSSSGMSVGWIRQPSGKGLEWLAHIWWSDDKSYNPALKSRLTISKDTSNNQVFLKIASVVTADTATYYCAREGSLGYGLDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:98)。
EVKLLESGGGLVQPGGSLKLSCAASGFDFRRYWMSWVRQAPGKGLEWIGQINPDSSMINYTPSLKDKFIISRDNAKNTLYLQMSEVRSEDTALYYCATYGHHATDSWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:99)。
QVQLQQPGAELVRPGTSVKMSCKASGYTFTSYWMHWVKQRPGQGLEWIGDIYPGSDSTNYHEKFKSKATLTVDTSSSTAYMQLSSLTSEDSAVYYCALDSSGYGFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:100)。
EVQLVESGGGLVQPGESLKLSCDSNDYEFPSHDMSWVRKTPEKRLELVAAINSDGGNTYYPDTMERRFIISRDNTKRTLYLQMSSLRSEDTALHYCARPRPTIGTTATGSSMSGAQGPRSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:101)。
SIVMTQSPKFLLVSAGDRVIITCKASQSVSNDVVWYQQKPGQSPKLLIYYGSHRNTGVPTRFTGSGYGTDFTFTISTVQAEDLAVYFCQQDFFSPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:102)。
DIVLTQSPASLAVSLGQRATISCRASESVDEYGISFMNWFQQKPGQPPRLLIYSASNQGSGVPARFTGSGSGTDFSLNILPMEEDDTAMYFCQQSKEVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:103)。
SIVMTQTPKFLLVSAGDRVTITCKASQSVSNDVVWYRQKPGQSPKLLIYYASNRYIGVPDRFTGSGYGTDFTFTISTVQAEDLAVYFCQQDYYSPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:104)。
DVVMTQSPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPDVRWRHQAGNQRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:105)。
DIQMTQTTSSLSASLGDRVTISCRASQDISNSLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFTGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPLTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:106)。
DIQMNQSPSSLSASLGDTITITCHANQNIYVWLSWYQQKPGNIPKLLIYEASNLHTGVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQGQSYPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:107)。
DIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSRNQKNRLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPRTFGGGTNLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:108)。
DVLMTQTPLSLPVSLGDQASISCRSSQSIVHTDGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:109)。
DIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFMHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:110)。
NIVMTQTPKFLLVSAGDRVTITRKASQSVSNDVVWYQQKPGQSPKLLMYYASYRYTGVPDRFTGSGYGTDFTFTISNVQAEDLAVYFCQQDYSSPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:111)。
DIVLTQSPASLAVSLGQRATISCRASQSVSTSTYNYMHWYQQKPGQPPKLLIKYASNLESGVPARFSGSGSGTDFTLNIHPVEEEDTATYYCQHSWEIPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:112)。
其中，在本申请中，上述SEQ ID NO:91和102所组成的抗体被称为3-6A4，上述SEQID NO:92和103所组成的抗体被称为5-20E11-5F2，上述SEQ ID NO:93和104所组成的抗体被称为3-5B2-2G4，上述SEQ ID NO:94和105所组成的抗体被称为3-5B2-7A4，上述SEQ IDNO:95和106所组成的抗体被称为3-2B5-3D2，上述SEQ ID NO:96和SEQ ID NO:107所组成的抗体被称为3-7C9-1A6，上述SEQ ID NO:97和SEQ ID NO:108所组成的抗体被称为3-9E1-3A2，上述SEQ ID NO:98和SEQ ID NO:109所组成的抗体被称为3-15D5-3A6，上述SEQ IDNO:99和SEQ ID NO:110所组成的抗体被称为3-15D5-6A1，上述SEQ ID NO:100和SEQ IDNO:111所组成的抗体被称为5-20E11-1A2，上述SEQ ID NO:101和SEQ ID NO:112所组成的抗体被称为5-21G2-1D3。
根据本发明的实施例，本发明所提出的人源化抗体具有SEQ ID NO:151～154任一项所示氨基酸序列的重链和具有SEQ ID NO:155～158任一项所示氨基酸序列的轻链。
QVQLVQSGAEVKKPGASVKVSCKASDYTFTNYWLGWVRQAPGQGLEWMGHIYPGGGYTNYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARVRSGNDALDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:151)。
QVQLVQSGAEVKKPGASVKVSCKASDYTFTNYWLGWVRQAPGQGLEWIGHIYPGGGYTNYNEKFKGRVTMTADTSTSTVYMELSSLRSEDTAVYFCARVRSGNDALDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:152)。
QVQLVQSGAEVKKPGASVKVSCKASDYTFTNYWLGWVRQAPGQGLEWIGHIYPGGGYTNYNEKFKGRATLTADTSTSTVYMELSSLRSEDTAVYFCARVRSGNDALDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:153)。
QVQLVQSGAEVKKPGASVKVSCKASDYTFTNYWLGWVRQAPGHGLEWIGHIYPGGGYTNYNEKFKGRATLTADTSTSTVYMELSSLRSEDTAVYFCARVRSGNDALDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:154)。
EIVLTQSPATLSLSPGERATLSCRASESVDEYGISFMNWYQQKPGQAPRLLIYSASNQGSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSKEVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:155)。
EIVLTQSPATLSLSPGERATLSCRASESVDEYGISFMNWYQQKPGQAPRLLIYSASNQGSGIPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSKEVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:156)。
EIVLTQSPATLSLSPGERATLSCRASESVDEYGISFMNWFQQKPGQAPRLLIYSASNQGSGIPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSKEVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:157)。
EIVLTQSPATLSLSPGERATLSCRASESVDEYGISFMNWFQQKPGQAPRLLIYSASNQGSGIPARFSGSGSGTDFTLTISSLEPEDFAMYFCQQSKEVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:158)。
根据本发明的实施例，所述抗体为单链抗体、多聚体抗体、CDR移植抗体或小分子抗体。
根据本发明的实施例，所述单链抗体包括SEQ ID NO:67-77任一项所示氨基酸序列的重链可变区和SEQ ID NO:78-88任一项所示氨基酸序列的轻链可变区，其中所述重链可变区的C端通过连接肽linker与所述轻链可变区的N端相连，或所述轻链可变区的C端通过连接肽linker与所述重链可变区的N端相连。需要说明的是，本申请所述的单链抗体的“连接肽linker”为用于连接抗体重链可变区和轻链可变区的连接肽，其可为制备单链抗体的常用连接肽linker，也可为经过科研工作者改造后的连接肽Linker。
根据本发明的实施例，所述小分子抗体包括Fab抗体、Fv抗体、单域抗体以及最小识别单位的至少之一。
在本发明的第二方面，本发明提出了一种核酸分子。根据本发明的实施例，所述核酸分子编码前面所述的抗体或其抗原结合片段。根据本发明实施例的核酸分子所编码的抗体或抗原结合片段可特异性靶向结合IL-11，阻断IL-11和IL-11受体的结合。
根据本发明的实施例，上述核酸分子还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述核酸分子为DNA。
根据本发明的实施例，所述核酸分子具有如SEQ ID NO:113～123任一项所示核苷酸序列或具有SEQ ID NO:124～134任一项所示核苷酸序列。
CAGATTCAATTGGTACAAAGCGGTCCCGAGCTCAAGAAACCTGGGGAGACTGTGAAAATTTCCTGTAAGGCCTCTGGCTACACCTTCACCACTAACGGTATCAACTGGGTGAAGCAGGCTGCAGGAAAGGGGCTCAAGTGGATGGGATGGATCAACACTAATACTGGAGAACCCACCAATGCTGAGGAACTTAAAGGCAGATTCGCCTTCTCTCTTGAGACTTCAGCCAGCACCGCCTACCTCCAAATTAACAATCTGAAAAATGAGGATGCCGCTATCTATTTTTGTGCCCGAGAGGGTGCATTCGGTCTTGATTACTGGGGTCAGGGCACCTCTGTGACAGTGTCTAGCGCCTCAACTAAGGGGCCCAGTGTTTTCCCCCTTGCCCCTTCCTCAAAATCAACTAGCGGAGGCACAGCCGCTCTTGGCTGTCTCGTGAAAGATTACTTCCCCGAGCCAGTGACAGTCTCTTGGAACAGCGGGGCACTCACCTCCGGCGTTCACACTTTTCCCGCAGTCCTCCAGTCTAGCGGATTGTATAGCCTGTCTTCTGTTGTCACAGTGCCATCCTCTAGCCTTGGCACCCAGACCTACATTTGTAATGTGAATCATAAGCCTTCAAACACAAAAGTCGATAAAAAAGTGGAGCCAAAGAGCTGTGACAAGACTCACACTTGCCCTCCATGCCCTGCCCCAGAACTCCTTGGCGGACCTAGCGTCTTCCTGTTTCCTCCTAAGCCAAAGGACACCCTGATGATCTCACGCACTCCTGAAGTGACCTGCGTTGTGGTAGACGTGAGCCACGAGGATCCAGAGGTGAAGTTCAACTGGTATGTGGATGGAGTCGAGGTGCATAATGCCAAAACAAAACCTAGGGAGGAGCAGTACAACTCTACCTACCGGGTGGTGTCTGTTTTGACCGTTCTGCACCAAGACTGGTTGAATGGCAAGGAGTACAAGTGCAAGGTGTCAAACAAAGCACTCCCAGCCCCTATAGAGAAGACCATCAGCAAAGCTAAGGGGCAGCCAAGAGAACCACAGGTTTACACCCTGCCCCCCTCACGGGATGAACTGACAAAGAACCAGGTGTCTCTGACTTGCCTCGTGAAAGGATTCTACCCTTCAGATATCGCAGTGGAGTGGGAGTCTAACGGCCAACCCGAGAATAATTACAAGACAACTCCCCCAGTCCTGGACAGTGATGGGTCTTTTTTCCTGTATTCTAAGCTCACTGTTGACAAAAGCCGCTGGCAGCAGGGTAATGTATTCTCCTGCTCCGTCATGCACGAAGCCCTGCACAACCACTATACCCAGAAGTCTCTGAGCTTGTCACCCGGCAAG(SEQ ID NO:113)。
CAAGTACAGTTGCAGCAGTCTGGAGCTGAGCTGGTTAGACCTGGAACCAGTGCCAAGATCTCCTGCAAAGCTAGTGATTATACTTTCACAAACTACTGGCTCGGTTGGCTGAAACAAAGACCCGGGCACGGTCTGGAATGGATAGGCCACATTTACCCAGGCGGCGGATACACCAACTATAACGAGAAGTTTAAGGGAAAGGCTACTCTGACAGCCGACACCTCATCCAGCACAGCCTACATGCAGCTTAGTAGTTTGACCAGTGAGGATTCCGCAGTGTACTTCTGTGCACGTGTGAGGTCAGGGAATGACGCCCTGGACTTCTGGGGCCAGGGTACTTCAGTGACAGTGTCCTCCGCTAGCACTAAGGGACCAAGCGTGTTTCCTCTGGCTCCAAGCTCTAAATCAACCTCAGGCGGAACCGCCGCTTTGGGATGTCTTGTGAAGGATTACTTCCCTGAGCCTGTCACCGTCTCCTGGAATAGCGGCGCCCTGACTTCCGGGGTGCATACATTCCCTGCCGTATTGCAGTCAAGCGGCCTGTATAGCCTTAGCTCTGTTGTAACTGTGCCATCTTCTTCCCTTGGCACACAGACCTACATCTGTAACGTGAACCATAAGCCATCCAATACAAAAGTTGATAAGAAGGTGGAGCCAAAATCATGTGACAAAACTCATACATGCCCTCCTTGTCCAGCACCTGAGCTGTTGGGCGGACCAAGTGTCTTTCTGTTCCCCCCAAAGCCAAAGGACACACTGATGATCAGTCGCACACCAGAAGTGACTTGCGTTGTTGTCGATGTGAGCCACGAAGACCCTGAGGTTAAGTTTAACTGGTACGTGGATGGTGTGGAGGTGCACAATGCCAAGACTAAGCCACGTGAAGAACAGTATAACTCCACCTATCGTGTGGTCTCTGTCCTGACAGTACTGCACCAGGACTGGCTCAATGGAAAAGAGTACAAGTGCAAGGTTAGTAACAAGGCCTTGCCCGCTCCTATCGAGAAAACTATCAGTAAGGCAAAGGGACAGCCAAGAGAACCACAGGTTTACACCCTGCCACCTAGCCGGGACGAATTGACTAAAAACCAAGTGAGTCTCACATGCCTCGTCAAGGGATTCTACCCATCTGACATTGCCGTAGAGTGGGAGTCCAATGGGCAGCCCGAGAATAATTATAAGACTACTCCACCTGTCCTGGATTCTGATGGATCCTTCTTTTTGTATTCCAAGCTTACCGTGGACAAAAGCAGGTGGCAGCAGGGCAATGTCTTTTCATGCAGCGTGATGCACGAAGCACTTCACAATCACTACACACAGAAGAGTCTGTCTCTCAGTCCTGGTAAG(SEQ ID NO:114)。
CAAATTCAGCTGGTGCAGTCCGGCCCAGAACTTAAGAAACCCGGTGAAACCGTGAAGATATCCTGCAAAGCTTCAGGCTATACCTTTACCAACTATGGCATGAATTGGGTGAAGCAAGCTCCCGGGAAGGGCCTTAAATGGATGGGCTGGATCAACACCAACACAGGTGAGCCAACCTATGCCGAAGAAATCAAAGGACGCTTTGCTTTCTCTCTCGAAACTAGCGCAAGTACCGCTTATTTGCAGATCAATAATCTGAAAAACGAGGACACCGCTACCTACTTTTGCTCAAGAGAGGGCATTTACGGCATGGATTCTTGGGGCCAGGGAACATCTGTCACCGTCTCATCTGCATCTACCAAGGGCCCTAGTGTGTTCCCACTGGCCCCTTCATCCAAGTCCACTTCTGGAGGAACAGCCGCCTTGGGCTGTCTCGTTAAGGACTACTTCCCCGAGCCTGTTACCGTGTCCTGGAACAGTGGCGCCCTGACCTCCGGTGTTCACACTTTCCCCGCTGTGTTGCAGTCCTCTGGCCTTTATTCCCTTTCCTCTGTAGTGACAGTGCCCAGTTCCAGTCTGGGTACACAGACCTACATTTGCAATGTCAACCATAAACCAAGTAATACCAAGGTAGATAAAAAGGTAGAGCCTAAGTCATGCGATAAAACTCACACATGTCCACCATGTCCTGCTCCAGAACTCTTGGGCGGTCCAAGTGTCTTTTTGTTCCCACCAAAACCTAAGGATACCCTCATGATCTCTAGGACCCCCGAGGTCACATGTGTGGTGGTCGACGTTAGTCACGAGGATCCCGAGGTTAAATTTAACTGGTATGTCGATGGGGTTGAAGTCCACAATGCCAAAACCAAACCAAGAGAGGAACAGTACAATTCCACTTACCGTGTGGTTTCAGTGCTGACCGTCCTTCATCAGGACTGGCTCAACGGGAAGGAGTACAAGTGCAAGGTCAGTAACAAGGCTCTTCCAGCCCCCATCGAAAAGACTATTTCCAAAGCCAAGGGACAACCAAGAGAGCCACAAGTGTACACTCTTCCCCCCAGCAGGGACGAACTCACAAAGAATCAGGTTTCTCTCACCTGTCTGGTTAAGGGCTTTTACCCCAGCGACATCGCAGTTGAGTGGGAGAGCAATGGCCAGCCTGAGAATAACTATAAGACAACACCCCCCGTGCTGGATTCTGACGGCAGCTTTTTCTTGTACTCTAAACTCACTGTAGACAAATCCAGGTGGCAGCAAGGCAACGTGTTTTCCTGCTCTGTCATGCACGAGGCATTGCACAATCACTATACTCAGAAATCACTTAGCCTGTCCCCCGGTAAG(SEQ ID NO:115)。
CAAGTACAATTGAAAGAGAGTGGACCAGGACTTGTGGCCCCTAGCCAGTCTCTGTCAATAACCTGTACTGTCAGTGGATTTTCCCTTACCAGCTATGGGGTACACTGGGTTAGGCAGCCACCTGGTAAAGGACTTGAGTGGCTGGGCATTATTTGGGCCGGAGGGCGGACAGACTATAATTCTGCACTGGTATCCAGACTCAATATCAGTAAGGACAACAGCAAAAGTCAAGTGTTTCTGAAAATGCATTCACTTCAAACCGATGACACCGCTATGTACTACTGTGCTAGGGAAGGCGGTTATGACTATGATGGAGATCTCTGGACTACCGGAGTCAAGGAGCCTCAAAGCCCCAGTCCTCAGGCCTCCACAAAAGGGCCTAGTGTTTTCCCCCTGGCCCCATCATCTAAGAGTACATCAGGAGGAACAGCAGCCCTTGGATGCCTGGTGAAAGACTACTTTCCAGAACCCGTTACCGTGTCCTGGAACTCAGGCGCACTTACCTCTGGCGTCCATACATTTCCCGCCGTATTGCAGAGCAGCGGACTGTACTCATTGTCATCCGTGGTGACAGTGCCTAGTAGTTCTCTTGGTACACAGACCTACATATGTAACGTGAATCATAAACCCTCAAATACTAAAGTCGACAAGAAGGTTGAGCCCAAGAGCTGTGATAAAACCCACACTTGTCCCCCATGCCCAGCACCTGAACTGCTCGGAGGCCCATCCGTCTTTCTCTTCCCTCCTAAGCCTAAGGATACACTTATGATTTCACGGACCCCTGAAGTGACATGTGTGGTCGTTGATGTGTCCCATGAGGACCCAGAAGTTAAATTTAACTGGTATGTCGATGGCGTGGAGGTGCACAACGCCAAGACAAAGCCCAGGGAAGAACAGTATAATTCAACATACCGCGTCGTTAGCGTGCTGACAGTTCTGCATCAGGATTGGCTTAACGGTAAAGAGTACAAGTGCAAGGTCTCCAACAAAGCTCTGCCTGCACCTATTGAAAAAACTATATCCAAGGCTAAGGGCCAGCCTCGCGAGCCTCAGGTATATACACTGCCACCCAGCAGGGACGAACTGACAAAGAATCAGGTCAGTCTGACTTGCCTCGTCAAGGGATTCTACCCTTCAGACATCGCCGTGGAGTGGGAGTCAAACGGTCAGCCCGAGAACAACTACAAGACAACACCCCCTGTACTGGACTCCGACGGCTCCTTTTTCCTGTATTCTAAGCTGACTGTCGATAAATCTCGCTGGCAGCAGGGAAACGTCTTTTCCTGCTCTGTGATGCACGAGGCTCTGCACAATCACTATACTCAGAAGTCACTGTCCTTGTCTCCCGGAAAG(SEQ IDNO:116)。
CAGGTACAATTGAAACAAAGTGGGCCAGGTCTTGTCCTTCCTTCCCAGTCTCTGAGTATTACCTGTACCGTCAGTGGATTTAGCCTTACAAGCTATGGAGTCCATTGGTTCAGGCAATCCCCAGGCACAGGCCTGGAATGGTTGGGGGTCATCTGGAGTGGTGGTATCACCGATTACAATGCAACCTTTATCCCCCGTCTGTCCATATCAAAGGACAACTCTAAGTCCCAGGTGTTTTTCAAAATGAACTCTCTCCAGGCAGATGACACAGCCATATATTACTGTGCTCGTAACTTCGACGGCTACTACTATTCCATAGATTATTGGGGCCAGGGCACTTCAGTCACCGTCAGTAGCGCCAGCACTAAGGGTCCTTCCGTTTTTCCCCTTGCTCCTTCTTCAAAGAGCACAAGTGGGGGGACTGCAGCTTTGGGCTGCTTGGTGAAGGATTATTTTCCTGAGCCTGTCACAGTCTCTTGGAATAGCGGGGCACTCACAAGCGGTGTTCATACCTTTCCAGCCGTGCTGCAGAGTTCTGGTCTGTATAGTCTCTCCTCAGTGGTGACCGTACCTTCTTCCTCTCTGGGCACCCAGACATACATATGCAATGTTAATCACAAGCCCTCCAACACAAAAGTGGATAAAAAAGTTGAGCCTAAGAGTTGTGACAAAACTCACACATGTCCTCCTTGCCCAGCTCCCGAACTCCTTGGAGGACCAAGTGTTTTTTTGTTTCCTCCTAAGCCCAAGGACACCCTGATGATTTCTAGAACTCCAGAGGTAACATGTGTGGTCGTGGACGTCAGCCATGAGGACCCCGAAGTAAAATTTAATTGGTACGTGGACGGGGTGGAGGTGCATAACGCCAAGACCAAACCCCGAGAGGAGCAGTATAATAGCACCTACAGAGTCGTGAGTGTTTTGACTGTCCTGCATCAAGATTGGCTCAACGGAAAGGAGTACAAGTGCAAGGTAAGTAATAAAGCCCTGCCAGCACCCATAGAGAAAACCATCAGCAAAGCAAAAGGGCAGCCAAGAGAGCCACAGGTTTATACACTCCCTCCATCTCGGGACGAGTTGACTAAGAACCAGGTTAGTCTGACATGTCTGGTGAAAGGCTTTTACCCCAGCGATATAGCTGTAGAGTGGGAAAGCAACGGGCAGCCTGAGAACAACTATAAGACCACTCCCCCCGTTCTGGATAGCGACGGTAGTTTCTTTCTTTATTCCAAGCTGACTGTGGATAAATCCCGATGGCAGCAGGGAAATGTCTTTTCCTGTTCCGTCATGCACGAAGCTCTCCATAATCACTACACTCAGAAATCTCTGTCCCTGAGTCCCGGTAAA(SEQ ID NO:117)。
CAAGTTCAACTTAAACAGAGTGGTCCTGGCCTGGTACAGCCAAGCCAGTCCCTGTCCATAACCTGTACAGTCTCAGGCTTTAGCCTTACTAACTATGGCGTCCACTGGGTTCGGCAGTCTCCTGGTAAGGGACTTGAATGGCTCGGAGCTATTTGGAGGGGAGGGTCCACCGACTATAATGCAGCATTCATGTCCCGGCTTTCTATTACCAAGGATAACAGCAAAAGTCAGGTGTTCTTTAAGATGAACTCCCTGCAGCCCGACGATACAGCCATCTACTACTGTGCCAAAAACCTGTATGGACCAGCTGCCATGGACTATTGGGGCCAGGGGACCTCCGTCACAGTTAGCAGCGCTTCTACTAAGGGCCCCTCTGTGTTTCCACTGGCACCATCCTCTAAGTCAACCAGTGGGGGCACTGCAGCTTTGGGCTGTCTGGTCAAGGATTACTTTCCAGAACCTGTCACCGTTTCCTGGAATTCCGGCGCCTTGACTTCTGGTGTGCACACCTTCCCAGCTGTCCTGCAGTCCAGTGGACTGTATTCACTGAGCTCCGTGGTCACAGTGCCTTCAAGTAGCCTGGGCACCCAGACCTATATCTGTAACGTAAACCACAAGCCTTCTAACACCAAGGTGGACAAAAAGGTGGAACCAAAAAGCTGTGACAAAACTCATACATGCCCACCTTGTCCAGCTCCAGAGCTGCTGGGTGGACCATCTGTGTTCTTGTTTCCCCCTAAGCCCAAAGACACCCTGATGATTTCACGGACCCCTGAGGTGACATGTGTCGTTGTGGACGTTAGTCACGAGGATCCTGAAGTAAAATTCAATTGGTACGTCGACGGCGTCGAAGTTCACAATGCCAAGACAAAGCCCCGAGAGGAACAGTACAATAGTACATACCGAGTCGTGAGCGTGTTGACAGTTCTCCACCAGGATTGGCTCAATGGCAAAGAGTACAAATGTAAGGTATCAAATAAAGCCCTCCCCGCTCCCATAGAGAAGACAATCTCAAAGGCCAAAGGGCAACCCAGGGAGCCTCAAGTCTACACCCTTCCCCCATCTCGCGACGAGCTCACCAAGAATCAGGTATCATTGACATGTCTGGTCAAAGGATTTTATCCTAGCGATATCGCCGTAGAGTGGGAGTCTAATGGCCAGCCCGAGAATAATTACAAAACCACTCCTCCTGTGCTGGATTCTGATGGATCTTTCTTCCTGTATAGTAAGTTGACAGTCGATAAGTCCCGGTGGCAACAGGGTAATGTTTTCAGCTGTTCCGTTATGCATGAGGCTCTCCACAACCATTACACCCAAAAGAGTCTTTCTCTTTCCCCCGGCAAG(SEQ ID NO:118)。
CAGATTCAGCTGGTGCAGTCCGGTCCTGAGTTGAAAAAGCCAGGAGAAACTGTCAACATCTCTTGCCGCGCCAGCGGGGACACATTCACCAACTACGCCGTGAACTGGGTGAAGCAGGCTCCCGGTAAGGGGCTCAAGTGGATGGGCTGGATAGACACCTACACAGGAGATCCTACCTACGCAGACGACTTGAAGGGCAGGTTCGCCTTCTCTCTTGAGACCTCCGCCACAACTGCTTATCTTCAGATCAACAATTTGAAAAACGAGGATACCGCCACTTACTTCTGTGCTGGGGATACCTGGTTCGCTTACTGGGGGCAGGGAACTTTGGTCACCGTGAGCGCTGCTTCCACCAAGGGGCCCAGCGTCTTCCCTCTCGCCCCTTCTAGCAAGAGCACCAGTGGTGGAACCGCTGCCCTTGGGTGCCTCGTGAAGGATTATTTCCCTGAACCTGTGACTGTATCTTGGAATAGCGGTGCACTCACCTCCGGTGTGCACACTTTTCCAGCTGTGCTGCAGTCTAGCGGGCTGTATAGCCTTAGCTCCGTGGTGACCGTGCCTTCTTCTTCTTTGGGTACCCAGACCTACATCTGCAACGTGAACCATAAGCCATCCAATACTAAGGTCGACAAGAAAGTGGAGCCCAAATCCTGCGATAAAACCCATACTTGTCCCCCATGCCCAGCTCCAGAACTGCTCGGAGGGCCCAGTGTGTTTCTTTTCCCCCCAAAGCCTAAGGACACTCTCATGATATCCCGAACCCCAGAGGTGACATGCGTCGTTGTGGATGTGTCACATGAAGATCCAGAGGTCAAGTTCAACTGGTATGTCGATGGAGTCGAGGTCCACAATGCTAAGACAAAACCAAGAGAGGAGCAGTATAACAGTACCTACCGAGTGGTCTCCGTGCTGACTGTTCTTCACCAAGATTGGCTCAATGGTAAAGAGTACAAATGCAAAGTATCCAACAAGGCCCTTCCTGCACCAATCGAAAAAACTATTTCCAAAGCAAAGGGCCAGCCCAGGGAGCCACAGGTCTACACACTGCCCCCAAGCAGGGATGAACTCACCAAGAACCAAGTGTCACTTACCTGCCTGGTTAAGGGATTCTACCCCTCCGATATTGCAGTAGAATGGGAGTCTAACGGTCAGCCTGAGAATAACTACAAGACCACCCCCCCCGTGCTCGATAGCGATGGTTCATTCTTCCTGTATAGCAAGCTGACCGTCGATAAGAGTAGGTGGCAACAAGGGAATGTGTTCAGTTGCTCTGTTATGCACGAAGCCCTCCACAACCATTACACACAAAAGTCCCTTTCCTTGTCTCCCGGTAAG(SEQ ID NO:119)。
CAGGTAACACTTAAGGAGAGCGGTCCAGGTATACTCCAGCCTAGTCAGACACTGAGCCTTACATGCAGCTTTAGTGGGTTCAGCCTGTCCAGTTCTGGCATGTCAGTAGGCTGGATCCGACAACCTAGCGGAAAGGGCCTGGAGTGGCTGGCTCATATCTGGTGGTCAGACGACAAGTCCTATAACCCAGCCCTCAAATCCCGTCTGACCATCTCAAAAGACACCAGTAATAATCAGGTTTTCCTTAAAATCGCCTCTGTGGTCACTGCAGATACAGCAACCTACTACTGTGCACGCGAGGGCTCTTTGGGCTATGGACTGGACTACTGGGGTCAGGGTACCACTCTGACTGTAAGCAGTGCTTCAACTAAGGGACCTAGCGTGTTTCCACTGGCACCCAGTTCTAAATCTACTTCTGGGGGAACTGCTGCTCTGGGATGCCTGGTGAAGGATTACTTTCCAGAGCCCGTCACTGTGAGTTGGAATAGCGGTGCCTTGACCTCCGGAGTGCACACCTTCCCAGCTGTGCTTCAATCCTCAGGCTTGTATTCTCTTTCCTCCGTGGTGACCGTGCCATCCTCCTCTCTCGGGACCCAGACTTACATATGTAATGTAAACCACAAGCCCTCTAACACAAAGGTAGATAAGAAGGTCGAGCCAAAGTCCTGTGATAAAACACATACATGTCCCCCTTGTCCCGCTCCAGAACTGCTTGGCGGACCCTCTGTGTTCCTGTTCCCACCTAAGCCAAAAGACACTCTTATGATTTCCAGGACTCCAGAGGTTACATGCGTTGTGGTGGACGTAAGCCATGAAGACCCTGAGGTGAAATTCAATTGGTATGTGGACGGTGTGGAGGTCCATAACGCTAAGACTAAGCCCAGGGAGGAACAGTACAACTCAACATATCGAGTCGTCTCTGTCCTGACAGTGCTCCACCAGGATTGGCTGAACGGAAAGGAATACAAATGCAAGGTGAGTAATAAAGCCCTGCCAGCTCCCATCGAAAAAACAATCAGCAAGGCTAAGGGTCAGCCCCGCGAACCACAGGTCTACACTCTGCCACCAAGTCGGGATGAATTGACTAAGAATCAGGTCTCCCTGACCTGTCTGGTGAAGGGTTTTTATCCCTCCGACATCGCAGTGGAGTGGGAGAGCAACGGGCAGCCTGAGAATAACTATAAGACAACTCCACCCGTCCTCGATTCTGACGGGTCTTTTTTTCTGTACAGCAAACTGACTGTGGACAAGTCTCGGTGGCAGCAAGGTAACGTCTTCAGCTGCTCCGTTATGCACGAAGCCCTCCACAACCACTACACTCAGAAATCTCTGTCCTTGAGTCCTGGAAAG(SEQ ID NO:120)。
GAAGTTAAACTCCTCGAATCTGGAGGAGGGTTGGTTCAGCCAGGTGGTTCTTTGAAGCTGTCTTGTGCAGCCTCTGGGTTTGACTTCCGAAGATATTGGATGAGTTGGGTGCGTCAGGCACCAGGGAAAGGTCTTGAATGGATCGGGCAGATTAACCCCGACAGTTCAATGATTAACTATACACCTTCTTTGAAAGATAAATTTATTATATCCCGTGACAACGCTAAAAACACCTTGTATCTGCAGATGAGTGAGGTGAGATCCGAAGACACTGCTCTTTACTACTGTGCCACCTATGGACACCACGCTACAGACTCCTGGGGCCAGGGTACCAGTGTGACAGTTTCCAGTGCCAGCACCAAGGGCCCATCCGTTTTCCCCCTGGCTCCCTCTTCTAAATCTACTTCAGGTGGTACTGCAGCACTTGGATGTTTGGTGAAGGACTACTTCCCTGAGCCAGTCACCGTGAGTTGGAACTCAGGCGCTCTTACATCCGGTGTCCACACATTTCCAGCCGTGCTGCAGAGCTCAGGACTCTATTCTCTCAGCTCCGTCGTGACAGTACCCAGCAGCTCACTTGGCACTCAGACCTATATCTGTAATGTCAACCATAAGCCATCTAACACTAAAGTCGACAAGAAGGTCGAGCCCAAGAGTTGCGACAAAACACATACCTGCCCCCCATGTCCCGCACCAGAACTCCTGGGTGGTCCAAGCGTGTTTTTGTTTCCACCTAAACCAAAGGACACCCTGATGATTAGCCGTACACCAGAGGTGACTTGCGTGGTGGTCGACGTGAGTCACGAGGATCCAGAGGTGAAGTTCAACTGGTATGTGGATGGCGTTGAAGTACATAACGCCAAAACCAAGCCCAGAGAGGAACAATACAATAGCACCTACCGAGTCGTCAGTGTGCTGACCGTGCTTCACCAAGACTGGCTCAATGGGAAAGAGTACAAGTGTAAGGTTAGCAATAAAGCTCTGCCTGCCCCAATCGAGAAGACTATCTCTAAGGCAAAGGGACAGCCTAGGGAGCCACAGGTCTATACACTCCCCCCCTCACGGGATGAGTTGACTAAGAATCAGGTGTCACTGACATGCCTTGTTAAGGGGTTTTATCCCTCTGACATCGCCGTCGAATGGGAGAGTAACGGACAGCCAGAGAACAACTACAAGACAACCCCACCAGTCCTGGACTCTGACGGCTCCTTCTTTCTGTATTCAAAGCTGACTGTGGACAAATCTAGATGGCAGCAGGGCAACGTCTTTAGTTGTAGTGTGATGCATGAGGCTCTGCATAACCATTATACACAGAAAAGTCTCAGTCTTAGCCCAGGAAAA(SEQ ID NO:121)。
CAAGTTCAGTTGCAGCAACCTGGTGCAGAATTGGTGAGACCCGGTACATCTGTCAAGATGAGCTGCAAGGCCAGCGGGTACACCTTTACTAGTTACTGGATGCATTGGGTGAAACAGCGACCCGGACAAGGATTGGAGTGGATCGGTGATATCTATCCAGGGTCCGACAGCACAAACTATCATGAGAAGTTTAAGAGCAAGGCCACCCTGACAGTCGACACCTCAAGCTCCACAGCTTACATGCAGCTGTCTTCCTTGACTAGCGAAGATTCTGCCGTGTACTATTGCGCTCTTGATAGCTCTGGGTATGGGTTCGCCTATTGGGGACAGGGTACTCTGGTGACAGTGTCCGCTGCCTCCACCAAAGGTCCCAGTGTATTTCCCTTGGCTCCATCTAGCAAGTCTACATCCGGCGGTACAGCCGCACTGGGGTGTCTTGTGAAGGACTACTTCCCTGAGCCTGTTACAGTATCTTGGAATTCAGGCGCTCTGACCTCAGGAGTCCACACCTTTCCCGCTGTCTTGCAGTCTAGCGGCCTTTATAGCCTGTCTTCCGTGGTGACTGTTCCCTCTAGTAGTCTCGGAACCCAGACCTACATCTGCAATGTGAATCACAAGCCCAGCAACACAAAAGTCGACAAGAAGGTGGAGCCTAAATCTTGCGACAAGACTCACACCTGTCCTCCATGCCCTGCTCCAGAACTGCTGGGGGGACCTTCAGTGTTTCTCTTCCCTCCAAAACCAAAGGACACCCTCATGATCTCCCGCACCCCAGAGGTCACCTGTGTGGTGGTGGACGTTTCACATGAGGATCCTGAGGTGAAGTTCAATTGGTATGTGGACGGTGTCGAAGTTCATAATGCCAAGACAAAGCCTCGCGAAGAGCAGTACAACAGCACTTACAGGGTGGTGTCCGTCCTGACTGTCTTGCACCAGGACTGGTTGAACGGCAAAGAATACAAATGCAAGGTGAGTAACAAGGCACTGCCTGCACCAATTGAGAAGACTATCTCTAAGGCCAAAGGCCAGCCTCGTGAGCCTCAAGTGTATACCCTCCCCCCTAGCAGAGACGAGTTGACAAAGAATCAGGTCAGCTTGACATGCCTGGTGAAGGGATTTTATCCCTCAGACATTGCCGTCGAATGGGAGAGTAACGGCCAGCCAGAAAATAACTACAAGACAACCCCCCCTGTCCTGGACAGCGATGGATCATTTTTCCTGTACTCAAAGCTGACTGTAGACAAGTCTCGATGGCAGCAAGGTAACGTATTCTCCTGCAGCGTGATGCACGAGGCACTGCATAATCACTATACCCAGAAGAGCCTGAGCCTGTCACCAGGGAAG(SEQ ID NO:122)。
GAGGTACAGTTGGTTGAATCTGGCGGTGGACTTGTACAACCAGGCGAATCCTTGAAACTGAGTTGCGACTCTAATGACTATGAATTCCCTAGTCACGATATGTCTTGGGTTCGGAAGACCCCTGAGAAACGGCTTGAGCTTGTGGCAGCCATCAACTCAGACGGTGGAAATACATATTACCCCGACACTATGGAGAGGAGATTTATTATCAGCCGCGATAATACCAAAAGGACACTTTATCTCCAGATGTCCTCTTTGCGCAGCGAGGATACCGCTCTGCATTATTGTGCCCGCCCACGACCAACTATCGGCACAACAGCCACTGGGTCTTCTATGTCTGGGGCACAGGGCCCAAGAAGCGCCTCTACAAAGGGCCCTTCAGTGTTTCCCCTTGCTCCATCATCTAAAAGTACTAGTGGAGGCACTGCTGCTCTCGGCTGTCTGGTCAAGGACTACTTTCCAGAGCCTGTGACCGTGTCCTGGAATAGTGGGGCACTTACATCTGGTGTACACACCTTTCCTGCTGTACTGCAGAGCTCTGGCCTGTATTCCCTGAGCAGCGTTGTCACAGTCCCATCAAGTAGCTTGGGAACTCAGACCTACATATGCAATGTGAATCACAAACCATCCAACACCAAGGTGGATAAGAAGGTCGAGCCTAAAAGTTGTGACAAAACCCATACATGCCCACCTTGTCCTGCTCCTGAGCTTCTGGGCGGCCCAAGTGTTTTCCTTTTCCCTCCCAAACCCAAAGACACACTCATGATTTCCCGTACACCCGAGGTTACTTGTGTGGTTGTTGATGTCAGCCACGAGGATCCTGAGGTCAAGTTCAACTGGTATGTCGACGGCGTTGAAGTCCACAACGCTAAGACCAAGCCTCGGGAGGAGCAGTATAATTCCACTTACAGGGTGGTTTCCGTTTTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTATAAATGCAAGGTAAGCAATAAAGCCTTGCCCGCACCCATCGAGAAAACTATTAGCAAAGCCAAGGGTCAGCCCAGAGAACCTCAAGTTTATACCCTCCCTCCCTCACGCGATGAACTCACTAAGAATCAGGTGTCACTCACATGTCTCGTGAAGGGTTTTTACCCCTCCGATATTGCTGTGGAGTGGGAGTCTAACGGCCAGCCCGAGAACAATTACAAGACCACCCCACCTGTGCTTGATAGCGATGGCTCCTTTTTCCTCTACAGTAAGCTGACAGTGGACAAATCTCGGTGGCAGCAGGGCAACGTTTTCTCCTGTTCAGTAATGCATGAGGCATTGCATAATCATTATACCCAAAAGAGCCTCTCACTTTCCCCAGGGAAG(SEQ ID NO:123)。
TCTATTGTGATGACTCAAAGTCCTAAATTTCTCCTCGTTTCCGCTGGAGACAGGGTGATAATAACTTGCAAAGCTTCACAGAGCGTGTCCAATGATGTAGTATGGTACCAGCAAAAGCCAGGCCAGAGCCCAAAACTTCTGATCTACTACGGTTCACACCGGAACACCGGAGTACCTACAAGGTTTACTGGTTCCGGCTATGGGACTGACTTCACATTCACTATTTCAACCGTCCAGGCTGAAGACCTGGCAGTCTATTTTTGTCAGCAGGATTTCTTCTCACCATGGACCTTCGGTGGCGGTACAAAATTGGAGATAAAGCGCACTGTTGCCGCCCCTTCCGTCTTTATATTTCCACCCTCCGATGAGCAGCTTAAGTCAGGGACAGCCTCTGTCGTGTGTCTGCTCAACAATTTTTACCCCCGTGAAGCCAAGGTGCAGTGGAAAGTGGATAACGCCCTGCAGTCTGGCAATTCTCAGGAGTCAGTGACCGAACAGGATTCAAAAGACTCTACATATAGCTTGTCATCCACCCTTACTCTGTCCAAAGCAGATTATGAGAAGCACAAAGTTTATGCTTGTGAAGTTACTCACCAGGGTCTGAGCAGCCCCGTAACAAAGAGTTTCAACCGGGGGGAGTGC(SEQ ID NO:124)。
GACATAGTTTTGACCCAGTCTCCTGCTAGTCTCGCCGTGTCTCTGGGACAACGAGCAACTATTAGCTGCCGAGCCAGCGAGAGCGTTGACGAATACGGGATTTCTTTCATGAACTGGTTCCAGCAGAAGCCAGGACAGCCCCCACGTCTGCTTATTTACAGCGCCTCTAACCAAGGGAGTGGAGTGCCAGCCAGATTTACAGGTAGTGGATCTGGAACAGATTTCTCCCTCAACATTCTGCCCATGGAGGAAGACGACACCGCTATGTATTTCTGTCAGCAGAGCAAAGAAGTGCCCTGGACCTTTGGGGGAGGGACCAAACTCGAAATTAAGCGAACTGTGGCTGCTCCCTCAGTCTTTATCTTCCCACCATCTGATGAGCAACTGAAGTCTGGCACTGCATCCGTGGTGTGTCTGCTGAATAATTTTTACCCTCGCGAGGCAAAAGTGCAGTGGAAGGTGGATAATGCTTTGCAGTCAGGAAATTCTCAGGAGAGTGTTACCGAACAAGATAGCAAGGACTCCACATATAGTTTGTCCTCTACACTTACTCTCTCCAAGGCAGACTACGAAAAACACAAGGTGTACGCTTGTGAGGTGACCCACCAGGGCCTGAGCTCACCAGTGACCAAATCCTTCAACCGCGGCGAGTGC(SEQ ID NO:125)。
AGTATTGTGATGACTCAGACCCCCAAGTTTCTTTTGGTGAGTGCAGGTGACAGAGTGACAATTACCTGCAAAGCTTCACAGAGCGTCAGCAACGATGTCGTCTGGTACCGACAGAAGCCAGGACAGAGCCCCAAGCTCCTCATCTACTACGCCTCTAATCGATACATCGGCGTGCCCGACAGGTTTACCGGTTCTGGCTATGGTACTGATTTTACCTTCACAATTTCTACTGTTCAGGCCGAAGATCTTGCCGTGTACTTTTGTCAACAGGATTACTATAGTCCCTGGACTTTCGGCGGGGGTACTAAGCTGGAGATTAAGCGAACAGTGGCCGCACCCTCCGTGTTTATCTTCCCACCCTCTGACGAGCAACTCAAGAGTGGAACTGCCTCTGTCGTGTGCTTGCTGAACAACTTTTATCCCAGAGAAGCCAAGGTGCAGTGGAAGGTGGATAATGCCCTGCAGAGCGGGAACTCTCAGGAATCCGTCACAGAACAGGATTCAAAGGACTCAACTTATTCCCTTTCTTCAACCCTGACACTCTCCAAGGCCGACTACGAGAAGCATAAAGTGTACGCTTGCGAGGTAACCCATCAGGGTCTCAGTAGCCCCGTCACTAAGAGCTTCAACAGGGGCGAATGC(SEQ ID NO:126)。
GATGTGGTTATGACTCAGTCCCCATTGTCCTTGCCAGTCTCTCTGGGTGATCAGGCATCTATTTCCTGCAGGTCCAGCCAGTCACTGGTGCATTCTAACGGGAACACCTACCTTCACTGGTACTTGCAAAAGCCCGGGCAGAGCCCTAAGCTGCTCATTTATAAGGTTTCTAATAGATTCAGCGGTGTGCCTGACAGATTTTCTGGTTCTGGATCTGGCACCGATTTTACCCTGAAGATCAGTCGAGTAGAGGCCGAAGACTTGGGAGTGTACTTTTGCTCCCAATCCACCCATGTCCCACCAGATGTGCGATGGCGTCATCAGGCTGGCAACCAAAGGACTGTGGCTGCCCCTAGTGTTTTTATATTCCCACCTTCAGACGAGCAGCTTAAAAGTGGCACCGCCTCAGTGGTTTGTTTGCTGAATAATTTCTATCCAAGGGAAGCAAAGGTTCAATGGAAGGTGGACAACGCTCTGCAAAGCGGAAACAGTCAGGAGAGCGTGACCGAACAGGATAGCAAGGACAGTACTTATAGTTTGAGCAGTACTCTCACTTTGTCCAAAGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAAGTGACCCATCAGGGGTTGTCAAGCCCTGTAACTAAAAGTTTTAATAGAGGCGAGTGT(SEQ ID NO:127)。
GATATCCAGATGACCCAGACCACTTCCAGTCTTTCTGCTAGTCTCGGCGATCGAGTGACCATCAGCTGCCGAGCATCTCAGGACATTTCAAATTCACTCAACTGGTATCAACAGAAACCAGATGGCACCGTCAAGCTGCTGATTTATTACACCAGCAGACTCCACAGTGGTGTGCCCAGCAGGTTCACAGGTTCTGGGAGTGGGACTGATTACTCCCTGACAATTTCTAACTTGGAACAGGAGGATATCGCCACTTATTTTTGCCAGCAGGGCAACACCCTTCCATTGACATTCGGCGCAGGAACCAAGCTTGAGTTGAAGAGAACCGTCGCCGCACCCTCTGTATTTATATTCCCACCATCTGACGAGCAACTGAAGTCCGGAACAGCCAGTGTGGTGTGCCTCCTTAATAATTTTTACCCTCGTGAAGCCAAGGTACAGTGGAAGGTTGATAACGCCCTGCAGAGTGGAAATAGTCAGGAGTCTGTAACCGAGCAGGATTCCAAGGATTCCACATATTCACTGTCCAGTACATTGACATTGTCAAAGGCTGACTACGAAAAGCATAAGGTATACGCCTGCGAAGTGACACATCAGGGGCTGTCTTCTCCCGTGACAAAGTCATTCAATCGCGGGGAGTGT(SEQ ID NO:128)。
GATATTCAGATGAACCAGTCTCCCTCCAGTTTGTCCGCCTCCCTCGGTGATACTATTACTATTACATGCCACGCTAACCAAAATATCTACGTGTGGCTGTCATGGTATCAACAGAAACCTGGCAACATTCCCAAGCTTCTCATCTACGAGGCATCAAACCTGCACACTGGCGTCCCTTCCAGGTTCTCAGGCTCAGGTTCCGGAACCGGTTTTACACTGACCATAAGTAGCCTGCAGCCTGAAGACATCGCAACCTACTATTGTCAGCAAGGCCAGAGCTACCCCTACACCTTCGGCGGAGGAACAAAGTTGGAGATAAAACGGACTGTCGCCGCACCATCTGTCTTCATCTTCCCCCCCAGTGATGAGCAGCTTAAGAGTGGGACTGCTTCTGTCGTCTGTCTGCTCAATAATTTTTATCCAAGAGAGGCTAAGGTACAGTGGAAAGTGGACAACGCTCTGCAGTCTGGTAACTCCCAGGAGAGTGTGACCGAACAGGATTCTAAGGACTCCACATACTCCCTGAGCTCTACACTTACACTCAGTAAAGCAGACTATGAGAAGCATAAAGTGTATGCATGTGAGGTGACACACCAGGGTCTGTCCTCTCCTGTGACCAAGTCTTTCAACAGAGGCGAGTGT(SEQ ID NO:129)。
GATATCGTCATGTCACAGAGCCCATCTAGCTTGGCTGTCTCAGTGGGCGAGAAAGTGACCATGTCATGCAAAAGCTCCCAATCCTTGTTGTACAGCCGCAATCAGAAAAATCGCCTTGCCTGGTACCAGCAGAAACCAGGTCAGTCCCCAAAACTGCTGATTTATTGGGCCAGCACAAGGGAGAGTGGTGTGCCCGATAGATTCACTGGGTCCGGGTCAGGCACCGATTTCACTCTGACCATCTCATCTGTTAAAGCAGAAGATCTGGCCGTCTACTATTGCCAGCAGTACTATAGTTATCCCAGAACTTTCGGGGGCGGCACCAACCTGGAGATTAAGCGTACCGTGGCAGCACCATCTGTCTTTATTTTCCCCCCATCAGACGAGCAGTTGAAATCAGGAACCGCCTCTGTCGTGTGCCTGCTGAACAATTTTTATCCAAGAGAGGCTAAGGTGCAGTGGAAGGTCGATAATGCTCTTCAGAGCGGTAATTCTCAAGAATCCGTGACTGAACAGGATTCAAAAGATAGCACATACAGTCTCTCCAGCACCCTGACCCTCAGCAAGGCCGACTACGAGAAGCACAAAGTGTATGCCTGTGAAGTGACACATCAAGGTCTCTCCAGCCCTGTAACTAAGAGTTTTAATAGAGGAGAATGC(SEQ ID NO:130)。
GATGTCCTGATGACCCAGACTCCATTGAGCCTTCCTGTCTCCTTGGGGGATCAAGCCTCCATTTCATGCAGGAGCTCCCAGAGCATAGTCCACACAGATGGAAACACTTACCTGGAGTGGTACTTGCAGAAGCCAGGCCAGTCTCCCAAACTGCTCATCTACAAAGTGTCTAATAGATTTTCCGGTGTGCCCGACCGTTTTTCAGGTAGCGGCTCTGGTACTGATTTCACTCTGAAGATCTCCCGGGTGGAGGCTGAGGATCTGGGCGTCTATTATTGTTTCCAGGGCTCCCACGTGCCATGGACCTTCGGTGGTGGCACCAAGTTGGAGATTAAGAGGACAGTGGCCGCACCATCCGTGTTCATATTTCCCCCTAGCGATGAACAGTTGAAAAGCGGTACTGCCTCCGTGGTTTGTCTGCTGAATAATTTCTACCCTAGAGAAGCTAAAGTGCAATGGAAGGTTGACAATGCCTTGCAGTCAGGCAATTCTCAGGAGTCTGTGACCGAACAGGACAGCAAGGACTCCACCTATTCTCTGTCTTCAACACTGACACTTAGTAAGGCTGATTACGAAAAGCATAAGGTATACGCCTGTGAGGTGACACACCAGGGCCTGAGTTCACCAGTGACCAAGTCCTTCAATCGCGGGGAGTGT(SEQ ID NO:131)。
GATATTGTGCTTACACAGTCCCCAGCTTCCCTGGCCGTTTCCCTTGGGCAGCGAGCCACAATCTCCTGCCGCGCATCTGAGTCCGTTGATAGCTACGGCAATTCTTTTATGCACTGGTACCAACAAAAACCTGGTCAGCCTCCAAAGTTGCTGATTTATCGCGCTTCCAACCTTGAGTCCGGTATTCCTGCTCGCTTTAGCGGCTCTGGGAGTAGAACCGACTTCACACTGACCATTAACCCAGTTGAGGCTGATGATGTGGCTACCTATTACTGTCAGCAGTCTAACGAAGACCCATTTACATTTGGGTCAGGCACTAAGCTGGAGATTAAGCGTACCGTGGCCGCCCCAAGCGTTTTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGTCCGGAACTGCCTCCGTCGTTTGTCTCTTGAACAATTTTTATCCTAGGGAAGCAAAAGTACAGTGGAAGGTAGATAACGCTCTGCAAAGCGGTAACTCCCAAGAATCCGTAACCGAACAAGACTCAAAGGACAGTACTTATTCCCTGTCCAGCACCCTGACTCTTTCTAAAGCTGATTATGAAAAGCATAAAGTTTATGCATGTGAGGTGACCCACCAGGGATTGTCCTCCCCAGTTACTAAATCTTTTAACCGGGGGGAATGC(SEQ ID NO:132)。
AATATCGTCATGACCCAGACTCCTAAATTTCTTCTGGTCTCCGCTGGAGACCGCGTCACTATAACTCGTAAAGCCAGCCAGTCCGTGTCTAATGACGTTGTGTGGTACCAGCAGAAGCCCGGGCAGTCCCCTAAGCTGCTCATGTATTACGCAAGTTATCGATACACCGGCGTGCCCGATCGATTCACCGGATCCGGTTATGGCACCGACTTCACATTTACTATTTCTAACGTTCAGGCCGAGGACCTCGCCGTATACTTTTGTCAACAAGACTACTCCAGCCCTTTTACATTTGGAAGCGGGACAAAATTGGAGATCAAGAGGACTGTTGCCGCACCTTCCGTGTTTATATTTCCACCTTCCGACGAGCAGCTGAAGTCCGGGACCGCAAGCGTGGTTTGTCTCCTCAATAATTTCTATCCTCGAGAGGCTAAGGTCCAGTGGAAGGTGGACAATGCTCTGCAGAGTGGCAACTCTCAGGAGTCAGTTACTGAACAAGACAGCAAGGACAGCACATATTCACTGTCATCCACTCTTACTCTCTCCAAGGCTGACTACGAAAAGCATAAGGTTTATGCCTGCGAGGTTACTCATCAGGGTCTGTCCAGTCCAGTGACCAAATCTTTTAATAGAGGAGAGTGC(SEQ ID NO:133)。
GATATTGTCTTGACCCAATCACCTGCTAGCCTGGCTGTGAGCTTGGGGCAGCGAGCAACCATCTCCTGTAGGGCCTCTCAGTCCGTCTCCACAAGTACTTACAACTACATGCATTGGTACCAGCAGAAACCTGGCCAACCACCAAAATTGCTCATTAAGTATGCTAGCAACCTTGAGTCAGGCGTCCCCGCAAGGTTTAGCGGATCTGGCTCAGGAACCGATTTTACTCTGAACATTCACCCCGTGGAGGAGGAGGACACTGCTACCTACTATTGCCAGCATAGTTGGGAGATACCCTTCACCTTTGGCAGTGGCACAAAGCTCGAGATTAAGCGCACTGTTGCCGCACCCAGCGTGTTTATCTTTCCACCTAGCGACGAACAGCTTAAGTCTGGTACTGCTAGTGTGGTGTGTTTGTTGAATAACTTCTACCCCCGTGAAGCCAAGGTTCAGTGGAAAGTGGATAACGCTCTCCAGAGCGGGAACAGTCAGGAGTCTGTTACCGAACAGGACTCAAAGGACAGCACTTACAGCCTGAGCAGTACTCTGACCCTGAGTAAGGCCGATTATGAAAAGCACAAGGTGTACGCCTGTGAGGTGACCCACCAGGGTCTGTCATCCCCTGTCACCAAGTCTTTTAATCGGGGTGAATGC(SEQ ID NO:134)。
其中，在本申请中，上述SEQ ID NO:113和124所示核苷酸序列分别编码3-6A4抗体的重链和轻链，上述SEQ ID NO:114和125所示核苷酸序列分别编码5-20E11-5F2抗体的重链和轻链，上述SEQ ID NO:115和126所示核苷酸序列分别编码3-5B2-2G4抗体的重链和轻链，上述SEQ ID NO:116和127所示核苷酸序列分别编码3-5B2-7A4抗体的重链和轻链，上述SEQ ID NO:117和128所示核苷酸序列分别编码3-2B5-3D2抗体的重链和轻链，上述SEQ IDNO:118和SEQ ID NO:129所示核苷酸序列分别编码3-7C9-1A6抗体的重链和轻链，上述SEQID NO:119和SEQ ID NO:130所示核苷酸序列分别编码3-9E1-3A2抗体的重链和轻链，上述SEQ ID NO:120和SEQ ID NO:131所示核苷酸序列分别编码3-15D5-3A6抗体的重链和轻链，上述SEQ ID NO:121和SEQ ID NO:132所示核苷酸序列分别编码3-15D5-6A1抗体的重链和轻链，上述SEQ ID NO:122和SEQ ID NO:133所示核苷酸序列分别编码5-20E11-1A2抗体的重链和轻链，上述SEQ ID NO:123和SEQ ID NO:134所示核苷酸序列分别编码5-21G2-1D3抗体的重链和轻链。
根据本发明的实施例，所述核酸分子具有如SEQ ID NO:159～162任一项所示核苷酸序列或具有SEQ ID NO:163～166任一项所示核苷酸序列。
CAAGTGCAGCTGGTTCAGAGCGGAGCTGAGGTGAAGAAGCCTGGAGCTAGCGTGAAGGTGTCTTGTAAAGCCAGCGACTACACCTTTACCAATTACTGGCTGGGCTGGGTCAGACAGGCCCCTGGCCAGGGCCTGGAATGGATGGGCCACATCTACCCCGGCGGAGGCTACACAAACTACAACGAGAAGTTCAAGGGCAGAGTGACAATGACCAGAGATACAAGCACCAGCACAGTGTATATGGAACTGTCTAGCCTGCGGAGCGAGGACACCGCCGTGTACTACTGCGCCAGAGTGCGGTCCGGCAACGACGCCCTGGATTTCTGGGGCCAGGGCACCCTGGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCTTCCGTGTTTCCACTGGCCCCCTCCTCTAAATCCACATCTGGCGGCACCGCCGCCCTGGGCTGTCTGGTGAAGGACTACTTCCCAGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACATCCGGCGTGCACACATTTCCAGCCGTGCTGCAGAGCTCCGGCCTGTACAGCCTGTCTAGCGTGGTGACAGTGCCCTCCTCTAGCCTGGGCACACAGACCTATATCTGCAACGTGAATCACAAGCCAAGCAATACCAAGGTGGACAAGAAGGTGGAGCCCAAGTCCTGTGATAAGACACACACCTGCCCCCCTTGTCCTGCTCCCGAGCTGCTGGGCGGCCCTAGCGTGTTCCTGTTTCCACCCAAGCCTAAGGACACCCTGATGATCTCCCGGACACCCGAGGTGACCTGCGTGGTGGTGGACGTGTCTCACGAGGATCCTGAGGTGAAGTTCAACTGGTATGTGGATGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACTCTACATATAGGGTGGTGAGCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTATAAGTGCAAGGTGTCCAATAAGGCCCTGCCCGCCCCCATCGAGAAGACAATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCACAGGTGTACACCCTGCCTCCATCCAGAGACGAGCTGACAAAGAACCAGGTGTCTCTGACATGTCTGGTGAAGGGCTTCTATCCTAGCGATATCGCCGTGGAGTGGGAGTCCAATGGCCAGCCAGAGAACAATTACAAGACCACACCCCCTGTGCTGGACTCCGATGGCTCCTTCTTTCTGTATTCCAAGCTGACCGTGGATAAGTCTCGGTGGCAGCAGGGCAACGTGTTCAGCTGTTCCGTGATGCACGAAGCCCTGCATAATCACTATACTCAGAAATCCCTGTCCCTGTCACCTGGAAAGTGATAA(SEQ IDNO:159)。
CAAGTGCAGCTGGTCCAGAGCGGCGCCGAGGTGAAAAAGCCTGGAGCTAGCGTGAAGGTGTCCTGCAAGGCCAGCGACTACACCTTCACCAACTATTGGCTGGGCTGGGTGCGGCAGGCCCCTGGACAGGGCCTGGAATGGATCGGCCACATCTACCCCGGAGGCGGCTACACCAATTACAACGAGAAGTTCAAGGGCAGAGTGACCATGACCGCCGATACAAGCACATCTACAGTGTACATGGAACTGAGCAGCCTGAGAAGCGAGGATACAGCTGTTTACTTCTGTGCCAGAGTGCGGTCCGGCAACGACGCCCTGGACTTTTGGGGCCAGGGCACCCTGGTGACCGTGTCTAGCGCCAGCACCAAGGGCCCTTCCGTGTTTCCACTGGCCCCCTCCTCTAAATCCACATCTGGCGGCACCGCCGCCCTGGGCTGTCTGGTGAAGGACTACTTCCCAGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACATCCGGCGTGCACACATTTCCAGCCGTGCTGCAGAGCTCCGGCCTGTACAGCCTGTCTAGCGTGGTGACAGTGCCCTCCTCTAGCCTGGGCACACAGACCTATATCTGCAACGTGAATCACAAGCCAAGCAATACCAAGGTGGACAAGAAGGTGGAGCCCAAGTCCTGTGATAAGACACACACCTGCCCCCCTTGTCCTGCTCCCGAGCTGCTGGGCGGCCCTAGCGTGTTCCTGTTTCCACCCAAGCCTAAGGACACCCTGATGATCTCCCGGACACCCGAGGTGACCTGCGTGGTGGTGGACGTGTCTCACGAGGATCCTGAGGTGAAGTTCAACTGGTATGTGGATGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACTCTACATATAGGGTGGTGAGCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTATAAGTGCAAGGTGTCCAATAAGGCCCTGCCCGCCCCCATCGAGAAGACAATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCACAGGTGTACACCCTGCCTCCATCCAGAGACGAGCTGACAAAGAACCAGGTGTCTCTGACATGTCTGGTGAAGGGCTTCTATCCTAGCGATATCGCCGTGGAGTGGGAGTCCAATGGCCAGCCAGAGAACAATTACAAGACCACACCCCCTGTGCTGGACTCCGATGGCTCCTTCTTTCTGTATTCCAAGCTGACCGTGGATAAGTCTCGGTGGCAGCAGGGCAACGTGTTCAGCTGTTCCGTGATGCACGAAGCCCTGCATAATCACTATACTCAGAAATCCCTGTCCCTGTCACCTGGAAAGTGATAA(SEQ IDNO:160)。
CAAGTGCAGCTGGTCCAGAGCGGCGCCGAGGTGAAAAAGCCTGGCGCTTCTGTGAAGGTGTCCTGCAAGGCCAGCGACTACACATTTACCAATTATTGGCTGGGCTGGGTGCGGCAGGCCCCTGGACAGGGCCTGGAATGGATCGGCCACATCTACCCCGGCGGAGGCTACACAAACTACAACGAGAAGTTCAAGGGCAGAGCCACACTCACCGCTGATACCAGCACAAGCACCGTGTACATGGAACTGAGCAGCCTGAGAAGCGAGGACACCGCCGTGTACTTCTGTGCCAGAGTGCGGTCCGGCAACGACGCCCTGGATTTCTGGGGACAGGGCACCCTGGTGACCGTGTCTAGCGCCAGCACCAAGGGCCCTTCCGTGTTTCCACTGGCCCCCTCCTCTAAATCCACATCTGGCGGCACCGCCGCCCTGGGCTGTCTGGTGAAGGACTACTTCCCAGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACATCCGGCGTGCACACATTTCCAGCCGTGCTGCAGAGCTCCGGCCTGTACAGCCTGTCTAGCGTGGTGACAGTGCCCTCCTCTAGCCTGGGCACACAGACCTATATCTGCAACGTGAATCACAAGCCAAGCAATACCAAGGTGGACAAGAAGGTGGAGCCCAAGTCCTGTGATAAGACACACACCTGCCCCCCTTGTCCTGCTCCCGAGCTGCTGGGCGGCCCTAGCGTGTTCCTGTTTCCACCCAAGCCTAAGGACACCCTGATGATCTCCCGGACACCCGAGGTGACCTGCGTGGTGGTGGACGTGTCTCACGAGGATCCTGAGGTGAAGTTCAACTGGTATGTGGATGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACTCTACATATAGGGTGGTGAGCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTATAAGTGCAAGGTGTCCAATAAGGCCCTGCCCGCCCCCATCGAGAAGACAATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCACAGGTGTACACCCTGCCTCCATCCAGAGACGAGCTGACAAAGAACCAGGTGTCTCTGACATGTCTGGTGAAGGGCTTCTATCCTAGCGATATCGCCGTGGAGTGGGAGTCCAATGGCCAGCCAGAGAACAATTACAAGACCACACCCCCTGTGCTGGACTCCGATGGCTCCTTCTTTCTGTATTCCAAGCTGACCGTGGATAAGTCTCGGTGGCAGCAGGGCAACGTGTTCAGCTGTTCCGTGATGCACGAAGCCCTGCATAATCACTATACTCAGAAATCCCTGTCCCTGTCACCTGGAAAGTGATAA(SEQ IDNO:161)。
CAAGTGCAGCTGGTTCAGAGCGGCGCCGAGGTGAAGAAGCCTGGCGCTAGCGTGAAGGTGTCTTGTAAAGCCAGCGACTACACATTTACCAATTACTGGCTGGGATGGGTCCGGCAGGCCCCTGGCCACGGCCTGGAATGGATCGGCCACATCTACCCCGGCGGAGGATATACAAACTACAACGAGAAGTTCAAGGGCAGAGCCACCCTGACCGCTGATACATCTACAAGCACCGTGTACATGGAACTGAGCAGCCTGAGAAGCGAGGATACCGCCGTGTACTTCTGCGCCAGAGTGCGGTCCGGCAACGACGCCCTGGACTTCTGGGGCCAGGGCACCCTGGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCTTCCGTGTTTCCACTGGCCCCCTCCTCTAAATCCACATCTGGCGGCACCGCCGCCCTGGGCTGTCTGGTGAAGGACTACTTCCCAGAGCCTGTGACAGTGTCCTGGAACTCTGGCGCCCTGACATCCGGCGTGCACACATTTCCAGCCGTGCTGCAGAGCTCCGGCCTGTACAGCCTGTCTAGCGTGGTGACAGTGCCCTCCTCTAGCCTGGGCACACAGACCTATATCTGCAACGTGAATCACAAGCCAAGCAATACCAAGGTGGACAAGAAGGTGGAGCCCAAGTCCTGTGATAAGACACACACCTGCCCCCCTTGTCCTGCTCCCGAGCTGCTGGGCGGCCCTAGCGTGTTCCTGTTTCCACCCAAGCCTAAGGACACCCTGATGATCTCCCGGACACCCGAGGTGACCTGCGTGGTGGTGGACGTGTCTCACGAGGATCCTGAGGTGAAGTTCAACTGGTATGTGGATGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACTCTACATATAGGGTGGTGAGCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTATAAGTGCAAGGTGTCCAATAAGGCCCTGCCCGCCCCCATCGAGAAGACAATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCACAGGTGTACACCCTGCCTCCATCCAGAGACGAGCTGACAAAGAACCAGGTGTCTCTGACATGTCTGGTGAAGGGCTTCTATCCTAGCGATATCGCCGTGGAGTGGGAGTCCAATGGCCAGCCAGAGAACAATTACAAGACCACACCCCCTGTGCTGGACTCCGATGGCTCCTTCTTTCTGTATTCCAAGCTGACCGTGGATAAGTCTCGGTGGCAGCAGGGCAACGTGTTCAGCTGTTCCGTGATGCACGAAGCCCTGCATAATCACTATACTCAGAAATCCCTGTCCCTGTCACCTGGAAAGTGATAA(SEQ IDNO:162)。
GAGATCGTGCTGACACAGAGCCCTGCTACACTCTCCCTGTCCCCAGGCGAGCGGGCCACACTGTCTTGTAGAGCCAGCGAGAGCGTCGACGAGTACGGCATTAGCTTCATGAACTGGTATCAGCAGAAACCTGGCCAGGCCCCTAGACTGCTGATCTACAGCGCCTCCAACCAGGGCAGCGGCATCCCCGCTAGATTCAGCGGCAGCGGATCTGGCACCGACTTCACCCTGACCATCAGCAGCCTGGAACCCGAGGATTTTGCCGTGTACTACTGCCAGCAATCTAAGGAAGTGCCTTGGACCTTCGGCGGAGGCACCAAGCTGGAAATCAAGAGGACAGTGGCCGCCCCAAGCGTGTTCATCTTTCCCCCTTCCGACGAGCAGCTGAAGTCTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCTCGGGAGGCCAAGGTCCAGTGGAAGGTGGATAACGCCCTGCAGTCTGGCAATAGCCAGGAGTCCGTGACCGAGCAGGACTCTAAGGATAGCACATATTCCCTGTCTAGCACCCTGACACTGAGCAAGGCCGATTACGAGAAGCACAAGGTGTATGCCTGTGAAGTCACCCATCAGGGGCTGTCATCACCCGTCACTAAGTCATTCAATCGCGGAGAATGCTGATAA(SEQ ID NO:163)。
GAGATCGTGCTGACCCAGAGCCCCGCCACCCTGTCCCTGAGCCCTGGCGAGCGGGCTACACTGTCTTGTAGAGCCAGCGAGAGCGTCGACGAGTACGGCATCTCTTTTATGAACTGGTATCAGCAGAAACCTGGACAGGCCCCTAGACTGCTGATCTACAGCGCCTCCAACCAGGGCAGCGGCATTCCTGCTAGATTCAGCGGCAGCGGCTCCGGCACAGATTTCACCCTCACCATCAGCAGCCTGGAACCCGAGGACTTCGCCGTGTACTTCTGCCAGCAATCTAAGGAAGTGCCATGGACATTCGGCGGAGGCACCAAGCTGGAAATCAAGAGGACAGTGGCCGCCCCAAGCGTGTTCATCTTTCCCCCTTCCGACGAGCAGCTGAAGTCTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCTCGGGAGGCCAAGGTCCAGTGGAAGGTGGATAACGCCCTGCAGTCTGGCAATAGCCAGGAGTCCGTGACCGAGCAGGACTCTAAGGATAGCACATATTCCCTGTCTAGCACCCTGACACTGAGCAAGGCCGATTACGAGAAGCACAAGGTGTATGCCTGTGAAGTCACCCATCAGGGGCTGTCATCACCCGTCACTAAGTCATTCAATCGCGGAGAATGCTGATAA(SEQ ID NO:164)。
GAGATCGTGCTGACCCAGTCTCCAGCCACCCTCTCCCTGAGCCCCGGCGAGCGGGCCACACTGTCTTGTAGAGCTAGCGAGAGCGTCGACGAGTACGGCATCTCCTTCATGAACTGGTTCCAGCAGAAACCTGGCCAGGCCCCTAGACTGCTGATCTACAGCGCCAGCAACCAGGGCTCCGGAATTCCTGCTAGATTCAGCGGCTCTGGCAGCGGCACAGATTTTACCCTGACAATCAGCAGCCTGGAACCCGAGGACTTTGCCGTGTACTTCTGCCAGCAAAGCAAGGAAGTGCCTTGGACCTTCGGCGGAGGCACCAAGCTGGAAATCAAGAGGACAGTGGCCGCCCCAAGCGTGTTCATCTTTCCCCCTTCCGACGAGCAGCTGAAGTCTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCTCGGGAGGCCAAGGTCCAGTGGAAGGTGGATAACGCCCTGCAGTCTGGCAATAGCCAGGAGTCCGTGACCGAGCAGGACTCTAAGGATAGCACATATTCCCTGTCTAGCACCCTGACACTGAGCAAGGCCGATTACGAGAAGCACAAGGTGTATGCCTGTGAAGTCACCCATCAGGGGCTGTCATCACCCGTCACTAAGTCATTCAATCGCGGAGAATGCTGATAA(SEQ ID NO:165)。
GAGATCGTGCTGACACAGAGCCCTGCTACACTCTCCCTGAGCCCCGGCGAGCGGGCCACCCTGTCTTGTAGAGCCAGCGAGAGCGTGGACGAGTACGGCATTAGCTTCATGAACTGGTTTCAGCAGAAACCTGGCCAGGCCCCTAGACTGCTGATCTACAGCGCCTCCAACCAGGGCTCTGGCATCCCCGCTAGATTCAGCGGATCTGGCTCCGGCACCGACTTCACCCTGACCATCAGCAGCCTGGAACCAGAGGATTTTGCCATGTACTTCTGCCAGCAAAGCAAGGAAGTGCCTTGGACCTTCGGCGGAGGCACAAAGCTGGAAATCAAGAGGACAGTGGCCGCCCCAAGCGTGTTCATCTTTCCCCCTTCCGACGAGCAGCTGAAGTCTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCTCGGGAGGCCAAGGTCCAGTGGAAGGTGGATAACGCCCTGCAGTCTGGCAATAGCCAGGAGTCCGTGACCGAGCAGGACTCTAAGGATAGCACATATTCCCTGTCTAGCACCCTGACACTGAGCAAGGCCGATTACGAGAAGCACAAGGTGTATGCCTGTGAAGTCACCCATCAGGGGCTGTCATCACCCGTCACTAAGTCATTCAATCGCGGAGAATGCTGATAA(SEQ ID NO:166)。
在本发明的第三方面，本发明提出了一种表达载体。根据本发明的实施例，所述表达载体携带前面所述的核酸分子。根据本发明实施例的表达载体导入合适的受体细胞后，可在调控系统的介导下，有效实现前面所述的特异性识别IL-11的抗体或其抗原结合片段表达，进而实现所述抗体或抗原结合片段的体外大量获得。
根据本发明的实施例，上述表达载体还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述表达载体为真核表达载体。进而实现前面所述的特异性识别IL-11的抗体或其抗原结合片段在真核细胞中的表达，如CHO细胞。
在本发明的第四方面，本发明提出了一种重组细胞。根据本发明的实施例，所述重组细胞携带前面所述的核酸分子，或者表达前面所述的抗体或其抗原结合片段。根据本发明实施例的重组细胞可用于前面所述的特异性识别IL-11的抗体或其抗原结合片段体外表达和大量获得。
根据本发明的实施例，上述重组细胞还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述重组细胞是通过将前面所述的表达载体引入至宿主细胞中而获得的。
根据本发明的实施例，通过电转导的方法将所述表达载体引入所述宿主细胞中。
根据本发明的实施例，所述重组细胞为真核细胞。
根据本发明的实施例，所述重组细胞为哺乳动物细胞。
在本发明的第五方面，本发明提出了一种药物组合物。根据本发明的实施例，所述药物组合物含有前面所述的抗体，前面所述的核酸分子，前面所述的表达载体或前面所述的重组细胞。根据本发明实施例的药物组合物中所包含的抗体或表达的抗体能够特异性的靶向结合IL-11，阻断IL-11和IL-11受体的结合。
在本发明的第六方面，本发明提出了前面所述的抗体、前面所述的核酸分子、前面所述的表达载体或前面所述的重组细胞、前面所述的药物组合物在制备药物中的用途，所述药物用于治疗或者肺纤维化(Pulmonary fibrosis),非酒精性脂肪肝炎(non-alcoholicsteatohepatitis,NASH)，慢性心力衰竭(Chronic heart failure,CHF)或由成纤维细胞向纤维化转化所导致的疾病。
在本发明的第七方面，本发明提出了一种检测IL-11的试剂盒。根据本发明的实施例，所述试剂盒包括前面任一所述的抗体。前面所述的IL-11抗体能够特异性靶向结合IL-11，根据本发明实施例的试剂盒可以实现IL-11的特异性检测，如当抗体结合有荧光基团时，可以采用荧光检测装置实现对IL-11的定位或实时检测。
在本发明的第八方面，本发明提出了前面所述的抗体、前面所述的核酸分子、前面所述的表达载体或前面所述的重组细胞在制备试剂盒中的用途，所述试剂盒用于检测IL-11或者诊断IL-11相关的疾病。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1是根据本发明实施例的优选抗体竞争性阻断IL-11与IL-11R结合的结果；
图2是根据本发明实施例的优选抗体竞争性阻断活性检测结果；
图3和图4是根据本发明实施例的优选抗体株抑制肺成纤维细胞HFL-1向纤维化转化的western检测结果；
图5是根据本发明实施例的优选抗体株抑制肺成纤维细胞HFL-1向纤维化转化统计分析结果；
图6和图7是根据本发明实施例的优选抗体在C57BL/6小鼠中抑制肺纤维化结果；
图8、图9、图10和图11是根据本发明实施例的优选抗体在Sprague Dawley大鼠中抑制肺纤维化结果；
图12是根据本发明实施例的人源化抗体竞争性阻断活性。
具体实施方式
下面详细描述本发明的实施例，所述实施例的示例在附图中示出。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
此外，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括至少一个该特征。在本发明的描述中，“多个”的含义是至少两个，例如两个，三个等，除非另有明确具体的限定。
抗体
本文中，术语“抗体”是能够与特异性抗原结合的免疫球蛋白分子。包括两条分子量较轻的轻链和两条分子量较重的重链，重链(H链)和轻链(L链)由二硫键连接形成一个四肽链分子。其中，肽链的氨基端(N端)氨基酸序列变化很大，称为可变区(V区)，羧基端(C端)相对稳定，变化很小，称为恒定区(C区)。L链和H链的V区分别称为VL和VH。
在可变区中某些区域氨基酸组成和排列顺序具有更高的变化程度，称为高变区(Hypervariable region，HVR)，高变区为抗原和抗体结合的位置，因此也称为决定簇互补区(complementarity-determining region，CDR)。重链可变区和轻链可变区上均有三个CDR区。抗体可变区内高变区之外的氨基酸组成和排列顺序变化相对较小，称为框架区(FR)。VH和VL内各有4个框架区，分别以FR1、FR2、FR3和FR4表示。
本发明利用IL-11抗原，通过免疫获得了高特异性的高亲和力的抗IL-11的Fab(antigen-binding fragment)抗体片段。利用该抗体片段能够与IL-11抗原特异性结合，从而可以靶向性治疗肺纤维化等疾病。
需要说明的是，“免疫原性”是指能引起免疫应答的性能，即抗原能刺激特定的免疫细胞，使免疫细胞活化、增殖、分化，最终产生免疫效应物质抗体和致敏淋巴细胞的特性。本申请的发明人进一步对筛选得到的鼠源的全新中和抗体序列进行人源化改造(人源化修饰)，得到人源化抗体，该人源化抗体既能保留亲本鼠单克隆抗体的亲和力和特异性，又大幅降低了其免疫原性，提高了其安全性。
在一些实施方案中，本发明提供了一种能够特异性识别IL-11的抗体或者抗原结合片段，所述抗体含有选自下列至少之一的CDR序列或与其具有至少95％同一性的氨基酸序列：重链可变区CDR序列：SEQ ID NO:1～33，轻链可变区CDR序列：SEQ IN NO:34～66。在另一些实施方案中，本发明所提供的抗体或者抗原结合片段与上述重链和轻链相比，具有保守氨基酸取代。“抗原结合片段”是指保持特异性结合抗原能力的抗体片段。“保守氨基酸取代”指的是氨基酸被另一氨基酸发生生物学上、化学上或者结构上相似的残基所取代。生物学上相似的指的是该取代不破坏IL-11抗体或者与IL-11抗原结合的生物学活性。结构上相似指的是氨基酸具有相似长度的侧链，如丙氨酸、甘氨酸或丝氨酸，或具有相似大小的侧链。化学相似性指的是氨基酸具有相同的荷电或者都是亲水或者疏水的。例如疏水残基异亮氨酸、缬氨酸、亮氨酸或者甲硫氨酸相互取代。或者极性氨基酸相互取代，例如用精氨酸取代赖氨酸、谷氨酸取代天冬氨酸、谷氨酰胺取代天冬酰胺，丝氨酸取代苏氨酸等等。
在一些实施方案中，本发明提供了一种抗体或抗原结合片段，所述抗体或抗原结合片段具有SEQ ID NO：67～77任一项所示氨基酸序列的重链可变区和具有如SEQ ID NO：78～88任一项所示氨基酸序列的轻链可变区。发明人通过抗体序列比对数据库(NCBI、IMGT)可得到上述抗重链可变区序列的CDR区(如SEQ ID NO:1～33所示)和轻链可变区序列的CDR区(如SEQ ID NO:34～66所示)。在另一些实施方案中，所述抗体或抗原结合片段的重链可变区序列与SEQ ID NO:67～77所示氨基酸序列相比，具有保守氨基酸取代。在一些实施方案中，所述抗体或抗原结合片段的轻链可变区序列与SEQ ID NO:78～88任一项所示氨基酸序列相比，具有保守氨基酸取代。当然，这些保守氨基酸取代不会对抗体或者抗原结合片段的生物学功能带来改变。在一些具体方式中，这些保守氨基酸取代可以发生在重链可变区和轻链可变区中除了CDR区之外的氨基酸上。
在一些优选方案中，本发明提供了一种抗IL-11抗体，该抗体具有SEQ ID NO:91～101任一项所示氨基酸序列的重链和具有SEQ ID NO:102～112任一项所示氨基酸序列的轻链。
在一些优选方案中，本发明提供了一种抗IL-11单链抗体。
核酸分子、表达载体、重组细胞
在制备或者获取这些抗体的过程中，可以利用表达这些抗体的核酸分子，与不同的载体连接，然后在不同细胞中表达，来获得相应抗体。
为此，本发明还提供了一种分离的核酸分子，所述核酸分子编码上述所述的抗体或抗原结合片段。
在一些实施方案中，所述分离核酸分子具有如SEQ ID NO:113～123任一项所示核苷酸序列或具有SEQ ID NO:124～134任一项所示核苷酸序列。
在一些实施方案中，所述分离的核酸分子与上述SEQ ID NO:113～123所示的核苷酸序列至少具有90％以上的同源性，优选具有95％以上的同源性，更优选具有98％、99％以上的同源性。在至少一些实施方案中，所述分离的多核苷酸与所述SEQ ID NO:124～134所示的核苷酸序列至少具有90％以上的同源性，优选具有95％以上的同源性，更优选具有98％、99％以上的同源性。这些与SEQ ID NO:113～123或者SEQ ID NO:124～134所示核苷酸序列具有同源性的序列，能够表达与SEQ ID NO:91～101和SEQ ID NO:102～112相似的氨基酸，从而能够与IL-11抗原特异性结合，实现抗体的靶向性功能。
在一些优选实施方式中，所述分离的核酸分子具有SEQ ID NO:113～123所示的重链核苷酸序列和SEQ ID NO:124～134所示的轻链核苷酸序列。这些核苷酸序列经过种属优化，更易在哺乳动物细胞中表达。
本发明还提供了一种表达载体，所述表达载体包含上述分离的核酸分子。在将上述分离的多核苷酸连接到载体上时，可以将多核苷酸与载体上的控制元件直接或者间接相连，只要这些控制元件能够控制多核苷酸的翻译和表达等即可。当然这些控制元件可以直接来自于载体本身，也可以是外源性的，即并非来自于载体本身。当然，多核苷酸与控制元件进行可操作地连接即可。本文中“可操作地连接”是指将外源基因连接到载体上，使得载体内的控制元件，例如转录控制序列和翻译控制序列等等，能够发挥其预期的调节外源基因的转录和翻译的功能。当然用来编码抗体重链和轻链的多核苷酸，可以分别独立的插入到不同的载体上，常见的是插入到同一载体上。常用的载体例如可以为质粒、噬菌体等等。例如Plasmid-X质粒。
本发明还提供了一种重组细胞，该重组细胞中包含有该表达载体。可以将表达载体导入到哺乳动物细胞中，构建获得重组细胞，然后利用这些重组细胞表达本发明提供的抗体或者抗原结合片段。通过该重组细胞进行培养，即可以获得相应抗体。这些可用的哺乳动物细胞例如可以为CHO细胞等。
药物组合物、试剂盒及制药用途和在制备试剂盒中的用途。
本发明还提供了一种药物组合物，所述药物组合物包括上述所述的抗体或者抗原结合片段和药学可接受的载体。
本文提供的抗IL-11抗体可以掺入适合受试者施用的药物组合物中。通常，这些药物组合物包括本文提供的抗IL-11抗体以及药学上可接受的载体。“药学上可接受的载体”可以包括生理学上相容的任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和延迟吸收剂等等。具体实例可以是水、盐水、磷酸盐缓冲盐水、葡萄糖、甘油、乙醇等以及它们的组合物中的一种或多种。有许多情况下，药物组合物中包括等渗剂，例如糖类、多元醇(如甘露醇、山梨醇)或氯化钠等。当然药学上可接受的载体还可包括微量的辅助物质，例如润湿剂或乳化剂、防腐剂或缓冲剂，用来延长抗体的保存限期或效力。
例如，本发明的抗体可掺入适用于胃肠外施用(例如静脉内、皮下、腹膜内、肌肉内)的药物组合物中。这些药物组合物可以被制备成各种形式。例如液体、半固体和固体剂型等，包括但不限于液体溶液(例如，注射溶液和输注溶液)、分散剂或悬浮剂、片剂、丸剂、粉末、脂质体和栓剂。典型的药物组合物为注射溶液或输注溶液形式。所述抗体可通过静脉输注或注射或肌肉内或皮下注射来施用。
当然，本文中的抗IL-11抗体还可以根据需要被制成试剂盒或者其他诊断性试剂的一部分。根据本发明的实施例，本发明还提供了一种试剂盒，所述试剂盒包括上述IL-11抗体。应用本发明提供的试剂盒，例如可以用于免疫印迹、免疫沉淀等涉及到利用IL-11抗原和抗体特异性结合性能，来检测的试剂盒等。这些试剂盒可包含下列中的任意一种或多种：拮抗剂、抗IL-11抗体或者药物参照材料；蛋白纯化柱；免疫球蛋白亲和纯化缓冲剂；细胞的测定稀释剂；说明书或者文献等。抗IL-11抗体可被用于不同类型的诊断测试，例如可以在体外或者体内检测各种各样的疾病或者药物、毒素或者其他蛋白等的存在。例如可以通过对受试者的血清或者血液进行检测，用来测试相关疾病。这种相关疾病可包括IL-11相关疾病，例如肺纤维化等等。当然本文提供的抗体也可以用于上述疾病的放射免疫检测和放射免疫治疗等等。
在利用本发明所提供的抗IL-11抗体治疗上述疾病时，可以将本发明提供的抗IL-11抗体提供给受试者即可。为此，本发明提供了一种用于治疗上述疾病的方法，包括向有需要的受试者施用本发明所提供的抗体或其抗原结合片段。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1重组人源蛋白抗原hu-IL-11-His tag的生产
载体的构建：人源IL-11氨基酸序列通过全球公共数据库UniProt(P20809：124294)获得。采用分子克隆的方法，构建了含人源IL-11基因序列的表达载体。采用电转染的方法，将编码人源IL-11的载体转染至哺乳动物细胞CHO进行表达14天。待表达完成收获细胞上清液，采用Protein A纯化柱(GE healthcare,Cat:17040201)进行初步纯化，然后再采用Superdex75(GE healthcare,Cat:29148721)进行精细纯化，最终获得可以用于免疫动物的重组蛋白抗原hu-IL-11-His tag。
实施例2动物免疫
为了得到能分泌针对hu-IL-11抗体的小鼠，我们对雌性Balb/c小鼠进行免疫。雌性Balb/c购买于湖南斯莱克景达实验动物有限公司(Hunan SJA Laboratory Animal Co.，Ltd)。重组蛋白抗原hu-IL-11-His tag与免疫佐剂经充分乳化后进行动物免疫，免疫流程见表1。
表1：免疫动物安排表
Figure BDA0003208429110000421
第35天收获少量的小鼠眼眶血，采用常规的Elisa方法进行抗体效价检测。
实施例3抗体分泌细胞融合与筛选
分离的小鼠脾细胞与永生化的小鼠骨髓瘤细胞SP2/0融合，并使用含10- 4MHypoxanthine,4x10-7 M Aminopterin,1.6x10-5 M Thymidine的RPMI-1640完全培养基静置培养约14天，待融合细胞长出克隆团后进行抗体亲和力的检测筛选。选取与IL-11结合的抗体克隆株，取其上清，再进行流式细胞术测定抗原抗体的竞争结合，选出高分泌特异性抗体细胞株进行扩大培养及冻存，结果见表2。具体方法是首先通过Elisa筛选获得与IL-11具有高亲和力的抗体株(OD450nm即为测定的亲和力值)，其中P.C.为采用购买的IL-11抗体(Abcam,ab130083)与IL-11蛋白之间的结合作为阳性对照。其次，通过构建稳表达IL-11R的细胞株，并用适量的IL-11蛋白与杂交瘤上清混合后，与稳转表达有IL-11R的细胞株进行共孵育，最终通过流式检测杂交瘤上清对IL-11/IL-11R之间的阻断效果(FITC-A mean值)，其中N.C.是未加杂交瘤上清检测的值，可以视其为完全没有阻断下的值(Negativecontrol)。表2中下划线表示选定的克隆株，经过多轮亚克隆化，最终得到单个抗体分泌细胞来源的单克隆抗体，其单克隆抗体所检测的亲和力(OD450nm)与流式阻断结果见表3。
表2：Elisa亲和实验及流式竞争实验检测结果
Figure BDA0003208429110000431
注：表2中的N/A表示：无数据
表3：Elisa亲和实验及流式竞争实验检测结果
样品编号 OD450 FITC Mean 样品编号 OD450 FITC Mean
3-6A4 1.584 3036 3-5B2-2G4 1.65 19751
5-20E11-5F2 1.596 3109 5-21G12-1D3 1.528 3362
5-20E11-1A2 1.634 3635 3-5B2-7A4 1.636 20958
3-15D5-3A6 1.688 10944 3-9E1-3A2 1.544 9067
3-7C9-1A6 1.601 3148 3-15D5-6A1 1.511 13639
3-2B5-3D2 1.614 15289 N.C.(流式) N/A 18433
注：表3中的N/A表示：无数据；因3-6A4在亚克隆化后的细胞经测序与亚克隆化前的序列一致，故其编号与表2中的编号相同。
实施例4单克隆抗体序列测定
取1*10^6～5*10^6个杂交瘤细胞，用Takara MiniBEST Universal RNAExtraction Kit试剂盒提取总RNA，用PrimeScript RT Reagent Kit(Takara公司)试剂盒反转录出cDNA。以上步骤按照厂家提供的说明书进行。抗体重链可变区(VH)和轻链可变区(VL)基因扩增引物设计主要参考Ig-Primer Sets(Novagen公司，货号：69831-3)中的引物对，由华大基因公司合成。从cDNA第一链中扩增重链可变区和轻链可变区基因，克隆到pMD18-T载体中，转化大肠杆菌DH5α后，挑取克隆由华大基因公司测序获得重链可变区(VH)和轻链可变区(VL)基因序列。所用到的引物序列及测序得到的抗体序列另见文档。
实施例5抗体亚型鉴定
将优选抗体株对应的单克隆杂交瘤细胞株采用常规方法注射到Balb/C小鼠中进行腹水抗体的生产及纯化。利用纯化的抗体进行抗体亚型分析，抗体亚型检测方法采用成熟的试剂盒进行检测(Proteintech,KMIM-2)，结果如下表4。
表4：候选抗体株的抗体亚型鉴定结果
Figure BDA0003208429110000441
实施例6优选单克隆抗体表达纯化
我们将优选的单抗隆抗体株3-6A4及5-20E11-5F2序列采用基因工程的方法构建至常规的表达载体中，然后在CHO细胞中进行表达。表达完成后采用Protein G层析柱(EzFast Protein G 4FF，博格隆)对收集的细胞培养液进行纯化，平衡液为20mM PBS，0.15M NaCl，pH7.4，洗脱液为0.1M甘氨酸pH3.0±0.2，收集目标吸收峰下蛋白洗脱液，用PBS缓冲液超滤后，取部分样品进行SDS-PAGE电泳检测，并采用SEC-HPLC方法测定多聚体含量。抗体的多聚体含量均在3％以内。
实施例7优选抗体竞争性阻断IL-11与IL-11R结合
为了检测优选抗体3-6A4及5-20E11-5F2的竞争结合情况，我们通过在Elisa检测板中包被适量的IL-11R-His蛋白，过夜孵育。然后通过加入适量的IL-11-Fc蛋白，并与不同浓度梯度的抗体进行共孵育。最后采用HRP耦联的Goat anti IgG-Fc二抗(ThermoFisher，31413)及TMB显色底物进行检测。我们检测到优选抗体及6D9A1(Abcam,ab130083)均能不同程度的抑制IL-11与IL-11R的结合，结果如图1所示。
实施例8优选抗体的交叉反应
IL-6细胞因子家族成员包括IL-6,IL-11,CNTF,CLC,LIF,CT-1,OSM,IL-27,IL-31。IL-11属于IL-6细胞因子家族成员。我们采用常规Elisa方法包被重组IL-6(Sinobiological-10395-HNAE),IL-27(R&D systems,2526-IL-010),LIF(Peprotech,300-05),CLC(R&D systems,962-CL-050),IL-11(LSBio,LS-G132887-10),OSM(Genscript-z03132),IL-31(Peprotech,200-31),CNTF(R&D systems,257-NT-010),CT-1(R&Dsystems,612-CD-010)蛋白，并检测了优选抗体3-6A4及5-20E11-5F2与IL-6细胞因子家族成员的结合情况。结果表明优选抗体除与IL-11细胞因子结合外，不与IL-6细胞因子家族其他成员发生交叉反应，Elisa结果(OD450 nm)如下表5所示。
表5：优选抗体株3-6A4及5-20E11-5F2与IL-6细胞因子家族不同成员的结合检测
Figure BDA0003208429110000451
实施例9优选IL-11单克隆抗体与抗原结合的亲和力测定
应用生物膜干涉技术(BLI)测定，采用Ni-NTA传感器捕获抗原IL-11(His tag)，优选抗体株3-6A4及5-20E11-5F2作为分析物，分析物稀释7个浓度梯度，结合时间为60s，解离时间为1000s。缓冲液为20mM PBS，0.15M NaCl，0.1％BSA，0.05％Tween 20，pH7.4。BLI动力学/亲和力软件分析，获得优选抗体与对应hu-IL-11配体的解离常数(kdis)及亲和力常数(KD)，具体结果见下表6。
表6：
Figure BDA0003208429110000452
实施例10优选抗体竞争性阻断活性检测
为了评估优选Anti-huIL-11抗体3-6A4及5-20E11-5F2与IL-11的结合，以及能否阻断配体与受体间的结合，我们构建了稳定表达IL-11R的细胞株membrane-IL-11R CHO，利用流式方法检测候选抗体及商业化抗体6D9A1(Abcam,ab130083)对IL-11与IL-11R的阻断活性。首选适量的带有Fc标签的IL-11重组蛋白与不同梯度的抗体共孵育15mins，然后再与1E+05个membrane-IL-11R CHO细胞孵育。检测采用的二抗为耦联有FITC荧光基团的二抗(Goat-anti-Fc-FITC)(Abcam,ab98529)，竞争结合结果表明3-6A4抗体中和活性IC50约为7μg/ml；5-20E11-5F2抗体中和活性IC50约为21μg/ml，并且候选抗体的阻断活性明显优于6D9A1克隆株抗体的阻断活性，结果如图2所示。
实施例11优选抗体株抑制肺成纤维细胞HFL-1向纤维化转化
HFL-1细胞作为肺成纤细胞，当被促纤维化因子如TGF-beta1诱导后会大量表达IL-11细胞因子，最终向纤维化转化。当HFL-1细胞向纤维化转化过种中，标志物ACTA2蛋白会不断累积。在此实例中，我们采用TGF-beta1细胞因子诱导HFL-1细胞向纤维化转化的同时加入优选3-6-A4、5-20E11-1A2及5-20E11-5F2抗体株时，培养48h后，收取细胞进行western检测分析，可以看到不同浓度的抗体均能够抑制HFL-1细胞向纤维化转化(ACTA2蛋白表达量降低)，如图3、图4及对应的统计分析图5。
实施例12优选抗体在C57BL/6小鼠中抑制肺纤维化
在由博来霉素诱导C57BL/6小鼠肺纤维化的动物模型中，具体来说，将10周齡的C57BL/6进行戊巴比妥麻醉剂全身麻醉后，经手术曝露出小鼠肺的主气管，然后采用滴注或雾化的方式向气管内注入适量的博来霉素。小鼠经过七天的博来霉素诱导后，肺部纤维化基本呈现。在第八天时，我们按每隔一天的方式进行注射优选抗体5-20E11-5F2或同型对照抗体lgG。连续注射14天后，将小鼠处死取其肺，进行肺部的炎症损伤检测以及纤维化评分检测。此药效模型下，可以看到候选抗体株可以减缓小鼠肺纤维化，结果如图6和图7所示。
实施例13优选抗体在Sprague Dawley大鼠中抑制肺纤维化
在大鼠中气管内滴注博来霉素是一种广泛用于研究肺纤维化的药效模型，本实验测试了优选抗体在体内降低博来霉素诱导大鼠单侧肺纤维化的能力。
将雄性动物分组成九组。采用25mg/kg戊巴比妥钠联合1-2.5％异氟烷呼吸麻醉维持动物麻醉深度。以博莱霉素气管注射方式诱导纤维化模型，假模型组以等体积生理盐水代替博莱霉素。模型建立第八天，每隔一天给予不同组以不同剂量的优选抗体治疗14天，其中吡啡尼酮(Esbriet)或尼达尼布(Ofev)药物作为治疗的参照(Esbriet与Ofev均采用100毫克/每千克/每天)。在治疗结束后，取肺进行免疫组化H&E染色及Masson三染色。小鼠肺的组织学检查发现对照组为正常肺，博来霉素处理的肺中，炎症损伤明显加重，优选抗体能够明显缓解炎症细胞在肺中的浸润见图8(图8，肺组织H&E染色，A为对照组；B为博来霉素诱导组；C为3-6A4 mAb-20mg/kg组；D为5-20E11-5F2 mAb-20mg/kg组)。此外优选抗体也很好的缓解肺纤维化进程见图9(图9，肺组织Masson三染色，A为对照组；B为博来霉素诱导组；C为3-6A4 mAb-20mg/kg组；D为5-20E11-5F2 mAb-20mg/kg)。统计分析结果显示优选抗体在不同剂量下均能缓解博来霉素引起的大鼠肺的炎症损伤及纤维化进程见图10(图10，###P<0.001vs.BLM Model；aaP<0.01vs.Ofev；bP<0.05vs.Esbriet,bbbP<0.001vs.Esbriet；cccP<0.001vs.3-6A4 mAb 30mg/kg)、图11(***P<0.001vs.Sham；##P<0.01vs.BLM Model,###P<0.001vs.BLM Model.)。
实施例14IL-11抗体的人源化改造
采用互补决定区嫁接法(CDR grafting)来进行上述实施例IL-11抗体的人源化。首先寻找与鼠源抗体的轻、重链可变区同源性最高的人胚系抗体(germline antibody)序列，抗体重链可变区人源化选取的胚系为IGHV1-46*01，轻链可变区人源化选取IGKV3-11*01。保留鼠源抗体的CDR区，将鼠源抗体的框架区(framework)序列用人胚系抗体的框架区序列替换。其次，建立鼠源抗体Fv片段结构模型，在PDB抗体数据库中进行BLAST，选定结构INQB作为模板进行同源建模。逐个对比人源抗体与相应鼠源抗体结构模型中的每个不同氨基酸位点，选择不符合FR结构规范的氨基酸、位于FR内核的氨基酸、位于VH-VL界面的氨基酸，回复突变为鼠源序列。
获得的IL-11人源化抗体的重链可变区和轻链可变区的序列如SEQ ID NO：143～146所示和SEQ ID NO：147～150所示。
IL-11人源化抗体重链可变区序列(VH1):
QVQLVQSGAEVKKPGASVKVSCKASDYTFTNYWLGWVRQAPGQGLEWMGHIYPGGGYTNYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARVRSGNDALDFWGQGTLVTVSS(SEQ ID NO：143)。
IL-11人源化抗体重链可变区序列(VH2):
QVQLVQSGAEVKKPGASVKVSCKASDYTFTNYWLGWVRQAPGQGLEWIGHIYPGGGYTNYNEKFKGRVTMTADTSTSTVYMELSSLRSEDTAVYFCARVRSGNDALDFWGQGTLVTVSS(SEQ ID NO：144)。
IL-11人源化抗体重链可变区序列(VH3):
QVQLVQSGAEVKKPGASVKVSCKASDYTFTNYWLGWVRQAPGQGLEWIGHIYPGGGYTNYNEKFKGRATLTADTSTSTVYMELSSLRSEDTAVYFCARVRSGNDALDFWGQGTLVTVSS(SEQ ID NO：145)。
IL-11人源化抗体重链可变区序列(VH4):
QVQLVQSGAEVKKPGASVKVSCKASDYTFTNYWLGWVRQAPGHGLEWIGHIYPGGGYTNYNEKFKGRATLTADTSTSTVYMELSSLRSEDTAVYFCARVRSGNDALDFWGQGTLVTVSS(SEQ ID NO：146)。
IL-11人源化抗体轻链可变区序列(VL1):
EIVLTQSPATLSLSPGERATLSCRASESVDEYGISFMNWYQQKPGQAPRLLIYSASNQGSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSKEVPWTFGGGTKLEIK(SEQ ID NO：147)。
IL-11人源化抗体轻链可变区序列(VL2):
EIVLTQSPATLSLSPGERATLSCRASESVDEYGISFMNWYQQKPGQAPRLLIYSASNQGSGIPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSKEVPWTFGGGTKLEIK(SEQ ID NO：148)。
IL-11人源化抗体轻链可变区序列(VL3):
EIVLTQSPATLSLSPGERATLSCRASESVDEYGISFMNWFQQKPGQAPRLLIYSASNQGSGIPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSKEVPWTFGGGTKLEIK(SEQ ID NO：149)。
IL-11人源化抗体轻链可变区序列(VL4):
EIVLTQSPATLSLSPGERATLSCRASESVDEYGISFMNWFQQKPGQAPRLLIYSASNQGSGIPARFSGSGSGTDFTLTISSLEPEDFAMYFCQQSKEVPWTFGGGTKLEIK(SEQ ID NO：150)。
合成编码IL-11人源化抗体的轻链和重链的核酸序列，并插入到真核表达载体pcDNA3.4中，将4个重链序列的载体分别与4个轻链序列的载体配对，共转染至哺乳动物细胞CHO中进行表达，得到scFv形式的单链抗体。一周后收集包含有scFv抗体的上清液进行亲和力检测。
实施例15IL-11人源化抗体亲和力排序
用Biacore测定各人源化抗体表达上清scFv与IL-11的结合，根据解离常数kd(1/s)进行排序，优选出3个解离常数kd(1/s)最小的人源化抗体。测定方法包括如下步骤：以10ul/min的流速捕获人源化抗体。切换流速到30ul/min，将400nM的IL-11抗原流经样品通道，结合时间为180s，解离时间为600s。最后用10mM甘氨酸缓冲液再生芯片。结果如表7所示，人源化抗体VH1+VL2、VH1+VL3、VH1+VL4与IL-11解离的速度比其他的人源化抗体慢。
表7：IL-11人源化抗体与IL-11抗原的亲和力
Figure BDA0003208429110000481
Figure BDA0003208429110000491
实施例16优选IL-11人源化抗体的表达纯化
将优选的IL-11人源化抗体VH1+VL2、VH1+VL3、VH1+VL4分别进行全长序列的构建(含Fc部分)，并转染至哺乳动物细胞CHO中进行表达。表达完成后采用Protein A层析柱对收集的细胞培养液进行纯化，平衡液为20mM PBS，pH7.4，洗脱液为0.1M甘氨酸pH3.0±0.2，收集目标吸收峰下蛋白洗脱液，用PBS缓冲液超滤后，取部分样品用HPLC测定浓度及进行SDS-PAGE电泳检测。
实施例17优选IL-11人源化抗体的亲和力检测
用Biacore测定各优选人源化全长(IgG形式)抗体样品与IL-11的结合。测定方法包括如下步骤：以10ul/min的流速捕获人源化抗体。切换流速到30ul/min，将不同浓度的IL-11抗原(400nM，200nM，100nM，50nM，25nM，12.5nM，6.25nM)流经样品通道和参比通道，结合时间为180s，解离时间为600s。最后用10mM甘氨酸缓冲液再生芯片。如表8所示，人源化抗体VH1+VL3的亲和力优于另外两个人源化抗体，与5-20E11-5F2抗体相比亲和力略有降低。
表8：优选人源化抗体与IL-11抗原的亲和力
Figure BDA0003208429110000501
实施例18优选人源化抗体竞争性阻断IL-11与IL-11R结合
为了评估优选人源化抗体能否阻断IL-11与IL-11R的结合。我们构建了稳定表达IL-11R的细胞株membrane-IL-11R CHO。测定方法包括如下步骤：取浓度为100μg/ml的IL-11-Fc蛋白10ul/孔加入到96孔U型板，与90ul梯度稀释的优选人源化抗体(100ug/ml、10ug/ml、1ug/ml、0.1ug/ml、0.01ug/ml、0.001ug/ml)室温孵育1h。然后与1.5*10^5个membrane-IL-11RCHO细胞(100ul/孔)室温孵育1h后，1500rpm离心5min，用PBS清洗3次，加入1:400稀释的流式二抗Goat-anti-Fc-FITC(Abcam，ab98529)，200ul/孔，4℃孵育1h，1500rpm离心5min，用PBS清洗3次，重悬细胞于180ulPBS中，流式上机检测。结果绘制S曲线见图12，结果表明人源化抗体的阻断活性与5-20E11-5F2抗体基本一致。
表9、人源化抗体竞争性阻断IL-11与IL-11R结合的EC50
抗体编号 5-20E11-5F2 VH1+VL2 VH1+VL3 VH1+VL4
EC50(ug/ml) 7.537 11.57 10.46 12.48
实施例19优选人源化抗体抑制肝成纤维细胞LX-2向纤维化转化
LX-2细胞是人肝星状细胞，当被促纤维化因子如TGF-beta1诱导后会大量表达IL-11细胞因子，最终向纤维化转化。当LX-2细胞向纤维化转化的过程中，标志物ACTA2蛋白会不断累积。在此实例中，我们以3*10^5个细胞/孔的密度将LX-2细胞铺于6孔板培养10h至细胞贴壁。用无血清DMEM培养基饥饿培养12h后，加入5ng/ml的TGF-beta1细胞因子进行刺激，同时加入梯度稀释的优选人源化抗体(50ug/ml，25ug/ml，5ug/ml)。培养24h后，吸出培养基，每孔加入200ul RIPA裂解液(碧云天，P0013B)，进行western blot检测分析。结果显示，不同浓度的人源化抗体均能抑制LX-2细胞向纤维化转化(ACTA2蛋白表达量降低)。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
SEQUENCE LISTING
<110> 广东东阳光药业有限公司
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<210> 11
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 11
<400> 11
Ile Trp Ala Gly Gly Arg Thr
1 5
<210> 12
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> 12
<400> 12
Ala Arg Glu Gly Gly Tyr Asp Tyr Asp Gly Asp Leu Trp Thr
1 5 10
<210> 13
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 13
<400> 13
Gly Phe Ser Leu Thr Ser Tyr Gly
1 5
<210> 14
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 14
<400> 14
Ile Trp Ser Gly Gly Ile Thr
1 5
<210> 15
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> 15
<400> 15
Ala Arg Asn Phe Asp Gly Tyr Tyr Tyr Ser Ile Asp Tyr
1 5 10
<210> 16
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 16
<400> 16
Gly Phe Ser Leu Thr Asn Tyr Gly
1 5
<210> 17
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 17
<400> 17
Ile Trp Arg Gly Gly Ser Thr
1 5
<210> 18
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 18
<400> 18
Ala Lys Asn Leu Tyr Gly Pro Ala Ala Met Asp Tyr
1 5 10
<210> 19
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 19
<400> 19
Gly Asp Thr Phe Thr Asn Tyr Ala
1 5
<210> 20
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 20
<400> 20
Ile Asp Thr Tyr Thr Gly Asp Pro
1 5
<210> 21
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 21
<400> 21
Ala Gly Asp Thr Trp Phe Ala Tyr
1 5
<210> 22
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 22
<400> 22
Gly Phe Ser Leu Ser Ser Ser Gly Met Ser
1 5 10
<210> 23
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 23
<400> 23
Ile Trp Trp Ser Asp Asp Lys
1 5
<210> 24
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 24
<400> 24
Ala Arg Glu Gly Ser Leu Gly Tyr Gly Leu Asp Tyr
1 5 10
<210> 25
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 25
<400> 25
Gly Phe Asp Phe Arg Arg Tyr Trp
1 5
<210> 26
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 26
<400> 26
Ile Asn Pro Asp Ser Ser Met Ile
1 5
<210> 27
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 27
<400> 27
Ala Thr Tyr Gly His His Ala Thr Asp Ser
1 5 10
<210> 28
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 28
<400> 28
Gly Tyr Thr Phe Thr Ser Tyr Trp
1 5
<210> 29
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 29
<400> 29
Ile Tyr Pro Gly Ser Asp Ser Thr
1 5
<210> 30
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 30
<400> 30
Ala Leu Asp Ser Ser Gly Tyr Gly Phe Ala Tyr
1 5 10
<210> 31
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 31
<400> 31
Asp Tyr Glu Phe Pro Ser His Asp
1 5
<210> 32
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 32
<400> 32
Ile Asn Ser Asp Gly Gly Asn Thr
1 5
<210> 33
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 33
<400> 33
Ala Arg Pro Arg Pro Thr Ile Gly Thr Thr Ala Thr Gly Ser Ser Met
1 5 10 15
<210> 34
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 34
<400> 34
Gln Ser Val Ser Asn Asp
1 5
<210> 35
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 36
<400> 35
Gln Gln Asp Phe Phe Ser Pro Trp Thr
1 5
<210> 36
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 37
<400> 36
Glu Ser Val Asp Glu Tyr Gly Ile Ser Phe
1 5 10
<210> 37
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 39
<400> 37
Gln Gln Ser Lys Glu Val Pro Trp Thr
1 5
<210> 38
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 40
<400> 38
Gln Ser Val Ser Asn Asp
1 5
<210> 39
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 42
<400> 39
Gln Gln Asp Tyr Tyr Ser Pro Trp Thr
1 5
<210> 40
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 43
<400> 40
Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr
1 5 10
<210> 41
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 45
<400> 41
Ser Gln Ser Thr His Val Pro Pro Asp
1 5
<210> 42
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 46
<400> 42
Gln Asp Ile Ser Asn Ser
1 5
<210> 43
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 48
<400> 43
Gln Gln Gly Asn Thr Leu Pro Leu Thr
1 5
<210> 44
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 49
<400> 44
Gln Asn Ile Tyr Val Trp
1 5
<210> 45
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 51
<400> 45
Gln Gln Gly Gln Ser Tyr Pro Tyr Thr
1 5
<210> 46
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 52
<400> 46
Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Arg
1 5 10
<210> 47
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 54
<400> 47
Gln Gln Tyr Tyr Ser Tyr Pro Arg Thr
1 5
<210> 48
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 55
<400> 48
Gln Ser Ile Val His Thr Asp Gly Asn Thr Tyr
1 5 10
<210> 49
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 57
<400> 49
Phe Gln Gly Ser His Val Pro Trp Thr
1 5
<210> 50
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 58
<400> 50
Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe
1 5 10
<210> 51
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 60
<400> 51
Gln Gln Ser Asn Glu Asp Pro Phe Thr
1 5
<210> 52
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 61
<400> 52
Gln Ser Val Ser Asn Asp
1 5
<210> 53
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 63
<400> 53
Gln Gln Asp Tyr Ser Ser Pro Phe Thr
1 5
<210> 54
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 64
<400> 54
Gln Ser Val Ser Thr Ser Thr Tyr Asn Tyr
1 5 10
<210> 55
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 66
<400> 55
Gln His Ser Trp Glu Ile Pro Phe Thr
1 5
<210> 56
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> 67
<400> 56
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Asn
20 25 30
Gly Ile Asn Trp Val Lys Gln Ala Ala Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Asn Ala Glu Glu Leu
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Ala Ala Ile Tyr Phe Cys
85 90 95
Ala Arg Glu Gly Ala Phe Gly Leu Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 57
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 68
<400> 57
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Ala Lys Ile Ser Cys Lys Ala Ser Asp Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Leu Gly Trp Leu Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly His Ile Tyr Pro Gly Gly Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Val Arg Ser Gly Asn Asp Ala Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 58
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> 69
<400> 58
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Glu Glu Ile
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ser Arg Glu Gly Ile Tyr Gly Met Asp Ser Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 59
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 70
<400> 59
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ile Ile Trp Ala Gly Gly Arg Thr Asp Tyr Asn Ser Ala Leu Val
50 55 60
Ser Arg Leu Asn Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met His Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Glu Gly Gly Tyr Asp Tyr Asp Gly Asp Leu Trp Thr Thr Gly Val
100 105 110
Lys Glu Pro Gln Ser Pro Ser Pro Gln
115 120
<210> 60
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 71
<400> 60
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Leu Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Phe Arg Gln Ser Pro Gly Thr Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Ile Thr Asp Tyr Asn Ala Thr Phe Ile
50 55 60
Pro Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Asn Phe Asp Gly Tyr Tyr Tyr Ser Ile Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 61
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 72
<400> 61
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ala Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Pro Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Lys Asn Leu Tyr Gly Pro Ala Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 62
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> 73
<400> 62
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Asn Ile Ser Cys Arg Ala Ser Gly Asp Thr Phe Thr Asn Tyr
20 25 30
Ala Val Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asp Thr Tyr Thr Gly Asp Pro Thr Tyr Ala Asp Asp Leu
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Thr Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Gly Asp Thr Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala
115
<210> 63
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> 74
<400> 63
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Ser Ser
20 25 30
Gly Met Ser Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala His Ile Trp Trp Ser Asp Asp Lys Ser Tyr Asn Pro Ala
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Asn Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Ala Ser Val Val Thr Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Glu Gly Ser Leu Gly Tyr Gly Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 64
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> 75
<400> 64
Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Arg Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Asn Pro Asp Ser Ser Met Ile Asn Tyr Thr Pro Ser Leu
50 55 60
Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Glu Val Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Thr Tyr Gly His His Ala Thr Asp Ser Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 65
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 76
<400> 65
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asp Ile Tyr Pro Gly Ser Asp Ser Thr Asn Tyr His Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Asp Ser Ser Gly Tyr Gly Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 66
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> 77
<400> 66
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Glu
1 5 10 15
Ser Leu Lys Leu Ser Cys Asp Ser Asn Asp Tyr Glu Phe Pro Ser His
20 25 30
Asp Met Ser Trp Val Arg Lys Thr Pro Glu Lys Arg Leu Glu Leu Val
35 40 45
Ala Ala Ile Asn Ser Asp Gly Gly Asn Thr Tyr Tyr Pro Asp Thr Met
50 55 60
Glu Arg Arg Phe Ile Ile Ser Arg Asp Asn Thr Lys Arg Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Leu His Tyr Cys
85 90 95
Ala Arg Pro Arg Pro Thr Ile Gly Thr Thr Ala Thr Gly Ser Ser Met
100 105 110
Ser Gly Ala Gln Gly Pro Arg Ser
115 120
<210> 67
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 78
<400> 67
Ser Ile Val Met Thr Gln Ser Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Gly Ser His Arg Asn Thr Gly Val Pro Thr Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Phe Phe Ser Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 68
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 79
<400> 68
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Glu Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Arg Leu Leu Ile Tyr Ser Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile Leu
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 69
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 80
<400> 69
Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Val Trp Tyr Arg Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Ile Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Tyr Ser Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 70
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> 81
<400> 70
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Asp Val Arg Trp Arg His Gln Ala Gly Asn Gln
100 105 110
<210> 71
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 82
<400> 71
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Ser
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 72
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 83
<400> 72
Asp Ile Gln Met Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Thr Ile Thr Ile Thr Cys His Ala Asn Gln Asn Ile Tyr Val Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Asn Ile Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 73
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> 84
<400> 73
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Arg Asn Gln Lys Asn Arg Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Arg Thr Phe Gly Gly Gly Thr Asn Leu Glu Ile
100 105 110
Lys
<210> 74
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> 85
<400> 74
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Thr
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 75
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 86
<400> 75
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 76
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 87
<400> 76
Asn Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Arg Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Met
35 40 45
Tyr Tyr Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Asn Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Ser Ser Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 77
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 88
<400> 77
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Thr Tyr Asn Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 78
<211> 330
<212> PRT
<213> Artificial Sequence
<220>
<223> 89
<400> 78
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 79
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 90
<400> 79
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 80
<211> 447
<212> PRT
<213> Artificial Sequence
<220>
<223> 91
<400> 80
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Asn
20 25 30
Gly Ile Asn Trp Val Lys Gln Ala Ala Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Asn Ala Glu Glu Leu
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Ala Ala Ile Tyr Phe Cys
85 90 95
Ala Arg Glu Gly Ala Phe Gly Leu Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 81
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> 92
<400> 81
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Ala Lys Ile Ser Cys Lys Ala Ser Asp Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Leu Gly Trp Leu Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly His Ile Tyr Pro Gly Gly Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Val Arg Ser Gly Asn Asp Ala Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 82
<211> 447
<212> PRT
<213> Artificial Sequence
<220>
<223> 93
<400> 82
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Glu Glu Ile
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ser Arg Glu Gly Ile Tyr Gly Met Asp Ser Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 83
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> 94
<400> 83
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ile Ile Trp Ala Gly Gly Arg Thr Asp Tyr Asn Ser Ala Leu Val
50 55 60
Ser Arg Leu Asn Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met His Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Glu Gly Gly Tyr Asp Tyr Asp Gly Asp Leu Trp Thr Thr Gly Val
100 105 110
Lys Glu Pro Gln Ser Pro Ser Pro Gln Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 84
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> 95
<400> 84
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Leu Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Phe Arg Gln Ser Pro Gly Thr Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Ile Thr Asp Tyr Asn Ala Thr Phe Ile
50 55 60
Pro Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Asn Phe Asp Gly Tyr Tyr Tyr Ser Ile Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 85
<211> 448
<212> PRT
<213> Artificial Sequence
<220>
<223> 96
<400> 85
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ala Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Pro Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Lys Asn Leu Tyr Gly Pro Ala Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser 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 Asp Glu Leu 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
<210> 86
<211> 445
<212> PRT
<213> Artificial Sequence
<220>
<223> 97
<400> 86
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Asn Ile Ser Cys Arg Ala Ser Gly Asp Thr Phe Thr Asn Tyr
20 25 30
Ala Val Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asp Thr Tyr Thr Gly Asp Pro Thr Tyr Ala Asp Asp Leu
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Thr Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Gly Asp Thr Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 87
<211> 450
<212> PRT
<213> Artificial Sequence
<220>
<223> 98
<400> 87
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Ser Ser
20 25 30
Gly Met Ser Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala His Ile Trp Trp Ser Asp Asp Lys Ser Tyr Asn Pro Ala
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Asn Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Ala Ser Val Val Thr Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Glu Gly Ser Leu Gly Tyr Gly Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 88
<211> 447
<212> PRT
<213> Artificial Sequence
<220>
<223> 99
<400> 88
Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Arg Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Asn Pro Asp Ser Ser Met Ile Asn Tyr Thr Pro Ser Leu
50 55 60
Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Glu Val Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Thr Tyr Gly His His Ala Thr Asp Ser Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 89
<211> 448
<212> PRT
<213> Artificial Sequence
<220>
<223> 100
<400> 89
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asp Ile Tyr Pro Gly Ser Asp Ser Thr Asn Tyr His Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Asp Ser Ser Gly Tyr Gly Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala 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 Asp Glu Leu 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
<210> 90
<211> 450
<212> PRT
<213> Artificial Sequence
<220>
<223> 101
<400> 90
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Glu
1 5 10 15
Ser Leu Lys Leu Ser Cys Asp Ser Asn Asp Tyr Glu Phe Pro Ser His
20 25 30
Asp Met Ser Trp Val Arg Lys Thr Pro Glu Lys Arg Leu Glu Leu Val
35 40 45
Ala Ala Ile Asn Ser Asp Gly Gly Asn Thr Tyr Tyr Pro Asp Thr Met
50 55 60
Glu Arg Arg Phe Ile Ile Ser Arg Asp Asn Thr Lys Arg Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Leu His Tyr Cys
85 90 95
Ala Arg Pro Arg Pro Thr Ile Gly Thr Thr Ala Thr Gly Ser Ser Met
100 105 110
Ser Gly Ala Gln Gly Pro Arg Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 91
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> 102
<400> 91
Ser Ile Val Met Thr Gln Ser Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Gly Ser His Arg Asn Thr Gly Val Pro Thr Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Phe Phe Ser Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 92
<211> 218
<212> PRT
<213> Artificial Sequence
<220>
<223> 103
<400> 92
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Glu Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Arg Leu Leu Ile Tyr Ser Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile Leu
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 93
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> 104
<400> 93
Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Val Trp Tyr Arg Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Ile Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Tyr Ser Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 94
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> 105
<400> 94
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Asp Val Arg Trp Arg His Gln Ala Gly Asn Gln
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 95
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> 106
<400> 95
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Ser
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 96
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> 107
<400> 96
Asp Ile Gln Met Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Thr Ile Thr Ile Thr Cys His Ala Asn Gln Asn Ile Tyr Val Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Asn Ile Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 97
<211> 220
<212> PRT
<213> Artificial Sequence
<220>
<223> 108
<400> 97
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Arg Asn Gln Lys Asn Arg Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Arg Thr Phe Gly Gly Gly Thr Asn 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> 98
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> 109
<400> 98
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Thr
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 99
<211> 218
<212> PRT
<213> Artificial Sequence
<220>
<223> 110
<400> 99
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 100
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> 111
<400> 100
Asn Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Arg Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Met
35 40 45
Tyr Tyr Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Asn Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Ser Ser Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 101
<211> 218
<212> PRT
<213> Artificial Sequence
<220>
<223> 112
<400> 101
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Thr Tyr Asn Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 102
<211> 1341
<212> DNA
<213> Artificial Sequence
<220>
<223> 113
<400> 102
cagattcaat tggtacaaag cggtcccgag ctcaagaaac ctggggagac tgtgaaaatt 60
tcctgtaagg cctctggcta caccttcacc actaacggta tcaactgggt gaagcaggct 120
gcaggaaagg ggctcaagtg gatgggatgg atcaacacta atactggaga acccaccaat 180
gctgaggaac ttaaaggcag attcgccttc tctcttgaga cttcagccag caccgcctac 240
ctccaaatta acaatctgaa aaatgaggat gccgctatct atttttgtgc ccgagagggt 300
gcattcggtc ttgattactg gggtcagggc acctctgtga cagtgtctag cgcctcaact 360
aaggggccca gtgttttccc ccttgcccct tcctcaaaat caactagcgg aggcacagcc 420
gctcttggct gtctcgtgaa agattacttc cccgagccag tgacagtctc ttggaacagc 480
ggggcactca cctccggcgt tcacactttt cccgcagtcc tccagtctag cggattgtat 540
agcctgtctt ctgttgtcac agtgccatcc tctagccttg gcacccagac ctacatttgt 600
aatgtgaatc ataagccttc aaacacaaaa gtcgataaaa aagtggagcc aaagagctgt 660
gacaagactc acacttgccc tccatgccct gccccagaac tccttggcgg acctagcgtc 720
ttcctgtttc ctcctaagcc aaaggacacc ctgatgatct cacgcactcc tgaagtgacc 780
tgcgttgtgg tagacgtgag ccacgaggat ccagaggtga agttcaactg gtatgtggat 840
ggagtcgagg tgcataatgc caaaacaaaa cctagggagg agcagtacaa ctctacctac 900
cgggtggtgt ctgttttgac cgttctgcac caagactggt tgaatggcaa ggagtacaag 960
tgcaaggtgt caaacaaagc actcccagcc cctatagaga agaccatcag caaagctaag 1020
gggcagccaa gagaaccaca ggtttacacc ctgcccccct cacgggatga actgacaaag 1080
aaccaggtgt ctctgacttg cctcgtgaaa ggattctacc cttcagatat cgcagtggag 1140
tgggagtcta acggccaacc cgagaataat tacaagacaa ctcccccagt cctggacagt 1200
gatgggtctt ttttcctgta ttctaagctc actgttgaca aaagccgctg gcagcagggt 1260
aatgtattct cctgctccgt catgcacgaa gccctgcaca accactatac ccagaagtct 1320
ctgagcttgt cacccggcaa g 1341
<210> 103
<211> 1347
<212> DNA
<213> Artificial Sequence
<220>
<223> 114
<400> 103
caagtacagt tgcagcagtc tggagctgag ctggttagac ctggaaccag tgccaagatc 60
tcctgcaaag ctagtgatta tactttcaca aactactggc tcggttggct gaaacaaaga 120
cccgggcacg gtctggaatg gataggccac atttacccag gcggcggata caccaactat 180
aacgagaagt ttaagggaaa ggctactctg acagccgaca cctcatccag cacagcctac 240
atgcagctta gtagtttgac cagtgaggat tccgcagtgt acttctgtgc acgtgtgagg 300
tcagggaatg acgccctgga cttctggggc cagggtactt cagtgacagt gtcctccgct 360
agcactaagg gaccaagcgt gtttcctctg gctccaagct ctaaatcaac ctcaggcgga 420
accgccgctt tgggatgtct tgtgaaggat tacttccctg agcctgtcac cgtctcctgg 480
aatagcggcg ccctgacttc cggggtgcat acattccctg ccgtattgca gtcaagcggc 540
ctgtatagcc ttagctctgt tgtaactgtg ccatcttctt cccttggcac acagacctac 600
atctgtaacg tgaaccataa gccatccaat acaaaagttg ataagaaggt ggagccaaaa 660
tcatgtgaca aaactcatac atgccctcct tgtccagcac ctgagctgtt gggcggacca 720
agtgtctttc tgttcccccc aaagccaaag gacacactga tgatcagtcg cacaccagaa 780
gtgacttgcg ttgttgtcga tgtgagccac gaagaccctg aggttaagtt taactggtac 840
gtggatggtg tggaggtgca caatgccaag actaagccac gtgaagaaca gtataactcc 900
acctatcgtg tggtctctgt cctgacagta ctgcaccagg actggctcaa tggaaaagag 960
tacaagtgca aggttagtaa caaggccttg cccgctccta tcgagaaaac tatcagtaag 1020
gcaaagggac agccaagaga accacaggtt tacaccctgc cacctagccg ggacgaattg 1080
actaaaaacc aagtgagtct cacatgcctc gtcaagggat tctacccatc tgacattgcc 1140
gtagagtggg agtccaatgg gcagcccgag aataattata agactactcc acctgtcctg 1200
gattctgatg gatccttctt tttgtattcc aagcttaccg tggacaaaag caggtggcag 1260
cagggcaatg tcttttcatg cagcgtgatg cacgaagcac ttcacaatca ctacacacag 1320
aagagtctgt ctctcagtcc tggtaag 1347
<210> 104
<211> 1341
<212> DNA
<213> Artificial Sequence
<220>
<223> 115
<400> 104
caaattcagc tggtgcagtc cggcccagaa cttaagaaac ccggtgaaac cgtgaagata 60
tcctgcaaag cttcaggcta tacctttacc aactatggca tgaattgggt gaagcaagct 120
cccgggaagg gccttaaatg gatgggctgg atcaacacca acacaggtga gccaacctat 180
gccgaagaaa tcaaaggacg ctttgctttc tctctcgaaa ctagcgcaag taccgcttat 240
ttgcagatca ataatctgaa aaacgaggac accgctacct acttttgctc aagagagggc 300
atttacggca tggattcttg gggccaggga acatctgtca ccgtctcatc tgcatctacc 360
aagggcccta gtgtgttccc actggcccct tcatccaagt ccacttctgg aggaacagcc 420
gccttgggct gtctcgttaa ggactacttc cccgagcctg ttaccgtgtc ctggaacagt 480
ggcgccctga cctccggtgt tcacactttc cccgctgtgt tgcagtcctc tggcctttat 540
tccctttcct ctgtagtgac agtgcccagt tccagtctgg gtacacagac ctacatttgc 600
aatgtcaacc ataaaccaag taataccaag gtagataaaa aggtagagcc taagtcatgc 660
gataaaactc acacatgtcc accatgtcct gctccagaac tcttgggcgg tccaagtgtc 720
tttttgttcc caccaaaacc taaggatacc ctcatgatct ctaggacccc cgaggtcaca 780
tgtgtggtgg tcgacgttag tcacgaggat cccgaggtta aatttaactg gtatgtcgat 840
ggggttgaag tccacaatgc caaaaccaaa ccaagagagg aacagtacaa ttccacttac 900
cgtgtggttt cagtgctgac cgtccttcat caggactggc tcaacgggaa ggagtacaag 960
tgcaaggtca gtaacaaggc tcttccagcc cccatcgaaa agactatttc caaagccaag 1020
ggacaaccaa gagagccaca agtgtacact cttcccccca gcagggacga actcacaaag 1080
aatcaggttt ctctcacctg tctggttaag ggcttttacc ccagcgacat cgcagttgag 1140
tgggagagca atggccagcc tgagaataac tataagacaa caccccccgt gctggattct 1200
gacggcagct ttttcttgta ctctaaactc actgtagaca aatccaggtg gcagcaaggc 1260
aacgtgtttt cctgctctgt catgcacgag gcattgcaca atcactatac tcagaaatca 1320
cttagcctgt cccccggtaa g 1341
<210> 105
<211> 1353
<212> DNA
<213> Artificial Sequence
<220>
<223> 116
<400> 105
caagtacaat tgaaagagag tggaccagga cttgtggccc ctagccagtc tctgtcaata 60
acctgtactg tcagtggatt ttcccttacc agctatgggg tacactgggt taggcagcca 120
cctggtaaag gacttgagtg gctgggcatt atttgggccg gagggcggac agactataat 180
tctgcactgg tatccagact caatatcagt aaggacaaca gcaaaagtca agtgtttctg 240
aaaatgcatt cacttcaaac cgatgacacc gctatgtact actgtgctag ggaaggcggt 300
tatgactatg atggagatct ctggactacc ggagtcaagg agcctcaaag ccccagtcct 360
caggcctcca caaaagggcc tagtgttttc cccctggccc catcatctaa gagtacatca 420
ggaggaacag cagcccttgg atgcctggtg aaagactact ttccagaacc cgttaccgtg 480
tcctggaact caggcgcact tacctctggc gtccatacat ttcccgccgt attgcagagc 540
agcggactgt actcattgtc atccgtggtg acagtgccta gtagttctct tggtacacag 600
acctacatat gtaacgtgaa tcataaaccc tcaaatacta aagtcgacaa gaaggttgag 660
cccaagagct gtgataaaac ccacacttgt cccccatgcc cagcacctga actgctcgga 720
ggcccatccg tctttctctt ccctcctaag cctaaggata cacttatgat ttcacggacc 780
cctgaagtga catgtgtggt cgttgatgtg tcccatgagg acccagaagt taaatttaac 840
tggtatgtcg atggcgtgga ggtgcacaac gccaagacaa agcccaggga agaacagtat 900
aattcaacat accgcgtcgt tagcgtgctg acagttctgc atcaggattg gcttaacggt 960
aaagagtaca agtgcaaggt ctccaacaaa gctctgcctg cacctattga aaaaactata 1020
tccaaggcta agggccagcc tcgcgagcct caggtatata cactgccacc cagcagggac 1080
gaactgacaa agaatcaggt cagtctgact tgcctcgtca agggattcta cccttcagac 1140
atcgccgtgg agtgggagtc aaacggtcag cccgagaaca actacaagac aacaccccct 1200
gtactggact ccgacggctc ctttttcctg tattctaagc tgactgtcga taaatctcgc 1260
tggcagcagg gaaacgtctt ttcctgctct gtgatgcacg aggctctgca caatcactat 1320
actcagaagt cactgtcctt gtctcccgga aag 1353
<210> 106
<211> 1347
<212> DNA
<213> Artificial Sequence
<220>
<223> 117
<400> 106
caggtacaat tgaaacaaag tgggccaggt cttgtccttc cttcccagtc tctgagtatt 60
acctgtaccg tcagtggatt tagccttaca agctatggag tccattggtt caggcaatcc 120
ccaggcacag gcctggaatg gttgggggtc atctggagtg gtggtatcac cgattacaat 180
gcaaccttta tcccccgtct gtccatatca aaggacaact ctaagtccca ggtgtttttc 240
aaaatgaact ctctccaggc agatgacaca gccatatatt actgtgctcg taacttcgac 300
ggctactact attccataga ttattggggc cagggcactt cagtcaccgt cagtagcgcc 360
agcactaagg gtccttccgt ttttcccctt gctccttctt caaagagcac aagtgggggg 420
actgcagctt tgggctgctt ggtgaaggat tattttcctg agcctgtcac agtctcttgg 480
aatagcgggg cactcacaag cggtgttcat acctttccag ccgtgctgca gagttctggt 540
ctgtatagtc tctcctcagt ggtgaccgta ccttcttcct ctctgggcac ccagacatac 600
atatgcaatg ttaatcacaa gccctccaac acaaaagtgg ataaaaaagt tgagcctaag 660
agttgtgaca aaactcacac atgtcctcct tgcccagctc ccgaactcct tggaggacca 720
agtgtttttt tgtttcctcc taagcccaag gacaccctga tgatttctag aactccagag 780
gtaacatgtg tggtcgtgga cgtcagccat gaggaccccg aagtaaaatt taattggtac 840
gtggacgggg tggaggtgca taacgccaag accaaacccc gagaggagca gtataatagc 900
acctacagag tcgtgagtgt tttgactgtc ctgcatcaag attggctcaa cggaaaggag 960
tacaagtgca aggtaagtaa taaagccctg ccagcaccca tagagaaaac catcagcaaa 1020
gcaaaagggc agccaagaga gccacaggtt tatacactcc ctccatctcg ggacgagttg 1080
actaagaacc aggttagtct gacatgtctg gtgaaaggct tttaccccag cgatatagct 1140
gtagagtggg aaagcaacgg gcagcctgag aacaactata agaccactcc ccccgttctg 1200
gatagcgacg gtagtttctt tctttattcc aagctgactg tggataaatc ccgatggcag 1260
cagggaaatg tcttttcctg ttccgtcatg cacgaagctc tccataatca ctacactcag 1320
aaatctctgt ccctgagtcc cggtaaa 1347
<210> 107
<211> 1344
<212> DNA
<213> Artificial Sequence
<220>
<223> 118
<400> 107
caagttcaac ttaaacagag tggtcctggc ctggtacagc caagccagtc cctgtccata 60
acctgtacag tctcaggctt tagccttact aactatggcg tccactgggt tcggcagtct 120
cctggtaagg gacttgaatg gctcggagct atttggaggg gagggtccac cgactataat 180
gcagcattca tgtcccggct ttctattacc aaggataaca gcaaaagtca ggtgttcttt 240
aagatgaact ccctgcagcc cgacgataca gccatctact actgtgccaa aaacctgtat 300
ggaccagctg ccatggacta ttggggccag gggacctccg tcacagttag cagcgcttct 360
actaagggcc cctctgtgtt tccactggca ccatcctcta agtcaaccag tgggggcact 420
gcagctttgg gctgtctggt caaggattac tttccagaac ctgtcaccgt ttcctggaat 480
tccggcgcct tgacttctgg tgtgcacacc ttcccagctg tcctgcagtc cagtggactg 540
tattcactga gctccgtggt cacagtgcct tcaagtagcc tgggcaccca gacctatatc 600
tgtaacgtaa accacaagcc ttctaacacc aaggtggaca aaaaggtgga accaaaaagc 660
tgtgacaaaa ctcatacatg cccaccttgt ccagctccag agctgctggg tggaccatct 720
gtgttcttgt ttccccctaa gcccaaagac accctgatga tttcacggac ccctgaggtg 780
acatgtgtcg ttgtggacgt tagtcacgag gatcctgaag taaaattcaa ttggtacgtc 840
gacggcgtcg aagttcacaa tgccaagaca aagccccgag aggaacagta caatagtaca 900
taccgagtcg tgagcgtgtt gacagttctc caccaggatt ggctcaatgg caaagagtac 960
aaatgtaagg tatcaaataa agccctcccc gctcccatag agaagacaat ctcaaaggcc 1020
aaagggcaac ccagggagcc tcaagtctac acccttcccc catctcgcga cgagctcacc 1080
aagaatcagg tatcattgac atgtctggtc aaaggatttt atcctagcga tatcgccgta 1140
gagtgggagt ctaatggcca gcccgagaat aattacaaaa ccactcctcc tgtgctggat 1200
tctgatggat ctttcttcct gtatagtaag ttgacagtcg ataagtcccg gtggcaacag 1260
ggtaatgttt tcagctgttc cgttatgcat gaggctctcc acaaccatta cacccaaaag 1320
agtctttctc tttcccccgg caag 1344
<210> 108
<211> 1335
<212> DNA
<213> Artificial Sequence
<220>
<223> 119
<400> 108
cagattcagc tggtgcagtc cggtcctgag ttgaaaaagc caggagaaac tgtcaacatc 60
tcttgccgcg ccagcgggga cacattcacc aactacgccg tgaactgggt gaagcaggct 120
cccggtaagg ggctcaagtg gatgggctgg atagacacct acacaggaga tcctacctac 180
gcagacgact tgaagggcag gttcgccttc tctcttgaga cctccgccac aactgcttat 240
cttcagatca acaatttgaa aaacgaggat accgccactt acttctgtgc tggggatacc 300
tggttcgctt actgggggca gggaactttg gtcaccgtga gcgctgcttc caccaagggg 360
cccagcgtct tccctctcgc cccttctagc aagagcacca gtggtggaac cgctgccctt 420
gggtgcctcg tgaaggatta tttccctgaa cctgtgactg tatcttggaa tagcggtgca 480
ctcacctccg gtgtgcacac ttttccagct gtgctgcagt ctagcgggct gtatagcctt 540
agctccgtgg tgaccgtgcc ttcttcttct ttgggtaccc agacctacat ctgcaacgtg 600
aaccataagc catccaatac taaggtcgac aagaaagtgg agcccaaatc ctgcgataaa 660
acccatactt gtcccccatg cccagctcca gaactgctcg gagggcccag tgtgtttctt 720
ttccccccaa agcctaagga cactctcatg atatcccgaa ccccagaggt gacatgcgtc 780
gttgtggatg tgtcacatga agatccagag gtcaagttca actggtatgt cgatggagtc 840
gaggtccaca atgctaagac aaaaccaaga gaggagcagt ataacagtac ctaccgagtg 900
gtctccgtgc tgactgttct tcaccaagat tggctcaatg gtaaagagta caaatgcaaa 960
gtatccaaca aggcccttcc tgcaccaatc gaaaaaacta tttccaaagc aaagggccag 1020
cccagggagc cacaggtcta cacactgccc ccaagcaggg atgaactcac caagaaccaa 1080
gtgtcactta cctgcctggt taagggattc tacccctccg atattgcagt agaatgggag 1140
tctaacggtc agcctgagaa taactacaag accacccccc ccgtgctcga tagcgatggt 1200
tcattcttcc tgtatagcaa gctgaccgtc gataagagta ggtggcaaca agggaatgtg 1260
ttcagttgct ctgttatgca cgaagccctc cacaaccatt acacacaaaa gtccctttcc 1320
ttgtctcccg gtaag 1335
<210> 109
<211> 1350
<212> DNA
<213> Artificial Sequence
<220>
<223> 120
<400> 109
caggtaacac ttaaggagag cggtccaggt atactccagc ctagtcagac actgagcctt 60
acatgcagct ttagtgggtt cagcctgtcc agttctggca tgtcagtagg ctggatccga 120
caacctagcg gaaagggcct ggagtggctg gctcatatct ggtggtcaga cgacaagtcc 180
tataacccag ccctcaaatc ccgtctgacc atctcaaaag acaccagtaa taatcaggtt 240
ttccttaaaa tcgcctctgt ggtcactgca gatacagcaa cctactactg tgcacgcgag 300
ggctctttgg gctatggact ggactactgg ggtcagggta ccactctgac tgtaagcagt 360
gcttcaacta agggacctag cgtgtttcca ctggcaccca gttctaaatc tacttctggg 420
ggaactgctg ctctgggatg cctggtgaag gattactttc cagagcccgt cactgtgagt 480
tggaatagcg gtgccttgac ctccggagtg cacaccttcc cagctgtgct tcaatcctca 540
ggcttgtatt ctctttcctc cgtggtgacc gtgccatcct cctctctcgg gacccagact 600
tacatatgta atgtaaacca caagccctct aacacaaagg tagataagaa ggtcgagcca 660
aagtcctgtg ataaaacaca tacatgtccc ccttgtcccg ctccagaact gcttggcgga 720
ccctctgtgt tcctgttccc acctaagcca aaagacactc ttatgatttc caggactcca 780
gaggttacat gcgttgtggt ggacgtaagc catgaagacc ctgaggtgaa attcaattgg 840
tatgtggacg gtgtggaggt ccataacgct aagactaagc ccagggagga acagtacaac 900
tcaacatatc gagtcgtctc tgtcctgaca gtgctccacc aggattggct gaacggaaag 960
gaatacaaat gcaaggtgag taataaagcc ctgccagctc ccatcgaaaa aacaatcagc 1020
aaggctaagg gtcagccccg cgaaccacag gtctacactc tgccaccaag tcgggatgaa 1080
ttgactaaga atcaggtctc cctgacctgt ctggtgaagg gtttttatcc ctccgacatc 1140
gcagtggagt gggagagcaa cgggcagcct gagaataact ataagacaac tccacccgtc 1200
ctcgattctg acgggtcttt ttttctgtac agcaaactga ctgtggacaa gtctcggtgg 1260
cagcaaggta acgtcttcag ctgctccgtt atgcacgaag ccctccacaa ccactacact 1320
cagaaatctc tgtccttgag tcctggaaag 1350
<210> 110
<211> 1341
<212> DNA
<213> Artificial Sequence
<220>
<223> 121
<400> 110
gaagttaaac tcctcgaatc tggaggaggg ttggttcagc caggtggttc tttgaagctg 60
tcttgtgcag cctctgggtt tgacttccga agatattgga tgagttgggt gcgtcaggca 120
ccagggaaag gtcttgaatg gatcgggcag attaaccccg acagttcaat gattaactat 180
acaccttctt tgaaagataa atttattata tcccgtgaca acgctaaaaa caccttgtat 240
ctgcagatga gtgaggtgag atccgaagac actgctcttt actactgtgc cacctatgga 300
caccacgcta cagactcctg gggccagggt accagtgtga cagtttccag tgccagcacc 360
aagggcccat ccgttttccc cctggctccc tcttctaaat ctacttcagg tggtactgca 420
gcacttggat gtttggtgaa ggactacttc cctgagccag tcaccgtgag ttggaactca 480
ggcgctctta catccggtgt ccacacattt ccagccgtgc tgcagagctc aggactctat 540
tctctcagct ccgtcgtgac agtacccagc agctcacttg gcactcagac ctatatctgt 600
aatgtcaacc ataagccatc taacactaaa gtcgacaaga aggtcgagcc caagagttgc 660
gacaaaacac atacctgccc cccatgtccc gcaccagaac tcctgggtgg tccaagcgtg 720
tttttgtttc cacctaaacc aaaggacacc ctgatgatta gccgtacacc agaggtgact 780
tgcgtggtgg tcgacgtgag tcacgaggat ccagaggtga agttcaactg gtatgtggat 840
ggcgttgaag tacataacgc caaaaccaag cccagagagg aacaatacaa tagcacctac 900
cgagtcgtca gtgtgctgac cgtgcttcac caagactggc tcaatgggaa agagtacaag 960
tgtaaggtta gcaataaagc tctgcctgcc ccaatcgaga agactatctc taaggcaaag 1020
ggacagccta gggagccaca ggtctataca ctccccccct cacgggatga gttgactaag 1080
aatcaggtgt cactgacatg ccttgttaag gggttttatc cctctgacat cgccgtcgaa 1140
tgggagagta acggacagcc agagaacaac tacaagacaa ccccaccagt cctggactct 1200
gacggctcct tctttctgta ttcaaagctg actgtggaca aatctagatg gcagcagggc 1260
aacgtcttta gttgtagtgt gatgcatgag gctctgcata accattatac acagaaaagt 1320
ctcagtctta gcccaggaaa a 1341
<210> 111
<211> 1344
<212> DNA
<213> Artificial Sequence
<220>
<223> 122
<400> 111
caagttcagt tgcagcaacc tggtgcagaa ttggtgagac ccggtacatc tgtcaagatg 60
agctgcaagg ccagcgggta cacctttact agttactgga tgcattgggt gaaacagcga 120
cccggacaag gattggagtg gatcggtgat atctatccag ggtccgacag cacaaactat 180
catgagaagt ttaagagcaa ggccaccctg acagtcgaca cctcaagctc cacagcttac 240
atgcagctgt cttccttgac tagcgaagat tctgccgtgt actattgcgc tcttgatagc 300
tctgggtatg ggttcgccta ttggggacag ggtactctgg tgacagtgtc cgctgcctcc 360
accaaaggtc ccagtgtatt tcccttggct ccatctagca agtctacatc cggcggtaca 420
gccgcactgg ggtgtcttgt gaaggactac ttccctgagc ctgttacagt atcttggaat 480
tcaggcgctc tgacctcagg agtccacacc tttcccgctg tcttgcagtc tagcggcctt 540
tatagcctgt cttccgtggt gactgttccc tctagtagtc tcggaaccca gacctacatc 600
tgcaatgtga atcacaagcc cagcaacaca aaagtcgaca agaaggtgga gcctaaatct 660
tgcgacaaga ctcacacctg tcctccatgc cctgctccag aactgctggg gggaccttca 720
gtgtttctct tccctccaaa accaaaggac accctcatga tctcccgcac cccagaggtc 780
acctgtgtgg tggtggacgt ttcacatgag gatcctgagg tgaagttcaa ttggtatgtg 840
gacggtgtcg aagttcataa tgccaagaca aagcctcgcg aagagcagta caacagcact 900
tacagggtgg tgtccgtcct gactgtcttg caccaggact ggttgaacgg caaagaatac 960
aaatgcaagg tgagtaacaa ggcactgcct gcaccaattg agaagactat ctctaaggcc 1020
aaaggccagc ctcgtgagcc tcaagtgtat accctccccc ctagcagaga cgagttgaca 1080
aagaatcagg tcagcttgac atgcctggtg aagggatttt atccctcaga cattgccgtc 1140
gaatgggaga gtaacggcca gccagaaaat aactacaaga caaccccccc tgtcctggac 1200
agcgatggat catttttcct gtactcaaag ctgactgtag acaagtctcg atggcagcaa 1260
ggtaacgtat tctcctgcag cgtgatgcac gaggcactgc ataatcacta tacccagaag 1320
agcctgagcc tgtcaccagg gaag 1344
<210> 112
<211> 1350
<212> DNA
<213> Artificial Sequence
<220>
<223> 123
<400> 112
gaggtacagt tggttgaatc tggcggtgga cttgtacaac caggcgaatc cttgaaactg 60
agttgcgact ctaatgacta tgaattccct agtcacgata tgtcttgggt tcggaagacc 120
cctgagaaac ggcttgagct tgtggcagcc atcaactcag acggtggaaa tacatattac 180
cccgacacta tggagaggag atttattatc agccgcgata ataccaaaag gacactttat 240
ctccagatgt cctctttgcg cagcgaggat accgctctgc attattgtgc ccgcccacga 300
ccaactatcg gcacaacagc cactgggtct tctatgtctg gggcacaggg cccaagaagc 360
gcctctacaa agggcccttc agtgtttccc cttgctccat catctaaaag tactagtgga 420
ggcactgctg ctctcggctg tctggtcaag gactactttc cagagcctgt gaccgtgtcc 480
tggaatagtg gggcacttac atctggtgta cacacctttc ctgctgtact gcagagctct 540
ggcctgtatt ccctgagcag cgttgtcaca gtcccatcaa gtagcttggg aactcagacc 600
tacatatgca atgtgaatca caaaccatcc aacaccaagg tggataagaa ggtcgagcct 660
aaaagttgtg acaaaaccca tacatgccca ccttgtcctg ctcctgagct tctgggcggc 720
ccaagtgttt tccttttccc tcccaaaccc aaagacacac tcatgatttc ccgtacaccc 780
gaggttactt gtgtggttgt tgatgtcagc cacgaggatc ctgaggtcaa gttcaactgg 840
tatgtcgacg gcgttgaagt ccacaacgct aagaccaagc ctcgggagga gcagtataat 900
tccacttaca gggtggtttc cgttttgacc gtgctgcacc aggattggct gaacggcaaa 960
gagtataaat gcaaggtaag caataaagcc ttgcccgcac ccatcgagaa aactattagc 1020
aaagccaagg gtcagcccag agaacctcaa gtttataccc tccctccctc acgcgatgaa 1080
ctcactaaga atcaggtgtc actcacatgt ctcgtgaagg gtttttaccc ctccgatatt 1140
gctgtggagt gggagtctaa cggccagccc gagaacaatt acaagaccac cccacctgtg 1200
cttgatagcg atggctcctt tttcctctac agtaagctga cagtggacaa atctcggtgg 1260
cagcagggca acgttttctc ctgttcagta atgcatgagg cattgcataa tcattatacc 1320
caaaagagcc tctcactttc cccagggaag 1350
<210> 113
<211> 642
<212> DNA
<213> Artificial Sequence
<220>
<223> 124
<400> 113
tctattgtga tgactcaaag tcctaaattt ctcctcgttt ccgctggaga cagggtgata 60
ataacttgca aagcttcaca gagcgtgtcc aatgatgtag tatggtacca gcaaaagcca 120
ggccagagcc caaaacttct gatctactac ggttcacacc ggaacaccgg agtacctaca 180
aggtttactg gttccggcta tgggactgac ttcacattca ctatttcaac cgtccaggct 240
gaagacctgg cagtctattt ttgtcagcag gatttcttct caccatggac cttcggtggc 300
ggtacaaaat tggagataaa gcgcactgtt gccgcccctt ccgtctttat atttccaccc 360
tccgatgagc agcttaagtc agggacagcc tctgtcgtgt gtctgctcaa caatttttac 420
ccccgtgaag ccaaggtgca gtggaaagtg gataacgccc tgcagtctgg caattctcag 480
gagtcagtga ccgaacagga ttcaaaagac tctacatata gcttgtcatc cacccttact 540
ctgtccaaag cagattatga gaagcacaaa gtttatgctt gtgaagttac tcaccagggt 600
ctgagcagcc ccgtaacaaa gagtttcaac cggggggagt gc 642
<210> 114
<211> 654
<212> DNA
<213> Artificial Sequence
<220>
<223> 125
<400> 114
gacatagttt tgacccagtc tcctgctagt ctcgccgtgt ctctgggaca acgagcaact 60
attagctgcc gagccagcga gagcgttgac gaatacggga tttctttcat gaactggttc 120
cagcagaagc caggacagcc cccacgtctg cttatttaca gcgcctctaa ccaagggagt 180
ggagtgccag ccagatttac aggtagtgga tctggaacag atttctccct caacattctg 240
cccatggagg aagacgacac cgctatgtat ttctgtcagc agagcaaaga agtgccctgg 300
acctttgggg gagggaccaa actcgaaatt aagcgaactg tggctgctcc ctcagtcttt 360
atcttcccac catctgatga gcaactgaag tctggcactg catccgtggt gtgtctgctg 420
aataattttt accctcgcga ggcaaaagtg cagtggaagg tggataatgc tttgcagtca 480
ggaaattctc aggagagtgt taccgaacaa gatagcaagg actccacata tagtttgtcc 540
tctacactta ctctctccaa ggcagactac gaaaaacaca aggtgtacgc ttgtgaggtg 600
acccaccagg gcctgagctc accagtgacc aaatccttca accgcggcga gtgc 654
<210> 115
<211> 642
<212> DNA
<213> Artificial Sequence
<220>
<223> 126
<400> 115
agtattgtga tgactcagac ccccaagttt cttttggtga gtgcaggtga cagagtgaca 60
attacctgca aagcttcaca gagcgtcagc aacgatgtcg tctggtaccg acagaagcca 120
ggacagagcc ccaagctcct catctactac gcctctaatc gatacatcgg cgtgcccgac 180
aggtttaccg gttctggcta tggtactgat tttaccttca caatttctac tgttcaggcc 240
gaagatcttg ccgtgtactt ttgtcaacag gattactata gtccctggac tttcggcggg 300
ggtactaagc tggagattaa gcgaacagtg gccgcaccct ccgtgtttat cttcccaccc 360
tctgacgagc aactcaagag tggaactgcc tctgtcgtgt gcttgctgaa caacttttat 420
cccagagaag ccaaggtgca gtggaaggtg gataatgccc tgcagagcgg gaactctcag 480
gaatccgtca cagaacagga ttcaaaggac tcaacttatt ccctttcttc aaccctgaca 540
ctctccaagg ccgactacga gaagcataaa gtgtacgctt gcgaggtaac ccatcagggt 600
ctcagtagcc ccgtcactaa gagcttcaac aggggcgaat gc 642
<210> 116
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> 127
<400> 116
gatgtggtta tgactcagtc cccattgtcc ttgccagtct ctctgggtga tcaggcatct 60
atttcctgca ggtccagcca gtcactggtg cattctaacg ggaacaccta ccttcactgg 120
tacttgcaaa agcccgggca gagccctaag ctgctcattt ataaggtttc taatagattc 180
agcggtgtgc ctgacagatt ttctggttct ggatctggca ccgattttac cctgaagatc 240
agtcgagtag aggccgaaga cttgggagtg tacttttgct cccaatccac ccatgtccca 300
ccagatgtgc gatggcgtca tcaggctggc aaccaaagga ctgtggctgc ccctagtgtt 360
tttatattcc caccttcaga cgagcagctt aaaagtggca ccgcctcagt ggtttgtttg 420
ctgaataatt tctatccaag ggaagcaaag gttcaatgga aggtggacaa cgctctgcaa 480
agcggaaaca gtcaggagag cgtgaccgaa caggatagca aggacagtac ttatagtttg 540
agcagtactc tcactttgtc caaagccgac tacgagaagc acaaggtgta cgcctgtgaa 600
gtgacccatc aggggttgtc aagccctgta actaaaagtt ttaatagagg cgagtgt 657
<210> 117
<211> 642
<212> DNA
<213> Artificial Sequence
<220>
<223> 128
<400> 117
gatatccaga tgacccagac cacttccagt ctttctgcta gtctcggcga tcgagtgacc 60
atcagctgcc gagcatctca ggacatttca aattcactca actggtatca acagaaacca 120
gatggcaccg tcaagctgct gatttattac accagcagac tccacagtgg tgtgcccagc 180
aggttcacag gttctgggag tgggactgat tactccctga caatttctaa cttggaacag 240
gaggatatcg ccacttattt ttgccagcag ggcaacaccc ttccattgac attcggcgca 300
ggaaccaagc ttgagttgaa gagaaccgtc gccgcaccct ctgtatttat attcccacca 360
tctgacgagc aactgaagtc cggaacagcc agtgtggtgt gcctccttaa taatttttac 420
cctcgtgaag ccaaggtaca gtggaaggtt gataacgccc tgcagagtgg aaatagtcag 480
gagtctgtaa ccgagcagga ttccaaggat tccacatatt cactgtccag tacattgaca 540
ttgtcaaagg ctgactacga aaagcataag gtatacgcct gcgaagtgac acatcagggg 600
ctgtcttctc ccgtgacaaa gtcattcaat cgcggggagt gt 642
<210> 118
<211> 642
<212> DNA
<213> Artificial Sequence
<220>
<223> 129
<400> 118
gatattcaga tgaaccagtc tccctccagt ttgtccgcct ccctcggtga tactattact 60
attacatgcc acgctaacca aaatatctac gtgtggctgt catggtatca acagaaacct 120
ggcaacattc ccaagcttct catctacgag gcatcaaacc tgcacactgg cgtcccttcc 180
aggttctcag gctcaggttc cggaaccggt tttacactga ccataagtag cctgcagcct 240
gaagacatcg caacctacta ttgtcagcaa ggccagagct acccctacac cttcggcgga 300
ggaacaaagt tggagataaa acggactgtc gccgcaccat ctgtcttcat cttccccccc 360
agtgatgagc agcttaagag tgggactgct tctgtcgtct gtctgctcaa taatttttat 420
ccaagagagg ctaaggtaca gtggaaagtg gacaacgctc tgcagtctgg taactcccag 480
gagagtgtga ccgaacagga ttctaaggac tccacatact ccctgagctc tacacttaca 540
ctcagtaaag cagactatga gaagcataaa gtgtatgcat gtgaggtgac acaccagggt 600
ctgtcctctc ctgtgaccaa gtctttcaac agaggcgagt gt 642
<210> 119
<211> 660
<212> DNA
<213> Artificial Sequence
<220>
<223> 130
<400> 119
gatatcgtca tgtcacagag cccatctagc ttggctgtct cagtgggcga gaaagtgacc 60
atgtcatgca aaagctccca atccttgttg tacagccgca atcagaaaaa tcgccttgcc 120
tggtaccagc agaaaccagg tcagtcccca aaactgctga tttattgggc cagcacaagg 180
gagagtggtg tgcccgatag attcactggg tccgggtcag gcaccgattt cactctgacc 240
atctcatctg ttaaagcaga agatctggcc gtctactatt gccagcagta ctatagttat 300
cccagaactt tcgggggcgg caccaacctg gagattaagc gtaccgtggc agcaccatct 360
gtctttattt tccccccatc agacgagcag ttgaaatcag gaaccgcctc tgtcgtgtgc 420
ctgctgaaca atttttatcc aagagaggct aaggtgcagt ggaaggtcga taatgctctt 480
cagagcggta attctcaaga atccgtgact gaacaggatt caaaagatag cacatacagt 540
ctctccagca ccctgaccct cagcaaggcc gactacgaga agcacaaagt gtatgcctgt 600
gaagtgacac atcaaggtct ctccagccct gtaactaaga gttttaatag aggagaatgc 660
<210> 120
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> 131
<400> 120
gatgtcctga tgacccagac tccattgagc cttcctgtct ccttggggga tcaagcctcc 60
atttcatgca ggagctccca gagcatagtc cacacagatg gaaacactta cctggagtgg 120
tacttgcaga agccaggcca gtctcccaaa ctgctcatct acaaagtgtc taatagattt 180
tccggtgtgc ccgaccgttt ttcaggtagc ggctctggta ctgatttcac tctgaagatc 240
tcccgggtgg aggctgagga tctgggcgtc tattattgtt tccagggctc ccacgtgcca 300
tggaccttcg gtggtggcac caagttggag attaagagga cagtggccgc accatccgtg 360
ttcatatttc cccctagcga tgaacagttg aaaagcggta ctgcctccgt ggtttgtctg 420
ctgaataatt tctaccctag agaagctaaa gtgcaatgga aggttgacaa tgccttgcag 480
tcaggcaatt ctcaggagtc tgtgaccgaa caggacagca aggactccac ctattctctg 540
tcttcaacac tgacacttag taaggctgat tacgaaaagc ataaggtata cgcctgtgag 600
gtgacacacc agggcctgag ttcaccagtg accaagtcct tcaatcgcgg ggagtgt 657
<210> 121
<211> 654
<212> DNA
<213> Artificial Sequence
<220>
<223> 132
<400> 121
gatattgtgc ttacacagtc cccagcttcc ctggccgttt cccttgggca gcgagccaca 60
atctcctgcc gcgcatctga gtccgttgat agctacggca attcttttat gcactggtac 120
caacaaaaac ctggtcagcc tccaaagttg ctgatttatc gcgcttccaa ccttgagtcc 180
ggtattcctg ctcgctttag cggctctggg agtagaaccg acttcacact gaccattaac 240
ccagttgagg ctgatgatgt ggctacctat tactgtcagc agtctaacga agacccattt 300
acatttgggt caggcactaa gctggagatt aagcgtaccg tggccgcccc aagcgttttc 360
atcttccccc caagcgacga gcagctgaag tccggaactg cctccgtcgt ttgtctcttg 420
aacaattttt atcctaggga agcaaaagta cagtggaagg tagataacgc tctgcaaagc 480
ggtaactccc aagaatccgt aaccgaacaa gactcaaagg acagtactta ttccctgtcc 540
agcaccctga ctctttctaa agctgattat gaaaagcata aagtttatgc atgtgaggtg 600
acccaccagg gattgtcctc cccagttact aaatctttta accgggggga atgc 654
<210> 122
<211> 642
<212> DNA
<213> Artificial Sequence
<220>
<223> 133
<400> 122
aatatcgtca tgacccagac tcctaaattt cttctggtct ccgctggaga ccgcgtcact 60
ataactcgta aagccagcca gtccgtgtct aatgacgttg tgtggtacca gcagaagccc 120
gggcagtccc ctaagctgct catgtattac gcaagttatc gatacaccgg cgtgcccgat 180
cgattcaccg gatccggtta tggcaccgac ttcacattta ctatttctaa cgttcaggcc 240
gaggacctcg ccgtatactt ttgtcaacaa gactactcca gcccttttac atttggaagc 300
gggacaaaat tggagatcaa gaggactgtt gccgcacctt ccgtgtttat atttccacct 360
tccgacgagc agctgaagtc cgggaccgca agcgtggttt gtctcctcaa taatttctat 420
cctcgagagg ctaaggtcca gtggaaggtg gacaatgctc tgcagagtgg caactctcag 480
gagtcagtta ctgaacaaga cagcaaggac agcacatatt cactgtcatc cactcttact 540
ctctccaagg ctgactacga aaagcataag gtttatgcct gcgaggttac tcatcagggt 600
ctgtccagtc cagtgaccaa atcttttaat agaggagagt gc 642
<210> 123
<211> 654
<212> DNA
<213> Artificial Sequence
<220>
<223> 134
<400> 123
gatattgtct tgacccaatc acctgctagc ctggctgtga gcttggggca gcgagcaacc 60
atctcctgta gggcctctca gtccgtctcc acaagtactt acaactacat gcattggtac 120
cagcagaaac ctggccaacc accaaaattg ctcattaagt atgctagcaa ccttgagtca 180
ggcgtccccg caaggtttag cggatctggc tcaggaaccg attttactct gaacattcac 240
cccgtggagg aggaggacac tgctacctac tattgccagc atagttggga gatacccttc 300
acctttggca gtggcacaaa gctcgagatt aagcgcactg ttgccgcacc cagcgtgttt 360
atctttccac ctagcgacga acagcttaag tctggtactg ctagtgtggt gtgtttgttg 420
aataacttct acccccgtga agccaaggtt cagtggaaag tggataacgc tctccagagc 480
gggaacagtc aggagtctgt taccgaacag gactcaaagg acagcactta cagcctgagc 540
agtactctga ccctgagtaa ggccgattat gaaaagcaca aggtgtacgc ctgtgaggtg 600
acccaccagg gtctgtcatc ccctgtcacc aagtctttta atcggggtga atgc 654
<210> 124
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> 135
<400> 124
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser
20 25
<210> 125
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 138
<400> 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 126
<211> 26
<212> PRT
<213> Artificial Sequence
<220>
<223> 139
<400> 126
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser
20 25
<210> 127
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 142
<400> 127
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 128
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 143
<400> 128
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Asp Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Leu Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly His Ile Tyr Pro Gly Gly Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Arg Ser Gly Asn Asp Ala Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 129
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 144
<400> 129
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Asp Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Leu Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly His Ile Tyr Pro Gly Gly Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Val Arg Ser Gly Asn Asp Ala Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 130
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 145
<400> 130
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Asp Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Leu Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly His Ile Tyr Pro Gly Gly Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Val Arg Ser Gly Asn Asp Ala Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 131
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 146
<400> 131
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Asp Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Leu Gly Trp Val Arg Gln Ala Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly His Ile Tyr Pro Gly Gly Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Val Arg Ser Gly Asn Asp Ala Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 132
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 147
<400> 132
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Glu Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ser Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 133
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 148
<400> 133
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Glu Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ser Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 134
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 149
<400> 134
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Glu Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ser Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 135
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 150
<400> 135
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Glu Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ser Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Met Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 136
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> 151
<400> 136
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Asp Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Leu Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly His Ile Tyr Pro Gly Gly Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Arg Ser Gly Asn Asp Ala Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 137
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> 152
<400> 137
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Asp Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Leu Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly His Ile Tyr Pro Gly Gly Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Val Arg Ser Gly Asn Asp Ala Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 138
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> 153
<400> 138
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Asp Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Leu Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly His Ile Tyr Pro Gly Gly Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Val Arg Ser Gly Asn Asp Ala Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 139
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> 154
<400> 139
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Asp Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Leu Gly Trp Val Arg Gln Ala Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly His Ile Tyr Pro Gly Gly Gly Tyr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Val Arg Ser Gly Asn Asp Ala Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 140
<211> 218
<212> PRT
<213> Artificial Sequence
<220>
<223> 155
<400> 140
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Glu Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ser Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 141
<211> 218
<212> PRT
<213> Artificial Sequence
<220>
<223> 156
<400> 141
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Glu Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ser Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 142
<211> 218
<212> PRT
<213> Artificial Sequence
<220>
<223> 157
<400> 142
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Glu Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ser Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 143
<211> 218
<212> PRT
<213> Artificial Sequence
<220>
<223> 158
<400> 143
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Glu Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ser Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Met Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 144
<211> 1353
<212> DNA
<213> Artificial Sequence
<220>
<223> 159
<400> 144
caagtgcagc tggttcagag cggagctgag gtgaagaagc ctggagctag cgtgaaggtg 60
tcttgtaaag ccagcgacta cacctttacc aattactggc tgggctgggt cagacaggcc 120
cctggccagg gcctggaatg gatgggccac atctaccccg gcggaggcta cacaaactac 180
aacgagaagt tcaagggcag agtgacaatg accagagata caagcaccag cacagtgtat 240
atggaactgt ctagcctgcg gagcgaggac accgccgtgt actactgcgc cagagtgcgg 300
tccggcaacg acgccctgga tttctggggc cagggcaccc tggtgaccgt gtccagcgcc 360
agcaccaagg gcccttccgt gtttccactg gccccctcct ctaaatccac atctggcggc 420
accgccgccc tgggctgtct ggtgaaggac tacttcccag agcctgtgac agtgtcctgg 480
aactctggcg ccctgacatc cggcgtgcac acatttccag ccgtgctgca gagctccggc 540
ctgtacagcc tgtctagcgt ggtgacagtg ccctcctcta gcctgggcac acagacctat 600
atctgcaacg tgaatcacaa gccaagcaat accaaggtgg acaagaaggt ggagcccaag 660
tcctgtgata agacacacac ctgcccccct tgtcctgctc ccgagctgct gggcggccct 720
agcgtgttcc tgtttccacc caagcctaag gacaccctga tgatctcccg gacacccgag 780
gtgacctgcg tggtggtgga cgtgtctcac gaggatcctg aggtgaagtt caactggtat 840
gtggatggcg tggaggtgca caatgccaag accaagccca gagaggagca gtacaactct 900
acatataggg tggtgagcgt gctgaccgtg ctgcaccagg actggctgaa cggcaaggag 960
tataagtgca aggtgtccaa taaggccctg cccgccccca tcgagaagac aatcagcaag 1020
gccaagggcc agcctcggga gccacaggtg tacaccctgc ctccatccag agacgagctg 1080
acaaagaacc aggtgtctct gacatgtctg gtgaagggct tctatcctag cgatatcgcc 1140
gtggagtggg agtccaatgg ccagccagag aacaattaca agaccacacc ccctgtgctg 1200
gactccgatg gctccttctt tctgtattcc aagctgaccg tggataagtc tcggtggcag 1260
cagggcaacg tgttcagctg ttccgtgatg cacgaagccc tgcataatca ctatactcag 1320
aaatccctgt ccctgtcacc tggaaagtga taa 1353
<210> 145
<211> 1353
<212> DNA
<213> Artificial Sequence
<220>
<223> 160
<400> 145
caagtgcagc tggtccagag cggcgccgag gtgaaaaagc ctggagctag cgtgaaggtg 60
tcctgcaagg ccagcgacta caccttcacc aactattggc tgggctgggt gcggcaggcc 120
cctggacagg gcctggaatg gatcggccac atctaccccg gaggcggcta caccaattac 180
aacgagaagt tcaagggcag agtgaccatg accgccgata caagcacatc tacagtgtac 240
atggaactga gcagcctgag aagcgaggat acagctgttt acttctgtgc cagagtgcgg 300
tccggcaacg acgccctgga cttttggggc cagggcaccc tggtgaccgt gtctagcgcc 360
agcaccaagg gcccttccgt gtttccactg gccccctcct ctaaatccac atctggcggc 420
accgccgccc tgggctgtct ggtgaaggac tacttcccag agcctgtgac agtgtcctgg 480
aactctggcg ccctgacatc cggcgtgcac acatttccag ccgtgctgca gagctccggc 540
ctgtacagcc tgtctagcgt ggtgacagtg ccctcctcta gcctgggcac acagacctat 600
atctgcaacg tgaatcacaa gccaagcaat accaaggtgg acaagaaggt ggagcccaag 660
tcctgtgata agacacacac ctgcccccct tgtcctgctc ccgagctgct gggcggccct 720
agcgtgttcc tgtttccacc caagcctaag gacaccctga tgatctcccg gacacccgag 780
gtgacctgcg tggtggtgga cgtgtctcac gaggatcctg aggtgaagtt caactggtat 840
gtggatggcg tggaggtgca caatgccaag accaagccca gagaggagca gtacaactct 900
acatataggg tggtgagcgt gctgaccgtg ctgcaccagg actggctgaa cggcaaggag 960
tataagtgca aggtgtccaa taaggccctg cccgccccca tcgagaagac aatcagcaag 1020
gccaagggcc agcctcggga gccacaggtg tacaccctgc ctccatccag agacgagctg 1080
acaaagaacc aggtgtctct gacatgtctg gtgaagggct tctatcctag cgatatcgcc 1140
gtggagtggg agtccaatgg ccagccagag aacaattaca agaccacacc ccctgtgctg 1200
gactccgatg gctccttctt tctgtattcc aagctgaccg tggataagtc tcggtggcag 1260
cagggcaacg tgttcagctg ttccgtgatg cacgaagccc tgcataatca ctatactcag 1320
aaatccctgt ccctgtcacc tggaaagtga taa 1353
<210> 146
<211> 1353
<212> DNA
<213> Artificial Sequence
<220>
<223> 161
<400> 146
caagtgcagc tggtccagag cggcgccgag gtgaaaaagc ctggcgcttc tgtgaaggtg 60
tcctgcaagg ccagcgacta cacatttacc aattattggc tgggctgggt gcggcaggcc 120
cctggacagg gcctggaatg gatcggccac atctaccccg gcggaggcta cacaaactac 180
aacgagaagt tcaagggcag agccacactc accgctgata ccagcacaag caccgtgtac 240
atggaactga gcagcctgag aagcgaggac accgccgtgt acttctgtgc cagagtgcgg 300
tccggcaacg acgccctgga tttctgggga cagggcaccc tggtgaccgt gtctagcgcc 360
agcaccaagg gcccttccgt gtttccactg gccccctcct ctaaatccac atctggcggc 420
accgccgccc tgggctgtct ggtgaaggac tacttcccag agcctgtgac agtgtcctgg 480
aactctggcg ccctgacatc cggcgtgcac acatttccag ccgtgctgca gagctccggc 540
ctgtacagcc tgtctagcgt ggtgacagtg ccctcctcta gcctgggcac acagacctat 600
atctgcaacg tgaatcacaa gccaagcaat accaaggtgg acaagaaggt ggagcccaag 660
tcctgtgata agacacacac ctgcccccct tgtcctgctc ccgagctgct gggcggccct 720
agcgtgttcc tgtttccacc caagcctaag gacaccctga tgatctcccg gacacccgag 780
gtgacctgcg tggtggtgga cgtgtctcac gaggatcctg aggtgaagtt caactggtat 840
gtggatggcg tggaggtgca caatgccaag accaagccca gagaggagca gtacaactct 900
acatataggg tggtgagcgt gctgaccgtg ctgcaccagg actggctgaa cggcaaggag 960
tataagtgca aggtgtccaa taaggccctg cccgccccca tcgagaagac aatcagcaag 1020
gccaagggcc agcctcggga gccacaggtg tacaccctgc ctccatccag agacgagctg 1080
acaaagaacc aggtgtctct gacatgtctg gtgaagggct tctatcctag cgatatcgcc 1140
gtggagtggg agtccaatgg ccagccagag aacaattaca agaccacacc ccctgtgctg 1200
gactccgatg gctccttctt tctgtattcc aagctgaccg tggataagtc tcggtggcag 1260
cagggcaacg tgttcagctg ttccgtgatg cacgaagccc tgcataatca ctatactcag 1320
aaatccctgt ccctgtcacc tggaaagtga taa 1353
<210> 147
<211> 1353
<212> DNA
<213> Artificial Sequence
<220>
<223> 162
<400> 147
caagtgcagc tggttcagag cggcgccgag gtgaagaagc ctggcgctag cgtgaaggtg 60
tcttgtaaag ccagcgacta cacatttacc aattactggc tgggatgggt ccggcaggcc 120
cctggccacg gcctggaatg gatcggccac atctaccccg gcggaggata tacaaactac 180
aacgagaagt tcaagggcag agccaccctg accgctgata catctacaag caccgtgtac 240
atggaactga gcagcctgag aagcgaggat accgccgtgt acttctgcgc cagagtgcgg 300
tccggcaacg acgccctgga cttctggggc cagggcaccc tggtgaccgt gtccagcgcc 360
agcaccaagg gcccttccgt gtttccactg gccccctcct ctaaatccac atctggcggc 420
accgccgccc tgggctgtct ggtgaaggac tacttcccag agcctgtgac agtgtcctgg 480
aactctggcg ccctgacatc cggcgtgcac acatttccag ccgtgctgca gagctccggc 540
ctgtacagcc tgtctagcgt ggtgacagtg ccctcctcta gcctgggcac acagacctat 600
atctgcaacg tgaatcacaa gccaagcaat accaaggtgg acaagaaggt ggagcccaag 660
tcctgtgata agacacacac ctgcccccct tgtcctgctc ccgagctgct gggcggccct 720
agcgtgttcc tgtttccacc caagcctaag gacaccctga tgatctcccg gacacccgag 780
gtgacctgcg tggtggtgga cgtgtctcac gaggatcctg aggtgaagtt caactggtat 840
gtggatggcg tggaggtgca caatgccaag accaagccca gagaggagca gtacaactct 900
acatataggg tggtgagcgt gctgaccgtg ctgcaccagg actggctgaa cggcaaggag 960
tataagtgca aggtgtccaa taaggccctg cccgccccca tcgagaagac aatcagcaag 1020
gccaagggcc agcctcggga gccacaggtg tacaccctgc ctccatccag agacgagctg 1080
acaaagaacc aggtgtctct gacatgtctg gtgaagggct tctatcctag cgatatcgcc 1140
gtggagtggg agtccaatgg ccagccagag aacaattaca agaccacacc ccctgtgctg 1200
gactccgatg gctccttctt tctgtattcc aagctgaccg tggataagtc tcggtggcag 1260
cagggcaacg tgttcagctg ttccgtgatg cacgaagccc tgcataatca ctatactcag 1320
aaatccctgt ccctgtcacc tggaaagtga taa 1353
<210> 148
<211> 660
<212> DNA
<213> Artificial Sequence
<220>
<223> 163
<400> 148
gagatcgtgc tgacacagag ccctgctaca ctctccctgt ccccaggcga gcgggccaca 60
ctgtcttgta gagccagcga gagcgtcgac gagtacggca ttagcttcat gaactggtat 120
cagcagaaac ctggccaggc ccctagactg ctgatctaca gcgcctccaa ccagggcagc 180
ggcatccccg ctagattcag cggcagcgga tctggcaccg acttcaccct gaccatcagc 240
agcctggaac ccgaggattt tgccgtgtac tactgccagc aatctaagga agtgccttgg 300
accttcggcg gaggcaccaa gctggaaatc aagaggacag tggccgcccc aagcgtgttc 360
atctttcccc cttccgacga gcagctgaag tctggcaccg ccagcgtggt gtgcctgctg 420
aacaacttct accctcggga ggccaaggtc cagtggaagg tggataacgc cctgcagtct 480
ggcaatagcc aggagtccgt gaccgagcag gactctaagg atagcacata ttccctgtct 540
agcaccctga cactgagcaa ggccgattac gagaagcaca aggtgtatgc ctgtgaagtc 600
acccatcagg ggctgtcatc acccgtcact aagtcattca atcgcggaga atgctgataa 660
<210> 149
<211> 660
<212> DNA
<213> Artificial Sequence
<220>
<223> 164
<400> 149
gagatcgtgc tgacccagag ccccgccacc ctgtccctga gccctggcga gcgggctaca 60
ctgtcttgta gagccagcga gagcgtcgac gagtacggca tctcttttat gaactggtat 120
cagcagaaac ctggacaggc ccctagactg ctgatctaca gcgcctccaa ccagggcagc 180
ggcattcctg ctagattcag cggcagcggc tccggcacag atttcaccct caccatcagc 240
agcctggaac ccgaggactt cgccgtgtac ttctgccagc aatctaagga agtgccatgg 300
acattcggcg gaggcaccaa gctggaaatc aagaggacag tggccgcccc aagcgtgttc 360
atctttcccc cttccgacga gcagctgaag tctggcaccg ccagcgtggt gtgcctgctg 420
aacaacttct accctcggga ggccaaggtc cagtggaagg tggataacgc cctgcagtct 480
ggcaatagcc aggagtccgt gaccgagcag gactctaagg atagcacata ttccctgtct 540
agcaccctga cactgagcaa ggccgattac gagaagcaca aggtgtatgc ctgtgaagtc 600
acccatcagg ggctgtcatc acccgtcact aagtcattca atcgcggaga atgctgataa 660
<210> 150
<211> 660
<212> DNA
<213> Artificial Sequence
<220>
<223> 165
<400> 150
gagatcgtgc tgacccagtc tccagccacc ctctccctga gccccggcga gcgggccaca 60
ctgtcttgta gagctagcga gagcgtcgac gagtacggca tctccttcat gaactggttc 120
cagcagaaac ctggccaggc ccctagactg ctgatctaca gcgccagcaa ccagggctcc 180
ggaattcctg ctagattcag cggctctggc agcggcacag attttaccct gacaatcagc 240
agcctggaac ccgaggactt tgccgtgtac ttctgccagc aaagcaagga agtgccttgg 300
accttcggcg gaggcaccaa gctggaaatc aagaggacag tggccgcccc aagcgtgttc 360
atctttcccc cttccgacga gcagctgaag tctggcaccg ccagcgtggt gtgcctgctg 420
aacaacttct accctcggga ggccaaggtc cagtggaagg tggataacgc cctgcagtct 480
ggcaatagcc aggagtccgt gaccgagcag gactctaagg atagcacata ttccctgtct 540
agcaccctga cactgagcaa ggccgattac gagaagcaca aggtgtatgc ctgtgaagtc 600
acccatcagg ggctgtcatc acccgtcact aagtcattca atcgcggaga atgctgataa 660
<210> 151
<211> 660
<212> DNA
<213> Artificial Sequence
<220>
<223> 166
<400> 151
gagatcgtgc tgacacagag ccctgctaca ctctccctga gccccggcga gcgggccacc 60
ctgtcttgta gagccagcga gagcgtggac gagtacggca ttagcttcat gaactggttt 120
cagcagaaac ctggccaggc ccctagactg ctgatctaca gcgcctccaa ccagggctct 180
ggcatccccg ctagattcag cggatctggc tccggcaccg acttcaccct gaccatcagc 240
agcctggaac cagaggattt tgccatgtac ttctgccagc aaagcaagga agtgccttgg 300
accttcggcg gaggcacaaa gctggaaatc aagaggacag tggccgcccc aagcgtgttc 360
atctttcccc cttccgacga gcagctgaag tctggcaccg ccagcgtggt gtgcctgctg 420
aacaacttct accctcggga ggccaaggtc cagtggaagg tggataacgc cctgcagtct 480
ggcaatagcc aggagtccgt gaccgagcag gactctaagg atagcacata ttccctgtct 540
agcaccctga cactgagcaa ggccgattac gagaagcaca aggtgtatgc ctgtgaagtc 600
acccatcagg ggctgtcatc acccgtcact aagtcattca atcgcggaga atgctgataa 660

Claims (28)

1.一种能够特异性识别IL-11的抗体或其抗原结合片段，其特征在于，所述抗体含有选自下列至少之一的CDR序列或与其具有至少95％同一性的氨基酸序列：
重链可变区CDR序列：SEQ ID NO:1～33，
轻链可变区CDR序列：SEQ IN NO:34～66。
2.根据权利要求1所述的抗体或其抗原结合片段，其特征在于，所述抗体包括：
分别如SEQ ID NO:1、2和3或者与SEQ ID NO:1、2和3具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:4、5和6或者与SEQ ID NO:4、5和6具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:7、8和9或者与SEQ ID NO:7、8和9具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:10、11和12或者与SEQ ID NO:10、11和12具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:13、14和15或者与SEQ ID NO:13、14和15具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:16、17和18或者与SEQ ID NO:16、17和18具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO19、20和21或者与SEQ ID NO:19、20和21具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:22、23和24或者与SEQ ID NO:22、23和24具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:25、26和27或者与SEQ ID NO:25、26和27具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:28、29和30或者与SEQ ID NO:28、29和30具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:31、32和33或者与SEQ ID NO:31、32和33具有至少95％同一性的氨基酸序列所示的重链可变区CDR1、CDR2、CDR3序列。
3.根据权利要求1所述的抗体或其抗原结合片段，其特征在于，所述抗体包括：
分别如SEQ ID NO:34、35和36或者与SEQ ID NO:34、35和36具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:37、38和39或者与SEQ ID NO:37、38和39具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:40、41和42或者与SEQ ID NO:40、41和42具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:43、44和45或者与SEQ ID NO:43、44和45具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:46、47和48或者与SEQ ID NO:46、47和48具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:49、50和51或者与SEQ ID NO:49、50和51具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:52、53和54或者与SEQ ID NO:52、53和54具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:55、56和57或者与SEQ ID NO:55、56和57具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:58、59和60或者与SEQ ID NO:58、59和60具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列；或者
分别如SEQ ID NO:61、62和63或者与SEQ ID NO:61、62和63具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列。
分别如SEQ ID NO:64、65和66或者与SEQ ID NO:64、65和66具有至少95％同一性的氨基酸序列所示的轻链可变区CDR1、CDR2、CDR3序列。
4.根据权利要求1所述的抗体或其抗原结合片段，其特征在于，所述抗体含有重链框架区序列和轻链框架区序列的至少之一，所述重链框架区序列和轻链框架区序列的至少之一的至少一部分来自于鼠源抗体、人源抗体、灵长目源抗体或其突变体的至少之一。
5.根据权利要求1所述的抗体或其抗原结合片段，其特征在于，所述抗体具有如SEQ IDNO：67～77任一项所示氨基酸序列的重链可变区。
6.根据权利要求1所述的抗体或其抗原结合片段，其特征在于，所述抗体具有如SEQ IDNO：78～88任一项所示氨基酸序列的轻链可变区。
7.根据权利要求1所述的抗体或其抗原结合片段，其特征在于，所述抗体含有重链恒定区和轻链恒定区的至少之一，所述重链恒定区和轻链恒定区的至少之一的至少一部分来自于鼠源抗体、人源抗体、灵长目源抗体或其突变体的至少之一。
8.根据权利要求1所述的抗体或其抗原结合片段，其特征在于，所述抗体的轻链恒定区和重链恒定区均来自于人源IgG抗体或其突变体。
9.根据权利要求1所述的抗体或其抗原结合片段，其特征在于，所述抗体的轻链恒定区来自于人源的Kappa轻链恒定区；重链恒定区来自于人源IgG1的重链恒定区。
10.根据权利要求7所述的抗体或其抗原结合片段，其特征在于，所述抗体恒定区的全长序列如SEQ ID NO:89或90所示。
11.根据权利要求10所述的抗体或其抗原结合片段，其特征在于，所述抗体具有SEQ IDNO:91～101任一项所示氨基酸序列的重链和具有SEQ ID NO:102～112任一项所示氨基酸序列的轻链。
12.根据权利要求1所述的抗体或其抗原结合片段，其特征在于，所述抗体为单链抗体、多聚体抗体、CDR移植抗体或小分子抗体。
13.根据权利要求12所述的抗体或其抗原结合片段，其特征在于，所述单链抗体包括SEQ ID NO:67-77任一项所示氨基酸序列的重链可变区和SEQ ID NO:78-88任一项所示氨基酸序列的轻链可变区，其中所述重链可变区的C端通过连接肽linker与所述轻链可变区的N端相连，或所述轻链可变区的C端通过连接肽linker与所述重链可变区的N端相连。
14.根据权利要求12所述的抗体或其抗原结合片段，其特征在于，所述小分子抗体包括Fab抗体、Fv抗体、单域抗体以及最小识别单位的至少之一。
15.一种核酸分子，其特征在于，所述核酸分子编码权利要求1～14任一项所述的抗体或其抗原结合片段。
16.根据权利要求15所述的核酸分子，其特征在于，所述核酸分子为DNA。
17.根据权利要求16所述的核酸分子，其特征在于，所述核酸分子具有如SEQ ID NO:113～123任一项所示核苷酸序列或具有SEQ ID NO:124～134任一项所示核苷酸序列。
18.一种表达载体，其特征在于，携带权利要求15～17任一项所述的核酸分子。
19.根据权利要求18所述的表达载体，其特征在于，所述表达载体为真核表达载体。
20.一种重组细胞，其特征在于，所述重组细胞携带权利要求15～17任一项所述的核酸分子，或者表达权利要求1～14任一项所述的抗体或其抗原结合片段。
21.根据权利要求20所述的重组细胞，其特征在于，所述重组细胞是通过将权利要求18或19所述的表达载体引入至宿主细胞中而获得的。
22.根据权利要求21所述的重组细胞，其特征在于，通过电转导的方法将所述表达载体引入所述宿主细胞中。
23.根据权利要求20所述的重组细胞，其特征在于，所述重组细胞为真核细胞。
24.根据权利要求20所述的重组细胞，其特征在于，所述重组细胞为哺乳动物细胞。
25.一种药物组合物，其特征在于，含有权利要求1～14任一项所述的抗体，权利要求15～17任一项所述的核酸分子，权利要求18～19任一项所述的表达载体或权利要求20～24任一项所述的重组细胞。
26.权利要求1～14任一项所述的抗体、权利要求15～17任一项所述的核酸分子、权利要求18～19任一项所述的表达载体或权利要求20～24任一项所述的重组细胞、权利要求25所述的药物组合物在制备药物中的用途，所述药物用于治疗或者预防肺纤维化,非酒精性脂肪肝炎，慢性心力衰竭或由成纤维细胞向纤维化转化所导致的疾病。
27.一种检测IL-11的试剂盒，其特征在于，包括权利要求利要求1～14任一项所述的抗体。
28.权利要求1～14任一项所述的抗体、权利要求15～17任一项所述的核酸分子、权利要求18～19任一项所述的表达载体或权利要求20～24任一项所述的重组细胞在制备试剂盒中的用途，所述试剂盒用于检测IL-11或者诊断IL-11相关的疾病。
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110382531A (zh) * 2016-12-16 2019-10-25 新加坡保健服务集团有限公司 Il-11抗体
WO2023016505A1 (zh) * 2021-08-12 2023-02-16 广东东阳光药业有限公司 Il-11人源化抗体及其应用
WO2023143590A1 (zh) * 2022-01-29 2023-08-03 迈威(上海)生物科技股份有限公司 采用抗il-11抗体的肿瘤组合疗法
WO2024146458A1 (zh) * 2023-01-06 2024-07-11 广东东阳光药业股份有限公司 抗il-11细胞因子人源化抗体

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110382531A (zh) * 2016-12-16 2019-10-25 新加坡保健服务集团有限公司 Il-11抗体
US20200031918A1 (en) * 2018-06-13 2020-01-30 Singapore Health Services Pte. Ltd. Il-11 antibodies

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2775402A1 (en) * 2009-10-15 2011-04-21 Abbott Laboratories Il-1 binding proteins
WO2012088094A2 (en) * 2010-12-21 2012-06-28 Abbott Laboratories Il-1 binding proteins
CN105497893B (zh) * 2015-12-10 2019-02-01 黑龙江省科学院高技术研究院 IL-11单克隆抗体在抑制PI3K/Akt信号通路中的应用
GB201522186D0 (en) * 2015-12-16 2016-01-27 Singapore Health Services Pte Ltd And Nat University Of Singapore The Treatment of fibrosis
GB201806918D0 (en) * 2018-04-27 2018-06-13 Enleofen Bio Pte Ltd Combination treatment for eye fibrosis
CA3126322A1 (en) * 2019-01-21 2020-07-30 Singapore Health Services Pte. Ltd. Treatment of hepatotoxicity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110382531A (zh) * 2016-12-16 2019-10-25 新加坡保健服务集团有限公司 Il-11抗体
US20200031918A1 (en) * 2018-06-13 2020-01-30 Singapore Health Services Pte. Ltd. Il-11 antibodies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
梁宇明等: "IL-11在心血管系统中的双向作用研究进展", 《山东医药》 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110382531A (zh) * 2016-12-16 2019-10-25 新加坡保健服务集团有限公司 Il-11抗体
CN110382531B (zh) * 2016-12-16 2023-10-17 新加坡保健服务集团有限公司 Il-11抗体
WO2023016505A1 (zh) * 2021-08-12 2023-02-16 广东东阳光药业有限公司 Il-11人源化抗体及其应用
WO2023143590A1 (zh) * 2022-01-29 2023-08-03 迈威(上海)生物科技股份有限公司 采用抗il-11抗体的肿瘤组合疗法
WO2024146458A1 (zh) * 2023-01-06 2024-07-11 广东东阳光药业股份有限公司 抗il-11细胞因子人源化抗体

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