CN112513091A - 抗il36r抗体 - Google Patents
抗il36r抗体 Download PDFInfo
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- CN112513091A CN112513091A CN201980050334.0A CN201980050334A CN112513091A CN 112513091 A CN112513091 A CN 112513091A CN 201980050334 A CN201980050334 A CN 201980050334A CN 112513091 A CN112513091 A CN 112513091A
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Abstract
本发明提供与人类IL‑36受体特异性结合的抗体和抗原结合片段(例如人类抗体)。还提供了使用所述抗体和片段治疗或预防由IL36R介导的疾病(例如皮肤或结肠发炎性病况,例如掌跖脓疱型牛皮癣、掌跖脓疱病、泛发性脓疱型牛皮癣、溃疡性结肠炎或IBD)的方法以及制备所述抗体和片段的方法。
Description
相关申请的交叉引用
本申请主张2018年7月16日提交的美国临时专利申请第62/698,482号、2019年5月13日提交的美国临时专利申请第62/846,989号和2019年6月25日提交的美国临时专利申请第62/866,028号的利益,所述申请中的每一个以全文引用的方式并入本文中。
技术领域
本发明领域部分地涉及与IL-36受体结合的抗体和这类抗体治疗包括牛皮癣(psoriasis)或发炎性肠病的发炎性病症的用途。
以引用的方式并入的序列表
序列表以引用的方式并入本文中,其呈ASCII文本文档形式,名为36432_10484US01_SequenceListing,大小为176KB,创建于2019年7月15日并且通过EFS-Web提交给美国专利和商标局(United States Patent and Trademark Office)。
背景技术
白细胞介素(IL)-36细胞因子包括3种激动剂,即IL-36α、IL-36β和IL-36γ,其与由IL-36R和IL-1RAcP构成的共同受体结合以刺激炎症反应。IL-36受体(IL-36R)为细胞因子IL-36α、IL-36β和IL-36γ的IL-1家族的子集的单向通过的膜受体,并且在与这些配位体中的任一者结合时,募集其共受体,即IL-1R辅助蛋白(IL-1RAcP),其诱导涉及NFκB和丝裂原激活激酶路径的信号级联(Sims等人,2010)。
一些发炎性皮肤病况(例如牛皮癣)的介体为IL-36。牛皮癣是常见的免疫介导的发炎性皮肤病,其包括变体斑块状牛皮癣和泛发性脓疱型牛皮癣。标准治疗性指南包括使用局部类固醇、局部维生素D、全身性免疫抑制剂和各种生物制剂,例如抗肿瘤坏死因子(TNF)α、抗白细胞介素(IL)-23和抗IL-17抗体。IL-36成员在斑块状牛皮癣的病变性皮肤中过度表达,并且激活IL-36R可与TNF-α/IL-23/IL-17/IL-22轴一起造成牛皮癣炎症的持久性和持续性。(Di Cesare等人,《牛皮癣免疫发病机理中的IL-23/Th17轴(The IL-23/Th17axis in the immunopathogenesis of psoriasis)》,《皮肤病学研究杂志(Journal ofInvestigative Dermatology)》129:1339-1350(2009)和Blumberg等人,《IL-1RL2和其配位体在牛皮癣中促成细胞因子网络(IL-1RL2 and its ligands contribute to thecytokine network in psoriasis)》.《免疫学杂志(J Immunol)》185:4354-4362(2010))。
然而,掌跖脓疱病(PPP)和掌跖脓疱型牛皮癣(PPPP)的当前可用治疗是有限的。佩索利单抗(spesolimab)和ANB019为临床发展中的抗IL36R抗体,其具有与免疫原性和效能相关的缺点。
发明内容
本发明提供呈现优异特性的抗IL36R抗体和其抗原结合片段。举例来说,我们观察到,在药代动力学研究中,在每组三只猕猴(cynomolgous monkey)(0.5和5mg/kg皮下剂量组;n=3只/组)中,本文中所阐述的抗IL36R抗体(例如H4H14708P2)呈现出比抗IL36R抗体APE6155高约1.2倍的暴露。此外,我们还观察到,APE6155呈现出比本文中所阐述的抗IL36R抗体更低的效能,例如在IMQ诱导的皮肤炎症中降低皮肤厚度和病理评分方面和在皮肤中减少促炎性细胞因子方面。佩索利单抗是人类化抗IL36R抗体,在患有GPP的人类个体中呈现出高含量的抗药物抗体。在1期临床试验中,在单次剂量之后,3/7的患者在第2周具有抗药物抗体,并且这些持续到第20周。佩索利单抗的这一特性对于慢性长期治疗将是不理想的。Amin,《自竞争对手抗IL36的GPP中的第一数据提供ANB019的概念验证(First Data inGPP from Competitor Anti-IL36 Provides Proof of Concept of ANB019)》,便笺(Flash Note),公司更新(Company Update),AnaptysBio,杰弗里斯(Jefferies)(2018年9月16日)。本发明的人类抗IL36R抗体并不预期在人类中具有高免疫原性。
本发明提供抗原结合蛋白(例如,抗体或其抗原结合片段,例如人类抗体或其抗原结合片段或多特异性抗体),其(i)与IL36R上与参考抗原结合蛋白相同的表位特异性结合;或(ii)与参考抗原结合蛋白竞争结合IL36R多肽,其中参考抗原结合蛋白包含:(a)重链免疫球蛋白,其包含有包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列的重链免疫球蛋白的CDR-H1、CDR-H2和CDR-H3;和/或(b)轻链免疫球蛋白,其包含有包含SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列的轻链免疫球蛋白的CDR-L1、CDR-L2和CDR-L3。举例来说,在本发明的一个实施例中,抗原结合蛋白包含:(i)重链免疫球蛋白,其包含有包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列的重链免疫球蛋白的CDR-H1、CDR-H2和CDR-H3;和/或(ii)轻链免疫球蛋白,其包含有包含SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列的轻链免疫球蛋白的CDR-L1、CDR-L2和CDR-L3。在本发明的一个实施例中,抗原结合蛋白包含(a)重链免疫球蛋白可变区,其包含与SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列具有至少90%的氨基酸序列一致性的氨基酸序列;和/或(b)轻链免疫球蛋白可变区,其包含与SEQID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列具有至少90%的氨基酸序列一致性的氨基酸序列。举例来说,在本发明的一个实施例中,抗原结合蛋白包含:(a)重链免疫球蛋白,其包含有包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列的重链免疫球蛋白的CDR-H1、CDR-H2和CDR-H3和与SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列至少90%的氨基酸序列一致性;和/或(b)轻链免疫球蛋白,其包含有包含SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列的轻链免疫球蛋白的CDR-L1、CDR-L2和CDR-L3和与SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列至少90%的氨基酸序列一致性。在本发明的一个实施例中,抗原结合蛋白包含:重链免疫球蛋白,其包含:包含SEQ ID NO:4中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:6中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:8中所阐述的氨基酸序列的CDR-H3和/或包含SEQ ID NO:20中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:22中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:24中所阐述的氨基酸序列的CDR-H3和/或包含SEQ IDNO:36中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:38中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:40中所阐述的氨基酸序列的CDR-H3和/或包含SEQ ID NO:52中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:54中所阐述的氨基酸序列的CDR-H2;和包含SEQID NO:56中所阐述的氨基酸序列的CDR-H3和/或包含SEQ ID NO:68中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:70中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:72中所阐述的氨基酸序列的CDR-H3和/或包含SEQ ID NO:84中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:86中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:88中所阐述的氨基酸序列的CDR-H3和/或包含SEQ ID NO:100中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:102中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:104中所阐述的氨基酸序列的CDR-H3和/或包含SEQ ID NO:116中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:118中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:120中所阐述的氨基酸序列的CDR-H3和/或包含SEQ ID NO:132中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:134中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:136中所阐述的氨基酸序列的CDR-H3和/或包含SEQ IDNO:140中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:142中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:144中所阐述的氨基酸序列的CDR-H3和/或包含SEQ ID NO:156中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:158中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:160中所阐述的氨基酸序列的CDR-H3和/或包含SEQ ID NO:172中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:174中所阐述的氨基酸序列的CDR-H2;和包含SEQ IDNO:176中所阐述的氨基酸序列的CDR-H3和/或包含SEQ ID NO:12中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:14中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:16中所阐述的氨基酸序列的CDR-L3和/或包含SEQ ID NO:28中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:30中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:32中所阐述的氨基酸序列的CDR-L3和/或包含SEQ ID NO:44中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:46中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:48中所阐述的氨基酸序列的CDR-L3和/或包含SEQ ID NO:60中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:62中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:64中所阐述的氨基酸序列的CDR-L3和/或包含SEQID NO:76中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:78中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:80中所阐述的氨基酸序列的CDR-L3和/或包含SEQ ID NO:92中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:94中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:96中所阐述的氨基酸序列的CDR-L3和/或包含SEQ ID NO:108中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:110中所阐述的氨基酸序列的CDR-L2;和包含SEQ IDNO:112中所阐述的氨基酸序列的CDR-L3和/或包含SEQ ID NO:124中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:126中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:128中所阐述的氨基酸序列的CDR-L3和/或包含SEQ ID NO:124中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:126中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:128中所阐述的氨基酸序列的CDR-L3和/或包含SEQ ID NO:148中所阐述的氨基酸序列的CDR-L1;包含SEQ IDNO:150中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:152中所阐述的氨基酸序列的CDR-L3和/或包含SEQ ID NO:164中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:166中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:168中所阐述的氨基酸序列的CDR-L3和/或包含SEQ ID NO:124中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:126中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:128中所阐述的氨基酸序列的CDR-L3。在本发明的一个实施例中,抗原结合蛋白包含:(1)重链免疫球蛋白可变区,其包含:包含SEQ ID NO:4中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:6中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:8中所阐述的氨基酸序列的CDR-H3;和轻链免疫球蛋白可变区,其包含:包含SEQID NO:12中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:14中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:16中所阐述的氨基酸序列的CDR-L3;(2)重链免疫球蛋白可变区,其包含:包含SEQ ID NO:20中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:22中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:24中所阐述的氨基酸序列的CDR-H3;和轻链免疫球蛋白可变区,其包含:包含SEQ ID NO:28中所阐述的氨基酸序列的CDR-L1;包含SEQID NO:30中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:32中所阐述的氨基酸序列的CDR-L3;(3)重链免疫球蛋白可变区,其包含:包含SEQ ID NO:36中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:38中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:40中所阐述的氨基酸序列的CDR-H3;和轻链免疫球蛋白可变区,其包含:包含SEQ ID NO:44中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:46中所阐述的氨基酸序列的CDR-L2;和包含SEQID NO:48中所阐述的氨基酸序列的CDR-L3;(4)重链免疫球蛋白可变区,其包含:包含SEQID NO:52中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:54中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:56中所阐述的氨基酸序列的CDR-H3;和轻链免疫球蛋白可变区,其包含:包含SEQ ID NO:60中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:62中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:64中所阐述的氨基酸序列的CDR-L3;(5)重链免疫球蛋白可变区,其包含:包含SEQ ID NO:68中所阐述的氨基酸序列的CDR-H1;包含SEQ IDNO:70中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:72中所阐述的氨基酸序列的CDR-H3;和轻链免疫球蛋白可变区,其包含:包含SEQ ID NO:76中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:78中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:80中所阐述的氨基酸序列的CDR-L3;(6)重链免疫球蛋白可变区,其包含:包含SEQ ID NO:84中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:86中所阐述的氨基酸序列的CDR-H2;和包含SEQID NO:88中所阐述的氨基酸序列的CDR-H3;和轻链免疫球蛋白可变区,其包含:包含SEQ IDNO:92中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:94中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:96中所阐述的氨基酸序列的CDR-L3;(7)重链免疫球蛋白可变区,其包含:包含SEQ ID NO:100中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:102中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:104中所阐述的氨基酸序列的CDR-H3;和轻链免疫球蛋白可变区,其包含:包含SEQ ID NO:108中所阐述的氨基酸序列的CDR-L1;包含SEQID NO:110中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:112中所阐述的氨基酸序列的CDR-L3;(8)重链免疫球蛋白可变区,其包含:包含SEQ ID NO:116中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:118中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:120中所阐述的氨基酸序列的CDR-H3;和轻链免疫球蛋白可变区,其包含:包含SEQ ID NO:124中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:126中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:128中所阐述的氨基酸序列的CDR-L3;(9)重链免疫球蛋白可变区,其包含:包含SEQ ID NO:132中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:134中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:136中所阐述的氨基酸序列的CDR-H3;和轻链免疫球蛋白可变区,其包含:包含SEQ ID NO:124中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:126中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:128中所阐述的氨基酸序列的CDR-L3;(10)重链免疫球蛋白可变区,其包含:包含SEQ ID NO:140中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:142中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:144中所阐述的氨基酸序列的CDR-H3;和轻链免疫球蛋白可变区,其包含:包含SEQ ID NO:148中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:150中所阐述的氨基酸序列的CDR-L2;和包含SEQID NO:152中所阐述的氨基酸序列的CDR-L3;(11)重链免疫球蛋白可变区,其包含:包含SEQID NO:156中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:158中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:160中所阐述的氨基酸序列的CDR-H3;和轻链免疫球蛋白可变区,其包含:包含SEQ ID NO:164中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:166中所阐述的氨基酸序列的CDR-L2;和包含SEQ ID NO:168中所阐述的氨基酸序列的CDR-L3;或(12)重链免疫球蛋白可变区,其包含:包含SEQ ID NO:172中所阐述的氨基酸序列的CDR-H1;包含SEQ ID NO:174中所阐述的氨基酸序列的CDR-H2;和包含SEQ ID NO:176中所阐述的氨基酸序列的CDR-H3;和轻链免疫球蛋白可变区,其包含:包含SEQ ID NO:124中所阐述的氨基酸序列的CDR-L1;包含SEQ ID NO:126中所阐述的氨基酸序列的CDR-L2;和包含SEQID NO:128中所阐述的氨基酸序列的CDR-L3。在本发明的一个实施例中,抗原结合蛋白包含(a)重链免疫球蛋白,其包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列;和/或(b)轻链免疫球蛋白,其包含SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列。本发明包括抗原结合蛋白(例如抗体或其抗原结合片段),其包含:(a)包含SEQ ID NO:2中所阐述的氨基酸序列的重链免疫球蛋白可变区,和包含SEQ ID NO:10中所阐述的氨基酸序列的轻链免疫球蛋白可变区;(b)包含SEQ ID NO:18中所阐述的氨基酸序列的重链免疫球蛋白可变区,和包含SEQID NO:26中所阐述的氨基酸序列的轻链免疫球蛋白可变区;(c)包含SEQ ID NO:34中所阐述的氨基酸序列的重链免疫球蛋白可变区,和包含SEQ ID NO:42中所阐述的氨基酸序列的轻链免疫球蛋白可变区;(d)包含SEQ ID NO:50中所阐述的氨基酸序列的重链免疫球蛋白可变区,和包含SEQ ID NO:58中所阐述的氨基酸序列的轻链免疫球蛋白可变区;(e)包含SEQ ID NO:66中所阐述的氨基酸序列的重链免疫球蛋白可变区,和包含SEQ ID NO:74中所阐述的氨基酸序列的轻链免疫球蛋白可变区;(f)包含SEQ ID NO:82中所阐述的氨基酸序列的重链免疫球蛋白可变区,和包含SEQ ID NO:90中所阐述的氨基酸序列的轻链免疫球蛋白可变区;(g)包含SEQ ID NO:98中所阐述的氨基酸序列的重链免疫球蛋白可变区,和包含SEQ ID NO:106中所阐述的氨基酸序列的轻链免疫球蛋白可变区;(h)包含SEQ ID NO:114中所阐述的氨基酸序列的重链免疫球蛋白可变区,和包含SEQ ID NO:122中所阐述的氨基酸序列的轻链免疫球蛋白可变区;(i)包含SEQ ID NO:130中所阐述的氨基酸序列的重链免疫球蛋白可变区,和包含SEQ ID NO:122中所阐述的氨基酸序列的轻链免疫球蛋白可变区;(j)包含SEQ ID NO:138中所阐述的氨基酸序列的重链免疫球蛋白可变区,和包含SEQ IDNO:146中所阐述的氨基酸序列的轻链免疫球蛋白可变区;(k)包含SEQ ID NO:154中所阐述的氨基酸序列的重链免疫球蛋白可变区,和包含SEQ ID NO:162中所阐述的氨基酸序列的轻链免疫球蛋白可变区;和/或(l)包含SEQ ID NO:170中所阐述的氨基酸序列的重链免疫球蛋白可变区,和包含SEQ ID NO:122中所阐述的氨基酸序列的轻链免疫球蛋白可变区-例如其中重链免疫球蛋白可变区与重链恒定区(例如,IgG(例如,IgG1或IgG4))连接,并且轻链免疫球蛋白可变区与轻链恒定区(例如,λ或κ)连接。举例来说,轻链和重链恒定区为人类恒定区。在本发明的一个实施例中,本发明的抗原结合蛋白(例如,抗体或其抗原结合片段)包含:(a)包含SEQ ID NO:180中所阐述的氨基酸序列的重链免疫球蛋白,和包含SEQ IDNO:182中所阐述的氨基酸序列的轻链免疫球蛋白;(b)包含SEQ ID NO:184中所阐述的氨基酸序列的重链免疫球蛋白,和包含SEQ ID NO:186中所阐述的氨基酸序列的轻链免疫球蛋白;(c)包含SEQ ID NO:188中所阐述的氨基酸序列的重链免疫球蛋白,和包含SEQ ID NO:190中所阐述的氨基酸序列的轻链免疫球蛋白;(d)包含SEQ ID NO:192中所阐述的氨基酸序列的重链免疫球蛋白,和包含SEQ ID NO:194中所阐述的氨基酸序列的轻链免疫球蛋白;(e)包含SEQ ID NO:196中所阐述的氨基酸序列的重链免疫球蛋白,和包含SEQ ID NO:198中所阐述的氨基酸序列的轻链免疫球蛋白;(f)包含SEQ ID NO:200中所阐述的氨基酸序列的重链免疫球蛋白,和包含SEQ ID NO:202中所阐述的氨基酸序列的轻链免疫球蛋白;(g)包含SEQ ID NO:204中所阐述的氨基酸序列的重链免疫球蛋白,和包含SEQ ID NO:206中所阐述的氨基酸序列的轻链免疫球蛋白;(h)包含SEQ ID NO:208中所阐述的氨基酸序列的重链免疫球蛋白,和包含SEQ ID NO:210中所阐述的氨基酸序列的轻链免疫球蛋白;(i)包含SEQ ID NO:212中所阐述的氨基酸序列的重链免疫球蛋白,和包含SEQ ID NO:214中所阐述的氨基酸序列的轻链免疫球蛋白;(j)包含SEQ ID NO:216中所阐述的氨基酸序列的重链免疫球蛋白,和包含SEQ ID NO:218中所阐述的氨基酸序列的轻链免疫球蛋白;(k)包含SEQID NO:220中所阐述的氨基酸序列的重链免疫球蛋白,和包含SEQ ID NO:222中所阐述的氨基酸序列的轻链免疫球蛋白;和/或(l)包含SEQ ID NO:224中所阐述的氨基酸序列的重链免疫球蛋白,和包含SEQ ID NO:226中所阐述的氨基酸序列的轻链免疫球蛋白。
在本发明的一个实施例中,本发明的抗原结合蛋白的特征可为以下特性中的一者或多者:
·在25℃下以约2.18nM到约13.9nM的KD或在37℃下以约4.25nM到约29.5nM的KD与人类IL36R结合;
·在25℃下以约7.87nM到约34.4nM的KD或在37℃下以约14.4nM到约58.2nM的KD与食蟹猴(Macaca fascicularis)IL36R结合;
·在25℃下以约173pM到约5.79nM的KD或在37℃下以约205pM到约28.7nM的KD和与小鼠IgG2a融合的人类IL36R结合;
·在25℃下以约212pM到约14nM的KD或在37℃下以约264pM到约40.9nM的KD与经表达具有小鼠IgG2a Fc标签的与IL1RAcP胞外结构域融合的人类IL36R结合;
·与H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2竞争结合IL36R;
·阻断在IL-1RAcP和IL36R配位体存在的情况下IL-36R(例如,人类或食蟹猴)激活在宿主细胞中与报告基因融合的一个或多个NFκB元件;
·在罹患皮肤炎症的个体中预防或改善皮肤炎症或降低皮肤厚度或总病理评分或降低促炎性细胞因子水平;
·在罹患结肠炎或结肠炎症的个体中预防或改善这类结肠炎或炎症或降低LCN2多肽的粪便水平;
·在结合时保护本文中在SEQ ID NO:227中所阐述的人类IL36R(IL-1RL2)的残基(a)113-119、113-122、116-119和/或116-122;和/或(b)264-271、267-271、268-271、268-276、268-277和/或271-276(或野生型IL-1RL2中的对应残基)免受胃蛋白酶和/或蛋白酶XIII消化和/或在氘存在的情况下氘化的影响;
·在包含本文中在SEQ ID NO:227中所阐述的氨基酸序列的人类IL36R的残基113-119、113-122、116-119、116-122、264-271、267-271、268-271、268-276、268-277和/或271-276(或野生型IL-1RL2中的对应残基)处与IL36R(IL-1RL2)(例如人类IL36R)结合;
·结合IL36R(IL-1RL2)(例如人类IL36R)的结构域II,例如其中覆盖率为约80.0、80.1、81.0或81.5%或约80-81或80-82%的覆盖率;和/或
·结合包含氨基酸序列YKQILHLGKD(SEQ ID:229)(SEQ IDNO:227的氨基酸113-122)的多肽;
·以约1、2、3、4、5或6nM或1-6nM的IC50抑制例如体外表皮角化细胞、肠道肌成纤维细胞和/或CD14+单核细胞中的IL36α、IL36β和/或IL36γ(例如浓度为约10nM);和/或
·竞争性地抑制IL36α、IL36β和/或IL36γ介导的IL36R对NFκB(例如,例如HEK293的细胞中的NFκB反应元件(5×)-荧光素酶-IRES-GFP报告因子)的激活;例如如斯切尔德分析形式(Schild Assay format)中所测量。
与本发明的抗原结合蛋白(例如,抗体或其抗原结合片段,例如,人类抗体或其抗原结合片段或多特异性抗体)复合的包含IL36R多肽或其抗原片段的复合物也在本发明的范围内。
本发明还提供用于制备本发明的抗原结合蛋白(例如,抗体或其抗原结合片段,例如,人类抗体或其抗原结合片段或多特异性抗体)或其免疫球蛋白链的方法,其包含:(a)将编码所述抗原结合蛋白的免疫球蛋白链的一个或多个多核苷酸引入宿主细胞(例如,中国仓鼠卵巢(Chinese hamster ovary;CHO)细胞)中;(b)在有利于表达所述多核苷酸的条件下培养所述宿主细胞;和(c)任选地,从所述宿主细胞和/或所述宿主细胞在其中生长的培养基中分离所述抗原结合蛋白或免疫球蛋白链。作为这类方法的产物的抗原结合蛋白和免疫球蛋白链也是本发明的一部分。
本发明还提供一种多肽,其包含:(a)包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列的免疫球蛋白链的免疫球蛋白重链可变区的CDR-H1、CDR-H2和CDR-H3;和/或(b)包含SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列的免疫球蛋白链的免疫球蛋白轻链可变区的CDR-L1、CDR-L2和CDR-L3;或本文中所阐述的任何氨基酸序列,例如,(c)选自由SEQ IDNO:1-226组成的群组的成员中所阐述的氨基酸序列。编码这类多肽中的一者或多者(例如2者,例如,本文中所阐述的重链和轻链免疫球蛋白)的多核苷酸也是本发明的一部分。载体,例如包含这类多核苷酸的质粒也是本发明的一部分。包含本文中所阐述的任何抗原结合蛋白或免疫球蛋白链或多肽或多核苷酸或载体的宿主细胞(例如CHO细胞)是本发明的一部分,例如,其中多核苷酸和/或载体被整合到宿主细胞的染色体中或为异位的。
任选地与另一种治疗剂(例如抗炎剂、抗TNFα抗体或其抗原结合片段、IL17抑制剂、IL23p19抑制剂、IL12p40抑制剂、古塞库单抗(guselkumab)、优特克单抗(ustekinumab)、布罗达单抗(brodalumab)、依奇珠单抗(ixekizumab)、苏金单抗(secukinumab)、一种或多种与免疫球蛋白连接的人类TNF受体或其片段、英利昔单抗(infliximab)、阿达木单抗(adalimumab)、依那西普(etanercept)、杜匹鲁单抗(dupilumab)、沙瑞卢单抗(sarilumab)、托珠单抗(tocilizumab)、戈利木单抗(golimumab)、阿巴西普(abatacept)、托法替尼(tofacitinib)、阿巴西普(abatacept)、非类固醇抗炎药(NSAID)、布洛芬(ibuprofen)、萘普生(naproxen)、对乙酰氨基酚(acetaminophen)、阿司匹林(aspirin)、塞内昔布(celecoxib)、环磷酰胺(cyclophosphamide)、甲氨蝶呤(methotrexate)、皮质类固醇(corticosteroid)、可的松(cortisone)和泼尼松(prednisone))结合包含本文中所阐述的抗原结合蛋白(例如抗体或其抗原结合片段,例如人类抗体或其抗原结合片段或多特异性抗体)中的一者或多者的组合物或试剂盒形成本发明的一部分。
包含本文中所阐述的抗原结合蛋白(例如抗体或其抗原结合片段,例如人类抗体或其抗原结合片段或多特异性抗体)和药学上可接受的载体以及任选的另一种治疗剂的药物组合物也是本发明的一部分。
本发明还提供包含本文中所阐述的抗原结合蛋白(例如预填充针筒)或组合物的容器或注射装置(例如抗体或其抗原结合片段,例如人类抗体或其抗原结合片段或多特异性抗体)。
本发明还提供一种治疗或预防有需要的个体(例如人类)的IL36R介导的病症(例如发炎性或自身免疫性疾病或发炎性肠病)的方法,其包含任选地与另一种治疗剂(例如抗炎剂)结合向个体施用(例如非经肠)治疗有效量的如本文中所阐述的抗原结合蛋白(例如抗体或其抗原结合片段,例如人类抗体或其抗原结合片段或多特异性抗体)。
本发明还提供一种向个体(例如人类)体内施用如本文中所阐述的抗原结合蛋白(例如抗体或其抗原结合片段,例如人类抗体或其抗原结合片段或多特异性抗体)的方法,其包含任选地与另一种治疗剂(例如抗炎剂)结合向个体体内注射(例如皮下、静脉内或肌肉内)抗原结合蛋白。
本发明涵盖包含SEQ ID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42、44、46、48、50、52、54、56、58、60、62、64、66、68、70、72、74、76、78、80、82、84、86、88、90、92、94、96、98、100、102、104、106、108、110、112、114、116、118、120、122、124、126、128、130、132、134、136、138、140、142、144、146、148、150、152、154、156、158、160、162、164、166、168、170、172、174、176、180、184、188、192、196、200、204、208、212、216、220、224、182、186、190、194、198、202、206、210、214、218、222和/或226中所阐述的氨基酸序列的任何多肽或其变体。
本发明包括包含SEQ ID NO:1、3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41、43、45、47、49、51、53、55、57、59、61、63、65、67、69、71、73、75、77、79、81、83、85、87、89、91、93、95、97、99、101、103、105、107、109、111、113、115、117、119、121、123、125、127、129、131、133、135、137、139、141、143、145、147、149、151、153、155、157、159、161、163、165、167、169、171、173,175、179、183、187、191、195、199、203、207、211、215、219、223、181、185、189、193、197、201、205、209、213、217、221和/或225中所阐述的核苷酸序列的任何多核苷酸或其变体。
附图说明
图1.H4H14706P2的生殖系与VH和VL之间的序列比较。
图2.H4H14708P2的生殖系与VH和VL之间的序列比较。
图3(A-F).H4H14706P2和H4H14708P2的浓度增大生成IL-36α(A及D)、IL-36β(B及E)或IL-36γ(C及F)剂量反应曲线的向右偏移,揭示H4H14706P2和H4H14708P2的抑制的竞争性(RLU,相对轻单元)
图4.皮下给药0.5mg/kg或5.0mg/kg抗体的食蟹猕猴中的H4H141706P2和APE6155药代动力学分析(随时间推移血清中抗体的浓度)。
具体实施方式
根据本发明,在本领域的技术范围内可以采用常规的分子生物学、微生物学、和重组DNA技术。在文献中充分解释了这类技术。参见例如Sambrook,Fritsch和Maniatis,《分子克隆:实验指南(Molecular Cloning:A Laboratory Manual)》,第二版(1989)纽约冷泉港的冷泉港实验室出版社(Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.)(本文中为“Sambrook,等人,1989”);《DNA克隆:实用方法(DNA Cloning:A PracticalApproach)》,第I和II卷(D.N.Glover编1985);《寡核苷酸合成(OligonucleotideSynthesis)》(M.J.Gait编1984);《核酸杂交(Nucleic Acid Hybridization)》(B.D.Hames和S.J.Higgins编(1985));《转录和翻译(Transcription And Translation)》(B.D.Hames和S.J.Higgins编(1984));《动物细胞培养(Animal Cell Culture)》(R.I.Freshney编(1986));《固定化细胞和酶(Immobilized Cells And Enzymes)》(IRL出版社(IRL Press),(1986));B.Perbal,《分子克隆实践指南(A Practical Guide To Molecular Cloning)》(1984);F.M.Ausubel,等人.(编),《现代分子生物学实验技术(Current Protocols inMolecular Biology)》,约翰·威利父子公司(John Wiley&Sons,Inc.)(1994)。
抗IL36R“抗原结合蛋白”为在IL1RL2亚单位(IL-1Rrp2)处与IL36受体特异性结合的超过一种多肽的单一多肽(例如单链可变片段(single chain variable fragment;ScFv))或复合物(例如四聚体IgG抗体)。IL-36R在结合其抗原结合蛋白的情况下是指IL-1RL2。在本发明的一个实施例中,抗原结合蛋白为单特异性或多特异性(例如双特异性)或单价或多价(例如二价)的抗体或抗原结合片段。单价抗原结合蛋白具有单个抗原结合结构域,而二价抗原结合蛋白具有两个抗原结合结构域。
多核苷酸包括DNA和RNA。本发明包括与启动子或其它表达控制序列可操作地连接的本发明的任何多核苷酸。
通常,“启动子”或“启动子序列”是能够结合细胞中的RNA聚合酶(例如,直接或通过其它启动子结合的蛋白质或物质)并起始编码序列转录的DNA调节区。启动子序列通常在其3'端由转录起始位点界定,并向上游(5'方向)延伸,以包括在任何水平起始转录所需的最小数量的碱基或元件。在所述启动子序列中可以发现转录起始位点(方便地定义,例如通过用核酸酶S1作图)以及负责结合RNA聚合酶的蛋白质结合结构域(共有序列)。所述启动子可以与其它表达控制序列(包括增强子序列和阻遏因子序列)或本发明的核酸可操作地相关联。可用于控制基因表达的启动子包括但不限于巨细胞病毒(CMV)启动子(美国专利第5,385,839号和第5,168,062号)、SV40早期启动子区(Benoist,等人,(1981)《自然(Nature)》290:304-310)、劳氏肉瘤病毒(Rous sarcoma virus)的3'长末端重复序列中所含的启动子(Yamamoto,等人,(1980)《细胞(Cell)》22:787-797)、疱疹胸苷激酶启动子(Wagner,等人,(1981)《美国国家科学院院刊(Proc.Natl.Acad.Sci.USA)》78:1441-1445)、金属硫蛋白基因的调节序列(Brinster,等人,(1982)《自然》296:39-42);原核表达载体,例如β-内酰胺酶启动子(VIIIa-Komaroff,等人,(1978)《美国国家科学院院刊》75:3727-3731)或tac启动子(DeBoer,等人,(1983)《美国国家科学院院刊》80:21-25);还参见《科学美国人(ScientificAmerican)》(1980)242:74-94中的“来自重组细菌的有用蛋白质(Useful proteins fromrecombinant bacteria)”;和来自酵母菌或其它真菌的启动子元件,例如Gal 4启动子、醇脱氢酶(alcohol dehydrogenase;ADC)启动子、磷酸甘油激酶(phosphoglycerol kinase;PGK)启动子或碱性磷酸酶启动子。
当在细胞中序列将编码序列的RNA聚合酶介导的转录引导到RNA,优选为mRNA中时,编码多肽的多核苷酸与启动子或其它表达控制序列“可操作地连接”,所述mRNA随后可以被RNA剪接(如果其含有内含子)以及任选地,翻译成由编码序列编码的蛋白质。
白细胞介素-36受体(IL36R)
IL-36R为含有六种受体蛋白质和两种诱饵受体和两种消极调节因子的IL-1受体家族的成员,所述受体蛋白质形成四种信号传导复合物:IL-1RI、IL-18R、IL-33R和IL-36R。IL-36R为由命名为IL-1Rrp2的受体亚单位(也称为IL-1RL2、白细胞介素1受体样2或白细胞介素1受体相关蛋白2)和共受体亚单位白细胞介素-1受体辅助蛋白IL-1RAcP组成的异二聚体。受体可识别三种不同激动剂IL-36α、IL-36β和IL-36γ(也称为IL-1F6、IL-1F8和IL-1F9)以诱导发炎性细胞因子的表达。也存在两种受体拮抗因子IL-36Ra和IL-38,其与IL-36受体结合并且减少发炎性细胞因子的表达。IL-36α、IL-36β和IL-36γ传信通过IL-36R/IL-1RAcP受体以激活NF-κB和MAPK,例如p38和JNK,并且促进炎症反应。
在本发明的一个实施例中,智人IL1RL2序列以基因库寄存编号NP_003845.2可用。在本发明的一个实施例中,智人IL1RL2的氨基酸序列阐述于SEQ ID NO:177中。
在本发明的一个实施例中,智人IL-1RAcP序列以基因库寄存编号NP_002173.1可用。在本发明的一个实施例中,智人IL-1RAcP的氨基酸序列阐述于SEQ ID NO:178中。
抗IL36抗体和其抗原结合片段
本发明提供抗原结合蛋白,例如抗体(例如人类抗体)和其抗原结合片段,其与IL36R蛋白或其抗原片段特异性结合。与IL36R上与本文中所阐述的抗原结合蛋白中的任一个相同的表位结合或而与本文中所阐述的抗原结合蛋白中的任一个竞争结合IL36R的抗原结合蛋白也是本发明的一部分。
如本文所用,术语“抗体”是指免疫球蛋白分子,其包含四条多肽链,即通过二硫键互连的两条重链(HC)和两条轻链(LC)(即“完整抗体分子”),以及其多聚体-例如H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2。在本发明的一个实施例中,每条重链(HC)包含重链可变区(“HCVR”或“VH”)(例如SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154或170或其变体)和重链恒定区(包括结构域CH1、CH2和CH3);和每条轻链(LC)包含轻链可变区(“LCVR”或“VL”)(例如SEQ ID NO:10、26、42、58、74、90、106、122、146或162或其变体)和轻链恒定区(CL)。VH和VL区可进一步细分为高变区,称为互补决定区(CDR),其间散布着更为保守的区域,称为框架区(FR)。每个VH和VL包含三个CDR和四个FR,其从氨基端到羧基端按以下次序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。在本发明的某些实施例中,抗体(或其抗原结合片段)的FR与人类生殖系序列一致,或经过天然地或人工地修饰。
通常,重和轻免疫球蛋白链两者的可变结构域包含三个高变区,也被称为互补决定区(CDR),位于相对保守的框架区(FR)内。通常,从N端到C端,轻链和重链可变结构域两者都包含FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。在本发明的一个实施例中,将氨基酸指配到每个结构域是根据《免疫学感兴趣的蛋白质的序列(Sequences of Proteins ofImmunological Interest),Kabat,等人;马里兰州贝塞斯达美国国家卫生研究院(National Institutes of Health,Bethesda,Md.);第5版;美国国立卫生研究院公共访问(NIH Publ.)第91-3242号(1991);Kabat(1978)《蛋白质化学进展(Adv.Prot.Chem.)》32:1-75;Kabat,等人,(1977)《生物化学杂志(J.Biol.Chem.)》252:6609-6616;Chothia,等人,(1987)《分子生物学杂志(J Mol.Biol.)》196:901-917或Chothia,等人,(1989)《自然》342:878-883的定义。
举例来说,本发明提供抗原结合蛋白,其包括(a)重链免疫球蛋白,其包含有包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154,170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列的重链免疫球蛋白的CDR-H1、CDR-H2和CDR-H3和与SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154,170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列至少70、80或90%的氨基酸序列一致性;和(b)轻链免疫球蛋白,其包含有包含SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列的轻链免疫球蛋白的CDR-L1、CDR-L2和CDR-L3和与SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列至少70、80或90%的氨基酸序列一致性。在本发明的一个实施例中,抗原结合蛋白包括(i)重链免疫球蛋白,其包含有包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列的重链免疫球蛋白的CDR-H1、CDR-H2和CDR-H3;或其变体;和(ii)轻链免疫球蛋白,其包含有包含SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列的轻链免疫球蛋白的CDR-L1、CDR-L2和CDR-L3;或其变体。
在本发明的一个实施例中,本发明的抗原结合蛋白包括包含VH的重链免疫球蛋白,所述重链免疫球蛋白包括CDR-H1、CDR-H2和CDR-H3,其中:
CDR-H1包含SEQ ID NO:4、20、36、52、68、84、100、116、132、140、156或172中所阐述的氨基酸序列或其变体;
CDR-H2包含SEQ ID NO:6、22、38、54、70、86、102、118、134、142、158或174中所阐述的氨基酸序列或其变体;并且
CDR-H3包含SEQ ID NO:8、24、40、56、72、88、104、120、136、144、160或176中所阐述的氨基酸序列或其变体;并且
包含VL的轻链免疫球蛋白,所述轻链免疫球蛋白包括CDR-L1、CDR-L2和CDR-L3,其中:
CDR-L1包含SEQ ID NO:12、28、44、60、76、92、108、124、124、148或164中所阐述的氨基酸序列或其变体;
CDR-L2包含SEQ ID NO:14、30、46、62、78、94、110、126、126、150或166中所阐述的氨基酸序列或其变体;并且
CDR-L3包含SEQ ID NO:16、32、48、64、80、96、112、128、128、152或168中所阐述的氨基酸序列或其变体。
本发明包括单株抗IL36R抗原结合蛋白,例如抗体和其抗原结合片段,以及包含多种分离的单克隆抗原结合蛋白的单克隆组合物。如本文所用,术语“单克隆抗体”或“mAb”是指基本上均质的抗体的群体的成员,即包含氨基酸序列相同,但其中可能以少量存在可能天然存在的突变的群体的抗体分子。组合物中的“多个”这类单克隆抗体和片段是指相同(即如上所论述,氨基酸序列相同,但其中可能以少量存在可能天然存在的突变)抗体和片段的浓度,所述浓度高于将天然存在于自然界中,例如宿主生物体(例如小鼠或人类)的血液中的抗体和片段的浓度。
在本发明的一个实施例中,抗IL36R抗原结合蛋白,例如抗体或抗原结合片段包含重链恒定结构域,例如IgA(例如IgA1或IgA2)、IgD、IgE、IgG(例如,IgG1、IgG2、IgG3和IgG4)或IgM型。在本发明的一个实施例中,抗原结合蛋白,例如抗体或抗原结合片段包含轻链恒定结构域,例如κ或λ型。
本发明包括人类抗原结合蛋白。如本文所用,术语“人类”抗原结合蛋白,例如抗体或抗原结合片段包括具有衍生自人类细胞中或移植到非人类细胞(例如小鼠细胞)中的人类生殖系免疫球蛋白序列的可变区和恒定区的抗体和片段。参见例如US8502018、US6596541或US5789215。本发明的人类mAb可以包括未由人类生殖系免疫球蛋白质序列编码的氨基酸残基(例如,通过体外随机或位点特异性诱变或体内体细胞突变引入的突变),例如在CDR并且特别是CDR3中。然而,如本文所用,术语“人类抗体”并不意图包括已将衍生自另一哺乳动物物种(例如小鼠)生殖系的CDR序列移植到人类FR序列上的mAb。所述术语包括在非人类哺乳动物中或在非人类哺乳动物的细胞中以重组方式产生的抗体。所述术语不意图包括从人类个体中直接分离的天然抗体。
本发明包括抗IL36R嵌合抗原结合蛋白,例如抗体和其抗原结合片段和其使用方法。如本文所用,“嵌合抗体”是具有来自第一抗体的可变结构域和来自第二抗体的恒定结构域的抗体,其中第一和第二抗体来自不同物种。(参见例如,US4816567;和Morrison等人,(1984)《美国国家科学院院刊》81:6851-6855)。
术语“重组”抗原结合蛋白,例如抗体或其抗原结合片段是指通过本领域中称为包括例如DNA剪接和转基因表达的重组DNA技术的技术或方法形成、表达、分离或获得的这类分子。所述术语包括在非人类哺乳动物(包括转基因非人类哺乳动物,例如转基因小鼠)或细胞(例如CHO细胞),例如细胞表达系统中表达或从重组组合人类抗体库中分离的抗体。
本文所公开的重组抗IL36R抗原结合蛋白,例如抗体和抗原结合片段也可在大肠杆菌(E.coli)/T7表达系统中产生。在这个实施例中,编码本发明的抗IL36R抗体免疫球蛋白分子(例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2)的核酸可以被插入pET类质粒中并且在大肠杆菌/T7系统中表达。举例来说,本发明包括在宿主细胞(例如,细菌宿主细胞,例如大肠杆菌,例如BL21或BL21DE3)中表达抗体或其抗原结合片段或其免疫球蛋白链的方法,其包含在还包括编码与T7启动子可操作地连接的免疫球蛋白链的多核苷酸的细胞中表达T7RNA聚合酶。举例来说,在本发明的一个实施例中,细菌宿主细胞,例如大肠杆菌包括编码与lac启动子可操作地连接的T7 RNA聚合酶基因的多核苷酸,并且聚合酶和链的表达通过与异丙基-β-D-硫代半乳糖吡喃糖苷(isopropyl-beta-D-thiogalactopyranoside;IPTG)一起培育宿主细胞来诱导。参见US4952496和US5693489或Studier和Moffatt,《使用噬菌体T7 RNA聚合酶引导克隆基因的选择性高水平表达(Use ofbacteriophage T7RNA polymerase to direct selective high-level expression ofcloned genes)》,《分子生物学杂志》1986年5月5日;189(1):113-30。
本领域中已知若干种产生重组抗体的方法。重组产生抗体的方法的一个实例公开于US4816567中。
转化可以通过将多核苷酸引入宿主细胞中的任何已知方法。将异源多核苷酸引入哺乳动物细胞中的方法在本领域中是众所周知的,并且包括右旋糖酐介导的转染、磷酸钙沉淀、聚凝胺介导的转染、原生质体融合、电穿孔、将多核苷酸封装在脂质体中、将DNA基因枪注射和直接微注射到细胞核中。另外,可以通过病毒载体将核酸分子引入哺乳动物细胞中。转化细胞的方法在本领域中是众所周知的。参见例如美国专利第4,399,216号;第4,912,040号;第4,740,461号和第4,959,455号。因此,本发明包括制备抗IL36R抗原结合蛋白,例如本发明的抗体或其抗原结合片段或其免疫球蛋白链的重组方法,其包含(i)引入一种或多种多核苷酸(例如,包括SEQ ID NO:1、3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41、43、45、47、49、51、53、55、57、59、61、63、65、67、69、71、73、75、77、79、81、83、85、87、89、91、93、95、97、99、101、103、105、107、109、111、113、115、117、119、121、123、125、127、129、131、133、135、137、139、141、143、145、147、149、151、153、155、157、159、161、163、165、167、169、171、173、175、179、181、183、185、187、189、191、193、195、197、199、201、203、205、207、209、211、213、215、217、219、221、223和/或225中的任一者或多者中的核苷酸序列;或其变体),所述一种或多种多核苷酸编码抗原结合蛋白,例如H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2的轻和/或重免疫球蛋白链,例如其中多核苷酸在载体中;和/或整合到宿主细胞染色体中和/或与启动子可操作地连接;(ii)在有利于表达多核苷酸的条件下培养宿主细胞(例如CHO或毕赤酵母(Pichia)或甲醇酵母(Pichia pastoris)),并且(iii)任选地,从宿主细胞和/或宿主细胞在其中生长的培养基中分离抗原结合蛋白(例如抗体或片段)或链。当制备包含超过一条免疫球蛋白链的抗原结合蛋白(例如抗体或抗原结合片段),例如包含两条重免疫球蛋白链和两条轻免疫球蛋白链的抗体时,如果分泌这类链,那么所述链在单一宿主细胞中的共表达使得所述链例如在细胞中或在细胞表面上或在细胞外部缔合,以形成抗原结合蛋白(例如抗体或抗原结合片段)。本发明的方法包括其中仅重免疫球蛋白链或仅轻免疫球蛋白链或两者(例如包括成熟片段和/或其可变结构域的本文所论述的免疫球蛋白链中的任一者)在细胞中表达的方法。举例来说,这类单链适用作包括这类链的抗体或抗原结合片段的表达中的中间物。举例来说,本发明还包括抗IL36R抗原结合蛋白,例如抗体和其抗原结合片段,其包含由多核苷酸编码的重链免疫球蛋白(或其可变结构域或包含其CDR),所述多核苷酸包含SEQ ID NO:1、17、33、49、65、81、97、113、129、137、153、169、179、183、187、191、195、199、203、207、211、215、219或223中所阐述的核苷酸序列;和由SEQ ID NO:9、25、41、57、73、89、105、121、145、161、181、185、189、193、197、201、205、209、213、217、221或225中所阐述的核苷酸序列编码的轻链免疫球蛋白(或其可变结构域或包含其CDR),所述抗[g15]IL36R[/g15]抗原结合蛋白是这类产生方法以及任选的本文中所阐述的纯化方法的产物。举例来说,在本发明的一个实施例中,所述方法的产物是抗IL36R抗原结合蛋白,其为抗体或片段,所述抗体或片段包含有包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154,170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列的重链免疫球蛋白或VH和包含SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列的轻链免疫球蛋白或VL。
在本发明的一个实施例中,用于制备抗IL36R抗原结合蛋白,例如抗体或其抗原结合片段的方法包括纯化抗原结合蛋白的方法,例如通过柱色谱法、沉淀和/或过滤。这类方法的产物还形成本发明的一部分。
真核和原核宿主细胞,包括哺乳动物细胞可用作表达抗IL36R抗原结合蛋白(例如抗体或其抗原结合片段)的宿主。这类宿主细胞在本领域中是众所周知的,并且许多可购自美国典型培养物保藏中心(American Type Culture Collection;ATCC)。这些宿主细胞尤其包括中国仓鼠卵巢(CHO)细胞、NSO、SP2细胞、海拉细胞(HeLa cell)、幼年仓鼠肾(BHK)细胞、猴肾细胞(COS)、人类肝细胞癌细胞(例如Hep G2)、A549细胞、3T3细胞、HEK-293细胞和多种其它细胞系。哺乳动物宿主细胞包括人类、小鼠、大鼠、狗、猴、猪、山羊、牛、马和仓鼠细胞。可使用的其它细胞系为昆虫细胞系(例如,草地贪夜蛾(Spodoptera frugiperda)或粉纹夜蛾(Trichoplusia ni))、两栖动物细胞、细菌细胞、植物细胞和真菌细胞。真菌细胞包括酵母菌和丝状真菌细胞,包括例如毕赤酵母、甲醇酵母)、芬兰毕赤酵母(Pichiafinlandica)、嗜海藻糖毕赤酵母(Pichia trehalophila)、克氏毕赤酵母(Pichiakoclamae)、膜醭毕赤酵母(Pichia membranaefaciens)、微小毕赤酵母(Pichia minuta)(甲醇诱导型酵母(Ogataea minuta)、林氏毕赤酵母(Pichia lindneri))、幸运毕赤酵母(Pichia opuntiae)、耐热毕赤酵母(Pichia thermotolerans)、萨利毕赤酵母(Pichiasalictaria)、松栎毕赤酵母(Pichia guercuum)、皮吉毕赤酵母(Pichia pijperi)、树干毕赤酵母(Pichia stiptis)、甲醇毕赤酵母(Pichia methanolica)、毕赤酵母属(Pichiasp.)、酿酒酵母(Saccharomyces cerevisiae)、酵母属(Saccharomyces sp.)、多形汉逊酵母(Hansenula polymorpha)、克鲁维酵母属(Kluyveromyces sp.)、乳酸克鲁维酵母(Kluyveromyces lactis)、白色假丝酵母菌(Candida albicans)、构巢曲霉(Aspergillusnidulans)、黑曲霉(Aspergillus niger)、米曲霉(Aspergillus oryzae)、里氏木霉(Trichoderma reesei)、勒克瑙金孢(Chrysosporium lucknowense)、镰刀霉属(Fusariumsp.)、禾谷镰孢菌(Fusarium gramineum)、镰孢霉(Fusarium venenatum)、小立碗藓(Physcomitrella patens)和粗糙脉孢菌(Neurospora crassa)。本发明包括分离的宿主细胞(例如上文所阐述的CHO细胞或任何类型的宿主细胞),其包含抗原结合蛋白,例如H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2;和/或编码一条或多条其免疫球蛋白链的多核苷酸。
本发明还包括表达与本发明的抗原结合蛋白结合的IL36R或其抗原片段或融合物(例如His6、Fc和/或myc)的细胞,所述抗原结合蛋白例如H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2,例如,其中细胞在个体体内或在体外。
另外,本发明还提供包含与IL36R多肽或其抗原片段或其融合物复合和/或与二级抗体或其抗原结合片段(例如可检测标记的二级抗体)复合的抗IL36R抗原结合蛋白,例如本文所论述的抗体或抗原结合片段的复合物,所述二级抗体或其抗原结合片段与抗IL36R抗体或片段特异性结合。在本发明的一个实施例中,复合物在体外(例如固定到固体基质上)或在个体体内。
术语“特异性结合”是指对抗原(例如IL36R蛋白)具有结合亲和力的那些抗原结合蛋白(例如mAb),表示为KD为至少约58nM(例如10-9M;10-10M、10-11M或10-12M),如例如在25℃或37℃下通过实时无标记生物层干涉测量分析,例如HTX生物传感器或通过表面等离子体共振,例如BIACORETM或通过溶液-亲和力ELISA测量。本发明包括与IL36R蛋白特异性结合的抗原结合蛋白。在本发明的一个实施例中,抗IL36R抗原结合蛋白包含用于与人类和/或食蟹猴IL36R结合的KD值,所述值阐述于表4-1到4-8中。
如本文所用,术语抗体或抗原结合蛋白的“抗原结合部分”或“抗原结合片段”和其类似术语包括任何天然存在的、可以酶方式获得的、合成的或基因工程改造的多肽或糖蛋白,其与抗原特异性结合以形成复合物。抗原结合片段的非限制性实例包括:(i)Fab片段;(ii)F(ab')2片段;(iii)Fd片段;(iv)Fv片段;(v)单链Fv(scFv)分子;和(vi)dAb片段;由模拟抗体高变区(例如分离的互补决定区(CDR),例如CDR3肽)或受约束的FR3-CDR3-FR4肽的氨基酸残基组成。其它经过工程改造的分子,例如结构域特异性抗体、单结构域抗体、结构域缺失抗体、嵌合抗体、CDR移植抗体、双功能抗体、三功能抗体、四功能抗体、微型抗体和小模块免疫药物(small modular immunopharmaceutical;SMIP)也涵盖在如本文所用的表述“抗原结合片段”内。在本发明的一个实施例中,抗原结合片段包含H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2的三种或更多种CDR(例如CDR-H1、CDR-H2和CDR-H3;或CDR-L1、CDR-L2和CDR-L3)。
在本发明的一个实施例中,抗体的抗原结合片段将包含至少一个可变结构域。可变结构域可以具有任何尺寸或氨基酸组成并且一般包含邻近一个或多个框架序列或与一个或多个框架序列同框的至少一个CDR。在具有VH结构域与VL结构域缔合的抗原结合片段中,VH和VL结构域可相对于彼此以任何合适的布置定位。举例来说,可变区可以是二聚体,并且含有VH-VH、VH-VL或VL-VL二聚体。可替代地,抗体的抗原结合片段可含有单体VH或VL结构域。
在某些实施例中,抗体的抗原结合片段可含有与至少一个恒定结构域共价连接的至少一个可变结构域。可见于本发明的抗体的抗原结合片段内的可变结构域和恒定结构域的非限制性例示性构型包括:(i)VH-CH1;(ii)VH-CH2;(iii)VH-CH3;(iv)VH-CH1-CH2;(v)VH-CH1-CH2-CH3;(vi)VH-CH2-CH3;(vii)VH-CL;(viii)VL-CH1;(ix)VL-CH2;(x)VL-CH3;(xi)VL-CH1-CH2;(xii)VL-CH1-CH2-CH3;(xiii)VL-CH2-CH3;和(xiv)VL-CL。在可变结构域和恒定结构域的任何构型,包括上文所列的任何例示性构型中,可变结构域和恒定结构域可以彼此直接连接或可以由完整或部分的铰链区或接头区连接。铰链区可以由在单一多肽分子中相邻可变结构域与/或恒定结构域之间产生柔性或半柔性键联的至少2个(例如,5个、10个、15个、20个、40个、60个或更多个)氨基酸组成。此外,本发明的抗体的抗原结合片段可以包含具有上文所列的可变结构域和恒定结构域构型中的任一个彼此和/或与一个或多个单体VH或VL结构域(例如,通过二硫键)呈非共价缔合的同二聚体或异二聚体(或其它多聚体)。
抗原结合蛋白(例如抗体和抗原结合片段)可以是单特异性或多特异性的(例如双特异性的)。本文进一步讨论了多特异性抗原结合蛋白。
在具体实施例中,本发明的抗原结合蛋白(例如抗体或抗体片段)可以与例如配位体、可检测标记或治疗性部分(“免疫缀合物”)、第二抗IL36R抗体或任何其它治疗性部分的部分缀合。
“分离的”抗原结合蛋白(例如抗体或其抗原结合片段)、多肽、多核苷酸和载体至少部分地不含来自产生其的细胞或细胞培养物的其它生物分子。这类生物分子包括核酸、蛋白质、其它抗体或抗原结合片段、脂质、碳水化合物或其它材料,例如细胞碎片和生长培养基。分离的抗原结合蛋白可进一步至少部分地不含表达系统组分,例如来自宿主细胞或其生长培养基的生物分子。一般来说,术语“分离”不意图指完全不存在这类生物分子,或指不存在水、缓冲液或盐,或指包括抗原结合蛋白(例如抗体或抗原结合片段)的药物配制物的组分。
本发明包括抗原结合蛋白,例如抗体或抗原结合片段,其结合到与本发明的抗原结合蛋白(例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2)相同的表位。
术语“表位”是指与抗原结合蛋白的特异性抗原结合位点(例如抗体分子的可变区,称为互补位)相互作用的抗原决定簇(例如在IL1RL2上)。单个抗原可以具有超过一个表位。因此,不同抗体可以与抗原上的不同区域结合并且可以具有不同的生物效应。术语“表位”还可指B和/或T细胞与其反应的抗原上的位点和/或与抗体结合的抗原的区域。表位可以定义为结构性或功能性的。功能性表位一般是结构性表位的子集并且具有直接促成相互作用的亲和力的那些残基。表位还可以是线性的或构象性的,即,由非线性氨基酸构成。在某些实施例中,表位可以包括作为分子的化学活性表面基团的决定簇,所述基团例如氨基酸、糖侧链、磷酰基或磺酰基,并且在某些实施例中,可具有特定三维结构特征和/或荷质比特征。
确定抗原结合蛋白,例如抗体或片段或多肽的表位的方法包括丙氨酸扫描突变分析、肽印迹分析(Reineke(2004)《分子生物学方法(Methods Mol.Biol.)》248:443-63)、肽裂解分析、结晶研究和NMR分析。另外,可采用例如抗原的表位切除、表位提取和化学修饰的方法(Tomer(2000)《蛋白质科学(Prot.Sci.)》9:487-496)。可用于鉴别抗原结合蛋白(例如抗体或片段或多肽)与其相互作用的多肽内的氨基酸的另一方法是通过质谱法检测的氢/氘交换。参见例如,Ehring(1999)《分析生物化学(Analytical Biochemistry)》267:252-259;Engen和Smith(2001))《分析化学(Anal.Chem.)》73:256A-265A。
本发明包括与本发明的抗原结合蛋白(例如、H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2)竞争结合IL36R(例如,如本文中所论述的变体IL36R表位)的抗原结合蛋白。如本文所用,术语“竞争”是指与抗原(例如IL1RL2)结合并且抑制或阻断另一种抗原结合蛋白(例如抗体或其抗原结合片段)与抗原的结合的抗原结合蛋白(例如抗体或其抗原结合片段)。所述术语还包括两种抗原结合蛋白(例如抗体)在两个定向上的竞争,即,第一抗体结合并且阻断第二抗体的结合,并且反之亦然。在某些实施例中,第一抗原结合蛋白(例如抗体)和第二抗原结合蛋白(例如抗体)可与相同的表位结合。可替代地,第一和第二抗原结合蛋白(例如抗体)可能与不同但例如重叠的表位结合,其中一者的结合抑制或阻断第二抗体的结合,例如通过位阻。抗原结合蛋白(例如抗体)之间的竞争可以通过本领域中已知的方法测量,例如通过实时无标记生物层干涉测量分析。此外,抗IL36R抗原结合蛋白(例如单克隆抗体(mAb))之间的结合竞争可使用实时无标记生物层干涉测量分析在Octet RED384生物传感器(帕尔福特生物公司(Pall ForteBio Corp.))上确定。
通常,一定程度上被修饰的本发明的抗体或抗原结合片段保留与IL36R特异性结合的能力,例如,当所述活性按摩尔计表达时,保留其IL36R结合活性的至少10%(与亲本抗体相比时)。优选地,本发明的抗体或抗原结合片段保留与亲本抗体的IL36R结合亲和力的至少20%、50%、70%、80%、90%、95%或100%或更多。还希望本发明的抗体或抗原结合片段可包括保守性或非保守性氨基酸取代(称为抗体的“保守性变体”或“功能保守变体”),这并未基本上改变其生物活性。
多肽的“变体”,例如免疫球蛋白链(例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2 VH、VL、HC或LC)是指包含与本文中所阐述的所引用氨基酸序列(例如,SEQ ID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42、44、46、48、50、52、54、56、58、60、62、64、66、68、70、72、74、76、78、80、82、84、86、88、90、92、94、96、98、100、102、104、106、108、110、112、114、116、118、120、122、124、126、128、130、132、134、136、138、140、142、144、146、148、150、152、154、156、158、160、162、164、166、168、170、172、174、176、180、182、184、186、188、190、192、194、196、198、200、202、204、206、208、210、212、214、216、218、220、222、224或226中的任一者)至少约70-99.9%(例如,70、72、74、75、76、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、99.5、99.9%)一致或类似的氨基酸序列的多肽;当比较通过BLAST算法进行时,其中选择算法的参数以在对应的参考序列的全长上得到对应的序列之间的最大匹配(例如,期望阈值:10;字长:3;查询范围内的最大匹配:0;BLOSUM62矩阵;空位成本:存在11、延长1;条件组合评分矩阵调整)。
多核苷酸的“变体”是指包含与本文中所阐述的所引用核苷酸序列(例如,SEQ IDNO:1、3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41、43、45、47、49、51、53、55、57、59、61、63、65、67、69、71、73、75、77、79、81、83、85、87、89、91、93、95、97、99、101、103、105、107、109、111、113、115、117、119、121、123、125、127、129、131、133、135、137、139、141、143、145、147、149、151、153、155、157、159、161、163、165、167、169、171、173,175、179、183、187、191、195、199、203、207、211、215、219、223、181、185、189、193、197、201、205、209、213、217、221和/或225中的任一者)至少约70-99.9%(例如,70、72、74、75、76、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、99.5、99.9%)一致的核苷酸序列的多核苷酸;当比较通过BLAST算法进行时,其中选择算法的参数以在对应的参考序列的全长上得到对应的序列之间的最大匹配(例如,期望阈值:10;字长:28;查询范围内的最大匹配:0;匹配/失配评分:1,-2;空位成本:线性)。
以下参考文献涉及经常用于序列分析的BLAST算法:BLAST算法:Altschul等人.(2005)《欧洲生化学会联合会杂志(FEBS J.)》272(20):5101-5109;Altschul,S.F.,等人,(1990)《分子生物学杂志》215:403-410;Gish,W.,等人,(1993)《自然·遗传学(NatureGenet.)》3:266-272;Madden,T.L.,等人,(1996)《《酶学方法(Meth.Enzymol.)》266:131-141;Altschul,S.F.,等人,(1997)《核酸研究(Nucleic Acids Res.)》25:3389-3402;Zhang,J.,等人,(1997)《基因组研究(Genome Res.)》7:649-656;Wootton,J.C.,等人,(1993)《计算化学(Comput.Chem.)》17:149-163;Hancock,J.M.等人,(1994)《计算机在生物科学中的应用(Comput.Appl.Biosci.)》10:67-70;比对评分系统:Dayhoff,M.O.,等人,“蛋白质进化变化模型(A model of evolutionary change in proteins.)”于《蛋白质序列和结构地图集(Atlas of Protein Sequence and Structure)》中,(1978)第5卷,增刊3.M.O.Dayhoff(编),第345-352页,《国家生物医学研究基金会(Natl.Biomed.Res.Found.)》,Washington,D.C.;Schwartz,R.M.,等人,“检测到远端关系的基质(Matrices for detecting distant relationships.)”于《蛋白质序列和结构地图集》中,(1978)第5卷,增刊3.”M.O.Dayhoff(编),第353-358页,《国家生物医学研究基金会》,Washington,D.C.;Altschul,S.F.,(1991)《分子生物学杂志》219:555-565;States,D.J.,等人,(1991)《方法(Methods)》3:66-70;Henikoff,S.,等人,(1992)《美国国家科学院院刊》89:10915-10919;Altschul,S.F.,等人,(1993)《分子演化期刊(J.Mol.Evol.)》36:290-300;比对统计数据:Karlin,S.,等人,(1990)《美国国家科学院院刊》87:2264-2268;Karlin,S.,等人,(1993)《美国国家科学院院刊》90:5873-5877;Dembo,A.,等人,(1994)Ann.Prob.22:2022-2039;和Altschul,S.F.“评估多个不同局部比对的统计显著性(Evaluating the statistical significance of multiple distinct localalignments.)”于《基因组研究中的理论与计算方法(Theoretical and ComputationalMethods in Genome Research)》(S.Suhai,编),(1997)第1-14页,Plenum,N.Y。
在本发明的一个实施例中抗IL36R抗原结合蛋白,例如本发明的抗体和其抗原结合片段包括:重链免疫球蛋白或其可变区,其与SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸具有至少70%(例如,80%、85%、90%、95%、99%)的氨基酸序列一致性;和/或轻链免疫球蛋白或其可变区,其与SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸具有至少70%(例如,80%、85%、90%、95%、99%)的氨基酸序列一致性。
另外,抗IL36R抗原结合蛋白可包括包含本文中所阐述的氨基酸序列的多肽,不同之处在于一个或多个(例如,1、2、3、4、5、6、7、8、9或10个)突变,例如错义突变(例如保守性取代)、无义突变、缺失或插入。举例来说,本发明包括抗IL36R抗原结合蛋白,其包括免疫球蛋白轻链(或VL)变体和/或免疫球蛋白重链(或VH)变体,所述免疫球蛋白轻链变体包含SEQID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列但具有这类突变中的一者或多者,所述免疫球蛋白重链变体包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列但具有这类突变中的一者或多者。在本发明的一个实施例中,抗IL36R抗原结合蛋白包括免疫球蛋白轻链变体和/或免疫球蛋白重链,所述免疫球蛋白轻链变体包含CDR-L1、CDR-L2和CDR-L3,其中这类CDR中的一者或多者(例如1或2或3者)具有这类突变(例如保守性取代)中的一者或多者,所述免疫球蛋白重链变体包含CDR-H1、CDR-H2和CDR-H3,其中这类CDR中的一者或多者(例如1或2或3者)具有这类突变(例如保守性取代)中的一者或多者。
本发明的实施例还包括抗原结合蛋白,例如抗IL36R抗体和其抗原结合片段,所述抗体和其抗原结合片段包含免疫球蛋白VH和VL;或HC和LC,其包含与本文中特定地阐述的对应的VH、VL、HC或LC的氨基酸序列具有70%或更多(例如,80%、85%、90%、95%、97%或99%)的整体氨基酸序列一致性或类似性的变体氨基酸序列,但其中这类免疫球蛋白的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2和CDR-H3不为变体,并且包含本文中特定阐述的氨基酸序列。因此,在这类实施例中,变体抗原结合蛋白内的CDR自身不为变体。
例如本文中所阐述的免疫球蛋白链的“保守修饰的变体”或“保守性取代”是指其中多肽中具有一个或多个氨基酸取代,而其它氨基酸具有类似特征(例如,电荷、侧链尺寸、疏水性/亲水性、主链构象和刚度等)的变体。可以经常进行这类改变,而不会显著破坏抗体或片段的生物活性。本领域技术人员应认识到,一般说来,多肽非必需区中的单一氨基酸取代基本上不会改变生物活性(参见例如,Watson等人(1987)《基因分子生物学(MolecularBiology of the Gene)》,本杰明/卡明斯出版公司(The Benjamin/Cummings Pub.Co.),第224页(第4版))。另外,在结构上或在功能上类似的氨基酸的取代不大可能显著破坏生物活性。本发明包括包含这类保守修饰的变体免疫球蛋白链的抗IL36R抗原结合蛋白。
侧链具有类似化学特性的氨基酸组的实例包括1)脂肪族侧链:甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸;2)脂肪族羟基侧链:丝氨酸和苏氨酸;3)含酰胺的侧链:天冬酰胺和谷氨酰胺;4)芳香族侧链:苯丙氨酸、酪氨酸和色氨酸;5)碱性侧链:赖氨酸、精氨酸和组氨酸;6)酸性侧链:天冬氨酸和谷氨酸;和7)含硫侧链:半胱氨酸和甲硫氨酸。优选的保守性氨基酸取代组是:缬氨酸-亮氨酸-异亮氨酸、苯丙氨酸-酪氨酸、赖氨酸-精氨酸、丙氨酸-缬氨酸、谷氨酸-天冬氨酸以及天冬酰胺-谷氨酰胺。可替代地,保守性替代是在以下文献中公开的PAM250对数似然矩阵中具有正值的任何变化:Gonnet等人(1992)《科学(Science)》256:1443 45。
例如包含变体免疫球蛋白链的本文中所阐述的抗IL36R抗原结合蛋白可呈现以下特性中的一者或多者:
·例如在25℃下以约2.18nM到约13.9nM的KD或例如在37℃下以约4.25nM到约29.5nM的KD与人类IL36R(例如IL1RL2)(例如与myc-myc-His6标签融合)结合;
·例如在25℃下以约7.87nM到约34.4nM的KD或例如在37℃下以约14.4nM到约58.2nM的KD与食蟹猴IL36R(例如IL1RL2)(例如,与myc-myc-His6标签融合)结合;
·与例如在25℃下以约173pM到约5.79nM的KD或例如在37℃下以约205pM到约28.7nM的KD与人类IL36R(例如IL1RL2)(例如,与小鼠IgG2a融合)结合;
·例如在25℃下以约212pM到约14nM的KD或例如在37℃下以约264pM到约40.9nM的KD与人类IL36R(例如IL1RL2)(例如,经表达具有小鼠IgG2a Fc标签的与IL1RAcP胞外结构域融合)结合;
·与以下一种或多种抗IL36R抗体竞争结合IL36R(例如IL1RL2):H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P和/或H4H14760P2,任选地其限制条件为与H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P和/或H4H14760P2竞争的这类抗IL36R抗体或片段不是抗体APE3798;APE4086;APE5125/APE5100;APE5216;APE5281;APE5214/APE4881;APE5280;APE5257;APE5258/APE5076;APE5212;APE5213/5066;APE5211;APE5217/APE5060;APE3849;APE3850;APE5600;APE5598;APE5627;APE6064;APE6060;APE6157;APE6155/APE6917;APE6194;APE3847;APE5713;APE6083;APE6903/APE7247;APE6904;和/或APE6907(例如APE6155)或其抗原结合片段或包含其CDR或可变区的抗原结合蛋白(参见WO2016/168542);
·阻断在IL-1RAcP和例如hIL-36α,hIL-36β和/或hIL-36γ的配位体存在的情况下IL-36R(例如,人类或食蟹猴)对NFκB的激活,例如,其中NFKB在例如HEK293的宿主细胞中,例如,含有NFκB反应元件(5×)-荧光素酶-IRES-GFP,例如,IC50为约1×10-10M-7×10- 9M;
·例如,相对于未用这类抗原结合蛋白治疗的个体,在罹患皮肤炎症(例如慢性或急性),例如化学诱导的皮肤炎症(例如咪喹莫特(imiquimod)诱导的)的个体,例如,小鼠,例如显示人类白细胞介素三十六受体拮抗因子缺乏(Deficiency of InterleukinThirty-six Receptor Antagonist;DITRA)疾病的症状的小鼠中预防或改善皮肤炎症(例如慢性或急性)或降低皮肤厚度或总病理评分或降低促炎性细胞因子水平(例如KC-GRO、IL6、IL1b和/或TNFα),所述疾病描述于例如Marrakchi等人,《白细胞介素-36-受体拮抗因子缺乏症和泛发性脓疱型牛皮癣(Interleukin-36-receptor antagonist deficiencyand generalized pustular psoriasis)》,《新英格兰医学杂志(N Engl J Med)》365:620-628(2011);和/或
·例如,相对于未用这类抗原结合蛋白治疗的个体,在罹患结肠炎或结肠炎症,例如化学诱导,例如右旋糖酐硫酸酯钠(DSS)或恶唑酮诱导的结肠炎或结肠炎症的个体,例如小鼠,例如DITRA小鼠中预防或改善这类结肠炎或炎症或减少LCN2多肽的粪便水平。
·在结合时保护包含SEQ ID NO:227中所阐述的氨基酸序列的IL36R多肽的残基(a)113-119、113-122、116-119和/或116-122;和/或(b)264-271、267-271、268-271、268-276、268-277和/或271-276免受胃蛋白酶和/或蛋白酶XIII(例如来自斋藤曲霉(Aspergillus saitoi))消化和/或在氘(例如D2O)存在的情况下氘化的影响;*
·在包含SEQ ID NO:227中所阐述的氨基酸序列的IL36R多肽的残基113-119、113-122、116-119、116-122、264-271、267-271、268-271、268-276、268-277和/或271-276处与IL36R,例如其IL1RL2亚单位结合;*
·结合IL36R的结构域II,例如其中覆盖率为约80.0、80.1、81.0或81.5%;
·结合包含氨基酸序列YKQILHLGKD(SEQ ID NO:229)(SEQ ID NO:227的氨基酸113-122)和/或GVETHVSFREHNYL(SEQ ID NO:230)(SEQ ID NO:227的氨基酸264-277)的多肽;
·以约1、2、3、4、5或6nM或1-6nM的IC50抑制例如体外表皮角化细胞、肠道肌成纤维细胞和/或CD14+单核细胞中的IL36α、IL36β和/或IL36γ(例如浓度为约10nM);和/或
·竞争性地抑制IL36α、IL36β和/或IL36γ介导的IL36R对NFκB(例如,例如HEK293的细胞中的NFκB反应元件(5×)-荧光素酶-IRES-GFP报告因子)的激活;例如如斯切尔德分析形式中所测量。
*包括在对应于包含SEQ ID NO:227中所阐述的氨基酸序列的被标记的IL36R多肽中所阐述的残基的残基处与例如如以UniProt寄存编号Q9HB29阐述的天然IL36R(IL1-RL2)结合的抗原结合蛋白。参见下文:
113-119:YKQILHL(SEQ ID NO:228)(SEQ ID NO:227的氨基酸113-119);
113-122:YKQILHLGKD(SEQ ID NO:229)(SEQ ID NO:227的氨基酸113-122);
116-119:ILHL(SEQ ID NO:231)(SEQ ID NO:227的氨基酸116-119);
116-122:ILHLGKD(SEQ ID NO:232)(SEQ ID NO:227的氨基酸116-122);
264-271:GVETHVSF(SEQ ID NO:233)(SEQ ID NO:227的氨基酸264-271);
267-271:THVSF(SEQ ID NO:234)(SEQ ID NO:227的氨基酸267-271);
268-271:HVSF(SEQ ID NO:235)(SEQ ID NO:227的氨基酸268-271);
268-276:HVSFREHNL(SEQ ID NO:236)(SEQ ID NO:227的氨基酸268-276);
268-277:HVSFREHNLY(SEQ ID NO:237)(SEQ ID NO:227的氨基酸268-277);
271-276:FREHNL(SEQ ID NO:238)(SEQ ID NO:227的氨基酸271-276)。
参见下文在人类IL36R(IL1RL2)中突出显示的残基:
(SEQ ID NO:117)
本发明包括“中和”或“拮抗性”抗IL36R抗原结合蛋白,例如抗体或抗原结合片段,其包括将IL36R的活性抑制到任何可检测程度(例如IL36配位体结合)的分子。
“H4H14699P2”、“H4H14700P2”、“H4H14706P2”、“H4H14708P2”、“H4H14709P”、“H4H14728P”、“H4H14731P”、“H4H14732P2”、“H4H14734P2”、“H4H14757P”、“H4H14758P”和“H4H14760P2”是指抗原结合蛋白,例如抗体和其抗原结合片段(包括多特异性抗原结合蛋白),其包含分别为SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224的免疫球蛋白重链或其可变区(VH)(或其变体);和分别为10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226的免疫球蛋白轻链或其可变区(VL)(或其变体);或其包含有包含其CDR(CDR-H1(或其变体)、CDR-H2(或其变体)和CDR-H3(或其变体))的重链或VH和/或包含其CDR(CDR-L1(或其变体)、CDR-L2(或其变体)和CDR-L3(或其变体))的轻链或VL,例如,其中免疫球蛋白链、可变区和/或CDR包含下文所述的具体氨基酸序列。在本发明的一个实施例中,VH与IgG恒定重链结构域(例如IgG1或IgG4)连接和/或VL与λ或κ恒定轻链结构域连接。
本发明的抗体和抗原结合片段包含包括本文中所阐述的氨基酸序列的免疫球蛋白链以及
对抗体或片段的细胞和体外翻译后修饰。举例来说,本发明包括与包含本文中所阐述的重和/或轻链氨基酸序列(例如,CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和/或CDR-L3)的IL36R特异性结合的抗体和其抗原结合片段以及以下抗体和片段,其中一个或多个天冬酰胺、丝氨酸和/或苏氨酸残基被糖基化,一个或多个天冬酰胺残基被脱酰胺被脱酰胺,一个或多个残基(例如Met、Trp和/或His)被氧化,N端谷氨酰胺为焦谷氨酸盐(pyroE)和/或C端赖氨酸缺失。
本发明提供包含本发明的抗IL36R抗原结合蛋白,例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2的容器(例如,塑料或玻璃小瓶,例如带有盖子或色谱柱、中空孔针或注射器针筒)。
本发明还提供包含一种或多种与IL36R,例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2特异性结合的抗原结合蛋白(例如抗体或抗原结合片段)或其药物组合物的注射装置。可以将注射装置包装到试剂盒中。注射装置为经由肠胃外途径,例如肌肉内、皮下或静脉内将物质引入个体体内的装置。例如,注射装置可以是注射器(例如,预填充有药物组合物的注射器,例如自动注射器),所述注射器例如包括用于容纳待注射的流体(例如,包含抗体或其片段或药物组合物)的针筒或筒管、用于刺穿皮肤和/或血管以注射流体的针;和用于将流体从针筒中推出并且通过针孔的活塞。
本发明还提供向个体施用本发明的抗IL36R抗原结合蛋白,例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2的方法,其包含将抗原结合蛋白引入个体(例如人类)体内,例如非经肠。举例来说,所述方法包含用注射器的针刺穿个体身体并且将抗原结合蛋白注入个体体内,例如注入个体的静脉、动脉、肿瘤、肌肉组织或皮下组织中。
人类抗体的制备
用于在转基因小鼠中产生人类抗体的方法是本领域中已知的。在本发明的背景下,任何这类已知方法都可用于制备与IL36R(例如IL1RL2)特异性结合的人类抗体。在本发明的某些实施例中,本发明的抗体获自用IL36R(例如,IL1RL2多肽或其免疫原性片段)或用活的减毒或灭活病毒或用编码蛋白质或其片段的DNA免疫的小鼠。可替代地,IL36R可以使用标准生化技术生产,并且进行修饰并用作免疫原。在本发明的某些实施例中,免疫原可以是IL36R(例如IL1RL2)多肽疫苗。在某些实施例中,可以施用一次或多次加强注射。在某些实施例中,所述免疫原可以是在大肠杆菌中或在任何其它真核细胞或哺乳动物细胞(例如中国仓鼠卵巢(CHO)细胞)中表达的重组IL36R多肽(例如IL1RL2)。
使用技术(参见例如US 6,596,541,再生元制药公司(Regeneron Pharmaceuticals),)或用于生成单克隆抗体的任何其它已知方法,可以首先分离出具有人类可变区和小鼠恒定区的高亲和力抗IL36R嵌合抗体。技术涉及生成转基因小鼠,所述转基因小鼠具有包含与内源性小鼠恒定区基因座可操作地连接的人类重链和轻链可变区的基因组,使得所述小鼠响应于抗原刺激产生包含人类可变区和小鼠恒定区的抗体。分离出编码抗体的重链和轻链可变区的DNA并且将其与编码人类重链和轻链恒定区的DNA可操作地连接。随后,在能够表达完全人类抗体的细胞中表达所述DNA。
一般来说,用所关注抗原攻击小鼠,并从表达抗体的小鼠中回收淋巴细胞(例如B细胞)。淋巴细胞可与骨髓瘤细胞系融合以制备无限增殖杂交瘤细胞系,并且对这类杂交瘤细胞系进行筛选和选择以鉴别出产生对所关注抗原具有特异性的抗体的杂交瘤细胞系。可将编码重链和轻链可变区的DNA分离并与所期望的重链和轻链的同种型恒定区连接。这类抗体蛋白可以在细胞(例如CHO细胞)中产生。可替代地,可直接从抗原特异性淋巴细胞中分离出编码抗原特异性嵌合抗体或轻链和重链可变结构域的DNA。
首先,分离出具有人类可变区和小鼠恒定区的高亲和力嵌合抗体。针对期望特征,包括亲和力、选择性、表位等表征并且选择抗体。小鼠恒定区被期望的人类恒定区置换以生成本发明的完全人类抗体,例如野生型或修饰的IgG1或IgG4。虽然所选择的恒定区可以根据具体用途而变化,但高亲和力抗原结合和靶特异性特征存在于可变区中。
包含Fc变体的抗IL36R抗体
根据本发明的某些实施例,提供了抗IL36R抗原结合蛋白,例如抗体或抗原结合片段,其包含Fc结构域,所述Fc结构域包含一个或多个突变,所述突变例如与中性pH相比在酸性pH下增强了或减少了抗体与FcRn受体的结合。举例来说,本发明包括在Fc结构域的CH2或CH3区中包含突变的抗IL36R抗体,其中所述突变增加了Fc结构域在酸性环境中(例如,在pH值范围为约5.5到约6.0的内体中)对FcRn的亲和力。当向动物施用时,这类突变可以导致抗体的血清半衰期增加。这类Fc修饰的非限制性实例包括例如位置250(例如E或Q);250和428(例如L或F);252(例如L/Y/F/W或T)、254(例如S或T)和256(例如S/R/Q/E/D或T)处的修饰;或位置428和/或433(例如H/L/R/S/P/Q或K)和/或434处的修饰(例如A、W、H、F或Y[N434A、N434W、N434H、N434F或N434Y]);或位置250和/或428处的修饰;或位置307或308处的修饰(例如308F、V308F)以及位置434处的修饰。在一个实施例中,修饰包含428L(例如M428L)和434S(例如N434S)修饰;428L、259I(例如V259I)和308F(例如V308F)修饰;433K(例如H433K)和434(例如434Y)修饰;252、254和256(例如252Y、254T和256E)修饰;250Q和428L修饰(例如T250Q和M428L);以及307和/或308修饰(例如308F或308P)。在又一实施例中,修饰包含265A(例如D265A)和/或297A(例如N297A)修饰。
举例来说,本发明包括抗IL36R抗原结合蛋白,例如抗体或抗原结合片段,其包含有包含一对或多对或者一组或多组选自由以下组成的群组的突变的Fc结构域:250Q和248L(例如T250Q和M248L);252Y、254T和256E(例如M252Y、S254T和T256E);428L和434S(例如M428L和N434S);257I和311I(例如P257I和Q311I);257I和434H(例如P257I和N434H);376V和434H(例如D376V和N434H);307A、380A和434A(例如T307A、E380A和N434A);以及433K和434F(例如H433K和N434F)。
抗IL36R抗原结合蛋白,例如抗体和其抗原结合片段涵盖在本发明的范围内,所述抗体和其抗原结合片段包含如本文中所阐述的VH和/或VL,其包含前述Fc结构域突变的任何可能的组合。
本发明还包括抗IL36R抗原结合蛋白、抗体或抗原结合片段,其包含本文中所阐述的VH和嵌合重链恒定(CH)区,其中嵌合CH区包含衍生自超过一种免疫球蛋白同种型的CH区的链段。举例来说,本发明的抗体可以包含嵌合CH区,所述区包含衍生自人类IgG1、人类IgG2或人类IgG4分子的CH2结构域的部分或全部,其与衍生自人类IgG1、人类IgG2或人类IgG4分子的CH3结构域的部分或全部组合。根据某些实施例,本发明的抗体包含具有嵌合铰链区的嵌合CH区。举例来说,嵌合铰链可以包含来源于人类IgG1、人类IgG2或人类IgG4铰链区的“上铰链”氨基酸序列(根据EU编号,位置216到227的氨基酸残基),其与来源于人类IgG1、人类IgG2或人类IgG4铰链区的“下铰链”序列(根据EU编号,位置228到236的氨基酸残基)组合。根据某些实施例,嵌合铰链区包含衍生自人类IgG1或人类IgG4上铰链的氨基酸残基,和衍生自人类IgG2下铰链的氨基酸残基。包含如本文所描述的嵌合CH区的抗体可以在某些实施例中呈现修饰的Fc效应功能,而不会不利地影响抗体的治疗或药代动力学特性。(参见例如WO2014/022540)。
多特异性抗原结合蛋白
本发明包括抗IL36R抗原结合蛋白,例如抗体和其抗原结合片段,以及其使用方法和制备这类抗原结合蛋白的方法。术语“抗IL36R”抗原结合蛋白,例如抗体或抗原结合片段包括多特异性(例如双特异性或双互补位)分子,其包括至少一个与IL36R(例如IL1RL2)特异性结合的第一抗原结合结构域(例如,来自H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2的抗原结合结构域)和至少一个与不同抗原或与IL36R中不同于第一抗原结合结构域的表位结合的第二抗原结合结构域(例如,IL23-p19、IL12/IL23-p40、TNFα、IL-22、MADCAM、a4b7、CCR9和/或CCR6)。在本发明的一个实施例中,第一和第二表位重叠。在本发明的另一实施例中,第一和第二表位不重叠。
“H4H14699P2”;“H4H14700P2”;“H4H14706P2”;“H4H14708P2”;“H4H14709P”;“H4H14728P”;“H4H14731P”;“H4H14732P2”;“H4H14734P2”;“H4H14757P”;“H4H14758P”或“H4H14760P2”包括多特异性分子,例如抗体或抗原结合片段,其分别包括H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2的HCDR和LCDR、VH和VL或HC和LC以及一个或多个与不同表位结合的抗原结合结构域。
在本发明的一个实施例中,可以包括在多特异性分子中的与IL36R(例如IL1RL2)特异性结合的抗原结合结构域包含:
(1)
(i)重链可变结构域(VH)序列,其包含来自选自以下的免疫球蛋白重链的CDR-H1、CDR-H2和CDR-H3:H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P和H4H14760P2,和
(ii)轻链可变结构域(VL)序列,其包含来自选自以下的免疫球蛋白重链的CDR-L1、CDR-L2和CDR-L3:分别为H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P和H4H14760P2;
或,
(2)
(i)重链可变结构域(VH)序列,其选自:H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P和H4H14760P2;和
(ii)轻链可变结构域(VL)序列,其选自:分别为H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P和H4H14760P2;
和
一个或多与不同表位结合的抗原结合结构域。
在本发明的一个实施例中,多特异性抗体或片段包括超过两个不同的结合特异性(例如三特异性分子),举例来说,一个或多个与第一和/或第二抗原结合结构域相同或不同的额外抗原结合结构域。
在本发明的一个实施例中,双特异性抗原结合片段包含对第一表位(例如IL36R)具有结合特异性的第一scFv(例如,其包含H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P和H4H14760P2的VH和VL)以及对第二个不同的表位具有结合特异性的第二scFv。举例来说,在本发明的一个实施例中,第一和第二scFv与连接子,例如肽连接子(例如GS连接子,例如(GGGGS)n(SEQ ID NO:177),其中n为例如1、2、3、4、5、6、7、8、9或10)系在一起。
其它双特异性抗原结合片段包括双特异性IgG抗体和另一种与不同表位结合的抗体的F(ab)2,所述双特异性IgG抗体包含H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P和H4H14760P2的重链和轻链CDR。
免疫缀合物
本发明涵盖抗IL36R抗原结合蛋白,例如抗体或抗原结合片段,其与另一部分,例如治疗性部分缀合(“免疫缀合物”)。在本发明的一个实施例中,抗IL36R抗原结合蛋白,例如抗体或抗原结合片段与本文中所阐述的其它治疗剂中的任一种缀合。如本文所用,术语“免疫缀合物”是指抗原结合蛋白,例如抗体或抗原结合片段,其与另一种抗原结合蛋白、放射性试剂、报告因子部分、酶、肽、蛋白质或治疗剂化学或生物连接。
治疗和预防方法
本发明提供通过向需要这类治疗或预防的个体(例如人类)施用治疗有效量的抗IL36R抗原结合蛋白,例如抗体或抗原结合片段(例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2)治疗或预防IL-36R介导的疾病的方法。
“治疗(treat/treating)”意指向患有IL36R介导的疾病的个体施用抗IL36R抗原结合蛋白,例如本发明的抗体或抗原结合片段(例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2),以使得IL36R介导的疾病的一种或多种病征和/或症状和/或临床标志消退或被消除,和/或其恶化受到抑制(例如,个体的疾病被稳定化、减少或消除)。
“预防”IL36R介导的疾病意指在个体体内的疾病表现出之前向个体施用抗IL36R抗原结合蛋白,例如,本发明的抗体或抗原结合片段(例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2)。
白细胞介素IL-36RN为IL-1细胞因子家庭成员,其在IL-36R处拮抗IL-36α、IL-36β和IL-36γ的促炎性信号。
IL-36R介导的疾病为由IL-36R的活性(例如,由于例如IL36γ,IL36γ和/或IL36γ的配位体的受体结合经由NFκB和MAP激酶激活下游发炎性传信),例如由于IL36R拮抗因子(例如IL-36RN)的缺乏引起或加剧的任何疾病。在本发明的一个实施例中,IL36RN中的突变是IL-36R介导的疾病的基础。这类疾病的实例是自身免疫性和/或发炎性病症。在本发明的实施例中,用抗IL36R抗原结合蛋白治疗的IL-36R介导的疾病为发炎性病症、自身免疫性病症、白细胞介素IL-36受体拮抗因子缺乏(DITRA)综合症、疱疹样脓疱病(impetigoherpetiformis)、肢端皮炎(acrodermatitis)、中性粒细胞脓疱型皮肤病、牛皮癣(psoriasis)、脓疱型疾病、泛发性脓疱型牛皮癣(GPP;例如家族性或偶发性)、寻常型牛皮癣/斑块状牛皮癣、掌跖脓疱型牛皮癣(PPPP)、掌跖脓疱病(PPP)、结肠炎、发炎性肠病、溃疡性结肠炎、克罗恩氏病(Crohn's disease)、化学诱导的结肠炎、炎症、气道炎症(例如,中性粒细胞气道炎症、慢性阻塞性肺病(chronic obstructive pulmonary disease;COPD)或哮喘)、关节炎症(例如,强直性脊柱炎、类风湿性关节炎或牛皮癣性关节炎)、肾脏炎症、斑秃、皮肤炎症(例如,化学诱导的皮肤炎症、牛皮癣、脓疱型牛皮癣、泛发性脓疱型牛皮癣、掌跖脓疱病、掌跖脓疱型牛皮癣、寻常型牛皮癣或牛皮癣性皮肤病变)、棘皮症(acanthosis)、角化过度(hyperkeratosis)、金德勒氏综合症(kindler syndrome)、全身性红斑狼疮(systemic lupus erythematosus;SLE)、肾病综合症、抗中性粒细胞胞质抗体(anti-neutrophil cytoplasmic antibody;ANCA)相关血管病变、肾小管间质病变和肾小球肾炎。
发炎性病症是特征为可能造成健康组织破坏的不受控或非所要炎症的病症。
自身免疫性病症为其免疫系统错误地攻击其自身主体的病况。
疱疹样脓疱病(IH)是罕见的妊娠皮肤病之一,其目前被认为是泛发性脓疱型牛皮癣的一种形式。在本发明的一个实施例中,IL36RN中的突变是IH的基础。
肢端皮炎是可能影响例如介于3月龄与15岁之间的儿童的皮肤病况,其特征在于身体上有瘙痒的红色或紫色水疱、腹胀、发烧和淋巴结肿胀、酸痛。肢端皮炎的病因可能是病毒。IL-36受体拮抗因子(例如IL-36Ra)的突变存在于大比例的患有GPP和持续性肢端皮炎(acrodermatitis continua)的患者中。在本发明的一个实施例中,IL36RN中的突变是肢端皮炎的基础。
牛皮癣是一种自身免疫性疾病,会引起皮肤斑块,这些斑块是厚的红色干燥皮肤的瘙痒或酸痛斑块。牛皮癣最常见的形式是寻常型牛皮癣(斑块状牛皮癣),其特征在于红色凸起皮肤界限分明的斑块,所述斑块可出现在皮肤的任何区域上,包括膝部、肘部、头皮和躯干。斑块顶部上的薄片状银白色聚集物称为鳞;其由死皮细胞构成。这种鳞是松动的,并且不断地从斑块中脱落。皮肤症状包括疼痛、瘙痒和龟裂。
泛发性脓疱型牛皮癣(GPP)是严重形式的牛皮癣。患有GPP的个体通常会有反复发作,大面积的皮肤变红并发炎,并且产生小的化脓水疱(脓疱)。一部分患有GPP的个体罹患斑块。皮肤问题可伴有发烧、极度疲劳(疲乏)、肌无力、白血细胞数量增加和整个身体的炎症(全身性炎症)的其它病征。IL-36细胞因子似乎在GPP的发展中起一定作用。在本发明的一个实施例中,IL36RN中的突变是GPP的基础。
掌跖脓疱型牛皮癣(PPPP;4P)是局部脓疱型牛皮癣的一种形式,其特征为斑块和脓疱存在于皮肤的手掌和足底表面上。PPPP可以与导致IL-36R拮抗因子功能畸变的纯合或复合杂合IL36RN基因突变相关联。在本发明的一个实施例中,IL36RN中的突变是PPPP的基础。
掌跖脓疱病(PPP;3P)是免疫介导的病症,其导致水疱样脓疱出现在你的手掌和你的足底上。一般来说,患有PPP的个体不会罹患斑块。在本发明的一个实施例中,IL36RN中的突变是PPP的基础。
白细胞介素IL-36受体拮抗因子缺乏(DITRA)综合症是由IL36RN中的突变引起的罕见的常染色体隐性疾病。DITRA是伴随有免疫缺乏疾病的罕见的遗传性自体发炎性综合症,其特征为由于IL36R拮抗因子缺乏引起的与高烧、乏力和全身性炎症相关联的泛发性脓疱型牛皮癣的复发和严重暴发。牛皮癣性指甲改变(例如点状凹陷和甲癣)和鱼鳞病(ichthyosis)可能偶尔相关。参见Marrakchi等人,《新英格兰医学杂志》365(7):620-628(2011)。在本发明的一个实施例中,IL36RN中的突变是DITRA的基础。
发炎性疾病是特征为个体体内一个或多个部位处有异常炎症的病况。自身免疫性疾病是特征为个体自身免疫系统异常攻击个体身体组织的病况。
ANCA相关血管病变(AAV)为发炎性病症,其包括肉芽肿性多血管炎(Granulomatosis with polyangiitis)(旧称为韦格纳肉芽肿(Wegener's))、显微镜下多血管炎和EGPA/查格施特劳斯综合症(Churg Strauss)。这些病况的特征为导致血管堵塞和流向重要器官(如肾脏)的血流减少的慢性炎症。
发炎性肠病(IBD)是包括特征为胃肠(GI)道的慢性炎症的两种病况(克罗恩氏病和溃疡性结肠炎)的术语。
中性粒细胞气道炎症是由中性粒细胞内流到肺中介导的气管的炎症。中性粒细胞气道炎症的病征和症状包括哮喘和喘息。
慢性阻塞性肺病(COPD)是造成来自肺的气流阻塞的慢性发炎性肺病。病征和症状包括呼吸困难、咳嗽、粘液(痰液)产生和喘息。
强直性脊柱炎(AS)是特征为脊椎(例如,骶髂(SI)关节和中轴骨)的长期炎症的疾病。随时间推移,AS可导致你的脊椎中的某些椎骨融合。症状包括你的下背和髋部疼痛和僵硬。
类风湿性关节炎是特征为关节炎症的自身免疫性病况。症状包括触痛、升温、关节肿胀;关节僵硬、疲乏、发烧和体重减轻。
牛皮癣性关节炎是影响患有牛皮癣的某些人的关节炎的一种形式。症状可包括手指和脚趾肿胀、脚痛和下背痛。
斑秃是特征为身体上小的秃发斑块的斑点秃发。
棘皮症是皮肤的棘层(棘细胞层)的弥漫性表皮增厚(增生),其可能看起来比其它皮肤更深。角化过度是皮肤的外层增厚。
角化过度是通常由于来自太阳、化学品或频繁摩擦或压力的刺激引起的皮肤增厚。皮肤增厚通常发生在皮肤外层,其含有坚固的保护性蛋白质,称为角蛋白。
金德勒氏综合症是常染色体隐性遗传性皮肤病,其特征为先天性肢端皮肤起水疱、光敏性、进行性皮肤异色病和弥漫性皮肤萎缩。粘膜表现是常见的,常常涉及口腔粘膜、牙龈和胃肠道。
全身性红斑狼疮(SLE)是自身免疫性疾病。在这种疾病中,身体免疫系统错误地攻击健康组织。SLE会影响皮肤、关节、肾脏、大脑和其它器官。
肾病综合症是导致你的主体在你的尿液中排出过多蛋白质的肾脏病症。肾病综合症通常是由从你的血液中过滤废料和过量水的肾脏中的小血管簇受损引起的。肾病综合症症状可包括肿胀(水肿),特别是脚和脚踝肿胀、泡沫状尿液、体重增加(由于液体潴留)、疲乏和食欲不振。
肾小球肾炎是肾小球的炎症。症状包括你的尿液中由于红血细胞引起的墨色或可乐色尿液(血尿症)、泡沫状尿液(由于蛋白尿)、血压高(高血压)、液体潴留(水肿)。
用于治疗或预防IL-36R介导的疾病的抗IL36R抗原结合蛋白,例如抗体或抗原结合片段(例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2)的有效剂量或治疗有效剂量是指足以缓解所治疗个体的疾病的临床标志、病征和/或症状中的一者或多者的抗体或片段的量,无论是否通过诱导这类标志、病征和/或症状的消退或消除或通过抑制这类标志、病征和/或症状的恶化。剂量可以取决于待施用的个体的年龄和体格、目标疾病、病况、施用途径等而变化。在本发明的一个实施例中,用于治疗或预防例如成人个体的IL36R介导的疾病的本发明的抗体或其抗原结合片段的有效剂量或治疗有效剂量是约1mg/kg或更多,例如,约1mg/kg到约25mg/kg。取决于感染的严重程度,可以调整治疗的频率和持续时间。在某些实施例中,本发明的抗原结合蛋白可以初始剂量,随后一个或多个二级剂量施用。在某些实施例中,初始剂量之后可以施用抗原结合蛋白的第二或多个后续剂量,其量可以大致等于或小于初始剂量的量,其中后续剂量间隔至少1天到3天;至少一周,至少2周;至少3周;至少4周;至少5周;至少6周;至少7周;至少8周;至少9周;至少10周;至少12周;或至少14周。
如本文所用,术语“个体”是指哺乳动物(例如大鼠、小鼠、猫、狗、奶牛、绵羊、马、山羊、兔),优选为例如需要预防和/或治疗IL-36R介导的疾病的人类。个体可能患有IL-36R介导的疾病或倾向于罹患这类疾病。在本发明的一个实施例中,个体具有纯合或杂合IL36RN突变基因型。
本发明涵盖向处于罹患IL36R介导的疾病的风险下的个体施用抗IL36R抗原结合蛋白的方法。举例来说,在本发明的一个实施例中,疾病是皮肤发炎性疾病或结肠发炎性疾病。本文中的实例5证实,在暴露于咪喹莫特和皮肤炎症症状发展之前,可在DITRA样小鼠模型中预防皮肤炎症疾病。在本发明的一个实施例中,在任何临床上明显的炎症,例如,皮肤炎症或炎症诱导的皮肤厚度、总病理评分(如本文中所论述)或在皮肤中促炎性细胞因子(KC-GRO、IL-6、IL-1β或TNFα)存在的情况下有任何增加之前,通过向个体施用预防性剂量的抗原结合蛋白预防IL36R介导的疾病(例如皮肤炎症)。在本发明的一个实施例中,用于预防IL36R介导的疾病的本发明的抗IL36R抗原结合蛋白的剂量是约1mg/kg到约10mg/kg。
组合和药物组合物
本发明提供包括抗IL36R抗原结合蛋白和一种或多种成分的组合物;以及其使用方法和制备这类组合物的方法。
为了制备抗IL36R抗原结合蛋白,例如抗体和其抗原结合片段(例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2)的药物组合物,将抗原结合蛋白与药学上可接受的载体或赋形剂掺合。参见例如,《雷明顿氏药物科学和美国药典:国家处方集(Remington's Pharmaceutical Sciences and U.S.Pharmacopeia:NationalFormulary)》,宾夕法尼亚州伊斯顿马克出版公司(Mack Publishing Company,Easton,Pa.)(1984);Hardman,等人(2001)《古德曼和吉尔曼氏治疗学的药理学基础(Goodman andGilman's The Pharmacological Basis of Therapeutics)》,纽约州纽约麦格劳希尔(McGraw-Hill,New York,N.Y.);Gennaro(2000)《雷明顿:药剂学科学和实践(Remington:The Science and Practice of Pharmacy)》,Lippincott,Williams和Wilkins,纽约州纽约;Avis,等人(编)(1993)《药学剂型:肠胃外药物(Pharmaceutical Dosage Forms:Parenteral Medications》,马塞尔德克(Marcel Dekker),纽约;Lieberman,等人(编)(1990)《药学剂型:片剂(Pharmaceutical Dosage Forms:Tablets)》,马塞尔德克,纽约;Lieberman,等人(编)(1990)《药学剂型:分散系统(Pharmaceutical Dosage Forms:Disperse Systems)》,马塞尔德克,纽约;Weiner和Kotkoskie(2000)《赋形剂毒性和安全性(Excipient Toxicity and Safety)》,马塞尔德克公司,纽约州纽约。在本发明的一个实施例中,药物组合物是无菌的。这类组合物是本发明的一部分。
本发明的药物组合物包括药学上可接受的载体、稀释剂、赋形剂和/或稳定剂,例如水、缓冲剂、稳定剂、防腐剂、等渗剂、非离子洗涤剂、抗氧化剂和/或其它混杂的添加剂。
本发明的范围包括干燥,例如冷冻干燥的组合物,其包含抗IL36R抗原结合蛋白,例如抗体或其抗原结合片段(例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2)或其药物组合物,所述药物组合物包括药学上可接受的载体但基本上缺乏水。
在本发明的另一个实施例中,根据《医师案头参考(the Physicians'DeskReference)》2003(汤姆森医疗(Thomson Healthcare);第57版(2002年11月1日))向个体施用本文所公开的与抗IL36R抗原结合蛋白,例如抗体或其抗原结合片段(例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2)结合向个体施用的另一种治疗剂。
施用抗原结合蛋白或其组合物的模式可以变化。施用途径包括经口、经直肠、经粘膜、肠道、肠胃外;肌肉内、皮下、皮内、髓内、鞘内、直接脑室内、静脉内、腹膜内、鼻内、眼内、吸入、吹入、局部、皮肤、经皮或动脉内。
本发明提供向个体施用抗IL36R抗原结合蛋白,例如抗体或其抗原结合片段(例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2)的方法,其包含将蛋白质或药物组合物或其组合引入个体体内。举例来说,在本发明的一个实施例中,所述方法包含例如用注射器的针刺穿个体身体,并且将抗原结合蛋白或药物组合物或其组合注射到个体体内,例如注射到个体的静脉、动脉、肿瘤、肌肉组织或皮下组织中。
本发明提供一种容器(例如,塑料或玻璃小瓶,例如带有盖子或色谱柱、中空孔针或注射器针筒),其包含抗IL36R抗原结合蛋白,例如抗体或其抗原结合片段(例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2)或包含药学上可接受的载体或其组合的药物组合物中的任一者。
本发明包括与一种或多种其它治疗剂结合包括抗IL36R抗原结合蛋白,例如本发明的抗体或其抗原结合片段(例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2)的组合。抗IL36R抗原结合蛋白和另一种治疗剂可在单一组合物中或在单独的组合物中。举例来说,在本发明的一个实施例中,另一种治疗剂是抗炎性药物。在本发明的一个实施例中,另一种治疗剂是另一种抗IL35R抗原结合蛋白、IL17抑制剂、IL23p19抑制剂、IL12p40抑制剂、古塞库单抗、优特克单抗、布罗达单抗、依奇珠单抗、苏金单抗、抗TNFα抗体或其抗原结合片段、一种或多种与免疫球蛋白连接的人类TNF受体或其片段(例如人类IgG1的Fc部分)、英利昔单抗、阿达木单抗、依那西普、杜匹鲁单抗、沙瑞卢单抗、托珠单抗、戈利木单抗、阿巴西普、托法替尼、阿巴西普、非类固醇抗炎药(NSAID)、布洛芬、萘普生、对乙酰氨基酚、阿司匹林、塞内昔布、环磷酰胺、甲氨蝶呤、皮质类固醇、可的松或泼尼松。
通过与另一种治疗剂结合施用抗IL36R抗原结合蛋白,例如,H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2治疗或预防需要所述治疗或预防的个体的IL-36介导的疾病的方法是本发明的一部分。
术语“与……结合”指示组分抗IL36R抗原结合蛋白,例如本发明的抗体或其抗原结合片段与另一种试剂(例如甲氨蝶呤)一起可以被配制成例如用于同时递送的单一组合物或被分开地配制成两种或更多种组合物(例如,包括每种组分的试剂盒)。每种组分可在与施用另一种组分不同的时间向个体施用;例如每次施用可以在给定时间段内以一定间隔不同时地(例如分开地或依序地)给定。此外,可以通过相同或不同的途径向个体施用单独的组分。
实例
阐述以下实例以便向本领域普通技术人员提供
如何制得并且使用本发明的方法和组合物的完整公开内容和描述,
并且所述实例不意图限制
本发明人认为是其发明的内容的范围。
实例1:与IL-36R特异性结合的人类抗体的生成
通过用包含全长IL36R(IL-1RL2)序列的DNA免疫原使VELOCIMMUNE小鼠(即,包含编码人类免疫球蛋白重链和κ轻链可变区的DNA的经过工程改造的小鼠)免疫,获得抗IL36R抗体。通过IL36R特异性免疫分析监测抗体,并且分离与纯化完全人类抗IL36R抗体。如本文中所阐述生成的抗体的VH和VL与其对应的生殖系之间的两个例示性比较阐述于图1和图2中。
表1.本发明的免疫球蛋白链序列*
*对应于VH、CDR-H1、CDR-H2、CDR-H3、VL、CDR-L1、CDR-L2和CDR-L3的数字是指本文中所阐述的SEQ ID NO。“PEP”是指氨基酸序列;“DNA”是指核苷酸序列。
SEQ ID NO:1
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTGCAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCGGCCTCTGGATTCACCTTTGATGATTATGCCATACACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGTTATCAGTTGGAATAGTGATATCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCGTCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAATAGTCTGAGAACTGAGGACACGGCCTTGTATTACTGTGCAAAAGGATATAACTGGAACTTCTTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA;
SEQ ID NO:2
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAIHWVRQAPGKGLEWVSVISWNSDIIGYADSVKGRFTVSRDNAKNSLYLQMNSLRTEDTALYYCAKGYNWNFFDYWGQGTLVTVSS;
SEQ ID NO:3
GGA TTC ACC TTT GAT GAT TAT GCC;
SEQ ID NO:4
G F T F D D Y A;
SEQ ID NO:5
ATC AGT TGG AAT AGT GAT ATC ATA;
SEQ ID NO:6
I S W N S D I I;
SEQ ID NO:7
GCA AAA GGA TAT AAC TGG AAC TTC TTT GAC TAT;
SEQ ID NO:8
A K G Y N W N F F D Y;
SEQ ID NO:9
GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTATCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAATGCAGCAAACAGGGCCACTGACATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA;
SEQ ID NO:10
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYNAANRATDIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK;
SEQ ID NO:11
CAG AGT GTT AGC AGC TAC;
SEQ ID NO:12
Q S V S S Y;
SEQ ID NO:13
AAT GCA GCA;
SEQ ID NO:14
N A A;
SEQ ID NO:15
CAG CAG CGT AGC AAC TGG CCT CTC ACT;
SEQ ID NO:16
Q Q R S N W P L T;
SEQ ID NO:17
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAACTCCAGGGAAGGGCCTGGAGTGGGTCTCAGTTATTAGTTGGAATAGTGATGTCATAGCCTATTCGGACTCTGTGAAGGGCCGCTTCACCATTTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGGGAACTGAGGACACGGCCTTATATTACTGTGCAAAAGGCCATAACTGGAACTTCTTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA;
SEQ ID NO:18
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQTPGKGLEWVSVISWNSDVIAYSDSVKGRFTISRDNAKNSLYLQMNSLGTEDTALYYCAKGHNWNFFDYWGQGTLVTVSS;
SEQ ID NO:19
GGA TTC ACC TTT GAT GAT TAT GCC;
SEQ ID NO:20
G F T F D D Y A;
SEQ ID NO:21
ATT AGT TGG AAT AGT GAT GTC ATA;
SEQ ID NO:22
I S W N S D V I;
SEQ ID NO:23
GCA AAA GGC CAT AAC TGG AAC TTC TTT GAC TAT;
SEQ ID NO:24
A K G H N W N F F D Y;
SEQ ID NO:25
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGAGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAATGTAGCCAACAGGGCCACAGACATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCGGCCTAGAGCCTGAAGATTTTGCAGTTTATTTCTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA;
SEQ ID NO:26
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYNVANRATDIPARFSGSGSGTDFTLTISGLEPEDFAVYFCQQRSNWPLTFGGGTKVEIK;
SEQ ID NO:27
CAG AGT GTT AGC AGC TAC;
SEQ ID NO:28
Q S V S S Y;
SEQ ID NO:29
AAT GTA GCC;
SEQ ID NO:30
N V A;
SEQ ID NO:31
CAG CAG CGT AGC AAC TGG CCT CTC ACT;
SEQ ID NO:32
Q Q R S N W P L T;
SEQ ID NO:33
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCTTTGATGATTATGCCATACACTGGGTCCGGCAATCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGTTATCAGTTGGAATAGTGATGTCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAGATGAATAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGGATATAACTGGAACTTCTTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA;
SEQ ID NO:34
EVQLVESGGGLVQPGRSLRLSCTASGFTFDDYAIHWVRQSPGKGLEWVSVISWNSDVIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKGYNWNFFDYWGQGTLVTVSS;
SEQ ID NO:35
GGA TTC ACC TTT GAT GAT TAT GCC;
SEQ ID NO:36
G F T F D D Y A;
SEQ ID NO:37
ATC AGT TGG AAT AGT GAT GTC ATA;
SEQ ID NO:38
I S W N S D V I;
SEQ ID NO:39
GCA AAA GGA TAT AAC TGG AAC TTC TTT GAC TAT;
SEQ ID NO:40
A K G Y N W N F F D Y;
SEQ ID NO:41
GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTATCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAATGCAGCAAACAGGGCCACTGACATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA;
SEQ ID NO:42
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYNAANRATDIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK;
SEQ ID NO:43
CAG AGT GTT AGC AGC TAC;
SEQ ID NO:44
Q S V S S Y;
SEQ ID NO:45
AAT GCA GCA;
SEQ ID NO:46
N A A;
SEQ ID NO:47
CAG CAG CGT AGC AAC TGG CCT CTC ACT;
SEQ ID NO:48
Q Q R S N W P L T;
SEQ ID NO:49
GAAGTGCAGCTGGTGGAGTCTGGGGGAGACTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAATGGGTCTCAGTTATTAGTTGGAATAGTGATGTCATAGCCTATTCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAACTGAGGACACGGCCTTATATTACTGTACAAAAGGCCATAAGTGGAGCTTCTTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA;
SEQ ID NO:50
EVQLVESGGDLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSVISWNSDVIAYSDSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCTKGHKWSFFDYWGQGTLVTVSS;
SEQ ID NO:51
GGA TTC ACC TTT GAT GAT TAT GCC;
SEQ ID NO:52
G F T F D D Y A;
SEQ ID NO:53
ATT AGT TGG AAT AGT GAT GTC ATA;
SEQ ID NO:54
I S W N S D V I;
SEQ ID NO:55
ACA AAA GGC CAT AAG TGG AGC TTC TTT GAC TAT;
SEQ ID NO:56
T K G H K W S F F D Y;
SEQ ID NO:57
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTTTAATGTAGCCAACAGGGCCACTGACATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA;
SEQ ID NO:58
EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIFNVANRATDIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK;
SEQ ID NO:59
CAG AGT ATT AGC AGC TAC;
SEQ ID NO:60
Q S I S S Y;
SEQ ID NO:61
AAT GTA GCC;
SEQ ID NO:62
N V A;
SEQ ID NO:63
CAG CAG CGT AGC AAC TGG CCT CTC ACT;
SEQ ID NO:64
Q Q R S N W P L T;
SEQ ID NO:65
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTTCAGCCTGGGGGGTCCCTGAGACTCTCCTGCGCAGCCTCTGGATTCACCTTTAGCGACTATGCCATGAGCTGGGTCCGCCAGGCTCCGGGGAAGGGGCTGGAGTGGGTCTCAGGTATTAGTGGAAATGGTGGTGACACATACTACGGAGACTTCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGGCGAGGACACGGCCGCATATTTCTGTGTGATAGATCTTGACTATTGGGGTCAGGGAACCCTGGTCACCGTCTCCTCA;
SEQ ID NO:66
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYAMSWVRQAPGKGLEWVSGISGNGGDTYYGDFVKGRFTISRDNSKNTLYLQMNSLRGEDTAAYFCVIDLDYWGQGTLVTVSS;
SEQ ID NO:67
GGA TTC ACC TTT AGC GAC TAT GCC;
SEQ ID NO:68
G F T F S D Y A;
SEQ ID NO:69
ATT AGT GGA AAT GGT GGT GAC ACA;
SEQ ID NO:70
I S G N G G D T;
SEQ ID NO:71
GTG ATA GAT CTT GAC TAT;
SEQ ID NO:72
V I D L D Y;
SEQ ID NO:73
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGAAGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGCTGGTTGGCCTGGTATCAACAGAAACCAGGAAAAGCCCCTAGGCTCCTGATCTATAAGGCGTCTATTTTAGGAGATGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCTACTTATTACTGCCACCAGTATAATAGTTATTTGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA;
SEQ ID NO:74
DIQMTQSPSTLSASEGDRVTITCRASQSISSWLAWYQQKPGKAPRLLIYKASILGDGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCHQYNSYLWTFGQGTKVEIK;
SEQ ID NO:75
CAG AGT ATT AGT AGC TGG;
SEQ ID NO:76
Q S I S S W;
SEQ ID NO:77
AAG GCG TCT;
SEQ ID NO:78
K A S;
SEQ ID NO:79
CAC CAG TAT AAT AGT TAT TTG TGG ACG;
SEQ ID NO:80
H Q Y N S Y L W T;
SEQ ID NO:81
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGCTGATTACTATTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGATCCATCTATTATACTGGGAGTACTTACTACAACCCGTCCCTCAAGAGTCGACTTACCATATCAATAGACACGTCTGAGAACCAGTTCTCTTTGAAACTGACCTCTCTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGCGAGGAGGCTAACTGGGGATCCCACTTTGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA;
SEQ ID NO:82
QVQLQESGPGLVKPSQTLSLTCTVSGGSISSADYYWSWIRQHPGKGLEWIGSIYYTGSTYYNPSLKSRLTISIDTSENQFSLKLTSLTAADTAVYYCASEEANWGSHFDSWGQGTLVTVSS;
SEQ ID NO:83
GGT GGC TCC ATC AGC AGT GCT GAT TAC TAT;
SEQ ID NO:84
G G S I S S A D Y Y;
SEQ ID NO:85
ATC TAT TAT ACT GGG AGT ACT;
SEQ ID NO:86
I Y Y T G S T;
SEQ ID NO:87
GCG AGC GAG GAG GCT AAC TGG GGA TCC CAC TTT GAC TCC;
SEQ ID NO:88
A S E E A N W G S H F D S;
SEQ ID NO:89
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTGACAACTTTTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCATCTTACTACTGTCAACATAGTCACAGTGCCCATCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA;
SEQ ID NO:90
DIQMTQSPSSLSASVGDRVTITCRASQSIDNFLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFASYYCQHSHSAHPITFGQGTRLEIK;
SEQ ID NO:91
CAG AGC ATT GAC AAC TTT;
SEQ ID NO:92
Q S I D N F;
SEQ ID NO:93
GCT GCA TCC;
SEQ ID NO:94
A A S;
SEQ ID NO:95
CAA CAT AGT CAC AGT GCC CAT CCG ATC ACC;
SEQ ID NO:96
Q H S H S A H P I T;
SEQ ID NO:97
CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGTAATTACTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGAGACTGGAGTGGATTGGGAGTATCTATTATAGTGGGAGCACCTACTACAACCCGTCCCTCAAGACTCGAGTCACCATATCCGTAGACACGTCCAAGAATCAGTTCTCCCTGAAGCTGACCTCTGTGACCGCCGCAGACACGGCTGTGTATTACTGTGCGAGAGAGGAAGCAGCAGCTTTGACGCACTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA;
SEQ ID NO:98
QLQLQESGPGLVKPSETLSLTCTVSGGSISSSNYYWGWIRQPPGKRLEWIGSIYYSGSTYYNPSLKTRVTISVDTSKNQFSLKLTSVTAADTAVYYCAREEAAALTHFDFWGQGTLVTVSS;
SEQ ID NO:99
GGT GGC TCC ATC AGC AGT AGT AAT TAC TAC;
SEQ ID NO:100
G G S I S S S N Y Y;
SEQ ID NO:101
ATC TAT TAT AGT GGG AGC ACC;
SEQ ID NO:102
I Y Y S G S T;
SEQ ID NO:103
GCG AGA GAG GAA GCA GCA GCT TTG ACG CAC TTT GAC TTC;
SEQ ID NO:104
A R E E A A A L T H F D F;
SEQ ID NO:105
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAACTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACATAGTCACAGTTCCCATCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA;
SEQ ID NO:106
DIQMTQSPSSLSASVGDRVTITCRASQSISNYLNWYQQKPGKAPKLLIFAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHSHSSHPITFGQGTRLEIK;
SEQ ID NO:107
CAG AGC ATT AGC AAC TAT;
SEQ ID NO:108
Q S I S N Y;
SEQ ID NO:109
GCT GCA TCC;
SEQ ID NO:110
A A S;
SEQ ID NO:111
CAA CAT AGT CAC AGT TCC CAT CCG ATC ACC;
SEQ ID NO:112
Q H S H S S H P I T;
SEQ ID NO:113
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAATTGGGCTGGTTATAACATAGACTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATATGCGTGGATTCAGTTATGGTTTCCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA;
SEQ ID NO:114
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGINWAGYNIDYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDMRGFSYGFPFDYWGQGTLVTVSS;
SEQ ID NO:115
GGA TTC ACC TTT GAT GAT TAT GCC;
SEQ ID NO:116
G F T F D D Y A;
SEQ ID NO:117
ATT AAT TGG GCT GGT TAT AAC ATA;
SEQ ID NO:118
I N W A G Y N I;
SEQ ID NO:119
GCA AAA GAT ATG CGT GGA TTC AGT TAT GGT TTC CCC TTT GAC TAC;
SEQ ID NO:120
A K D M R G F S Y G F P F D Y;
SEQ ID NO:121
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA;
SEQ ID NO:122
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK;
SEQ ID NO:123
CAG AGC ATT AGC AGC TAT;
SEQ ID NO:124
Q S I S S Y;
SEQ ID NO:125
GCT GCA TCC;
SEQ ID NO:126
A A S;
SEQ ID NO:127
CAA CAG AGT TAC AGT ACC CCT CCG ATC ACC;
SEQ ID NO:128
Q Q S Y S T P P I T;
SEQ ID NO:129
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCGGGGGGGTCCCTTAGACTCTCCTGTGCAGCCTCTGGATTTATTTTCAGTAACGCCTGGATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGACTGGCGTGGGTTGGCCGTATTAAAACCGAAACTGATGGTGGGACAACAGACTACGCTGCACCCGTAAAAGGCAGATTCACCATCTCAAGAGATGACTCAAAAAACACGCTGTATCTGCAAATGAACAGCGTGAAAACCGAGGACACAGCCGTGTATTACTGTACAGGGGGATACAGCTATGGTGACGATAGCAGCAGCTGGAACGAGGGCTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA;
SEQ ID NO:130
EVQLVESGGGLVKPGGSLRLSCAASGFIFSNAWMNWVRQAPGKGLAWVGRIKTETDGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSVKTEDTAVYYCTGGYSYGDDSSSWNEGYYYYGMDVWGQGTTVTVSS;
SEQ ID NO:131
GGA TTT ATT TTC AGT AAC GCC TGG;
SEQ ID NO:132
G F I F S N A W;
SEQ ID NO:133
ATT AAA ACC GAA ACT GAT GGT GGG ACA ACA;
SEQ ID NO:134
I K T E T D G G T T;
SEQ ID NO:135
ACA GGG GGA TAC AGC TAT GGT GAC GAT AGC AGC AGC TGG AAC GAG GGC TACTAC TAC TACGGT ATG GAC GTC;
SEQ ID NO:136
T G G Y S Y G D D S S S W N E G Y Y Y YG M D V;
SEQ ID NO:137
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTCGTTGGAATGGTGGTAGTATAGGCTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAAGTCCCTGCATCTGCAAATGAACAGTCTAAAAACTGAGGACACGGCCTTGTATTACTGTGCAAAAGATATAGGCGATATTTTGACTGGTTTTTATGGAGAATACGGAATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA;
SEQ ID NO:138
EVQLVESGGGLVQPGRSLRLSCTASGFTFDDYAMHWVRQAPGKGLEWVSGIRWNGGSIGYVDSVKGRFTISRDNAKKSLHLQMNSLKTEDTALYYCAKDIGDILTGFYGEYGMDVWGQGTTVTVSS;
SEQ ID NO:139
GGA TTC ACC TTT GAT GAT TAT GCC;
SEQ ID NO:140
G F T F D D Y A;
SEQ ID NO:141
ATT CGT TGG AAT GGT GGT AGT ATA;
SEQ ID NO:142
I R W N G G S I;
SEQ ID NO:143
GCA AAA GAT ATA GGC GAT ATT TTG ACT GGT TTT TAT GGA GAA TAC GGA ATGGAC GTC;
SEQ ID NO:144
A K D I G D I L T G F Y G E Y G M D V;
SEQ ID NO:145
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGAAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAAGCAGGGAAAGCCCCTAACCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGAGTACACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACATTATCCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA;
SEQ ID NO:146
DIQMTQSPSSLSASEGDRVTITCRASQSISSYLNWYQQKAGKAPNLLIYAASSLQSGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQSYIIPYTFGQGTKLEIK;
SEQ ID NO:147
CAG AGC ATT AGC AGC TAT;
SEQ ID NO:148
Q S I S S Y;
SEQ ID NO:149
GCT GCA TCC;
SEQ ID NO:150
A A S;
SEQ ID NO:151
CAA CAG AGT TAC ATT ATC CCG TAC ACT;
SEQ ID NO:152
Q Q S Y I I P Y T;
SEQ ID NO:153
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGGTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAAGTGTTAGGTGGAATGGTGGTATTATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGACCTGAGGACACGGCCCTCTATTACTGTGCAAAAGATATAGGCGATGTTTTGACTGGTTATTATGGAGAATACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA;
SEQ ID NO:154
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSSVRWNGGIIGYADSVKGRFTISRDNAKNSLYLQMNSLRPEDTALYYCAKDIGDVLTGYYGEYGMDVWGQGTTVTVSS;
SEQ ID NO:155
GGA TTC ACC TTT GAT GAT TAT GCC;
SEQ ID NO:156
G F T F D D Y A;
SEQ ID NO:157
GTT AGG TGG AAT GGT GGT ATT ATA;
SEQ ID NO:158
V R W N G G I I;
SEQ ID NO:159
GCA AAA GAT ATA GGC GAT GTT TTG ACT GGT TAT TAT GGA GAA TAC GGT ATGGAC GTC;
SEQ ID NO:160
A K D I G D V L T G Y Y G E Y G M D V;
SEQ ID NO:161
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGACAGAGTCACCATCGCTTGCCGGGCAAGTCAGAGCATTACCACCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGTAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACATTTCCCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA;
SEQ ID NO:162
DIQMTQSPSSLSASVGDRVTIACRASQSITTYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYISPYTFGQGTKLEIK;
SEQ ID NO:163
CAG AGC ATT ACC ACC TAT;
SEQ ID NO:164
Q S I T T Y;
SEQ ID NO:165
GCT GCA TCC;
SEQ ID NO:166
A A S;
SEQ ID NO:167
CAA CAG AGT TAC ATT TCC CCG TAC ACT;
SEQ ID NO:168
Q Q S Y I S P Y T;
SEQ ID NO:169
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAAGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAATTATGGCATACACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCGATTATATTATATGATGGAAGTAATCAACACTATGCAGATTCCGTGAAGGGCCGATTCACCATTTCCAGAGACAATTCCAAAAACACGCTGTATCTTCAAATGAACAACCTGAGAGCTGAGGACACGGCCGTTTATTACTGTGCGAGAGATCTTGATCTTTGGAGTGGTTATTATACAAACGGGGACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA;
SEQ ID NO:170
QVQLVESGGGVVQPGKSLRLSCAASGFTFSNYGIHWVRQAPGKGLEWVAIILYDGSNQHYADSVKGRFTISRDNSKNTLYLQMNNLRAEDTAVYYCARDLDLWSGYYTNGDGMDVWGQGTTVTVSS;
SEQ ID NO:171
GGA TTC ACC TTC AGT AAT TAT GGC;
SEQ ID NO:172
G F T F S N Y G;
SEQ ID NO:173
ATA TTA TAT GAT GGA AGT AAT CAA;
SEQ ID NO:174
I L Y D G S N Q;
SEQ ID NO:175
GCG AGA GAT CTT GAT CTT TGG AGT GGT TAT TAT ACA AAC GGG GAC GGT ATGGAC GTC;
SEQ ID NO:176
A R D L D L W S G Y Y T N G D G M D V;
包括本发明的抗原结合蛋白的恒定结构域的重链和轻链免疫球蛋白的氨基酸和核苷酸序列阐述于下文:
H4H14699P2
重链DNA
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTGCAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCGGCCTCTGGATTCACCTTTGATGATTATGCCATACACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGTTATCAGTTGGAATAGTGATATCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCGTCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAATAGTCTGAGAACTGAGGACACGGCCTTGTATTACTGTGCAAAAGGATATAACTGGAACTTCTTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA
(SEQ ID NO:179)
重链多肽
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAIHWVRQAPGKGLEWVSVISWNSDIIGYADSVKGRFTVSRDNAKNSLYLQMNSLRTEDTALYYCAKGYNWNFFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:180)
轻链DNA
GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTATCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAATGCAGCAAACAGGGCCACTGACATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
(SEQ ID NO:181)
轻链多肽
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYNAANRATDIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:182)
H4H14700P2
重链DNA
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAACTCCAGGGAAGGGCCTGGAGTGGGTCTCAGTTATTAGTTGGAATAGTGATGTCATAGCCTATTCGGACTCTGTGAAGGGCCGCTTCACCATTTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGGGAACTGAGGACACGGCCTTATATTACTGTGCAAAAGGCCATAACTGGAACTTCTTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA
(SEQ ID NO:183)
重链多肽
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQTPGKGLEWVSVISWNSDVIAYSDSVKGRFTISRDNAKNSLYLQMNSLGTEDTALYYCAKGHNWNFFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:184)
轻链DNA
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGAGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAATGTAGCCAACAGGGCCACAGACATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCGGCCTAGAGCCTGAAGATTTTGCAGTTTATTTCTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
(SEQ ID NO:185)
轻链多肽
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYNVANRATDIPARFSGSGSGTDFTLTISGLEPEDFAVYFCQQRSNWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:186)
H4H14706P2
重链DNA
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCTTTGATGATTATGCCATACACTGGGTCCGGCAATCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGTTATCAGTTGGAATAGTGATGTCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAGATGAATAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGGATATAACTGGAACTTCTTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA
(SEQ ID NO:187)
重链多肽
EVQLVESGGGLVQPGRSLRLSCTASGFTFDDYAIHWVRQSPGKGLEWVSVISWNSDVIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKGYNWNFFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:188)
轻链DNA
GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTATCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAATGCAGCAAACAGGGCCACTGACATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
(SEQ ID NO:189)
轻链多肽
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYNAANRATDIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:190)
H4H14708P2
重链DNA
GAAGTGCAGCTGGTGGAGTCTGGGGGAGACTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAATGGGTCTCAGTTATTAGTTGGAATAGTGATGTCATAGCCTATTCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAACTGAGGACACGGCCTTATATTACTGTACAAAAGGCCATAAGTGGAGCTTCTTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA
(SEQ ID NO:191)
重链多肽
EVQLVESGGDLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSVISWNSDVIAYSDSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCTKGHKWSFFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:192)
轻链DNA
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTTTAATGTAGCCAACAGGGCCACTGACATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
(SEQ ID NO:193)
轻链多肽
EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIFNVANRATDIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:194)
H4H14709P
重链DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTTCAGCCTGGGGGGTCCCTGAGACTCTCCTGCGCAGCCTCTGGATTCACCTTTAGCGACTATGCCATGAGCTGGGTCCGCCAGGCTCCGGGGAAGGGGCTGGAGTGGGTCTCAGGTATTAGTGGAAATGGTGGTGACACATACTACGGAGACTTCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGGCGAGGACACGGCCGCATATTTCTGTGTGATAGATCTTGACTATTGGGGTCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA
(SEQ ID NO:195)
重链多肽
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYAMSWVRQAPGKGLEWVSGISGNGGDTYYGDFVKGRFTISRDNSKNTLYLQMNSLRGEDTAAYFCVIDLDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:196)
轻链DNA
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGAAGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGCTGGTTGGCCTGGTATCAACAGAAACCAGGAAAAGCCCCTAGGCTCCTGATCTATAAGGCGTCTATTTTAGGAGATGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCTACTTATTACTGCCACCAGTATAATAGTTATTTGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
(SEQ ID NO:197)
轻链多肽
DIQMTQSPSTLSASEGDRVTITCRASQSISSWLAWYQQKPGKAPRLLIYKASILGDGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCHQYNSYLWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:198)
H4H14728P
重链DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGCTGATTACTATTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGATCCATCTATTATACTGGGAGTACTTACTACAACCCGTCCCTCAAGAGTCGACTTACCATATCAATAGACACGTCTGAGAACCAGTTCTCTTTGAAACTGACCTCTCTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGCGAGGAGGCTAACTGGGGATCCCACTTTGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA
(SEQ ID NO:199)
重链多肽
QVQLQESGPGLVKPSQTLSLTCTVSGGSISSADYYWSWIRQHPGKGLEWIGSIYYTGSTYYNPSLKSRLTISIDTSENQFSLKLTSLTAADTAVYYCASEEANWGSHFDSWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:200)
轻链DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTGACAACTTTTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCATCTTACTACTGTCAACATAGTCACAGTGCCCATCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
(SEQ ID NO:201)
轻链多肽
DIQMTQSPSSLSASVGDRVTITCRASQSIDNFLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFASYYCQHSHSAHPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:202)
H4H14731P
重链DNA
CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGTAATTACTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGAGACTGGAGTGGATTGGGAGTATCTATTATAGTGGGAGCACCTACTACAACCCGTCCCTCAAGACTCGAGTCACCATATCCGTAGACACGTCCAAGAATCAGTTCTCCCTGAAGCTGACCTCTGTGACCGCCGCAGACACGGCTGTGTATTACTGTGCGAGAGAGGAAGCAGCAGCTTTGACGCACTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA
(SEQ ID NO:203)
重链多肽
QLQLQESGPGLVKPSETLSLTCTVSGGSISSSNYYWGWIRQPPGKRLEWIGSIYYSGSTYYNPSLKTRVTISVDTSKNQFSLKLTSVTAADTAVYYCAREEAAALTHFDFWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:204)
轻链DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAACTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACATAGTCACAGTTCCCATCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
(SEQ ID NO:205)
轻链多肽
DIQMTQSPSSLSASVGDRVTITCRASQSISNYLNWYQQKPGKAPKLLIFAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHSHSSHPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:206)
H4H14732P2
重链DNA
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAATTGGGCTGGTTATAACATAGACTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATATGCGTGGATTCAGTTATGGTTTCCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA
(SEQ ID NO:207)
重链多肽
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGINWAGYNIDYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDMRGFSYGFPFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:208)
轻链DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
(SEQ ID NO:209)
轻链多肽
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:210)
H4H14734P2
重链DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCGGGGGGGTCCCTTAGACTCTCCTGTGCAGCCTCTGGATTTATTTTCAGTAACGCCTGGATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGACTGGCGTGGGTTGGCCGTATTAAAACCGAAACTGATGGTGGGACAACAGACTACGCTGCACCCGTAAAAGGCAGATTCACCATCTCAAGAGATGACTCAAAAAACACGCTGTATCTGCAAATGAACAGCGTGAAAACCGAGGACACAGCCGTGTATTACTGTACAGGGGGATACAGCTATGGTGACGATAGCAGCAGCTGGAACGAGGGCTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA
(SEQ ID NO:211)
重链多肽
EVQLVESGGGLVKPGGSLRLSCAASGFIFSNAWMNWVRQAPGKGLAWVGRIKTETDGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSVKTEDTAVYYCTGGYSYGDDSSSWNEGYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:212)
轻链DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
(SEQ ID NO:213)
轻链多肽
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:214)
H4H14757P
重链DNA
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTCGTTGGAATGGTGGTAGTATAGGCTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAAGTCCCTGCATCTGCAAATGAACAGTCTAAAAACTGAGGACACGGCCTTGTATTACTGTGCAAAAGATATAGGCGATATTTTGACTGGTTTTTATGGAGAATACGGAATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA
(SEQ ID NO:215)
重链多肽
EVQLVESGGGLVQPGRSLRLSCTASGFTFDDYAMHWVRQAPGKGLEWVSGIRWNGGSIGYVDSVKGRFTISRDNAKKSLHLQMNSLKTEDTALYYCAKDIGDILTGFYGEYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:216)
轻链DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGAAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAAGCAGGGAAAGCCCCTAACCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGAGTACACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACATTATCCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
(SEQ ID NO:217)
轻链多肽
DIQMTQSPSSLSASEGDRVTITCRASQSISSYLNWYQQKAGKAPNLLIYAASSLQSGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQSYIIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:218)
H4H14758P
重链DNA
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGGTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAAGTGTTAGGTGGAATGGTGGTATTATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGACCTGAGGACACGGCCCTCTATTACTGTGCAAAAGATATAGGCGATGTTTTGACTGGTTATTATGGAGAATACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA
(SEQ ID NO:219)
重链多肽
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSSVRWNGGIIGYADSVKGRFTISRDNAKNSLYLQMNSLRPEDTALYYCAKDIGDVLTGYYGEYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:220)
轻链DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGACAGAGTCACCATCGCTTGCCGGGCAAGTCAGAGCATTACCACCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGTAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACATTTCCCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
(SEQ ID NO:221)
轻链多肽
DIQMTQSPSSLSASVGDRVTIACRASQSITTYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYISPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:222)
H4H14760P2
重链DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAAGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAATTATGGCATACACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCGATTATATTATATGATGGAAGTAATCAACACTATGCAGATTCCGTGAAGGGCCGATTCACCATTTCCAGAGACAATTCCAAAAACACGCTGTATCTTCAAATGAACAACCTGAGAGCTGAGGACACGGCCGTTTATTACTGTGCGAGAGATCTTGATCTTTGGAGTGGTTATTATACAAACGGGGACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA
(SEQ ID NO:223)
重链多肽
QVQLVESGGGVVQPGKSLRLSCAASGFTFSNYGIHWVRQAPGKGLEWVAIILYDGSNQHYADSVKGRFTISRDNSKNTLYLQMNNLRAEDTAVYYCARDLDLWSGYYTNGDGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:224)
轻链DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
(SEQ ID NO:225)
轻链多肽
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:226)
实例2:利用HEK293/D9(NFκB-荧光素酶)/hIL-36R和HEK293/NFκB-荧光素酶/mfIL-36R细胞的生物分析.
IL-36受体(IL-36R)为细胞因子IL-36α、IL-36β和IL-36γ的IL-1家族的成员的子集的单向通过的膜受体,并且在与这些配位体结合时,募集其共受体,即IL-1R辅助蛋白(IL-1RAcP),其诱导涉及NFκB和丝裂原激活激酶路径的信号级联(Sims等人,2010)。研发出生物分析以检测使用报告因子细胞系经由IL-36R激活的NFκB的转录激活,所述报告因子细胞系与荧光素酶报告因子[NFκB反应元件(5×)-荧光素酶-IRES-GFP]一起在HEK293细胞中稳定表达全长人类IL-36R(hIL-36R;寄存编号NP_003845.2的氨基酸1到575)或食蟹猴IL-36R(MfIL-36R)。IL-1RAcP在HEK293细胞系中内源性地表达。所得稳定细胞系被称为HEK293/NFκB-luc/hIL-36R和HEK293/NFκB-luc/MfIL-36R,在含有10%FBS、NEAA、青霉素/链霉素/谷氨酰胺和500μg/mL G418的DMEM中分离和维持。
对于生物分析,在补充有0.1%FBS的OPTIMEM中以10,000个细胞/孔将细胞接种到96孔分析盘中,并且然后在5%CO2中在37℃下培育过夜。第二天,为了确定配位体的剂量反应,将人类IL-36α(hIL-36α;安迪生物公司(R&D Systems),#6995/IL)、人类IL-36β(hIL-36β;安迪生物公司,#6334-IL)或人类IL-36γ(hIL-36γ;安迪生物公司,#6835-IL)以1:3(10nM到0.0002nM)连续稀释并且添加到细胞中。还将含有稀释缓冲液但无IL-36配位体的对照物添加到一个细胞样品中。为了测量抑制,将抗体以1:3(100nM到0.002nM)加上不含抗体的对照样品连续稀释,并且与细胞一起预培育,随后添加恒定浓度的hIL-36α、hIL-36β或hIL-36γ。对于利用HEK293/NFκB-luc/hIL-36R细胞的测试,以恒定浓度使用20pM hIL-36α、15pM hIL-36β或10pM hIL-36γ,并且对于利用HEK293/NFκB-luc/mfIL-36R细胞的测试,以恒定浓度使用500pM hIL-36α、600pM hIL-36β或300pM hIL-36γ。在37℃下在5%CO2中培育5.5小时之后,将OneGlo试剂(普洛麦格公司(Promega),#E6051)添加到样品中,并且然后使用维克托X(Victor X)(珀金埃尔默(Perkin Elmer))盘读取器测量荧光素酶活性。
使用非线性回归(4参数逻辑)与Prism 6软件(GraphPad)对结果进行分析,以获得EC50和IC50值。为了确定最大抑制,对于每种抗体介于最大与最小RLU值之间的范围被计算为介于无IL-36配位体与每次分析所使用的IL-36配位体的恒定量之间的RLU范围的百分比。
如表2-1所示,所测试本发明的抗IL-36R抗体中有9/12完全阻断IC50值在100pM到970pM的范围内的20pM hIL-36α对HEK293/NFkB-luc/hIL-36R细胞的刺激。所测试IL-36R抗体中之一证实HEK293/NFkB-luc/hIL-36R细胞的hIL-36α刺激的部分阻断,其中最大阻断百分比为22%。所测试IL-36R抗体中之一证实HEK293/NFkB-luc/hIL-36R细胞的hIL-36α刺激的微弱阻断,其中最大阻断百分比为61%,而所测试抗IL-36R抗体中的另一个并未证实hIL-36α刺激的任何抑制。所测试本发明的抗IL-36R抗体中有6/12完全阻断IC50值在120pM到1.3nM的范围内的15pM hIL-36β对HEK293/NFkB-luc/hIL-36R细胞的刺激。所测试IL-36R抗体中之一证实HEK293/NFkB-luc/hIL-36R细胞的hIL-36β刺激的微弱阻断,其中最大阻断百分比为69%,并且5种所测试抗IL-36R抗体并未证实hIL-36β刺激的可测量抑制。所测试本发明的抗IL-36R抗体中有6/12完全阻断IC50值在120pM到1.2nM的范围内的10pM hIL-36γ对HEK293/NFkB-luc/hIL-36R细胞的刺激。四种所测试本发明的抗IL-36R抗体证实hIL-36γ刺激的部分阻断,其中最大阻断百分比在24%到87%的范围内。一种所测试本发明的抗IL-36R抗体展示hIL-36γ刺激的微弱阻断,其中最大阻断百分比为69%,并且一种本发明的抗IL36R抗体并未证实hIL-36γ刺激的抑制。所测试同种型对照抗体并未证实HEK293/NFkB-luc/hIL-36R细胞的IL-36配位体刺激的抑制。如表2-1所示,hIL-36α、hIL-36β和hIL-36γ分别激活EC50值为12pM、14pM和8.4pM的HEK293/NFkB-luc/hIL-36R细胞。
如表2-2所示,所测试本发明的抗IL-36R抗体中有6/12完全或几乎完全阻断IC50值在60pM到3.1nM的范围内的500pM hIL-36α对HEK293/NFkB-luc/MfIL-36R细胞的刺激。两种所测试本发明的抗IL-36R抗体证实HEK293/NFkB-luc/MfIL-36R细胞的hIL-36α刺激的微弱阻断,其中最大阻断百分比为29%和47%,而4种抗IL-36R抗体并未展示这一细胞系的hIL-36α刺激的抑制。所测试本发明的抗IL-36R抗体中有6/12完全阻断IC50值在120pM到7.1nM的范围内的600pM hIL-36β对HEK293/NFkB-luc/MfIL-36R细胞的刺激。三种所测试本发明的抗IL-36R抗体证实HEK293/NFkB-luc/MfIL-36R细胞的hIL-36β刺激的微弱阻断,其中最大阻断百分比为36%到48%,而三种本发明的抗IL-36R抗体并未展示这一细胞系的hIL-36β刺激的抑制。所测试本发明的抗IL-36R抗体中有六种完全或几乎完全阻断IC50值在85pM到5.4nM的范围内的300pM hIL-36γ对HEK293/NFkB-luc/MfIL-36R细胞的刺激。三种所测试本发明的抗IL-36R抗体证实HEK293/NFkB-luc/MfIL-36R细胞的hIL-36γ刺激的微弱阻断,其中最大阻断百分比为25%到43%,而三种本发明的抗IL-36R抗体并未展示这一细胞系的hIL-36γ刺激的抑制。所测试同种型对照抗体并未证实HEK293/NFkB-luc/MfIL-36R细胞的IL-36配位体刺激的抑制。如表2-1所示,hIL-36α、hIL-36β和hIL-36γ分别激活EC50值为170pM、270pM和62pM的HEK293/NFkB-luc/MfIL-36R细胞。
表2-1.hIL-36配位体对HEK293/NFκB-luc/hIL-36R细胞的刺激的抗IL-36R抗体抑制.
表2-2.hIL-36配位体对HEK293/NFκB-luc/MfIL-36R细胞的刺激的抗IL-36R抗体抑制.
实例3:IL-36R Octet交叉竞争
在HTX生物传感器(福特生物公司,帕尔生命科学部门(A Division ofPall Life Sciences))上使用实时无标记生物层干涉测量分析测定一组不同抗IL-36R抗体之间的结合竞争。整个实验在25℃下在0.01M HEPES pH 7.4、0.15M NaCl、3mM EDTA、0.05%v/v Surfactant Tween-20、0.002%NaN3和1mg/mL BSA(HBS-ET动力学缓冲液)中进行,其中盘以1000rpm的速度振荡。为了评估两种抗体是否能够彼此竞争结合其在经表达具有C端myc-myc-六组氨酸标签的重组人类IL-36R胞外结构域(hIL-36R-MMH:mROR1信号序列(M1-A29)-人类IL36R(D20-Y337)-mycmycHis6)上对应的表位,首先通过将生物传感器浸没到含有30μg/mL hIL-36R-MMH的孔中维持3分钟将约0.3nM hIL-36R-MMH捕获到抗His抗体涂布的Octet生物传感器(福特生物公司,#18-5079)上。然后通过浸没到含有50μg/mL第一抗IL-36R抗体(随后被称为mAb-1)溶液的孔中维持4分钟使抗原捕获的生物传感器饱和有mAb-1。然后将生物传感器浸没到含有50μg/mL第二抗IL-36R抗体(随后被称为mAb-2)溶液的孔中维持3分钟。在实验的每个步骤之间,在HBS-ET动力学缓冲液中洗涤生物传感器。在整个实验过程中监测实时结合反应,并记录所有步骤的最大结合反应。比较mAb-2结合到与mAb-1预先复合的hIL-36R-MMH[/g12的反应,并如表3-1中所示,测定不同抗IL-36R抗体的竞争性/非竞争性行为。
表3-1.抗IL-36R抗体与人类IL-36R-MMH结合的交叉竞争
实例4:抗体结合动力学
使用Biacore 4000仪器,使用实时表面等离子体共振生物传感器来确定IL-36R与纯化的抗IL-36R抗体结合的平衡解离常数(KD值)。Biacore传感器表面首先通过与单克隆小鼠抗人类Fc抗体(GE,#BR-1008-39)胺偶合进行衍生化以捕获抗IL-36R单克隆抗体。所有结合研究在0.01M Hepes pH 7.4、0.15M NaCl、3mM EDTA和0.05%v/v Surfactant Tween-20(HBS-ET操作缓冲液)中在25℃和37℃下进行。以30μL/分钟的流动速率经过4分钟在抗IL-36R抗体捕获的表面上注射不同浓度的含IL-36R试剂、经表达具有C端myc-myc-六组氨酸标签的人类IL-36R胞外结构域(hIL-36R-MMH)、经表达具有C端myc-myc-六组氨酸标签的食蟹猴IL-36R胞外结构域(mfIL-36R-MMH:mROR1信号序列(M1-A29).食蟹猴IL36R_ecto结构域(D20-A336).mycmycHis6)、经表达具有C端小鼠IgG2a Fc标签的人类IL-36R胞外结构域(hIL-36R-mFc:mROR1信号序列(M1-A29)-人类IL36R(D20-Y337)-小鼠IgG2aFc(E98-K330))或经表达具有IgG2a Fc标签的人类IL-36R胞外结构域(hIL-36R-Trap-mFc:mROR1信号序列(M1-A29)-人类IL36R ecto结构域(D20-Y337)-人类IL1RacP ecto结构域(S21-E359)-小鼠IgG2aFc)和IL1RAcP胞外结构域的系内融合蛋白的HBS-ET操作缓冲液(在100nM到3.7nM的范围内,3倍稀释),并且监测其在HBS-ET操作缓冲液中的解离10分钟。通过使用Scrubber 2.0c曲线拟合软件将实时传感图拟合为1:1结合模型来确定动力学缔合速率常数(ka)和解离速率常数(kd)。根据动力学速率常数计算结合解离平衡常数(KD)和解离半衰期(t1/2):
在25℃和37℃下hIL-36R-MMH、mfIL-36R-MMH或hIL-36R.mFc与本发明的不同抗IL-36R抗体结合的结合动力学参数展示于表4-1至4-8中。如表4-1中所示,在25℃下,hIL-36R-MMH与KD值在2.18nM到13.9nM的范围内的所有本发明的抗IL-36R抗体结合。如表4-2中所示,在37℃下,hIL-36R-MMH与KD值在4.25nM到29.5nM的范围内的所有本发明的抗IL-36R抗体结合。如表4-3中所示,在25℃下,mfIL-36R-MMH与KD值在7.87nM到34.4nM的范围内的本发明的抗IL-36R抗体中的9/12结合。如表4-4中所示,在37℃下,mfIL-36R-MMH与KD值在14.4nM到58.2nM的范围内的本发明的抗IL-36R抗体中的9/12结合。如表4-5中所示,在25℃下,mfIL-36R-MMH与KD值在173pM到5.79nM的范围内的本发明的抗IL-36R抗体中的11/12结合。一种本发明的抗IL-36R抗体证实在实验条件下在25℃下与hIL-36R-mFc不确定结合。如表4-6中所示,在37℃下,hIL-36R-mFc与KD值在205pM到28.7nM的范围内的所有本发明的抗IL-36R抗体结合。如表4-7中所示,在25℃下,hIL-36R-Trap-mFc与KD值在212pM到14nM的范围内的所有本发明的抗IL-36R抗体结合。如表4-8中所示,在37℃下,hIL-36R-Trap-mFc与KD值在264pM到40.9nM的范围内的所有本发明的抗IL-36R抗体结合。
表4-1.在25℃下抗IL-36R抗体与hIL-36R-MMH结合的结合动力学参数.
表4-2.在37℃下抗IL-36R抗体与hIL-36R-MMH结合的结合动力学参数.
表4-3.在25℃下抗IL-36R抗体与mfIL-36R-MMH结合的结合动力学参数.
*NB指示在实验条件下,mfIL-36R-MMH试剂并不与所捕获抗IL-36R抗体结合
表4-4.在37℃下抗IL-36R抗体与mfIL-36R-MMH结合的结合动力学参数.
*NB指示在实验条件下,mfIL-36R-MMH试剂并不与所捕获抗IL-36R抗体结合
表4-5.在25℃下抗IL-36R抗体与hIL-36R-mFc结合的结合动力学参数.
*IC指示在实验条件下,hIL-36R.mFc结合是不确定的
表4-6.在37℃下抗IL-36R抗体与hIL-36R-mFc结合的结合动力学参数.
表4-7.在25℃下抗IL-36R抗体与hIL-36R-Trap-mFc结合的结合动力学参数.
表4-8.在37℃下抗IL-36R抗体与hIL-36R-Trap-mFc结合的结合动力学参数.
进行额外结合实验以判定pH对与纯化的抗IL-36R抗体结合的IL-36R的解离速率的影响,所述解离速率使用Biacore T200仪器使用实时表面等离子体共振生物传感器测定。Biacore传感器表面首先通过与单克隆小鼠抗人类Fc抗体(GE,#BR-1008-39)胺偶合进行衍生化以捕获抗IL-36R抗体。这些Biacore结合研究使用两种操作缓冲液PBS-T,pH 7.4(8.1mM Na2HPO4、1.9mM NaH2PO4、3mM KCl、137mM NaCl、0.05%v/v Tween-20,调整到pH7.4)和PBS-T,pH 6.0(6.6mM Na2HPO4、3.4mM NaH2PO4、3mM KCl、137mM NaCl、0.05%v/vTween-20,调整到pH 6.0)进行。以50μL/分钟的流动速率经过4分钟在抗IL-36R抗体捕获的表面上方注射在PBS-T,pH7.4缓冲液(在100nM到11.11nM的范围内,3倍稀释)中制备的不同浓度的hIL-36R-MMH和mfIL-36R-MMH,并且监测其在两种操作缓冲液PBS-T,pH 7.4和PBS-T,pH 6.0中的解离10分钟。所有这些结合动力学实验在25℃和37℃下进行。通过使用Scrubber 2.0c曲线拟合软件将实时传感图拟合为1:1结合模型来确定动力学解离速率常数(kd)。结合解离半衰期(t1/2)由kd计算为:
在25℃和37℃下在两种操作缓冲液PBS-T,pH 7.4和PBS-T,pH6.0中hIL-36R-MMH或mfIL-36R-MMH与不同抗IL-36R抗体结合的结合解离速率常数展示于表4-9到4-12中。
表4-9.在25℃下进行的两种操作缓冲液中抗IL-36R单克隆抗体与hIL-36R-MMH结合的结合解离速率常数.
表4-10.在37℃下进行的两种操作缓冲液中抗IL-36R单克隆抗体与hIL-36R-MMH结合的结合解离速率常数.
表4-11.在25℃下进行的两种操作缓冲液中抗IL-36R单克隆抗体与mfIL-36R-MMH结合的结合解离速率常数.
*NB指示在当前实验条件下,未观察到mfIL-36R-MMH与抗hFc捕获的抗IL-36R mAb的结合。
表4-12.在37℃下进行的两种操作缓冲液中抗IL-36R单克隆抗体与mfIL-36R-MMH结合的结合解离速率常数.
*NB指示在当前实验条件下,未观察到mfIL-36R-MMH与抗hFc捕获的抗IL-36R mAb的结合
实例5:IMQ诱导的皮肤炎症和慢性结肠炎小鼠模型中的抗IL36R的体内评估.
在人类化IL-36R/hIL-36α、β、γ小鼠中在急性和慢性咪喹莫特(IMQ)诱导的皮肤炎症和慢性右旋糖苷硫酸钠(DSS)诱导的结肠炎中体内测试本发明的抗人类IL-36R单克隆抗体。细胞因子检测使用促炎性第1小组(小鼠)多重免疫分析试剂盒在皮肤和结肠匀浆中进行。使用小鼠Duoset Lipocalin-2/NGAL ELISA试剂盒进行脂质运载蛋白2(Lcn2)在粪便匀浆中的检测。使用小鼠MPO ELISA试剂盒进行结肠匀浆中髓过氧物酶(MPO)活性的测量。
抗IL36R抗体H4H14706P2和H4H14708P2与人类同种型匹配的对照IgG4抗体一起使用。
为了检查IL-36R在皮肤炎症和肠道炎症中的作用,并且为了测试体内hIL-36R拮抗作用的功效,本发明的抗人类IL-36R单克隆抗体在咪喹莫特(IMQ)诱导的皮肤炎症和DSS诱导的慢性结肠炎的鼠类模型中进行测试。在两种模型中,使用表达人类IL-36R和人类IL-36α、β、γ的Velocigene生成的纯合小鼠和内源性小鼠IL-36Ra(由于小鼠IL-36Ra对人类IL-36R的亲和力减少,所得小鼠被称为DITRA样小鼠,这类似于DITRA(白细胞介素三十六受体拮抗因子缺乏症)患者中观察到的突变(Marrakchi等人,《白细胞介素36受体拮抗因子缺乏症和泛发性脓疱型牛皮癣(Interleukin-36-receptor antagonist deficiency andgeneralized pustular psoriasis)》,《新英格兰医学杂志》365:620-628(2011))。
生成具有基因型Il1rl2hu/hu Il1f6hu/hu Il1f8hu/hu Il1f9hu/hu的小鼠人类化品系。在这一小鼠品系中,人类IL1F6、IL1F8和IL1F9替代内源性小鼠IL1F6、IL1F8和IL1F9(分别也被称为IL36α、β和γ);和嵌合IL1RL2替代内源性小鼠IL1RL2。嵌合IL1RL2具有人类IL1RL2胞外结构域和小鼠胞内结构域。这产生嵌合受体,其维持小鼠的胞内传信特异性,同时呈现胞外结构域人类,并且因此能够与人类配位体IL1F6、IL1F8和IL1F9结合。
DITRA样小鼠中的急性和慢性IMQ诱导的皮肤炎症诱导和抗体治疗.为了诱导皮肤炎症,使用小鼠毛发修剪器(Oster,MiniMax,目录号78049-100)对8-10周龄人类化DITRA样雌性小鼠的背部进行剃毛,并在应用IMQ乳霜前三天用0.5g Veet脱毛凝胶对皮肤进行脱毛。在小鼠剃过毛的背部皮肤上应用可商购获得IMQ乳膏(5%)(Aldara,GM健康护理有限公司(GM Health Care Limited),NDC 99207-206-12)或凡士林(Vaseline)(CVS药局(CVSPharmacy))的62.5mg每日局部剂量,对于急性疾病诱导持续连续四天,对于慢性疾病诱导持续九天。62.5mg每日局部剂量的Aldara转化为3.125mg每日剂量的活性化合物。在急性IMQ诱导的皮肤炎症中,在开始IMQ施用之前三天(-3d)和之后一天(d1)以10mg/kg和1mg/kg向背部皮肤中皮下施用抗人类IL-36R抗体H4H14706P2和H4H14708P2。对照组接受PBS和10mg/kg的hIgG4同种型对照注射。在慢性IMQ诱导的皮肤炎症中,在d4和d8以10mg/kg向背部皮肤中治疗性地皮下施用抗人类IL-36R抗体H4H14706P2和H4H14708P2。开始IMQ应用后两天或三天,小鼠的背部皮肤开始出现红斑、鳞片化和增厚的病征。每天使用改良版的临床牛皮癣面积和严重程度指数测量炎症的严重程度。根据评分表将红斑、鳞片化和增厚独立地评分为0-4:0,无;1,轻微;2,中度;3,明显;和4,非常明显(van der Fits等人,《咪喹莫特诱导的牛皮癣样皮肤炎症经由IL-23/IL-17轴(Imiquimod-induced psoriasis-like skininflammation in mice is mediated via the IL-23/IL-17axis)》.《免疫学杂志》2009,182:5836-5845)。在急性IMQ诱导的皮肤炎症的d4和慢性IMQ诱导的皮肤炎症的d11,使用卡尺(Kaefer)测量皮肤厚度。
组织病理学.将从鼠背6mm直径的皮肤组织固定在10%缓冲福尔马林中,并用苏木精(hematoxylin)和曙红(eosin)对4-5μm石蜡包埋的切片进行染色。不知情地评价皮肤切片中的角化不全(parakeratosis)、正角化(orthokeratosis)、芒罗微脓肿(Munro'smicroabscess)、棘皮症、表皮溃疡、真皮和皮下组织的炎症、真皮和皮下组织的血管充血、滤泡性角化过度和上皮增生的存在。使用0-4评分量表:0-在正常范围内,1-最小程度,2-轻度,3-中度和4-重度。通过将各个组织病理学特点评分相加,计算出每只小鼠的总病理评分。使用GraphPad Prism㈤软件进行数据分析。Danilenko,《综述论文:牛皮癣的临床前模型(Review paper:preclinical models of psoriasis)》,《兽医病理学(Vet Pathol)》.2008年7月;45(4):563-75;Lowes等人,《牛皮癣的发病机制和疗法(Pathogenesis andtherapy of psoriasis)》,《自然》.2007年2月22日;445(7130):866-73;Mecklenburg等人,《大鼠和小鼠皮肤的增殖性和非增殖性病变(Proliferative and non-proliferativelesions of the rat and mouse integument)》,《毒理病理学杂志(J Toxicol Pathol)》.2013;26(3增刊):27S-57S;Uribe-Herranz等人,《IL-1R1传信促进牛皮癣形咪喹莫特诱导的皮肤炎症中的芒罗微脓肿形成(IL-1R1 signaling facilitates Munro'smicroabscess formation in psoriasiform imiquimod-induced skin inflammation)》,《皮肤病学研究杂志》.2013年6月;133(6):1541-9;van der Fits等人,《小鼠中咪喹莫特诱导的牛皮癣样皮肤炎症经由IL-23/IL-17轴介导(Imiquimod-induced psoriasis-likeskin inflammation in mice is mediated via the IL-23/IL-17axis)》,《免疫学杂志》.2009年5月1日;182(9):5836-45。
皮肤匀浆中细胞因子的测量.取自鼠背的直径为6mm的全厚度皮肤组织,并将其放在含有T-per缓冲液(赛默科技公司(Thermo Scientific),目录号378510)和1×Halt蛋白酶抑制剂混合物(赛默科技公司,目录号87786)和5M EDTA溶液(赛默科技公司,目录号378429)的15mL管中。使用Polytron(PT10-35 GT-D,目录号9158158)以28000rpm将皮肤组织破坏1分钟,并放在冰上。将所生成的皮肤匀浆在4℃下以1500rpm离心8分钟,并将上清液收集到96孔盘中。使用蛋白质分析染料(伯乐(BioRad),目录号500-0006)对皮肤匀浆进行Bradford蛋白质分析,以定量总蛋白含量。根据制造商的说明书使用促炎性第1小组(小鼠)多重免疫分析试剂盒(MesoScale Discovery,目录号K15048D)测量皮肤匀浆中的细胞因子浓度。简单来说,将50μL/孔的校准物和样品(在稀释剂41中稀释)添加到预先用捕获抗体涂布的盘中,并在室温下以700rpm振荡的同时培育2小时。然后将盘用含有0.05%(w/v)Tween-20的1×PBS洗涤3次,随后添加在稀释剂45中稀释的25μL检测抗体溶液。在室温下在振荡的同时培育2小时后,将盘洗涤3次,并且向每个孔中添加150μL的2×读取缓冲液。立即在MSD仪器上读取电化学发光。使用GraphPad Prism㈤软件进行数据分析。将细胞因子水平相对于总蛋白含量进行归一化。
在DITRA样小鼠中DSS诱导的慢性结肠炎模型的诱导和抗体治疗.为了诱导慢性DSS介导的结肠炎,向12-20周龄、平均体重超过23g的雌性DITRA样小鼠给予在饮用水中的3%DSS(西格玛-奥德里奇公司(Sigma-Aldrich)目录号87786)持续7天,随后给予蒸馏水持续10天。重复这一循环两次直到d28。在研究期间,对照组接受蒸馏水。从d7开始,每两周以10mg/kg和5mg/kg腹膜內施用抗人类IL-36R抗体H4H14706P2和H4H14708P2。对照组接受PBS和10mg/kg的hIgG4同种型对照注射。每天给小鼠称重并监测结肠炎的临床病征(例如大便稠度和粪便血)。在d28,处死小鼠并测量其结肠长度。
结肠匀浆中Lcn-2的测量.为了在整个研究期间监测肠道炎症,每周将来自个体DITRA样小鼠的粪便收集到2mL深孔盘中,并储存在-80℃下。研究完成后,将不同天收集的粪便进行均质化。简单来说,将粪便样品用含有0.1%Tween-20、1×Halt蛋白酶抑制剂混合物(赛默科技公司,目录号87786)和5M EDTA溶液(赛默科技公司,目录号3 78429)的1mLPBS进行重构。在向孔中添加2颗3mm碳化钨珠(凯杰(Qiagen),目录号69997)之后,将盘在振荡器上以最高速度于4℃下放置过夜。将均质的粪便悬浮液在4℃下以1200rpm离心10分钟,并将上清液收集到96孔盘中。根据制造商的说明书使用小鼠Duoset Lipocalin-2/NGALELISA试剂盒(安迪生物公司,目录号DY1857)测量粪便脂质运载蛋白-2(Lcn2)水平。使用GraphPad Prism㈤软件进行数据分析。
结肠匀浆中的髓过氧化物酶(MPO)活性的测量.取几片结肠远端部分放入2mL微量离心管中,所述微量离心管含有2颗3mm碳化钨珠(凯杰,目录号69997)并含有T-per缓冲液(赛默科技公司,目录号378510)、1×Halt蛋白酶抑制剂混合物(赛默科技公司,目录号87786)和5M EDTA溶液(赛默科技公司,目录号78429)。使用凯杰Tissue Lyser II以27.5s-1的频率破坏结肠组织10分钟。将管在4℃下以1500rpm离心8分钟,并将上清液收集到96孔盘中。使用蛋白质分析染料(伯乐,目录号500-0006)对结肠匀浆进行Bradford蛋白质分析,以定量总蛋白含量。根据制造商的说明书使用小鼠MPO ELISA试剂盒(Hycult Biotech,目录号HK210-02)测量结肠匀浆中的髓过氧化物酶(MPO)活性。使用GraphPad Prism㈤软件进行数据分析。将MPO水平相对于总蛋白含量进行归一化。
结肠匀浆中的细胞因子的测量.根据制造商的说明书使用促炎性第1小组(小鼠)多重免疫分析试剂盒(MesoScale Discovery,目录号K15048D)测量结肠匀浆中的细胞因子浓度。简单来说,将50μL/孔的校准物和样品(在稀释剂41中稀释)添加到预先用捕获抗体涂布的盘中,并在室温下以700rpm振荡的同时培育2小时。然后将盘用含有0.05%(w/v)Tween-20的1×PBS洗涤3次,随后添加在稀释剂45中稀释的25μL检测抗体溶液。在室温下在振荡的同时培育2小时后,将盘洗涤3次,并且向每个孔中添加150μL的2×读取缓冲液。立即在MSD仪器上读取电化学发光。使用GraphPad Prism㈤软件进行数据分析。将细胞因子水平相对于总蛋白含量进行归一化。
统计分析.各组内的统计显著性通过单因数方差分析(one-way Anova)与图基多重比较后检验(Tukey's multiple comparison post-test)测定(#,*p<0.01;##,**p<0.001;###,***p<0.001;####,****p<0.0001)。
结果概述和结论
在预防性给药下,抗人类IL-36R单克隆抗体抑制DITRA样小鼠中的急性皮肤炎症。为了检查IL-36R在皮肤炎症中的作用,在牛皮癣形皮炎的IMQ诱导的模型中测试两种抗人类IL-36R单克隆抗体H4H14706P2和H4H14708P2,所述牛皮癣形皮炎在表型和组织学特征方面十分类似于人类牛皮癣病变(van der Fits等人,《小鼠中咪喹莫特诱导的牛皮癣样皮肤炎症经由IL-23/IL-17轴介导》,《免疫学杂志》2009,182:5836-5845;Swindell等人,《五个小鼠模型的基因组宽的表达谱鉴别人类牛皮癣的类似性和差异(Genome-wide expressionprofiling of five mouse models identifies similarities and differences withhuman psoriasis)》,《科学公共图书馆综合卷(PLoS One)》2011,6:e18266;Okayasu等人,《小鼠中可靠的实验性和慢性溃疡性结肠炎的诱导的新颖模型(A novel model in theinduction of reliable experimental and chronic ulcerative colitis in mice)》,《胃肠病学(Gastroenterology)》1990,98:694-702)。连续四天每天向DITRA样小鼠的剃过毛的背部皮肤应用IMQ。在-3d和d1以10mg/kg和1mg/kg施用H4H14706P2和H4H14708P2抗体。对照组接受PBS和10mg/kg的hIgG4同种型对照注射。在d4,测量皮肤厚度,并收集组织用于随后的组织病理学评估和蛋白质分离。H4H14706P2和H4H14708P2抗体两者与同种型对照相比都以剂量依赖性方式显著减少IMQ诱导的皮肤厚度(表5-1)。皮肤病变的组织病理学评估揭示利用抗人类IL-36R抗体治疗包括角化不全和芒罗微脓肿的总病理评分的降低显著(表5-2)。
表5-1.抗人类IL-36R抗体减少急性IMQ诱导的皮肤炎症中的皮肤厚度。厚度以μm为单位呈现。各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定,并且平均值标准误差(SEM±)计算为:#显著不同于凡士林治疗组;*显著不同于PBS治疗组和同种型治疗组。N=9只/组。
p值:#,*p<0.01;##,**p<0.001;###,***p<0.001;####,****p<0.0001
表5-2.抗人类IL-36R抗体减少急性IMQ诱导的皮肤炎症中的总病理评分。各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定,并且平均值标准误差(SEM±)计算为:#显著不同于凡士林治疗组;*显著不同于PBS治疗组和同种型治疗组。N=9只/组。
p值:#,*p<0.01;##,**p<0.001;###,***p<0.001;####,****p<0.0001
另外,利用H4H14706P2和H4H14708P2抗体的hIL-36R阻断在皮肤匀浆中使得KC-GRO、IL-6、IL-1β和TNFα产量降低66-93%(表5-3)。
表5-3.hIL-36R拮抗作用显著减少DITRA样小鼠的IMQ治疗的皮肤(急性皮肤炎症模型)中的促炎性细胞因子。从所有治疗组中减去PBS/凡士林对照组中的细胞因子水平。各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定,并且平均值标准误差(SEM±)计算为:*显著不同于PBS治疗组和同种型治疗组。N=9只/组。
p值:#,*p<0.01;##,**p<0.001;###,***p<0.001;####,****p<0.0001
在治疗性给药下,抗人类IL-36R单克隆抗体抑制慢性皮肤炎症。为了进一步检查体内hIL-36R拮抗作用的治疗功效,在皮肤炎症的慢性IMQ诱导的模型中测试抗人类IL-36R抗体。在两周的持续时间内,由不进行应用的两天间隔的连续九天将IMQ应用于DITRA样小鼠的剃过毛的背部皮肤。H4H14706P2和H4H14708P2抗体以10mg/kg剂量在d4和d8皮下施用。对照组接受PBS和10mg/kg的hIgG4同种型对照注射。在d11,测量皮肤厚度,并收集组织用于随后的组织病理学评估和蛋白质分离。如表5-4和5-5中所示,H4H14706P2和H4H14708P2抗体展示减少的IMQ诱导的皮肤厚度中的显著和相当功效以及DITRA样小鼠中的病理病变评分。H4H14706P2和H4H14708P2的治疗性施用导致在DITRA样小鼠的皮肤中IMQ诱导的促炎性细胞因子产生的显著抑制(表5-6)
表5-4.抗人类IL-36R抗体的治疗性施用减少慢性IMQ诱导的皮肤炎症中的皮肤厚度。厚度以μm为单位呈现。各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定,并且平均标准误差(SEM±)计算为:#显著不同于凡士林治疗组;*显著不同于PBS治疗组和同种型治疗组。N=9只/组。
p值:#,*p<0.01;##,**p<0.001;###,***p<0.001;####,****p<0.0001
表5-5.抗人类IL-36R抗体的治疗性施用降低慢性IMQ诱导的皮肤炎症中的总病理评分。各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定,并且平均标准误差(SEM±)计算为:#显著不同于凡士林治疗组;*显著不同于PBS治疗组和同种型治疗组。N=9只/组。
p值:#,*p<0.01;##,**p<0.001;###,***p<0.001;####,****p<0.0001
表5-6.hIL-36R拮抗作用显著抑制慢性IMQ诱导的皮肤炎症中的促炎性细胞因子。从所有治疗组中减去PBS/凡士林对照组中的细胞因子水平。各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定,并且平均值标准误差(SEM±)计算为:*显著不同于PBS治疗组和同种型治疗组。N=9只/组。
p值:#,*p<0.01;##,**p<0.001;###,***p<0.001;####,****p<0.0001
总之,这些数据证实抗人类IL-36R抗体在改善体内IMQ诱导的皮肤炎症中的预防功效和治疗功效。H4H14706P2和H4H14708P2抗体显示显著降低DITRA样小鼠中的急性和慢性两种IMQ诱导的皮肤病理的能力相当。
在治疗性给药下,抗人类IL-36R单克隆抗体改善DITRA样小鼠中的DSS诱导的慢性结肠炎。为了探究IL-36R拮抗作用在肠道炎症中的作用,使用肠道受损的化学模型。这一模型使用损害结肠上皮细胞的DSS的口服施用(Okayasu等人,《小鼠中的可靠的实验性和慢性溃疡性结肠炎的诱导的新颖模型(A novel model in the induction of reliableexperimental and chronic ulcerative colitis in mice)》,《胃肠病学》1990,98:694-702)和呈现IBD-尤其是溃疡性结肠炎的主要特点的所触发的有效炎症反应(Rakoff-Nahoum等人,《需要通过Toll样受体识别共生微生物群以用于肠道稳态(Recognition ofcommensal microflora by toll-like receptors is required for intestinalhomeostasis)》.《细胞》2004,118:229-241)。通过施用2-3%DSS维持7天,随后施用10天的水,循环两次,使DITRA样小鼠经历慢性DSS诱导的结肠炎。从d7开始,每两周以10mg/kg和5mg/kg施用H4H14706P2和H4H14708P2抗体。对照组接受PBS和10mg/kg的hIgG4同种型对照腹膜内注射。为了监测疾病的不同阶段时的肠道炎症,每周收集个别小鼠的粪便以测量粪便脂质运载蛋白-2(Lcn2)蛋白质,即肠道损伤中的炎症的非侵入性生物标记(Thorsvik等人,《粪便中性粒细胞明胶酶相关脂质运载蛋白作为发炎性肠病的生物标记(Fecalneutrophil gelatinase-associated lipocalin as a biomarker for inflammatorybowel disease)》.《胃肠病学与肝脏病学杂志(J Gastroenterol Hepatol)》2017,32:128-135)。如表5-7中所示,与仅有水相比,PBS治疗组和hIgG4治疗组显示在d12、19(未图示)和28粪便Lcn2水平显著上调。相反,与PBS治疗组和同种型治疗组相比,在d12,H4H14706P2和H4H14708P2的两次治疗性施用使得Lcn2水平以剂量依赖性方式显著降低。在d19(未图示)和d28在抗人类IL-36抗体治疗组中观察到粪便Lcn2水平持续降低,这支持抗IL-36R抗体在减少DITRA样小鼠的肠道炎症中的作用(表5-7)。与H4H14708P2相比,H4H14706P2抗体显示减少Lcn2水平,并且因此减少肠道炎症的能力更好(表5-7)。
表5-7.hIL-36R拮抗作用显著减少慢性DSS诱导的结肠炎中DITRA样小鼠中的粪便Lcn2水平。各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定,并且平均值标准误差(SEM±)计算为:#显著不同于水治疗组;*显著不同于PBS治疗组和同种型治疗组。N=6-8只/组。
p值:#,*p<0.01;##,**p<0.001;###,***p<0.001;####,****p<0.0001
在DSS治疗的DITRA样小鼠的结肠中,利用H4H14706P2和H4H14708P2抗体的hIL-36R阻断使得MPO活性降低(表5-8),并且促炎性细胞因子减少61-95%(表5-9)。
表5-8.抗人类IL-36R抗体的治疗性施用降低DSS治疗的DITRA样小鼠的结肠中的MPO活性。MPO水平以ng/mg的总蛋白为单位呈现。各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定,并且平均值标准误差(SEM±)计算为:#显著不同于水治疗组;*显著不同于PBS治疗组和同种型治疗组。N=6-8只/组。
p值:#,*p<0.01;##,**p<0.001;###,***p<0.001;####,****p<0.0001
表5-9.抗人类IL-36R抗体的治疗性施用减少DSS治疗的DITRA样小鼠的结肠中的促炎性细胞因子。MPO水平以ng/mg的总蛋白为单位呈现。各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定,并且平均值标准误差(SEM±)计算为:#显著不同于水治疗组;*显著不同于PBS治疗组和同种型治疗组。N=6-8只/组。
p值:#*p<0.01;##,**p<0.001;###,***p<0.001;####,****p<0.0001
与Lcn2水平减少更多的观察结果一致,与H4H14708P2相比,H4H14706P2抗体显示在结肠中减少MPO活性和促炎性细胞因子方面的优异功效。
实例6.H4H14706P2、H4H14708P2和H4H14731P通过氢氘交换与IL-36R结合的表位作图.
进行氘交换表位作图与质谱法(HDX-MS)以测定与H4H14706P2、H4H14708P2和H4H14731P(抗hIL-36R单克隆抗体)相互作用的IL-36R(重组人类IL-36R指定为hIL-36R.mmH,并且具有如SEQ ID NO:227中所阐述的氨基酸序列)的氨基酸残基。关于H/D交换方法的大体说明阐述于例如Ehring(1999)《分析生物化学(Analytical Biochemistry)》267(2):252-259;以及Engen和Smith(2001)《分析化学(Anal.Chem.)》73:256A-265A中。
在集成的HDX/MS平台上进行HDX-MS实验,所述平台由用于氘标记和淬灭的Leaptec HDX PAL系统、用于样品消化和负载的沃特斯(Waters)Acquity M级(辅助溶剂管理器)、用于分析梯度的沃特斯Acquity M级(μ二元溶剂管理器)以及用于肽质量测量的Thermo Q Exactive HF质谱仪组成。
在pD 7.0下,将标记溶液制备为D2O中的PBS缓冲液(10mM磷酸盐缓冲液、140mMNaCl和3mM KCl,在25℃下相当于pH 7.4)。对于氘标记,在20℃下与44μL D2O标记溶液一起培育11μL IL-36R.mmH(REGN2105,在H4H14706P2和H4H14708P2实验中45.6μM,或在H4H14731P实验中63.3μM)或与H4H14706P2、H4H14708P2或H4H14731P以1:0.7摩尔比预混合的IL-36R.mmH(Ag-Ab络合物)维持不同时间点,重复两次(例如,未氘化对照物=0秒;氘标记5分钟和10分钟)。通过向每份样品中添加55μL预冷却的淬灭缓冲液(0.5M TCEP-HCl,8M尿素和1%甲酸)以在20℃下培育5分钟来淬灭氘化反应。然后将淬灭的样品注射到沃特斯HDX管理器中,以进行在线胃蛋白酶/蛋白酶XIII消化。通过C8柱(1.0mm*50mm,NovaBioassays)从10%-32%B(移动相A:0.5%甲酸,于水中,移动相B:0.1%甲酸,乙腈中)中以13分钟的梯度分离消化的肽。通过Q Exactive HF质谱法以LC-MS/MS或LC-MS模式下分析洗脱的肽。
使用Byonic搜索引擎(Protein Metrics),针对包含IL-36R和其随机序列的数据库搜索未氘化的IL-36R样品的LC-MS/MS数据。使用非特异性酶消化和人类糖基化作为常见的变量修饰,将搜索参数(在ELN中)设置为默认值。然后将鉴定出的肽列表导入HDX工作台软件(3.3版),以计算通过LC-MS从所有氘化样品中检测到的每种肽的氘吸收量。对于给定的肽,使用每个时间点的质心质量(强度加权平均质量)来计算氘吸收量(D)和氘吸收量百分比(%D)。
从单独的hIL-36R.mmH和与H4H14706P2样品的复合物中的hIL-36R.mmH中鉴别出总共163个来自REGN2105的肽(hIL-36R.mmH),表示hIL-36R的81.5%序列覆盖率。展示出高于5%的D-吸收量值差异百分比的任何肽均被定义为受到显著保护。对应于REGN2105上氨基酸113-122(YKQILHLGKD)(SEQ ID NO:229)(SEQ ID NO:227的氨基酸113-122)的肽受到H4H14706P2显著保护。
从单独的hIL-36R.mmH和与H4H14708P2样品的复合物中的hIL-36R.mmH中鉴别出总共148个来自REGN2105的肽(hIL-36R.mmH),表示hIL-36R的80.1%序列覆盖率。展示出高于5%的D-吸收量值差异百分比的任何肽均被定义为受到显著保护。对应于REGN2105上氨基酸113-122(YKQILHLGKD)(SEQ ID NO:229)(SEQ ID NO:227的氨基酸113-122)的肽受到H4H14708P2显著保护。
从单独的hIL-36R.mmH和与H4H14731P样品的复合物中的hIL-36R.mmH中鉴别出总共237个来自REGN2105的肽(hIL-36R.mmH),表示hIL-36R的88.2%序列覆盖率。展示出高于5%的D-吸收量值差异百分比的任何肽均被定义为受到显著保护。对应于REGN2105上氨基酸264-277(GVETHVSFREHNLY)(SEQ ID NO:230)(SEQ ID NO:227的氨基酸264-277)的肽受到H4H14731P显著保护。
表6-1:与H4H14706P2结合后具有显著保护的IL-36R.mmH肽
表6-2:与H4H14708P2结合后具有显著保护的IL-36R.mmH肽
表6-3:在与H4H14731P结合后具有显著保护的IL-36R.mmH肽
重组人类IL-36R(IL1RL2;白细胞介素1受体样2;REGN2105)(hIL36R.mmH)的氨基酸序列:单体人类IL-36R(氨基酸D20-Y337,寄存编号Q9HB29),具有C端myc-myc-六组氨酸(mmH)标签(加下划线):
DGCKDIFMKNEILSASQPFAFNCTFPPITSGEVSVTWYKNSSKIPVSKIIQSRIHQDETWILFLPMEWGDSGVYQCVIKGRDSCHRIHVNLTVFEKHWCDTSIGGLPNLSDEYKQILHLGKDDSLTCHLHFPKSCVLGPIKWYKDCNEIKGERFTVLETRLLVSNVSAEDRGNYACQAILTHSGKQYEVLNGITVSITERAGYGGSVPKIIYPKNHSIEVQLGTTLIVDCNVTDTKDNTNLRCWRVNNTLVDDYYDESKRIREGVETHVSFREHNLYTVNITFLEVKMEDYGLPFMCHAGVSTAYIILQLPAPDFRAYEQKLISEEDLGGEQKLISEEDLHHHHHH(SEQ ID NO:227)。
实例7:IMQ诱导和恶唑酮诱导的皮肤炎症和慢性结肠炎小鼠模型中的抗IL36R的体内评估.
本发明的抗人类IL-36R单克隆抗体在体外初级人类细胞分析中进行测试;并且在人类化IL-36R/IL-36R/hIL-36α、β、γ小鼠中在体内咪喹莫特(IMQ)诱导的皮肤炎症分析中与其它抗人类IL-36R单克隆抗体进行比较。此外,本发明的抗人类IL-36R单克隆抗体在人类化IL-36R/hIL-36α、β、γ小鼠中在结肠炎的恶唑酮诱导的模型中进行体内测试。
在培养上清液中使用人类CXCL8/IL-8的DuoSet ELISA试剂盒(安迪生物公司)检测IL-8,并且在皮肤和结肠匀浆中使用促炎性第1小组(小鼠和人类)多重免疫分析试剂盒(MSD)检测细胞因子。所测试单克隆抗体为H4H14706P2、H4H14708P2、APE6155(IgG4)和人类IgG4同种型对照(REGN1002)。
APE6155重链(包含IgG4恒定结构域)包含氨基酸序列:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWMNWVRQAPRQGLEWMGMFHPTGDVTRLNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARTTSMIIGGFAYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:239)
APE6155轻链(包含κ恒定结构域)包含氨基酸序列:
DIVMTQTPLSLSVTPGQPASISCRSSKSLLHRNAITYFYWYLHKPGQPPQLLIYQMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:240)
参见WO2016/168542。
在体外初级人类细胞分析中测试体外抗人类IL-36R抗体.正常人类表皮角化细胞(NHLF;Lonza,目录号00192627,批号254498)和肠道成肌纤维细胞(InMyoFib;Lonza,目录号CC-2902,批号0000254498)分别在补充有BulletKitTM(Lonza,目录号CC-00192060,批号0000484385)的KGM-GoldTM和补充有BulletKitTM(Lonza,目录号CC-3182,批号00004736694)的SmGmTM-2中体外培养4-5次传代。根据制造商的说明书使用EasySep人类单核细胞分离试剂盒(StemCell,目录号19359)从3个不同供体的外周血中分离人类CD14+单核细胞。在分析之前一天,将初级人类细胞以96孔平底盘中10000每孔涂铺在对应的培养基中并且在37℃下培育过夜。在恒定浓度(10nM)或连续稀释的(从1500nM开始)rhIL-36α/IL-1F6[aa6-158](安迪生物公司,目录号6995-IL-010/CF,批号DAFZ0313051)、rhIL-36β/IL-1F8[aa5-157](安迪生物公司,目录号6834-IL-010/CF,批号DAKU0514062和rhIL-36γ/IL-1F9[aa18-169](安迪生物公司,目录号6835-IL-010/CF,批号DAPK0215011)存在的情况下单独或以组合方式刺激细胞。将从抗人类IL-36R抗体的2400nM开始的连续稀释液添加到孔中。在37℃下培育盘24小时,并且收集上清液以使用人类CXCL8/IL-8的DuoSet ELISA研发系统(安迪生物公司,目录号DY208-05,批号325963)测量IL-8。为了获得EC50和IC50值,在GraphPad Prism㈤软件中使用非线性回归(4参数逻辑)对结果进行分析。
在IMQ诱导的皮肤炎症中测试和比较抗人类IL-36R抗体.为了诱导皮肤炎症,使用小鼠毛发修剪器(Oster,MiniMax,目录号78049-100)对8-10周龄人类化DITRA样雌性小鼠的背部进行剃毛,并在应用IMQ乳霜前三天用0.5g Veet脱毛凝胶对皮肤进行脱毛。连续四天在小鼠剃过毛的背部皮肤上应用可商购获得IMQ乳膏(5%)(Aldara,GM健康护理有限公司,NDC 99207-206-12,批号QJ044A)或凡士林(Vaseline)(CVS药局,NDC 59779-902-88)的62.5mg每日局部剂量。62.5mg每日局部剂量的Aldara转化为3.125mg每日剂量的活性化合物。在-3d和d1以10mg/kg向背部皮肤皮下施用抗人类IL-36R抗体-H4H14706P2、H4H14708P2和APE6155(IgG4)。对照组接受PBS和10mg/kg的hIgG4同种型对照(REGN1002)注射。开始IMQ应用后两天或三天,小鼠的背部皮肤开始出现红斑、鳞片化和增厚的病征。每天使用改良版的临床牛皮癣面积和严重程度指数测量炎症的严重程度。根据评分表将红斑、鳞片化和增厚独立地评分为0-4:0,无;1,轻微;2,中度;3,明显;和4,非常明显(van der Fits等人,《咪喹莫特诱导的牛皮癣样皮肤炎症经由IL-23/IL-17轴》.《免疫学杂志》2009,182:5836-5845)。在d5使用卡尺(Kaefer)测量皮肤厚度。
组织病理学.将从鼠背6mm直径的皮肤组织固定在10%缓冲福尔马林中,并用苏木精(hematoxylin)和曙红(eosin)对4-5μm石蜡包埋的切片进行染色。不知情地评价皮肤切片中的角化不全、正角化、芒罗微脓肿、棘皮症、表皮溃疡、真皮和皮下组织的炎症、真皮和皮下组织的血管充血、滤泡性角化过度和上皮增生的存在。使用0-4评分量表:0-在正常范围内,1-最小程度,2-轻度,3-中度和4-重度。通过将各个组织病理学特点评分相加,计算出每只小鼠的总病理评分。使用GraphPad Prism㈤软件进行数据分析。
皮肤匀浆中细胞因子的测量.取自鼠背的直径为6mm的全厚度皮肤组织,并将其置于含有T-per缓冲液(赛默科技公司,目录号378510,批号RF236217)和1×Halt蛋白酶抑制剂混合物(赛默科技公司,目录号87786,批号QG221763)和5M EDTA溶液(赛默科技公司,目录号3 78429)的15mL管中。使用Polytron(PT10-35 GT-D,目录号9158158)以28000rpm将皮肤组织破坏1分钟,并放在冰上。将所生成的皮肤匀浆在4℃下以1500rpm离心8分钟,并将上清液收集到96孔盘中。使用蛋白质分析染料(伯乐,目录号500-0006,批号210008149)对皮肤匀浆进行Bradford蛋白质分析,以定量总蛋白含量。根据制造商的说明书使用促炎性第1小组(小鼠)多重免疫分析试剂盒(MesoScale Discovery,目录号K15048D)测量皮肤匀浆中的细胞因子浓度。简单来说,将50μL/孔的校准物和样品(在稀释剂41中稀释)添加到预先用捕获抗体涂布的盘中,并在室温下以700rpm振荡的同时培育2小时。然后将盘用含有0.05%(w/v)Tween-20的1×PBS洗涤3次,随后添加在稀释剂45中稀释的25μL检测抗体溶液。在室温下在振荡的同时培育2小时后,将盘洗涤3次,并且向每个孔中添加150μL的2×读取缓冲液。立即在MSD仪器上读取电化学发光。使用GraphPad Prism㈤软件进行数据分析。将细胞因子水平相对于总蛋白含量进行归一化。
在DITRA样小鼠中在恶唑酮诱导的肠道炎症-慢性结肠炎的恶唑酮诱导的模型的诱导和抗体治疗中测试抗人类IL-36R单克隆抗体.如先前描述诱导恶唑酮结肠炎(Heller等人,《类似于溃疡性结肠炎的恶唑酮结肠炎,Th2结肠炎模型由IL-13-产生的NK-T细胞介导(Oxazolone colitis,a Th2 colitis model resembling ulcerative colitis,ismediated by IL-13-producing NK-T cells)》.《免疫(Immunity)》2002,17:629-638)。简单来说,为了使DITRA样小鼠预致敏,将腹部皮肤的2×2cm2区域剃毛,并且施加在100%乙醇中稀释的100μl 3%溶液恶唑酮((4-乙氧基亚甲基-2-苯基-2-恶唑啉-5-酮;西格玛-奥德里奇公司)。在预致敏之后第5天和第7天,在全身麻醉下用在50%乙醇中稀释的50μl1.5%恶唑酮直肠内攻击小鼠。对照小鼠用100%乙醇预致敏并且接受50%乙醇的直肠内注射。从d2、5和7开始,以10mg/kg腹膜內施用抗人类IL-36R抗体-H4H14706P2和H4H14708P2。对照组接受PBS和10mg/kg的hIgG4同种型对照(REGN1002)注射。每天给小鼠称重并监测结肠炎的临床病征(例如大便稠度和粪便血)。在d8,处死小鼠并且收集结肠。
结肠匀浆中细胞因子的测量.取几片结肠远端部分放入2mL微量离心管中,所述微量离心管含有2颗3mm碳化钨珠(凯杰),含有T-per缓冲液(赛默科技公司)、1×Halt蛋白酶抑制剂混合物(赛默科技公司)和5M EDTA溶液(赛默科技公司)。使用凯杰Tissue Lyser II以27.5s-1的频率破坏结肠组织10分钟。将管在4℃下以1500rpm离心8分钟,并将上清液收集到96孔盘中。使用蛋白质分析染料(伯乐)对所有组织匀浆进行Bradford蛋白质分析,以定量总蛋白含量。
根据制造商的说明书使用促炎性第1小组(小鼠)多重免疫分析试剂盒(MesoScaleDiscovery目录号K15048D)测量结肠匀浆中的细胞因子浓度。简单来说,将50μL/孔的校准物和样品(在稀释剂41中稀释)添加到预先用捕获抗体涂布的盘中,并在室温下以700rpm振荡的同时培育2小时。然后将盘用含有0.05%(w/v)Tween-20的1×PBS洗涤3次,随后添加在稀释剂45中稀释的25μL检测抗体溶液。在室温下在振荡的同时培育2小时后,将盘洗涤3次,并且向每个孔中添加150μL的2×读取缓冲液。立即在MSD仪器上读取电化学发光。使用GraphPad Prism㈤软件进行数据分析。将细胞因子水平相对于总蛋白含量进行归一化。
统计分析.各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定(*p<0.05,**p<0.005,***p<0.0005,****p<0.00001)。
结果概述和结论-抗人类IL-36R单克隆抗体在体外初级人类细胞中有效地抑制人类IL-36R传信。用10nM IL-36α、β和γ体外刺激人类表皮角化细胞(NHEK)、人类肠道肌成纤维细胞(InMyoFib)和外周血(PB)-衍生的CD14+单核细胞。向培养物中添加连续稀释的抗人类IL-36R单克隆抗体(H4H14706P2和H4H14708P2),培育后24小时收集上清液,并且测量响应于IL-36刺激的人类IL-8产量。抗人类IL-36R单克隆抗体在IC50为1-6nM的体外人类表皮角化细胞、人类肠道肌成纤维细胞和外周血(PB)-衍生的CD14+单核细胞中有效地抑制所有三种IL-36细胞因子(表7-1)。
表7-1.抗人类IL-36R抗体H4H14706P2和H4H14708P2在人类初级细胞中体外抑制人类IL-36α、β和γ。
在DITRA样小鼠中抑制IMQ诱导的皮肤炎症方面,抗人类IL-36R单克隆抗体H4H14706P2和H4H14708P2比APE6155抗体更有效。在牛皮癣形皮炎的IMQ诱导的模型中对H4H14706P2和H4H14708P2和APE6155抗人类IL-36R单克隆抗体进行头对头测试。连续四天每天向DITRA样小鼠的剃过毛的背部皮肤应用IMQ。在-3d和d1,以10mg/kg施用H4H14706P2和H4H14708P2和APE6155抗体。对照组接受PBS和10mg/kg的hIgG4同种型对照注射。在d5,测量皮肤厚度,并收集组织用于随后的组织病理学评估和蛋白质分离。与APE6155相比,在显著减少IMQ诱导的皮肤厚度方面H4H14706P2和H4H14708P2抗体两者都显示出更大的效能(表7-2)。皮肤病变的组织病理学评估揭示利用抗人类IL-36R抗体治疗包括角化不全和芒罗微脓肿的总病理评分的降低更大(表7-3)。
表7-2.在IMQ诱导的皮肤炎症中减少皮肤厚度方面,抗人类IL-36R抗体H4H14706P2和H4H14708P2比APE6155抗人类IL-36R抗体更有效。~
~厚度以μm为单位呈现。各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定,并且平均值标准误差(SEM±)计算为:*显著不同于PBS治疗组和同种型治疗组。n=9只/组。
表7-3.在IMQ诱导的皮肤炎症中降低总病理评分方面,抗人类IL-36R抗体H4H14706P2和H4H14708P2显示出比APE6155更大的效能。$
$各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定,并且平均值标准误差(SEM±)计算为:*显著不同于PBS治疗组和同种型治疗组。n=9只/组。
另外,与COMP5382相比,利用H4H14706P2和H4H14708P2抗体的人类IL-36R阻断在皮肤匀浆中使得KC-GRO、IL-6、IL-1β和TNFα产量降低更多(表7-4)。
表7-4.在皮肤中减少促炎性细胞因子方面,抗人类IL-36R抗体H4H14706P2和H4H14708P2显示出比APE6155更大的效能。∞
∞值以“pg/mg总组织”为单位呈现。各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定,并且平均值标准误差(SEM±)计算为:*显著不同于PBS治疗组和同种型治疗组。n=9只/组。
抗人类IL-36R单克隆抗体改善DITRA样小鼠的恶唑酮诱导的结肠炎。为了进一步探究IL-36在肠中的生物功能,我们测试了IL-36R阻断在恶唑酮诱导的结肠炎中的功效,所述恶唑酮诱导的结肠炎是IBD的另一临床前模型,其在组织学上与人类溃疡性结肠炎类似(Heller等人)。如IL-4、IL-6和TNF-α在恶唑酮治疗的DITRA样小鼠的结肠中的水平所反映,与PBS和同种型对照治疗组相比,预防性施用抗人类IL-36R抗体H4H14706P2和H4H14708P2显著降低DITRA样小鼠中的恶唑酮诱导的疾病严重程度(表7-5)。
表7-5.人类IL-36R拮抗作用体外改善了DITRA样小鼠中的恶唑酮诱导的结肠炎。◆
◆用溶解于100%乙醇中的3%恶唑酮溶液对DITRA样小鼠进行预致敏,并在5天后直肠内施用1.5%恶唑酮和媒剂(50%乙醇)。在预致敏后第2天、第5天和第7天,向小鼠腹膜内注射PBS、抗人类IL-36R mAb和hIgG4同种型对照。注射有PBS、抗人类IL-36R mAb和hIgG4同种型对照的恶唑酮治疗和媒剂治疗的DITRA样小鼠中的结肠匀浆中的促炎性细胞因子水平。值以“pg/mg总组织”为单位呈现。各组内的统计显著性通过单因数方差分析与图基多重比较后检验测定,并且平均值标准误差(SEM±)计算为:*表示与PBS治疗组的显著差异。n=5只/组。
实例8:使用人类HEK293/NFkB-luc/hIL36R细胞系进行生物分析以用于斯切尔德分析
为了表征抗IL36R抗体H4H14706P2和H4H14708P2的抑制特性,进行了斯切尔德分析。这一方法评估抑制因子的拮抗作用的性质,并且测量在满足多种条件时竞争性拮抗因子的亲和力(Colquhoun,《为何斯切尔德方法比斯切尔德实现地更佳(Why the Schildmethod is better than Schild realized)》,《药物科学趋势(Trends Pharmacol Sci.)》2007年12月;28(12):608-14)。
对于生物分析,在低血清培养基、0.1%FBS和OPTIMEM中以10,000个细胞/孔将HEK293/NFκB-luc/hIL-36R细胞接种到96孔分析盘上,并且在37℃和5%CO2下培育过夜。第二天,将抗体以不同的固定浓度(9nM、3nM、1nM、0.3nM或0.1nM)添加到细胞中并且在室温下与细胞一起预培育15分钟。还包括不含抗体的条件。然后将IL-36α、IL-36β或IL-36γ从100nM到2pM或100nM到0.1pM连续稀释,并且与无任何配位体的样品一起添加到细胞中。在37℃和5%CO2下与维克托X5或EnVision Multilabel盘读取器(珀金埃尔默)一起培育5.5小时之后检测荧光素酶活性,并且利用Prism 7(GraphPad)使用Gaddum/Schild EC50偏移分析结果。
H4H14706P2和H4H14708P2的斯切尔德分析展示增加量的抗体引起IL36配位体剂量反应曲线平行地向右偏移,并且H4H14706P2和H4H14708P2的抑制作用可由增加量的IL36配位体克服,表明H4H14706P2和H4H14708P2的竞争性抑制(图3(A-F))。
实例9:药代动力学(PK)研究
将雌性食蟹猕猴分配到用于PK表征的剂量组;动物(3只动物/组)接受5或0.5mg/kg的H4H14708P2或APE6155的单次SC注射。在给药前和在给药后4、24、48、72、120、168、240、336、504、576、672、840、912、1008、1080、1176、1248、1344、1512和1680小时从所有动物中收集血液样品。总H4H14708P2或APE6155在血清中的浓度使用未验证的酶联免疫吸附分析(ELISA)测定。所述方法被设计成测量食蟹猕猴血清中的总人类IgG浓度。使用非房室分析估计药代动力学参数。观察到H4H14708P2在5mg/kg剂量下比APE6155暴露得多约1.3倍,并且在0.5mg/kg剂量下比APE6155暴露得多约1.2倍。参见图4。
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序列表
<110> 再生元制药公司
<120> 抗IL36R抗体
<130> 36432PCT (10484WO01)
<150> 62/698,482
<151> 2018-07-16
<150> 62/846,989
<151> 2019-05-13
<150> 62/866,028
<151> 2019-06-25
<160> 240
<170> PatentIn version 3.5
<210> 1
<211> 354
<212> DNA
<213> 智人
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<212> PRT
<213> 智人
<400> 4
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 5
<211> 24
<212> DNA
<213> 智人
<400> 5
atcagttgga atagtgatat cata 24
<210> 6
<211> 8
<212> PRT
<213> 智人
<400> 6
Ile Ser Trp Asn Ser Asp Ile Ile
1 5
<210> 7
<211> 33
<212> DNA
<213> 智人
<400> 7
gcaaaaggat ataactggaa cttctttgac tat 33
<210> 8
<211> 11
<212> PRT
<213> 智人
<400> 8
Ala Lys Gly Tyr Asn Trp Asn Phe Phe Asp Tyr
1 5 10
<210> 9
<211> 321
<212> DNA
<213> 智人
<400> 9
gaaattgtgt tgacgcagtc tccagccacc ctgtctttat ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120
ggccaggctc ccaggctcct catctataat gcagcaaaca gggccactga catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctctcac tttcggcgga 300
gggaccaagg tggagatcaa a 321
<210> 10
<211> 107
<212> PRT
<213> 智人
<400> 10
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 Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asn Ala Ala Asn Arg Ala Thr Asp Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 11
<211> 18
<212> DNA
<213> 智人
<400> 11
cagagtgtta gcagctac 18
<210> 12
<211> 6
<212> PRT
<213> 智人
<400> 12
Gln Ser Val Ser Ser Tyr
1 5
<210> 13
<211> 9
<212> DNA
<213> 智人
<400> 13
aatgcagca 9
<210> 14
<211> 3
<212> PRT
<213> 智人
<400> 14
Asn Ala Ala
1
<210> 15
<211> 27
<212> DNA
<213> 智人
<400> 15
cagcagcgta gcaactggcc tctcact 27
<210> 16
<211> 9
<212> PRT
<213> 智人
<400> 16
Gln Gln Arg Ser Asn Trp Pro Leu Thr
1 5
<210> 17
<211> 354
<212> DNA
<213> 智人
<400> 17
gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaaact 120
ccagggaagg gcctggagtg ggtctcagtt attagttgga atagtgatgt catagcctat 180
tcggactctg tgaagggccg cttcaccatt tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctggg aactgaggac acggccttat attactgtgc aaaaggccat 300
aactggaact tctttgacta ttggggccag ggaaccctgg tcaccgtctc ctca 354
<210> 18
<211> 118
<212> PRT
<213> 智人
<400> 18
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser Trp Asn Ser Asp Val Ile Ala Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Gly Thr Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Gly His Asn Trp Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 19
<211> 24
<212> DNA
<213> 智人
<400> 19
ggattcacct ttgatgatta tgcc 24
<210> 20
<211> 8
<212> PRT
<213> 智人
<400> 20
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 21
<211> 24
<212> DNA
<213> 智人
<400> 21
attagttgga atagtgatgt cata 24
<210> 22
<211> 8
<212> PRT
<213> 智人
<400> 22
Ile Ser Trp Asn Ser Asp Val Ile
1 5
<210> 23
<211> 33
<212> DNA
<213> 智人
<400> 23
gcaaaaggcc ataactggaa cttctttgac tat 33
<210> 24
<211> 11
<212> PRT
<213> 智人
<400> 24
Ala Lys Gly His Asn Trp Asn Phe Phe Asp Tyr
1 5 10
<210> 25
<211> 321
<212> DNA
<213> 智人
<400> 25
gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccaggaga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120
ggccaggctc ccaggctcct catctataat gtagccaaca gggccacaga catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcgg cctagagcct 240
gaagattttg cagtttattt ctgtcagcag cgtagcaact ggcctctcac tttcggcgga 300
gggaccaagg tggagatcaa a 321
<210> 26
<211> 107
<212> PRT
<213> 智人
<400> 26
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 Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asn Val Ala Asn Arg Ala Thr Asp Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 27
<211> 18
<212> DNA
<213> 智人
<400> 27
cagagtgtta gcagctac 18
<210> 28
<211> 6
<212> PRT
<213> 智人
<400> 28
Gln Ser Val Ser Ser Tyr
1 5
<210> 29
<211> 9
<212> DNA
<213> 智人
<400> 29
aatgtagcc 9
<210> 30
<211> 3
<212> PRT
<213> 智人
<400> 30
Asn Val Ala
1
<210> 31
<211> 27
<212> DNA
<213> 智人
<400> 31
cagcagcgta gcaactggcc tctcact 27
<210> 32
<211> 9
<212> PRT
<213> 智人
<400> 32
Gln Gln Arg Ser Asn Trp Pro Leu Thr
1 5
<210> 33
<211> 354
<212> DNA
<213> 智人
<400> 33
gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtacag cctctggatt cacctttgat gattatgcca tacactgggt ccggcaatct 120
ccagggaagg gcctggagtg ggtctcagtt atcagttgga atagtgatgt cataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcagatga atagtctgag agctgaggac acggccttgt attactgtgc aaaaggatat 300
aactggaact tctttgacta ttggggccag ggaaccctgg tcaccgtctc ctca 354
<210> 34
<211> 118
<212> PRT
<213> 智人
<400> 34
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Ile His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser Trp Asn Ser Asp Val Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Gly Tyr Asn Trp Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 35
<211> 24
<212> DNA
<213> 智人
<400> 35
ggattcacct ttgatgatta tgcc 24
<210> 36
<211> 8
<212> PRT
<213> 智人
<400> 36
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 37
<211> 24
<212> DNA
<213> 智人
<400> 37
atcagttgga atagtgatgt cata 24
<210> 38
<211> 8
<212> PRT
<213> 智人
<400> 38
Ile Ser Trp Asn Ser Asp Val Ile
1 5
<210> 39
<211> 33
<212> DNA
<213> 智人
<400> 39
gcaaaaggat ataactggaa cttctttgac tat 33
<210> 40
<211> 11
<212> PRT
<213> 智人
<400> 40
Ala Lys Gly Tyr Asn Trp Asn Phe Phe Asp Tyr
1 5 10
<210> 41
<211> 321
<212> DNA
<213> 智人
<400> 41
gaaattgtgt tgacgcagtc tccagccacc ctgtctttat ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120
ggccaggctc ccaggctcct catctataat gcagcaaaca gggccactga catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctctcac tttcggcgga 300
gggaccaagg tggagatcaa a 321
<210> 42
<211> 107
<212> PRT
<213> 智人
<400> 42
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 Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asn Ala Ala Asn Arg Ala Thr Asp Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 43
<211> 18
<212> DNA
<213> 智人
<400> 43
cagagtgtta gcagctac 18
<210> 44
<211> 6
<212> PRT
<213> 智人
<400> 44
Gln Ser Val Ser Ser Tyr
1 5
<210> 45
<211> 9
<212> DNA
<213> 智人
<400> 45
aatgcagca 9
<210> 46
<211> 3
<212> PRT
<213> 智人
<400> 46
Asn Ala Ala
1
<210> 47
<211> 27
<212> DNA
<213> 智人
<400> 47
cagcagcgta gcaactggcc tctcact 27
<210> 48
<211> 9
<212> PRT
<213> 智人
<400> 48
Gln Gln Arg Ser Asn Trp Pro Leu Thr
1 5
<210> 49
<211> 354
<212> DNA
<213> 智人
<400> 49
gaagtgcagc tggtggagtc tgggggagac ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggaatg ggtctcagtt attagttgga atagtgatgt catagcctat 180
tcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag aactgaggac acggccttat attactgtac aaaaggccat 300
aagtggagct tctttgacta ttggggccag ggaaccctgg tcaccgtctc ctca 354
<210> 50
<211> 118
<212> PRT
<213> 智人
<400> 50
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser Trp Asn Ser Asp Val Ile Ala Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Thr Lys Gly His Lys Trp Ser Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 51
<211> 24
<212> DNA
<213> 智人
<400> 51
ggattcacct ttgatgatta tgcc 24
<210> 52
<211> 8
<212> PRT
<213> 智人
<400> 52
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 53
<211> 24
<212> DNA
<213> 智人
<400> 53
attagttgga atagtgatgt cata 24
<210> 54
<211> 8
<212> PRT
<213> 智人
<400> 54
Ile Ser Trp Asn Ser Asp Val Ile
1 5
<210> 55
<211> 33
<212> DNA
<213> 智人
<400> 55
acaaaaggcc ataagtggag cttctttgac tat 33
<210> 56
<211> 11
<212> PRT
<213> 智人
<400> 56
Thr Lys Gly His Lys Trp Ser Phe Phe Asp Tyr
1 5 10
<210> 57
<211> 321
<212> DNA
<213> 智人
<400> 57
gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtattagc agctacttag cctggtacca acagaaacct 120
ggccaggctc ccagactcct catctttaat gtagccaaca gggccactga catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctctcac tttcggcgga 300
gggaccaagg tggagatcaa a 321
<210> 58
<211> 107
<212> PRT
<213> 智人
<400> 58
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 Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Phe Asn Val Ala Asn Arg Ala Thr Asp Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 59
<211> 18
<212> DNA
<213> 智人
<400> 59
cagagtatta gcagctac 18
<210> 60
<211> 6
<212> PRT
<213> 智人
<400> 60
Gln Ser Ile Ser Ser Tyr
1 5
<210> 61
<211> 9
<212> DNA
<213> 智人
<400> 61
aatgtagcc 9
<210> 62
<211> 3
<212> PRT
<213> 智人
<400> 62
Asn Val Ala
1
<210> 63
<211> 27
<212> DNA
<213> 智人
<400> 63
cagcagcgta gcaactggcc tctcact 27
<210> 64
<211> 9
<212> PRT
<213> 智人
<400> 64
Gln Gln Arg Ser Asn Trp Pro Leu Thr
1 5
<210> 65
<211> 339
<212> DNA
<213> 智人
<400> 65
gaggtgcagc tggtggagtc tgggggaggc ttggttcagc ctggggggtc cctgagactc 60
tcctgcgcag cctctggatt cacctttagc gactatgcca tgagctgggt ccgccaggct 120
ccggggaagg ggctggagtg ggtctcaggt attagtggaa atggtggtga cacatactac 180
ggagacttcg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag aggcgaggac acggccgcat atttctgtgt gatagatctt 300
gactattggg gtcagggaac cctggtcacc gtctcctca 339
<210> 66
<211> 113
<212> PRT
<213> 智人
<400> 66
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Gly Asn Gly Gly Asp Thr Tyr Tyr Gly Asp Phe Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr Ala Ala Tyr Phe Cys
85 90 95
Val Ile Asp Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 67
<211> 24
<212> DNA
<213> 智人
<400> 67
ggattcacct ttagcgacta tgcc 24
<210> 68
<211> 8
<212> PRT
<213> 智人
<400> 68
Gly Phe Thr Phe Ser Asp Tyr Ala
1 5
<210> 69
<211> 24
<212> DNA
<213> 智人
<400> 69
attagtggaa atggtggtga caca 24
<210> 70
<211> 8
<212> PRT
<213> 智人
<400> 70
Ile Ser Gly Asn Gly Gly Asp Thr
1 5
<210> 71
<211> 18
<212> DNA
<213> 智人
<400> 71
gtgatagatc ttgactat 18
<210> 72
<211> 6
<212> PRT
<213> 智人
<400> 72
Val Ile Asp Leu Asp Tyr
1 5
<210> 73
<211> 321
<212> DNA
<213> 智人
<400> 73
gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgaaggaga cagagtcacc 60
atcacttgcc gggccagtca gagtattagt agctggttgg cctggtatca acagaaacca 120
ggaaaagccc ctaggctcct gatctataag gcgtctattt taggagatgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgattttg ctacttatta ctgccaccag tataatagtt atttgtggac gttcggccaa 300
gggaccaagg tggaaatcaa a 321
<210> 74
<211> 107
<212> PRT
<213> 智人
<400> 74
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Glu Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ile Leu Gly Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys His Gln Tyr Asn Ser Tyr Leu Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 75
<211> 18
<212> DNA
<213> 智人
<400> 75
cagagtatta gtagctgg 18
<210> 76
<211> 6
<212> PRT
<213> 智人
<400> 76
Gln Ser Ile Ser Ser Trp
1 5
<210> 77
<211> 9
<212> DNA
<213> 智人
<400> 77
aaggcgtct 9
<210> 78
<211> 3
<212> PRT
<213> 智人
<400> 78
Lys Ala Ser
1
<210> 79
<211> 27
<212> DNA
<213> 智人
<400> 79
caccagtata atagttattt gtggacg 27
<210> 80
<211> 9
<212> PRT
<213> 智人
<400> 80
His Gln Tyr Asn Ser Tyr Leu Trp Thr
1 5
<210> 81
<211> 363
<212> DNA
<213> 智人
<400> 81
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagc agtgctgatt actattggag ctggatccgc 120
cagcacccag ggaagggcct ggagtggatt ggatccatct attatactgg gagtacttac 180
tacaacccgt ccctcaagag tcgacttacc atatcaatag acacgtctga gaaccagttc 240
tctttgaaac tgacctctct gactgccgcg gacacggccg tgtattactg tgcgagcgag 300
gaggctaact ggggatccca ctttgactcc tggggccagg gaaccctggt caccgtctcc 360
tca 363
<210> 82
<211> 121
<212> PRT
<213> 智人
<400> 82
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ala
20 25 30
Asp Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Ser Ile Tyr Tyr Thr Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Glu Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Thr Ser Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Ser Glu Glu Ala Asn Trp Gly Ser His Phe Asp Ser Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 83
<211> 30
<212> DNA
<213> 智人
<400> 83
ggtggctcca tcagcagtgc tgattactat 30
<210> 84
<211> 10
<212> PRT
<213> 智人
<400> 84
Gly Gly Ser Ile Ser Ser Ala Asp Tyr Tyr
1 5 10
<210> 85
<211> 21
<212> DNA
<213> 智人
<400> 85
atctattata ctgggagtac t 21
<210> 86
<211> 7
<212> PRT
<213> 智人
<400> 86
Ile Tyr Tyr Thr Gly Ser Thr
1 5
<210> 87
<211> 39
<212> DNA
<213> 智人
<400> 87
gcgagcgagg aggctaactg gggatcccac tttgactcc 39
<210> 88
<211> 13
<212> PRT
<213> 智人
<400> 88
Ala Ser Glu Glu Ala Asn Trp Gly Ser His Phe Asp Ser
1 5 10
<210> 89
<211> 324
<212> DNA
<213> 智人
<400> 89
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattgac aactttttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg catcttacta ctgtcaacat agtcacagtg cccatccgat caccttcggc 300
caagggacac gactggagat taaa 324
<210> 90
<211> 108
<212> PRT
<213> 智人
<400> 90
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asp Asn Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Ser Tyr Tyr Cys Gln His Ser His Ser Ala His Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 91
<211> 18
<212> DNA
<213> 智人
<400> 91
cagagcattg acaacttt 18
<210> 92
<211> 6
<212> PRT
<213> 智人
<400> 92
Gln Ser Ile Asp Asn Phe
1 5
<210> 93
<211> 9
<212> DNA
<213> 智人
<400> 93
gctgcatcc 9
<210> 94
<211> 3
<212> PRT
<213> 智人
<400> 94
Ala Ala Ser
1
<210> 95
<211> 30
<212> DNA
<213> 智人
<400> 95
caacatagtc acagtgccca tccgatcacc 30
<210> 96
<211> 10
<212> PRT
<213> 智人
<400> 96
Gln His Ser His Ser Ala His Pro Ile Thr
1 5 10
<210> 97
<211> 363
<212> DNA
<213> 智人
<400> 97
cagctgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagc agtagtaatt actactgggg ctggatccgc 120
cagcccccag ggaagagact ggagtggatt gggagtatct attatagtgg gagcacctac 180
tacaacccgt ccctcaagac tcgagtcacc atatccgtag acacgtccaa gaatcagttc 240
tccctgaagc tgacctctgt gaccgccgca gacacggctg tgtattactg tgcgagagag 300
gaagcagcag ctttgacgca ctttgacttc tggggccagg gaaccctggt caccgtctcc 360
tca 363
<210> 98
<211> 121
<212> PRT
<213> 智人
<400> 98
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Arg Leu Glu
35 40 45
Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Thr Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Glu Ala Ala Ala Leu Thr His Phe Asp Phe Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 99
<211> 30
<212> DNA
<213> 智人
<400> 99
ggtggctcca tcagcagtag taattactac 30
<210> 100
<211> 10
<212> PRT
<213> 智人
<400> 100
Gly Gly Ser Ile Ser Ser Ser Asn Tyr Tyr
1 5 10
<210> 101
<211> 21
<212> DNA
<213> 智人
<400> 101
atctattata gtgggagcac c 21
<210> 102
<211> 7
<212> PRT
<213> 智人
<400> 102
Ile Tyr Tyr Ser Gly Ser Thr
1 5
<210> 103
<211> 39
<212> DNA
<213> 智人
<400> 103
gcgagagagg aagcagcagc tttgacgcac tttgacttc 39
<210> 104
<211> 13
<212> PRT
<213> 智人
<400> 104
Ala Arg Glu Glu Ala Ala Ala Leu Thr His Phe Asp Phe
1 5 10
<210> 105
<211> 324
<212> DNA
<213> 智人
<400> 105
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc aactatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctttgct gcatccagtt tacaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacat agtcacagtt cccatccgat caccttcggc 300
caagggacac gactggagat taaa 324
<210> 106
<211> 108
<212> PRT
<213> 智人
<400> 106
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Phe Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Ser His Ser Ser His Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 107
<211> 18
<212> DNA
<213> 智人
<400> 107
cagagcatta gcaactat 18
<210> 108
<211> 6
<212> PRT
<213> 智人
<400> 108
Gln Ser Ile Ser Asn Tyr
1 5
<210> 109
<211> 9
<212> DNA
<213> 智人
<400> 109
gctgcatcc 9
<210> 110
<211> 3
<212> PRT
<213> 智人
<400> 110
Ala Ala Ser
1
<210> 111
<211> 30
<212> DNA
<213> 智人
<400> 111
caacatagtc acagttccca tccgatcacc 30
<210> 112
<211> 10
<212> PRT
<213> 智人
<400> 112
Gln His Ser His Ser Ser His Pro Ile Thr
1 5 10
<210> 113
<211> 366
<212> DNA
<213> 智人
<400> 113
gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attaattggg ctggttataa catagactat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagatatg 300
cgtggattca gttatggttt cccctttgac tactggggcc agggaaccct ggtcaccgtc 360
tcctca 366
<210> 114
<211> 122
<212> PRT
<213> 智人
<400> 114
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Ala Gly Tyr Asn Ile Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Met Arg Gly Phe Ser Tyr Gly Phe Pro Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 115
<211> 24
<212> DNA
<213> 智人
<400> 115
ggattcacct ttgatgatta tgcc 24
<210> 116
<211> 8
<212> PRT
<213> 智人
<400> 116
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 117
<211> 24
<212> DNA
<213> 智人
<400> 117
attaattggg ctggttataa cata 24
<210> 118
<211> 8
<212> PRT
<213> 智人
<400> 118
Ile Asn Trp Ala Gly Tyr Asn Ile
1 5
<210> 119
<211> 45
<212> DNA
<213> 智人
<400> 119
gcaaaagata tgcgtggatt cagttatggt ttcccctttg actac 45
<210> 120
<211> 15
<212> PRT
<213> 智人
<400> 120
Ala Lys Asp Met Arg Gly Phe Ser Tyr Gly Phe Pro Phe Asp Tyr
1 5 10 15
<210> 121
<211> 324
<212> DNA
<213> 智人
<400> 121
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccgtca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta cccctccgat caccttcggc 300
caagggacac gactggagat taaa 324
<210> 122
<211> 108
<212> PRT
<213> 智人
<400> 122
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 123
<211> 18
<212> DNA
<213> 智人
<400> 123
cagagcatta gcagctat 18
<210> 124
<211> 6
<212> PRT
<213> 智人
<400> 124
Gln Ser Ile Ser Ser Tyr
1 5
<210> 125
<211> 9
<212> DNA
<213> 智人
<400> 125
gctgcatcc 9
<210> 126
<211> 3
<212> PRT
<213> 智人
<400> 126
Ala Ala Ser
1
<210> 127
<211> 30
<212> DNA
<213> 智人
<400> 127
caacagagtt acagtacccc tccgatcacc 30
<210> 128
<211> 10
<212> PRT
<213> 智人
<400> 128
Gln Gln Ser Tyr Ser Thr Pro Pro Ile Thr
1 5 10
<210> 129
<211> 399
<212> DNA
<213> 智人
<400> 129
gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc cgggggggtc ccttagactc 60
tcctgtgcag cctctggatt tattttcagt aacgcctgga tgaactgggt ccgccaggct 120
ccagggaagg gactggcgtg ggttggccgt attaaaaccg aaactgatgg tgggacaaca 180
gactacgctg cacccgtaaa aggcagattc accatctcaa gagatgactc aaaaaacacg 240
ctgtatctgc aaatgaacag cgtgaaaacc gaggacacag ccgtgtatta ctgtacaggg 300
ggatacagct atggtgacga tagcagcagc tggaacgagg gctactacta ctacggtatg 360
gacgtctggg gccaagggac cacggtcacc gtctcctca 399
<210> 130
<211> 133
<212> PRT
<213> 智人
<400> 130
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Ala Trp Val
35 40 45
Gly Arg Ile Lys Thr Glu Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Val Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Gly Gly Tyr Ser Tyr Gly Asp Asp Ser Ser Ser Trp Asn
100 105 110
Glu Gly Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
115 120 125
Val Thr Val Ser Ser
130
<210> 131
<211> 24
<212> DNA
<213> 智人
<400> 131
ggatttattt tcagtaacgc ctgg 24
<210> 132
<211> 8
<212> PRT
<213> 智人
<400> 132
Gly Phe Ile Phe Ser Asn Ala Trp
1 5
<210> 133
<211> 30
<212> DNA
<213> 智人
<400> 133
attaaaaccg aaactgatgg tgggacaaca 30
<210> 134
<211> 10
<212> PRT
<213> 智人
<400> 134
Ile Lys Thr Glu Thr Asp Gly Gly Thr Thr
1 5 10
<210> 135
<211> 72
<212> DNA
<213> 智人
<400> 135
acagggggat acagctatgg tgacgatagc agcagctgga acgagggcta ctactactac 60
ggtatggacg tc 72
<210> 136
<211> 24
<212> PRT
<213> 智人
<400> 136
Thr Gly Gly Tyr Ser Tyr Gly Asp Asp Ser Ser Ser Trp Asn Glu Gly
1 5 10 15
Tyr Tyr Tyr Tyr Gly Met Asp Val
20
<210> 137
<211> 378
<212> DNA
<213> 智人
<400> 137
gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtacag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attcgttgga atggtggtag tataggctat 180
gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa gtccctgcat 240
ctgcaaatga acagtctaaa aactgaggac acggccttgt attactgtgc aaaagatata 300
ggcgatattt tgactggttt ttatggagaa tacggaatgg acgtctgggg ccaagggacc 360
acggtcaccg tctcctca 378
<210> 138
<211> 126
<212> PRT
<213> 智人
<400> 138
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Arg Trp Asn Gly Gly Ser Ile Gly Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu His
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Ile Gly Asp Ile Leu Thr Gly Phe Tyr Gly Glu Tyr Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 139
<211> 24
<212> DNA
<213> 智人
<400> 139
ggattcacct ttgatgatta tgcc 24
<210> 140
<211> 8
<212> PRT
<213> 智人
<400> 140
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 141
<211> 24
<212> DNA
<213> 智人
<400> 141
attcgttgga atggtggtag tata 24
<210> 142
<211> 8
<212> PRT
<213> 智人
<400> 142
Ile Arg Trp Asn Gly Gly Ser Ile
1 5
<210> 143
<211> 57
<212> DNA
<213> 智人
<400> 143
gcaaaagata taggcgatat tttgactggt ttttatggag aatacggaat ggacgtc 57
<210> 144
<211> 19
<212> PRT
<213> 智人
<400> 144
Ala Lys Asp Ile Gly Asp Ile Leu Thr Gly Phe Tyr Gly Glu Tyr Gly
1 5 10 15
Met Asp Val
<210> 145
<211> 321
<212> DNA
<213> 智人
<400> 145
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgaaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaagca 120
gggaaagccc ctaacctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagag tacactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacatta tcccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 146
<211> 107
<212> PRT
<213> 智人
<400> 146
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Glu Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Ala Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ile Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 147
<211> 18
<212> DNA
<213> 智人
<400> 147
cagagcatta gcagctat 18
<210> 148
<211> 6
<212> PRT
<213> 智人
<400> 148
Gln Ser Ile Ser Ser Tyr
1 5
<210> 149
<211> 9
<212> DNA
<213> 智人
<400> 149
gctgcatcc 9
<210> 150
<211> 3
<212> PRT
<213> 智人
<400> 150
Ala Ala Ser
1
<210> 151
<211> 27
<212> DNA
<213> 智人
<400> 151
caacagagtt acattatccc gtacact 27
<210> 152
<211> 9
<212> PRT
<213> 智人
<400> 152
Gln Gln Ser Tyr Ile Ile Pro Tyr Thr
1 5
<210> 153
<211> 378
<212> DNA
<213> 智人
<400> 153
gaagtgcagc tggtggagtc tgggggaggg ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaagt gttaggtgga atggtggtat tataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag acctgaggac acggccctct attactgtgc aaaagatata 300
ggcgatgttt tgactggtta ttatggagaa tacggtatgg acgtctgggg ccaagggacc 360
acggtcaccg tctcctca 378
<210> 154
<211> 126
<212> PRT
<213> 智人
<400> 154
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Val Arg Trp Asn Gly Gly Ile Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Ile Gly Asp Val Leu Thr Gly Tyr Tyr Gly Glu Tyr Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 155
<211> 24
<212> DNA
<213> 智人
<400> 155
ggattcacct ttgatgatta tgcc 24
<210> 156
<211> 8
<212> PRT
<213> 智人
<400> 156
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 157
<211> 24
<212> DNA
<213> 智人
<400> 157
gttaggtgga atggtggtat tata 24
<210> 158
<211> 8
<212> PRT
<213> 智人
<400> 158
Val Arg Trp Asn Gly Gly Ile Ile
1 5
<210> 159
<211> 57
<212> DNA
<213> 智人
<400> 159
gcaaaagata taggcgatgt tttgactggt tattatggag aatacggtat ggacgtc 57
<210> 160
<211> 19
<212> PRT
<213> 智人
<400> 160
Ala Lys Asp Ile Gly Asp Val Leu Thr Gly Tyr Tyr Gly Glu Tyr Gly
1 5 10 15
Met Asp Val
<210> 161
<211> 321
<212> DNA
<213> 智人
<400> 161
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtgggaga cagagtcacc 60
atcgcttgcc gggcaagtca gagcattacc acctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaaactcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagtag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacattt ccccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 162
<211> 107
<212> PRT
<213> 智人
<400> 162
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Ala Cys Arg Ala Ser Gln Ser Ile Thr Thr Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 163
<211> 18
<212> DNA
<213> 智人
<400> 163
cagagcatta ccacctat 18
<210> 164
<211> 6
<212> PRT
<213> 智人
<400> 164
Gln Ser Ile Thr Thr Tyr
1 5
<210> 165
<211> 9
<212> DNA
<213> 智人
<400> 165
gctgcatcc 9
<210> 166
<211> 3
<212> PRT
<213> 智人
<400> 166
Ala Ala Ser
1
<210> 167
<211> 27
<212> DNA
<213> 智人
<400> 167
caacagagtt acatttcccc gtacact 27
<210> 168
<211> 9
<212> PRT
<213> 智人
<400> 168
Gln Gln Ser Tyr Ile Ser Pro Tyr Thr
1 5
<210> 169
<211> 378
<212> DNA
<213> 智人
<400> 169
caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaagtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt aattatggca tacactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcgatt atattatatg atggaagtaa tcaacactat 180
gcagattccg tgaagggccg attcaccatt tccagagaca attccaaaaa cacgctgtat 240
cttcaaatga acaacctgag agctgaggac acggccgttt attactgtgc gagagatctt 300
gatctttgga gtggttatta tacaaacggg gacggtatgg acgtctgggg ccaagggacc 360
acggtcaccg tctcctca 378
<210> 170
<211> 126
<212> PRT
<213> 智人
<400> 170
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Lys
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Leu Tyr Asp Gly Ser Asn Gln His Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Leu Asp Leu Trp Ser Gly Tyr Tyr Thr Asn Gly Asp Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 171
<211> 24
<212> DNA
<213> 智人
<400> 171
ggattcacct tcagtaatta tggc 24
<210> 172
<211> 8
<212> PRT
<213> 智人
<400> 172
Gly Phe Thr Phe Ser Asn Tyr Gly
1 5
<210> 173
<211> 24
<212> DNA
<213> 智人
<400> 173
atattatatg atggaagtaa tcaa 24
<210> 174
<211> 8
<212> PRT
<213> 智人
<400> 174
Ile Leu Tyr Asp Gly Ser Asn Gln
1 5
<210> 175
<211> 57
<212> DNA
<213> 智人
<400> 175
gcgagagatc ttgatctttg gagtggttat tatacaaacg gggacggtat ggacgtc 57
<210> 176
<211> 19
<212> PRT
<213> 智人
<400> 176
Ala Arg Asp Leu Asp Leu Trp Ser Gly Tyr Tyr Thr Asn Gly Asp Gly
1 5 10 15
Met Asp Val
<210> 177
<211> 575
<212> PRT
<213> 智人
<400> 177
Met Trp Ser Leu Leu Leu Cys Gly Leu Ser Ile Ala Leu Pro Leu Ser
1 5 10 15
Val Thr Ala Asp Gly Cys Lys Asp Ile Phe Met Lys Asn Glu Ile Leu
20 25 30
Ser Ala Ser Gln Pro Phe Ala Phe Asn Cys Thr Phe Pro Pro Ile Thr
35 40 45
Ser Gly Glu Val Ser Val Thr Trp Tyr Lys Asn Ser Ser Lys Ile Pro
50 55 60
Val Ser Lys Ile Ile Gln Ser Arg Ile His Gln Asp Glu Thr Trp Ile
65 70 75 80
Leu Phe Leu Pro Met Glu Trp Gly Asp Ser Gly Val Tyr Gln Cys Val
85 90 95
Ile Lys Gly Arg Asp Ser Cys His Arg Ile His Val Asn Leu Thr Val
100 105 110
Phe Glu Lys His Trp Cys Asp Thr Ser Ile Gly Gly Leu Pro Asn Leu
115 120 125
Ser Asp Glu Tyr Lys Gln Ile Leu His Leu Gly Lys Asp Asp Ser Leu
130 135 140
Thr Cys His Leu His Phe Pro Lys Ser Cys Val Leu Gly Pro Ile Lys
145 150 155 160
Trp Tyr Lys Asp Cys Asn Glu Ile Lys Gly Glu Arg Phe Thr Val Leu
165 170 175
Glu Thr Arg Leu Leu Val Ser Asn Val Ser Ala Glu Asp Arg Gly Asn
180 185 190
Tyr Ala Cys Gln Ala Ile Leu Thr His Ser Gly Lys Gln Tyr Glu Val
195 200 205
Leu Asn Gly Ile Thr Val Ser Ile Thr Glu Arg Ala Gly Tyr Gly Gly
210 215 220
Ser Val Pro Lys Ile Ile Tyr Pro Lys Asn His Ser Ile Glu Val Gln
225 230 235 240
Leu Gly Thr Thr Leu Ile Val Asp Cys Asn Val Thr Asp Thr Lys Asp
245 250 255
Asn Thr Asn Leu Arg Cys Trp Arg Val Asn Asn Thr Leu Val Asp Asp
260 265 270
Tyr Tyr Asp Glu Ser Lys Arg Ile Arg Glu Gly Val Glu Thr His Val
275 280 285
Ser Phe Arg Glu His Asn Leu Tyr Thr Val Asn Ile Thr Phe Leu Glu
290 295 300
Val Lys Met Glu Asp Tyr Gly Leu Pro Phe Met Cys His Ala Gly Val
305 310 315 320
Ser Thr Ala Tyr Ile Ile Leu Gln Leu Pro Ala Pro Asp Phe Arg Ala
325 330 335
Tyr Leu Ile Gly Gly Leu Ile Ala Leu Val Ala Val Ala Val Ser Val
340 345 350
Val Tyr Ile Tyr Asn Ile Phe Lys Ile Asp Ile Val Leu Trp Tyr Arg
355 360 365
Ser Ala Phe His Ser Thr Glu Thr Ile Val Asp Gly Lys Leu Tyr Asp
370 375 380
Ala Tyr Val Leu Tyr Pro Lys Pro His Lys Glu Ser Gln Arg His Ala
385 390 395 400
Val Asp Ala Leu Val Leu Asn Ile Leu Pro Glu Val Leu Glu Arg Gln
405 410 415
Cys Gly Tyr Lys Leu Phe Ile Phe Gly Arg Asp Glu Phe Pro Gly Gln
420 425 430
Ala Val Ala Asn Val Ile Asp Glu Asn Val Lys Leu Cys Arg Arg Leu
435 440 445
Ile Val Ile Val Val Pro Glu Ser Leu Gly Phe Gly Leu Leu Lys Asn
450 455 460
Leu Ser Glu Glu Gln Ile Ala Val Tyr Ser Ala Leu Ile Gln Asp Gly
465 470 475 480
Met Lys Val Ile Leu Ile Glu Leu Glu Lys Ile Glu Asp Tyr Thr Val
485 490 495
Met Pro Glu Ser Ile Gln Tyr Ile Lys Gln Lys His Gly Ala Ile Arg
500 505 510
Trp His Gly Asp Phe Thr Glu Gln Ser Gln Cys Met Lys Thr Lys Phe
515 520 525
Trp Lys Thr Val Arg Tyr His Met Pro Pro Arg Arg Cys Arg Pro Phe
530 535 540
Pro Pro Val Gln Leu Leu Gln His Thr Pro Cys Tyr Arg Thr Ala Gly
545 550 555 560
Pro Glu Leu Gly Ser Arg Arg Lys Lys Cys Thr Leu Thr Thr Gly
565 570 575
<210> 178
<211> 570
<212> PRT
<213> 智人
<400> 178
Met Thr Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu
1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met
20 25 30
Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro
35 40 45
Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala
50 55 60
Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80
Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125
Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140
Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys
145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr
165 170 175
Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro
180 185 190
Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly
195 200 205
Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His
210 215 220
Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala
225 230 235 240
Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys
245 250 255
Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe
260 265 270
Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys
275 280 285
Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His
290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys
305 310 315 320
Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser
325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350
Ala Pro Arg Tyr Thr Val Glu Leu Ala Cys Gly Phe Gly Ala Thr Val
355 360 365
Leu Leu Val Val Ile Leu Ile Val Val Tyr His Val Tyr Trp Leu Glu
370 375 380
Met Val Leu Phe Tyr Arg Ala His Phe Gly Thr Asp Glu Thr Ile Leu
385 390 395 400
Asp Gly Lys Glu Tyr Asp Ile Tyr Val Ser Tyr Ala Arg Asn Ala Glu
405 410 415
Glu Glu Glu Phe Val Leu Leu Thr Leu Arg Gly Val Leu Glu Asn Glu
420 425 430
Phe Gly Tyr Lys Leu Cys Ile Phe Asp Arg Asp Ser Leu Pro Gly Gly
435 440 445
Ile Val Thr Asp Glu Thr Leu Ser Phe Ile Gln Lys Ser Arg Arg Leu
450 455 460
Leu Val Val Leu Ser Pro Asn Tyr Val Leu Gln Gly Thr Gln Ala Leu
465 470 475 480
Leu Glu Leu Lys Ala Gly Leu Glu Asn Met Ala Ser Arg Gly Asn Ile
485 490 495
Asn Val Ile Leu Val Gln Tyr Lys Ala Val Lys Glu Thr Lys Val Lys
500 505 510
Glu Leu Lys Arg Ala Lys Thr Val Leu Thr Val Ile Lys Trp Lys Gly
515 520 525
Glu Lys Ser Lys Tyr Pro Gln Gly Arg Phe Trp Lys Gln Leu Gln Val
530 535 540
Ala Met Pro Val Lys Lys Ser Pro Arg Arg Ser Ser Ser Asp Glu Gln
545 550 555 560
Gly Leu Ser Tyr Ser Ser Leu Lys Asn Val
565 570
<210> 179
<211> 1338
<212> DNA
<213> 智人
<400> 179
gaagtgcagc tggtggagtc tgggggaggc ttggtgcagc ctggcaggtc cctgagactc 60
tcctgtgcgg cctctggatt cacctttgat gattatgcca tacactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcagtt atcagttgga atagtgatat cataggctat 180
gcggactctg tgaagggccg attcaccgtc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga atagtctgag aactgaggac acggccttgt attactgtgc aaaaggatat 300
aactggaact tctttgacta ttggggccag ggaaccctgg tcaccgtctc ctcagcctcc 360
accaagggcc catcggtctt ccccctggcg ccctgctcca ggagcacctc cgagagcaca 420
gccgccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcacgaa gacctacacc 600
tgcaacgtag atcacaagcc cagcaacacc aaggtggaca agagagttga gtccaaatat 660
ggtcccccat gcccaccctg cccagcacct gagttcctgg ggggaccatc agtcttcctg 720
ttccccccaa aacccaagga cactctcatg atctcccgga cccctgaggt cacgtgcgtg 780
gtggtggacg tgagccagga agaccccgag gtccagttca actggtacgt ggatggcgtg 840
gaggtgcata atgccaagac aaagccgcgg gaggagcagt tcaacagcac gtaccgtgtg 900
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaacg gcaaggagta caagtgcaag 960
gtctccaaca aaggcctccc gtcctccatc gagaaaacca tctccaaagc caaagggcag 1020
ccccgagagc cacaggtgta caccctgccc ccatcccagg aggagatgac caagaaccag 1080
gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtgggag 1140
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1200
tccttcttcc tctacagcag gctcaccgtg gacaagagca ggtggcagga ggggaatgtc 1260
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacacagaa gtccctctcc 1320
ctgtctctgg gtaaatga 1338
<210> 180
<211> 445
<212> PRT
<213> 智人
<400> 180
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser Trp Asn Ser Asp Ile Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Gly Tyr Asn Trp Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu Asp Pro Glu Val Gln
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 Phe 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 Gly Leu Pro Ser Ser 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
Gln Glu Glu Met 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 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Glu 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 Leu Gly Lys
435 440 445
<210> 181
<211> 642
<212> DNA
<213> 智人
<400> 181
gaaattgtgt tgacgcagtc tccagccacc ctgtctttat ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120
ggccaggctc ccaggctcct catctataat gcagcaaaca gggccactga catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctctcac tttcggcgga 300
gggaccaagg tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 182
<211> 214
<212> PRT
<213> 智人
<400> 182
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 Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asn Ala Ala Asn Arg Ala Thr Asp Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val 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> 183
<211> 1338
<212> DNA
<213> 智人
<400> 183
gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaaact 120
ccagggaagg gcctggagtg ggtctcagtt attagttgga atagtgatgt catagcctat 180
tcggactctg tgaagggccg cttcaccatt tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctggg aactgaggac acggccttat attactgtgc aaaaggccat 300
aactggaact tctttgacta ttggggccag ggaaccctgg tcaccgtctc ctcagcctcc 360
accaagggcc catcggtctt ccccctggcg ccctgctcca ggagcacctc cgagagcaca 420
gccgccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcacgaa gacctacacc 600
tgcaacgtag atcacaagcc cagcaacacc aaggtggaca agagagttga gtccaaatat 660
ggtcccccat gcccaccctg cccagcacct gagttcctgg ggggaccatc agtcttcctg 720
ttccccccaa aacccaagga cactctcatg atctcccgga cccctgaggt cacgtgcgtg 780
gtggtggacg tgagccagga agaccccgag gtccagttca actggtacgt ggatggcgtg 840
gaggtgcata atgccaagac aaagccgcgg gaggagcagt tcaacagcac gtaccgtgtg 900
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaacg gcaaggagta caagtgcaag 960
gtctccaaca aaggcctccc gtcctccatc gagaaaacca tctccaaagc caaagggcag 1020
ccccgagagc cacaggtgta caccctgccc ccatcccagg aggagatgac caagaaccag 1080
gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtgggag 1140
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1200
tccttcttcc tctacagcag gctcaccgtg gacaagagca ggtggcagga ggggaatgtc 1260
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacacagaa gtccctctcc 1320
ctgtctctgg gtaaatga 1338
<210> 184
<211> 445
<212> PRT
<213> 智人
<400> 184
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser Trp Asn Ser Asp Val Ile Ala Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Gly Thr Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Gly His Asn Trp Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu Asp Pro Glu Val Gln
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 Phe 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 Gly Leu Pro Ser Ser 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
Gln Glu Glu Met 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 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Glu 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 Leu Gly Lys
435 440 445
<210> 185
<211> 642
<212> DNA
<213> 智人
<400> 185
gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccaggaga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120
ggccaggctc ccaggctcct catctataat gtagccaaca gggccacaga catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcgg cctagagcct 240
gaagattttg cagtttattt ctgtcagcag cgtagcaact ggcctctcac tttcggcgga 300
gggaccaagg tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 186
<211> 214
<212> PRT
<213> 智人
<400> 186
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 Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asn Val Ala Asn Arg Ala Thr Asp Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val 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> 187
<211> 1338
<212> DNA
<213> 智人
<400> 187
gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtacag cctctggatt cacctttgat gattatgcca tacactgggt ccggcaatct 120
ccagggaagg gcctggagtg ggtctcagtt atcagttgga atagtgatgt cataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcagatga atagtctgag agctgaggac acggccttgt attactgtgc aaaaggatat 300
aactggaact tctttgacta ttggggccag ggaaccctgg tcaccgtctc ctcagcctcc 360
accaagggcc catcggtctt ccccctggcg ccctgctcca ggagcacctc cgagagcaca 420
gccgccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcacgaa gacctacacc 600
tgcaacgtag atcacaagcc cagcaacacc aaggtggaca agagagttga gtccaaatat 660
ggtcccccat gcccaccctg cccagcacct gagttcctgg ggggaccatc agtcttcctg 720
ttccccccaa aacccaagga cactctcatg atctcccgga cccctgaggt cacgtgcgtg 780
gtggtggacg tgagccagga agaccccgag gtccagttca actggtacgt ggatggcgtg 840
gaggtgcata atgccaagac aaagccgcgg gaggagcagt tcaacagcac gtaccgtgtg 900
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaacg gcaaggagta caagtgcaag 960
gtctccaaca aaggcctccc gtcctccatc gagaaaacca tctccaaagc caaagggcag 1020
ccccgagagc cacaggtgta caccctgccc ccatcccagg aggagatgac caagaaccag 1080
gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtgggag 1140
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1200
tccttcttcc tctacagcag gctcaccgtg gacaagagca ggtggcagga ggggaatgtc 1260
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacacagaa gtccctctcc 1320
ctgtctctgg gtaaatga 1338
<210> 188
<211> 445
<212> PRT
<213> 智人
<400> 188
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Ile His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser Trp Asn Ser Asp Val Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Gly Tyr Asn Trp Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu Asp Pro Glu Val Gln
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 Phe 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 Gly Leu Pro Ser Ser 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
Gln Glu Glu Met 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 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Glu 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 Leu Gly Lys
435 440 445
<210> 189
<211> 642
<212> DNA
<213> 智人
<400> 189
gaaattgtgt tgacgcagtc tccagccacc ctgtctttat ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120
ggccaggctc ccaggctcct catctataat gcagcaaaca gggccactga catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctctcac tttcggcgga 300
gggaccaagg tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 190
<211> 214
<212> PRT
<213> 智人
<400> 190
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 Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asn Ala Ala Asn Arg Ala Thr Asp Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val 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> 191
<211> 1338
<212> DNA
<213> 智人
<400> 191
gaagtgcagc tggtggagtc tgggggagac ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggaatg ggtctcagtt attagttgga atagtgatgt catagcctat 180
tcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag aactgaggac acggccttat attactgtac aaaaggccat 300
aagtggagct tctttgacta ttggggccag ggaaccctgg tcaccgtctc ctcagcctcc 360
accaagggcc catcggtctt ccccctggcg ccctgctcca ggagcacctc cgagagcaca 420
gccgccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcacgaa gacctacacc 600
tgcaacgtag atcacaagcc cagcaacacc aaggtggaca agagagttga gtccaaatat 660
ggtcccccat gcccaccctg cccagcacct gagttcctgg ggggaccatc agtcttcctg 720
ttccccccaa aacccaagga cactctcatg atctcccgga cccctgaggt cacgtgcgtg 780
gtggtggacg tgagccagga agaccccgag gtccagttca actggtacgt ggatggcgtg 840
gaggtgcata atgccaagac aaagccgcgg gaggagcagt tcaacagcac gtaccgtgtg 900
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaacg gcaaggagta caagtgcaag 960
gtctccaaca aaggcctccc gtcctccatc gagaaaacca tctccaaagc caaagggcag 1020
ccccgagagc cacaggtgta caccctgccc ccatcccagg aggagatgac caagaaccag 1080
gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtgggag 1140
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1200
tccttcttcc tctacagcag gctcaccgtg gacaagagca ggtggcagga ggggaatgtc 1260
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacacagaa gtccctctcc 1320
ctgtctctgg gtaaatga 1338
<210> 192
<211> 445
<212> PRT
<213> 智人
<400> 192
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser Trp Asn Ser Asp Val Ile Ala Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Thr Lys Gly His Lys Trp Ser Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu Asp Pro Glu Val Gln
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 Phe 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 Gly Leu Pro Ser Ser 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
Gln Glu Glu Met 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 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Glu 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 Leu Gly Lys
435 440 445
<210> 193
<211> 642
<212> DNA
<213> 智人
<400> 193
gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtattagc agctacttag cctggtacca acagaaacct 120
ggccaggctc ccagactcct catctttaat gtagccaaca gggccactga catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctctcac tttcggcgga 300
gggaccaagg tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 194
<211> 214
<212> PRT
<213> 智人
<400> 194
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 Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Phe Asn Val Ala Asn Arg Ala Thr Asp Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val 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> 195
<211> 1323
<212> DNA
<213> 智人
<400> 195
gaggtgcagc tggtggagtc tgggggaggc ttggttcagc ctggggggtc cctgagactc 60
tcctgcgcag cctctggatt cacctttagc gactatgcca tgagctgggt ccgccaggct 120
ccggggaagg ggctggagtg ggtctcaggt attagtggaa atggtggtga cacatactac 180
ggagacttcg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag aggcgaggac acggccgcat atttctgtgt gatagatctt 300
gactattggg gtcagggaac cctggtcacc gtctcctcag cctccaccaa gggcccatcg 360
gtcttccccc tggcgccctg ctccaggagc acctccgaga gcacagccgc cctgggctgc 420
ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 480
agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 540
gtggtgaccg tgccctccag cagcttgggc acgaagacct acacctgcaa cgtagatcac 600
aagcccagca acaccaaggt ggacaagaga gttgagtcca aatatggtcc cccatgccca 660
ccctgcccag cacctgagtt cctgggggga ccatcagtct tcctgttccc cccaaaaccc 720
aaggacactc tcatgatctc ccggacccct gaggtcacgt gcgtggtggt ggacgtgagc 780
caggaagacc ccgaggtcca gttcaactgg tacgtggatg gcgtggaggt gcataatgcc 840
aagacaaagc cgcgggagga gcagttcaac agcacgtacc gtgtggtcag cgtcctcacc 900
gtcctgcacc aggactggct gaacggcaag gagtacaagt gcaaggtctc caacaaaggc 960
ctcccgtcct ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agagccacag 1020
gtgtacaccc tgcccccatc ccaggaggag atgaccaaga accaggtcag cctgacctgc 1080
ctggtcaaag gcttctaccc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1140
gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 1200
agcaggctca ccgtggacaa gagcaggtgg caggagggga atgtcttctc atgctccgtg 1260
atgcatgagg ctctgcacaa ccactacaca cagaagtccc tctccctgtc tctgggtaaa 1320
tga 1323
<210> 196
<211> 440
<212> PRT
<213> 智人
<400> 196
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Gly Asn Gly Gly Asp Thr Tyr Tyr Gly Asp Phe Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr Ala Ala Tyr Phe Cys
85 90 95
Val Ile Asp Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 197
<211> 642
<212> DNA
<213> 智人
<400> 197
gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgaaggaga cagagtcacc 60
atcacttgcc gggccagtca gagtattagt agctggttgg cctggtatca acagaaacca 120
ggaaaagccc ctaggctcct gatctataag gcgtctattt taggagatgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgattttg ctacttatta ctgccaccag tataatagtt atttgtggac gttcggccaa 300
gggaccaagg tggaaatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 198
<211> 214
<212> PRT
<213> 智人
<400> 198
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Glu Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ile Leu Gly Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys His Gln Tyr Asn Ser Tyr Leu Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val 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> 199
<211> 1347
<212> DNA
<213> 智人
<400> 199
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagc agtgctgatt actattggag ctggatccgc 120
cagcacccag ggaagggcct ggagtggatt ggatccatct attatactgg gagtacttac 180
tacaacccgt ccctcaagag tcgacttacc atatcaatag acacgtctga gaaccagttc 240
tctttgaaac tgacctctct gactgccgcg gacacggccg tgtattactg tgcgagcgag 300
gaggctaact ggggatccca ctttgactcc tggggccagg gaaccctggt caccgtctcc 360
tcagcctcca ccaagggccc atcggtcttc cccctggcgc cctgctccag gagcacctcc 420
gagagcacag ccgccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacgaag 600
acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gagagttgag 660
tccaaatatg gtcccccatg cccaccctgc ccagcacctg agttcctggg gggaccatca 720
gtcttcctgt tccccccaaa acccaaggac actctcatga tctcccggac ccctgaggtc 780
acgtgcgtgg tggtggacgt gagccaggaa gaccccgagg tccagttcaa ctggtacgtg 840
gatggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagtt caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaacgg caaggagtac 960
aagtgcaagg tctccaacaa aggcctcccg tcctccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagagcc acaggtgtac accctgcccc catcccagga ggagatgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctacagcagg ctcaccgtgg acaagagcag gtggcaggag 1260
gggaatgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacacagaag 1320
tccctctccc tgtctctggg taaatga 1347
<210> 200
<211> 448
<212> PRT
<213> 智人
<400> 200
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ala
20 25 30
Asp Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Ser Ile Tyr Tyr Thr Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Glu Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Thr Ser Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Ser Glu Glu Ala Asn Trp Gly Ser His Phe Asp Ser Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly
210 215 220
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu Asp Pro
260 265 270
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Glu 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 Leu Gly Lys
435 440 445
<210> 201
<211> 645
<212> DNA
<213> 智人
<400> 201
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattgac aactttttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg catcttacta ctgtcaacat agtcacagtg cccatccgat caccttcggc 300
caagggacac gactggagat taaacgaact gtggctgcac catctgtctt catcttcccg 360
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645
<210> 202
<211> 215
<212> PRT
<213> 智人
<400> 202
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asp Asn Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Ser Tyr Tyr Cys Gln His Ser His Ser Ala His Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 203
<211> 1347
<212> DNA
<213> 智人
<400> 203
cagctgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagc agtagtaatt actactgggg ctggatccgc 120
cagcccccag ggaagagact ggagtggatt gggagtatct attatagtgg gagcacctac 180
tacaacccgt ccctcaagac tcgagtcacc atatccgtag acacgtccaa gaatcagttc 240
tccctgaagc tgacctctgt gaccgccgca gacacggctg tgtattactg tgcgagagag 300
gaagcagcag ctttgacgca ctttgacttc tggggccagg gaaccctggt caccgtctcc 360
tcagcctcca ccaagggccc atcggtcttc cccctggcgc cctgctccag gagcacctcc 420
gagagcacag ccgccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacgaag 600
acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gagagttgag 660
tccaaatatg gtcccccatg cccaccctgc ccagcacctg agttcctggg gggaccatca 720
gtcttcctgt tccccccaaa acccaaggac actctcatga tctcccggac ccctgaggtc 780
acgtgcgtgg tggtggacgt gagccaggaa gaccccgagg tccagttcaa ctggtacgtg 840
gatggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagtt caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaacgg caaggagtac 960
aagtgcaagg tctccaacaa aggcctcccg tcctccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagagcc acaggtgtac accctgcccc catcccagga ggagatgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctacagcagg ctcaccgtgg acaagagcag gtggcaggag 1260
gggaatgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacacagaag 1320
tccctctccc tgtctctggg taaatga 1347
<210> 204
<211> 448
<212> PRT
<213> 智人
<400> 204
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Arg Leu Glu
35 40 45
Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Thr Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Glu Ala Ala Ala Leu Thr His Phe Asp Phe Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly
210 215 220
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu Asp Pro
260 265 270
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Glu 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 Leu Gly Lys
435 440 445
<210> 205
<211> 645
<212> DNA
<213> 智人
<400> 205
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc aactatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctttgct gcatccagtt tacaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacat agtcacagtt cccatccgat caccttcggc 300
caagggacac gactggagat taaacgaact gtggctgcac catctgtctt catcttcccg 360
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645
<210> 206
<211> 215
<212> PRT
<213> 智人
<400> 206
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Phe Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Ser His Ser Ser His Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 207
<211> 1350
<212> DNA
<213> 智人
<400> 207
gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attaattggg ctggttataa catagactat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagatatg 300
cgtggattca gttatggttt cccctttgac tactggggcc agggaaccct ggtcaccgtc 360
tcctcagcct ccaccaaggg cccatcggtc ttccccctgg cgccctgctc caggagcacc 420
tccgagagca cagccgccct gggctgcctg gtcaaggact acttccccga accggtgacg 480
gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540
tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacg 600
aagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagagagtt 660
gagtccaaat atggtccccc atgcccaccc tgcccagcac ctgagttcct ggggggacca 720
tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 780
gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 840
gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 960
tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctacagc aggctcaccg tggacaagag caggtggcag 1260
gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1320
aagtccctct ccctgtctct gggtaaatga 1350
<210> 208
<211> 449
<212> PRT
<213> 智人
<400> 208
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Ala Gly Tyr Asn Ile Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Met Arg Gly Phe Ser Tyr Gly Phe Pro Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu Asp
260 265 270
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln Glu Glu Met 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 Arg Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Glu 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 Leu Gly
435 440 445
Lys
<210> 209
<211> 645
<212> DNA
<213> 智人
<400> 209
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccgtca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta cccctccgat caccttcggc 300
caagggacac gactggagat taaaactgtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 645
<210> 210
<211> 214
<212> PRT
<213> 智人
<400> 210
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 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> 211
<211> 1383
<212> DNA
<213> 智人
<400> 211
gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc cgggggggtc ccttagactc 60
tcctgtgcag cctctggatt tattttcagt aacgcctgga tgaactgggt ccgccaggct 120
ccagggaagg gactggcgtg ggttggccgt attaaaaccg aaactgatgg tgggacaaca 180
gactacgctg cacccgtaaa aggcagattc accatctcaa gagatgactc aaaaaacacg 240
ctgtatctgc aaatgaacag cgtgaaaacc gaggacacag ccgtgtatta ctgtacaggg 300
ggatacagct atggtgacga tagcagcagc tggaacgagg gctactacta ctacggtatg 360
gacgtctggg gccaagggac cacggtcacc gtctcctcag cctccaccaa gggcccatcg 420
gtcttccccc tggcgccctg ctccaggagc acctccgaga gcacagccgc cctgggctgc 480
ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 540
agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 600
gtggtgaccg tgccctccag cagcttgggc acgaagacct acacctgcaa cgtagatcac 660
aagcccagca acaccaaggt ggacaagaga gttgagtcca aatatggtcc cccatgccca 720
ccctgcccag cacctgagtt cctgggggga ccatcagtct tcctgttccc cccaaaaccc 780
aaggacactc tcatgatctc ccggacccct gaggtcacgt gcgtggtggt ggacgtgagc 840
caggaagacc ccgaggtcca gttcaactgg tacgtggatg gcgtggaggt gcataatgcc 900
aagacaaagc cgcgggagga gcagttcaac agcacgtacc gtgtggtcag cgtcctcacc 960
gtcctgcacc aggactggct gaacggcaag gagtacaagt gcaaggtctc caacaaaggc 1020
ctcccgtcct ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agagccacag 1080
gtgtacaccc tgcccccatc ccaggaggag atgaccaaga accaggtcag cctgacctgc 1140
ctggtcaaag gcttctaccc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1200
gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 1260
agcaggctca ccgtggacaa gagcaggtgg caggagggga atgtcttctc atgctccgtg 1320
atgcatgagg ctctgcacaa ccactacaca cagaagtccc tctccctgtc tctgggtaaa 1380
tga 1383
<210> 212
<211> 460
<212> PRT
<213> 智人
<400> 212
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Asn Ala
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Ala Trp Val
35 40 45
Gly Arg Ile Lys Thr Glu Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Val Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Gly Gly Tyr Ser Tyr Gly Asp Asp Ser Ser Ser Trp Asn
100 105 110
Glu Gly Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
115 120 125
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
130 135 140
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
145 150 155 160
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
165 170 175
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
180 185 190
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
195 200 205
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
210 215 220
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
225 230 235 240
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
245 250 255
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
260 265 270
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
275 280 285
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
290 295 300
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
305 310 315 320
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
325 330 335
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
340 345 350
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
355 360 365
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
370 375 380
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
385 390 395 400
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
405 410 415
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
420 425 430
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
435 440 445
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
450 455 460
<210> 213
<211> 645
<212> DNA
<213> 智人
<400> 213
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccgtca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta cccctccgat caccttcggc 300
caagggacac gactggagat taaaactgtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 645
<210> 214
<211> 214
<212> PRT
<213> 智人
<400> 214
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 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> 215
<211> 1362
<212> DNA
<213> 智人
<400> 215
gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtacag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attcgttgga atggtggtag tataggctat 180
gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa gtccctgcat 240
ctgcaaatga acagtctaaa aactgaggac acggccttgt attactgtgc aaaagatata 300
ggcgatattt tgactggttt ttatggagaa tacggaatgg acgtctgggg ccaagggacc 360
acggtcaccg tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcgccctgc 420
tccaggagca cctccgagag cacagccgcc ctgggctgcc tggtcaagga ctacttcccc 480
gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 540
gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 600
agcttgggca cgaagaccta cacctgcaac gtagatcaca agcccagcaa caccaaggtg 660
gacaagagag ttgagtccaa atatggtccc ccatgcccac cctgcccagc acctgagttc 720
ctggggggac catcagtctt cctgttcccc ccaaaaccca aggacactct catgatctcc 780
cggacccctg aggtcacgtg cgtggtggtg gacgtgagcc aggaagaccc cgaggtccag 840
ttcaactggt acgtggatgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 900
cagttcaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 960
aacggcaagg agtacaagtg caaggtctcc aacaaaggcc tcccgtcctc catcgagaaa 1020
accatctcca aagccaaagg gcagccccga gagccacagg tgtacaccct gcccccatcc 1080
caggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctacccc 1140
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1200
cctcccgtgc tggactccga cggctccttc ttcctctaca gcaggctcac cgtggacaag 1260
agcaggtggc aggaggggaa tgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1320
cactacacac agaagtccct ctccctgtct ctgggtaaat ga 1362
<210> 216
<211> 453
<212> PRT
<213> 智人
<400> 216
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Arg Trp Asn Gly Gly Ser Ile Gly Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu His
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Ile Gly Asp Ile Leu Thr Gly Phe Tyr Gly Glu Tyr Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser
115 120 125
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr
130 135 140
Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
145 150 155 160
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
165 170 175
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
180 185 190
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr
195 200 205
Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val
210 215 220
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
325 330 335
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Leu Gly Lys
450
<210> 217
<211> 642
<212> DNA
<213> 智人
<400> 217
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgaaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaagca 120
gggaaagccc ctaacctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagag tacactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacatta tcccgtacac ttttggccag 300
gggaccaagc tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 218
<211> 214
<212> PRT
<213> 智人
<400> 218
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Glu Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Ala Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ile Pro Tyr
85 90 95
Thr Phe Gly Gln 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> 219
<211> 1362
<212> DNA
<213> 智人
<400> 219
gaagtgcagc tggtggagtc tgggggaggg ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaagt gttaggtgga atggtggtat tataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag acctgaggac acggccctct attactgtgc aaaagatata 300
ggcgatgttt tgactggtta ttatggagaa tacggtatgg acgtctgggg ccaagggacc 360
acggtcaccg tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcgccctgc 420
tccaggagca cctccgagag cacagccgcc ctgggctgcc tggtcaagga ctacttcccc 480
gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 540
gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 600
agcttgggca cgaagaccta cacctgcaac gtagatcaca agcccagcaa caccaaggtg 660
gacaagagag ttgagtccaa atatggtccc ccatgcccac cctgcccagc acctgagttc 720
ctggggggac catcagtctt cctgttcccc ccaaaaccca aggacactct catgatctcc 780
cggacccctg aggtcacgtg cgtggtggtg gacgtgagcc aggaagaccc cgaggtccag 840
ttcaactggt acgtggatgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 900
cagttcaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 960
aacggcaagg agtacaagtg caaggtctcc aacaaaggcc tcccgtcctc catcgagaaa 1020
accatctcca aagccaaagg gcagccccga gagccacagg tgtacaccct gcccccatcc 1080
caggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctacccc 1140
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1200
cctcccgtgc tggactccga cggctccttc ttcctctaca gcaggctcac cgtggacaag 1260
agcaggtggc aggaggggaa tgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1320
cactacacac agaagtccct ctccctgtct ctgggtaaat ga 1362
<210> 220
<211> 453
<212> PRT
<213> 智人
<400> 220
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Val Arg Trp Asn Gly Gly Ile Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Ile Gly Asp Val Leu Thr Gly Tyr Tyr Gly Glu Tyr Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser
115 120 125
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr
130 135 140
Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
145 150 155 160
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
165 170 175
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
180 185 190
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr
195 200 205
Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val
210 215 220
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
325 330 335
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Leu Gly Lys
450
<210> 221
<211> 642
<212> DNA
<213> 智人
<400> 221
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtgggaga cagagtcacc 60
atcgcttgcc gggcaagtca gagcattacc acctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaaactcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagtag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacattt ccccgtacac ttttggccag 300
gggaccaagc tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 222
<211> 214
<212> PRT
<213> 智人
<400> 222
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Ala Cys Arg Ala Ser Gln Ser Ile Thr Thr Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ser Pro Tyr
85 90 95
Thr Phe Gly Gln 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> 223
<211> 1362
<212> DNA
<213> 智人
<400> 223
caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaagtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt aattatggca tacactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcgatt atattatatg atggaagtaa tcaacactat 180
gcagattccg tgaagggccg attcaccatt tccagagaca attccaaaaa cacgctgtat 240
cttcaaatga acaacctgag agctgaggac acggccgttt attactgtgc gagagatctt 300
gatctttgga gtggttatta tacaaacggg gacggtatgg acgtctgggg ccaagggacc 360
acggtcaccg tctcctcagc ctccaccaag ggcccatcgg tcttccccct ggcgccctgc 420
tccaggagca cctccgagag cacagccgcc ctgggctgcc tggtcaagga ctacttcccc 480
gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 540
gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 600
agcttgggca cgaagaccta cacctgcaac gtagatcaca agcccagcaa caccaaggtg 660
gacaagagag ttgagtccaa atatggtccc ccatgcccac cctgcccagc acctgagttc 720
ctggggggac catcagtctt cctgttcccc ccaaaaccca aggacactct catgatctcc 780
cggacccctg aggtcacgtg cgtggtggtg gacgtgagcc aggaagaccc cgaggtccag 840
ttcaactggt acgtggatgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 900
cagttcaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 960
aacggcaagg agtacaagtg caaggtctcc aacaaaggcc tcccgtcctc catcgagaaa 1020
accatctcca aagccaaagg gcagccccga gagccacagg tgtacaccct gcccccatcc 1080
caggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctacccc 1140
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1200
cctcccgtgc tggactccga cggctccttc ttcctctaca gcaggctcac cgtggacaag 1260
agcaggtggc aggaggggaa tgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1320
cactacacac agaagtccct ctccctgtct ctgggtaaat ga 1362
<210> 224
<211> 453
<212> PRT
<213> 智人
<400> 224
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Lys
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Leu Tyr Asp Gly Ser Asn Gln His Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Leu Asp Leu Trp Ser Gly Tyr Tyr Thr Asn Gly Asp Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser
115 120 125
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr
130 135 140
Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
145 150 155 160
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
165 170 175
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
180 185 190
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr
195 200 205
Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val
210 215 220
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
325 330 335
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Leu Gly Lys
450
<210> 225
<211> 645
<212> DNA
<213> 智人
<400> 225
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccgtca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta cccctccgat caccttcggc 300
caagggacac gactggagat taaaactgtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 645
<210> 226
<211> 214
<212> PRT
<213> 智人
<400> 226
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 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> 227
<211> 346
<212> PRT
<213> 人工序列
<220>
<223> 重组人类IL-36R多肽(hIL-36R.mmH)
<400> 227
Asp Gly Cys Lys Asp Ile Phe Met Lys Asn Glu Ile Leu Ser Ala Ser
1 5 10 15
Gln Pro Phe Ala Phe Asn Cys Thr Phe Pro Pro Ile Thr Ser Gly Glu
20 25 30
Val Ser Val Thr Trp Tyr Lys Asn Ser Ser Lys Ile Pro Val Ser Lys
35 40 45
Ile Ile Gln Ser Arg Ile His Gln Asp Glu Thr Trp Ile Leu Phe Leu
50 55 60
Pro Met Glu Trp Gly Asp Ser Gly Val Tyr Gln Cys Val Ile Lys Gly
65 70 75 80
Arg Asp Ser Cys His Arg Ile His Val Asn Leu Thr Val Phe Glu Lys
85 90 95
His Trp Cys Asp Thr Ser Ile Gly Gly Leu Pro Asn Leu Ser Asp Glu
100 105 110
Tyr Lys Gln Ile Leu His Leu Gly Lys Asp Asp Ser Leu Thr Cys His
115 120 125
Leu His Phe Pro Lys Ser Cys Val Leu Gly Pro Ile Lys Trp Tyr Lys
130 135 140
Asp Cys Asn Glu Ile Lys Gly Glu Arg Phe Thr Val Leu Glu Thr Arg
145 150 155 160
Leu Leu Val Ser Asn Val Ser Ala Glu Asp Arg Gly Asn Tyr Ala Cys
165 170 175
Gln Ala Ile Leu Thr His Ser Gly Lys Gln Tyr Glu Val Leu Asn Gly
180 185 190
Ile Thr Val Ser Ile Thr Glu Arg Ala Gly Tyr Gly Gly Ser Val Pro
195 200 205
Lys Ile Ile Tyr Pro Lys Asn His Ser Ile Glu Val Gln Leu Gly Thr
210 215 220
Thr Leu Ile Val Asp Cys Asn Val Thr Asp Thr Lys Asp Asn Thr Asn
225 230 235 240
Leu Arg Cys Trp Arg Val Asn Asn Thr Leu Val Asp Asp Tyr Tyr Asp
245 250 255
Glu Ser Lys Arg Ile Arg Glu Gly Val Glu Thr His Val Ser Phe Arg
260 265 270
Glu His Asn Leu Tyr Thr Val Asn Ile Thr Phe Leu Glu Val Lys Met
275 280 285
Glu Asp Tyr Gly Leu Pro Phe Met Cys His Ala Gly Val Ser Thr Ala
290 295 300
Tyr Ile Ile Leu Gln Leu Pro Ala Pro Asp Phe Arg Ala Tyr Glu Gln
305 310 315 320
Lys Leu Ile Ser Glu Glu Asp Leu Gly Gly Glu Gln Lys Leu Ile Ser
325 330 335
Glu Glu Asp Leu His His His His His His
340 345
<210> 228
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 228
Tyr Lys Gln Ile Leu His Leu
1 5
<210> 229
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 229
Tyr Lys Gln Ile Leu His Leu Gly Lys Asp
1 5 10
<210> 230
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 230
Gly Val Glu Thr His Val Ser Phe Arg Glu His Asn Tyr Leu
1 5 10
<210> 231
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 231
Ile Leu His Leu
1
<210> 232
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 232
Ile Leu His Leu Gly Lys Asp
1 5
<210> 233
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 233
Gly Val Glu Thr His Val Ser Phe
1 5
<210> 234
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 234
Thr His Val Ser Phe
1 5
<210> 235
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 235
His Val Ser Phe
1
<210> 236
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 236
His Val Ser Phe Arg Glu His Asn Leu
1 5
<210> 237
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 237
His Val Ser Phe Arg Glu His Asn Leu Tyr
1 5 10
<210> 238
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 238
Phe Arg Glu His Asn Leu
1 5
<210> 239
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 多肽:APE6155重链(包含IgG4恒定结构域)
<400> 239
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 Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Arg Gln Gly Leu Glu Trp Met
35 40 45
Gly Met Phe His Pro Thr Gly Asp Val Thr Arg Leu Asn Gln Lys Phe
50 55 60
Lys Asp 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 Thr Thr Ser Met Ile Ile Gly Gly Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 240
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 多肽:APE6155轻链(包含κ恒定结构域)
<400> 240
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Arg
20 25 30
Asn Ala Ile Thr Tyr Phe Tyr Trp Tyr Leu His Lys Pro Gly Gln Pro
35 40 45
Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala 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 Val Gly Val Tyr Tyr Cys Ala Gln Asn
85 90 95
Leu Glu Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val 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
Claims (32)
1.一种分离的抗原结合蛋白,其为抗体或其抗原结合片段,所述抗体或其抗原结合片段:
在残基113-119、113-122、116-119、116-122、264-271、267-271、268-271、268-276、268-277和/或271-276处与包含SEQ ID NO:227中所阐述的氨基酸序列的多肽结合;
或,
(i)与IL36R上与参考抗体或其抗原结合片段相同的表位特异性结合;或
(ii)与参考抗体或其抗原结合片段竞争结合IL36R多肽,
其中所述参考抗体或其抗原结合片段包含:
(a)重链免疫球蛋白或其可变区,其包含有包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列的重链免疫球蛋白或其可变区的CDR-H1、CDR-H2和CDR-H3;或其变体;和/或
(b)轻链免疫球蛋白或其可变区,其包含有包含SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列的轻链免疫球蛋白或其可变区的CDR-L1、CDR-L2和CDR-L3;或其变体。
2.一种分离的抗原结合蛋白,其包含:
(i)重链免疫球蛋白或其可变区,其包含有包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列的重链免疫球蛋白或其可变区的CDR-H1、CDR-H2和CDR-H3;或其变体;和/或
(ii)轻链免疫球蛋白或其可变区,其包含有包含SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列的轻链免疫球蛋白或其可变区的CDR-L1、CDR-L2和CDR-L3;或其变体。
3.根据权利要求1至2中任一项所述的抗原结合蛋白,其包含:
(a)重链免疫球蛋白或其可变区,其包含与SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列具有至少90%的氨基酸序列一致性的氨基酸序列;和/或
(b)轻链免疫球蛋白或其可变区,其包含与SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列具有至少90%的氨基酸序列一致性的氨基酸序列。
4.根据权利要求1至3中任一项所述的抗原结合蛋白,其包含:
(a)重链免疫球蛋白或其可变区,其包含有包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列的重链免疫球蛋白或其可变区的CDR-H1、CDR-H2和CDR-H3和与SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列至少90%的氨基酸序列一致性;和/或
(b)轻链免疫球蛋白或其可变区,其包含有包含SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列的轻链免疫球蛋白或其可变区的CDR-L1、CDR-L2和CDR-L3和与SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列至少90%的氨基酸序列一致性。
5.根据权利要求1至4中任一项所述的抗原结合蛋白,其包含:
重链免疫球蛋白或其可变区,其包含:
包含SEQ ID NO:4中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:6中所阐述的氨基酸序列的CDR-H2或其变体;和
包含SEQ ID NO:8中所阐述的氨基酸序列的CDR-H3或其变体
和/或
包含SEQ ID NO:20中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:22中所阐述的氨基酸序列的CDR-H2或其变体;和
包含SEQ ID NO:24中所阐述的氨基酸序列的CDR-H3或其变体
和/或
包含SEQ ID NO:36中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:38中所阐述的氨基酸序列的CDR-H2或其变体;和
包含SEQ ID NO:40中所阐述的氨基酸序列的CDR-H3或其变体
和/或
包含SEQ ID NO:52中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:54中所阐述的氨基酸序列的CDR-H2或其变体;和
包含SEQ ID NO:56中所阐述的氨基酸序列的CDR-H3或其变体
和/或
包含SEQ ID NO:68中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:70中所阐述的氨基酸序列的CDR-H2或其变体;和
包含SEQ ID NO:72中所阐述的氨基酸序列的CDR-H3或其变体
和/或
包含SEQ ID NO:84中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:86中所阐述的氨基酸序列的CDR-H2或其变体;和
包含SEQ ID NO:88中所阐述的氨基酸序列的CDR-H3或其变体
和/或
包含SEQ ID NO:100中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:102中所阐述的氨基酸序列的CDR-H2或其变体;和
包含SEQ ID NO:104中所阐述的氨基酸序列的CDR-H3或其变体
和/或
包含SEQ ID NO:116中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:118中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:120中所阐述的氨基酸序列的CDR-H3或其变体
和/或
包含SEQ ID NO:132中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:134中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:136中所阐述的氨基酸序列的CDR-H3或其变体
和/或
包含SEQ ID NO:140中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:142中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:144中所阐述的氨基酸序列的CDR-H3或其变体
和/或
包含SEQ ID NO:156中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:158中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:160中所阐述的氨基酸序列的CDR-H3或其变体
和/或
包含SEQ ID NO:172中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:174中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:176中所阐述的氨基酸序列的CDR-H3或其变体和/或
轻链免疫球蛋白或其可变区,其包含:
包含SEQ ID NO:12中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:14中所阐述的氨基酸序列的CDR-L2或其变体;和
包含SEQ ID NO:16中所阐述的氨基酸序列的CDR-L3或其变体
和/或
包含SEQ ID NO:28中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:30中所阐述的氨基酸序列的CDR-L2或其变体;和
包含SEQ ID NO:32中所阐述的氨基酸序列的CDR-L3或其变体
和/或
包含SEQ ID NO:44中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:46中所阐述的氨基酸序列的CDR-L2或其变体;和
包含SEQ ID NO:48中所阐述的氨基酸序列的CDR-L3或其变体
和/或
包含SEQ ID NO:60中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:62中所阐述的氨基酸序列的CDR-L2或其变体;和
包含SEQ ID NO:64中所阐述的氨基酸序列的CDR-L3或其变体
和/或
包含SEQ ID NO:76中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:78中所阐述的氨基酸序列的CDR-L2或其变体;和
包含SEQ ID NO:80中所阐述的氨基酸序列的CDR-L3或其变体
和/或
包含SEQ ID NO:92中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:94中所阐述的氨基酸序列的CDR-L2或其变体;和
包含SEQ ID NO:96中所阐述的氨基酸序列的CDR-L3或其变体
和/或
包含SEQ ID NO:108中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:110中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:112中所阐述的氨基酸序列的CDR-L3或其变体
和/或
包含SEQ ID NO:124中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:126中所阐述的氨基酸序列的CDR-L2或其变体;和
包含SEQ ID NO:128中所阐述的氨基酸序列的CDR-L3或其变体
和/或
包含SEQ ID NO:148中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:150中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:152中所阐述的氨基酸序列的CDR-L3或其变体
和/或
包含SEQ ID NO:164中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:166中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:168中所阐述的氨基酸序列的CDR-L3或其变体。
6.根据权利要求1至5中任一项所述的抗体或其抗原结合片段,其包含:
(1)
重链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:4中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:6中所阐述的氨基酸序列的CDR-H2或其变体;和
包含SEQ ID NO:8中所阐述的氨基酸序列的CDR-H3或其变体;
和
轻链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:12中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:14中所阐述的氨基酸序列的CDR-L2或其变体;
和包含SEQ ID NO:16中所阐述的氨基酸序列的CDR-L3或其变体;
(2)
重链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:20中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:22中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:24中所阐述的氨基酸序列的CDR-H3或其变体;
和
轻链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:28中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:30中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:32中所阐述的氨基酸序列的CDR-L3或其变体;
(3)
重链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:36中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:38中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:40中所阐述的氨基酸序列的CDR-H3或其变体;
和
轻链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:44中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:46中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:48中所阐述的氨基酸序列的CDR-L3或其变体;
(4)
重链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:52中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:54中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:56中所阐述的氨基酸序列的CDR-H3或其变体;
和
轻链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:60中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:62中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:64中所阐述的氨基酸序列的CDR-L3或其变体;
(5)
重链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:68中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:70中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:72中所阐述的氨基酸序列的CDR-H3或其变体;
和
轻链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:76中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:78中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:80中所阐述的氨基酸序列的CDR-L3或其变体;
(6)
重链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:84中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:86中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:88中所阐述的氨基酸序列的CDR-H3或其变体;
和
轻链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:92中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:94中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:96中所阐述的氨基酸序列的CDR-L3或其变体;
(7)
重链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:100中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:102中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:104中所阐述的氨基酸序列的CDR-H3或其变体;
和
轻链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:108中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:110中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:112中所阐述的氨基酸序列的CDR-L3或其变体;
(8)
重链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:116中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:118中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:120中所阐述的氨基酸序列的CDR-H3或其变体;
和
轻链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:124中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:126中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:128中所阐述的氨基酸序列的CDR-L3或其变体;
(9)
重链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:132中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:134中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:136中所阐述的氨基酸序列的CDR-H3或其变体;
和
轻链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:124中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:126中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:128中所阐述的氨基酸序列的CDR-L3或其变体;
(10)
重链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:140中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:142中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:144中所阐述的氨基酸序列的CDR-H3或其变体;
和
轻链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:148中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:150中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:152中所阐述的氨基酸序列的CDR-L3或其变体;
(11)
重链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:156中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:158中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:160中所阐述的氨基酸序列的CDR-H3或其变体;
和
轻链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:164中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:166中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:168中所阐述的氨基酸序列的CDR-L3或其变体;
或
(12)
重链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:172中所阐述的氨基酸序列的CDR-H1或其变体;
包含SEQ ID NO:174中所阐述的氨基酸序列的CDR-H2或其变体;
和
包含SEQ ID NO:176中所阐述的氨基酸序列的CDR-H3或其变体;
和
轻链免疫球蛋白或其可变区,其包含有
包含SEQ ID NO:124中所阐述的氨基酸序列的CDR-L1或其变体;
包含SEQ ID NO:126中所阐述的氨基酸序列的CDR-L2或其变体;
和
包含SEQ ID NO:128中所阐述的氨基酸序列的CDR-L3或其变体。
7.根据权利要求1至6中任一项所述的抗原结合蛋白,其包含:
(a)重链免疫球蛋白或其可变区,其包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列或其变体;
和/或
(b)轻链免疫球蛋白或其可变区,其包含SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列或其变体。
8.根据权利要求1至7中任一项所述的抗原结合蛋白,其包含:
(a)重链免疫球蛋白可变区,其包含SEQ ID NO:2中所阐述的氨基酸序列,和轻链免疫球蛋白可变区,其包含SEQ ID NO:10中所阐述的氨基酸序列;
(b)重链免疫球蛋白可变区,其包含SEQ ID NO:18中所阐述的氨基酸序列,和轻链免疫球蛋白可变区,其包含SEQ ID NO:26中所阐述的氨基酸序列;
(c)重链免疫球蛋白可变区,其包含SEQ ID NO:34中所阐述的氨基酸序列,和轻链免疫球蛋白可变区,其包含SEQ ID NO:42中所阐述的氨基酸序列;
(d)重链免疫球蛋白可变区,其包含SEQ ID NO:50中所阐述的氨基酸序列,和轻链免疫球蛋白可变区,其包含SEQ ID NO:58中所阐述的氨基酸序列;
(e)重链免疫球蛋白可变区,其包含SEQ ID NO:66中所阐述的氨基酸序列,和轻链免疫球蛋白可变区,其包含SEQ ID NO:74中所阐述的氨基酸序列;
(f)重链免疫球蛋白可变区,其包含SEQ ID NO:82中所阐述的氨基酸序列,和轻链免疫球蛋白可变区,其包含SEQ ID NO:90中所阐述的氨基酸序列;
(g)重链免疫球蛋白可变区,其包含SEQ ID NO:98中所阐述的氨基酸序列,和轻链免疫球蛋白可变区,其包含SEQ ID NO:106中所阐述的氨基酸序列;
(h)重链免疫球蛋白可变区,其包含SEQ ID NO:114中所阐述的氨基酸序列,和轻链免疫球蛋白可变区,其包含SEQ ID NO:122中所阐述的氨基酸序列;
(i)重链免疫球蛋白可变区,其包含SEQ ID NO:130中所阐述的氨基酸序列,和轻链免疫球蛋白可变区,其包含SEQ ID NO:122中所阐述的氨基酸序列;
(j)重链免疫球蛋白可变区,其包含SEQ ID NO:138中所阐述的氨基酸序列,和轻链免疫球蛋白可变区,其包含SEQ ID NO:146中所阐述的氨基酸序列;
(k)重链免疫球蛋白可变区,其包含SEQ ID NO:154中所阐述的氨基酸序列,和轻链免疫球蛋白可变区,其包含SEQ ID NO:162中所阐述的氨基酸序列;和/或
(l)重链免疫球蛋白可变区,其包含SEQ ID NO:170中所阐述的氨基酸序列,和轻链免疫球蛋白可变区,其包含SEQ ID NO:122中所阐述的氨基酸序列。
9.根据权利要求1至8中任一项所述的抗原结合蛋白,其中所述重链免疫球蛋白可变区与IgG、IgG1或IgG4重链恒定区连接,并且所述轻链免疫球蛋白可变区与κ或λ轻链恒定区连接。
10.根据权利要求1至9中任一项所述的抗原结合蛋白,其包含:
(a)重链免疫球蛋白,其包含SEQ ID NO:180中所阐述的氨基酸序列,和轻链免疫球蛋白,其包含SEQ ID NO:182中所阐述的氨基酸序列;
(b)重链免疫球蛋白,其包含SEQ ID NO:184中所阐述的氨基酸序列,和轻链免疫球蛋白,其包含SEQ ID NO:186中所阐述的氨基酸序列;
(c)重链免疫球蛋白,其包含SEQ ID NO:188中所阐述的氨基酸序列,和轻链免疫球蛋白,其包含SEQ ID NO:190中所阐述的氨基酸序列;
(d)重链免疫球蛋白,其包含SEQ ID NO:192中所阐述的氨基酸序列,和轻链免疫球蛋白,其包含SEQ ID NO:194中所阐述的氨基酸序列;
(e)重链免疫球蛋白,其包含SEQ ID NO:196中所阐述的氨基酸序列,和轻链免疫球蛋白,其包含SEQ ID NO:198中所阐述的氨基酸序列;
(f)重链免疫球蛋白,其包含SEQ ID NO:200中所阐述的氨基酸序列,和轻链免疫球蛋白,其包含SEQ ID NO:202中所阐述的氨基酸序列;
(g)重链免疫球蛋白,其包含SEQ ID NO:204中所阐述的氨基酸序列,和轻链免疫球蛋白,其包含SEQ ID NO:206中所阐述的氨基酸序列;
(h)重链免疫球蛋白,其包含SEQ ID NO:208中所阐述的氨基酸序列,和轻链免疫球蛋白,其包含SEQ ID NO:210中所阐述的氨基酸序列;
(i)重链免疫球蛋白,其包含SEQ ID NO:212中所阐述的氨基酸序列,和轻链免疫球蛋白,其包含SEQ ID NO:214中所阐述的氨基酸序列;
(j)重链免疫球蛋白,其包含SEQ ID NO:216中所阐述的氨基酸序列,和轻链免疫球蛋白,其包含SEQ ID NO:218中所阐述的氨基酸序列;
(k)重链免疫球蛋白,其包含SEQ ID NO:220中所阐述的氨基酸序列,和轻链免疫球蛋白,其包含SEQ ID NO:222中所阐述的氨基酸序列;和/或
(l)重链免疫球蛋白,其包含SEQ ID NO:224中所阐述的氨基酸序列,和轻链免疫球蛋白,其包含SEQ ID NO:226中所阐述的氨基酸序列。
11.根据权利要求1至10中任一项所述的抗原结合蛋白,其为抗体或其抗原结合片段。
12.根据权利要求1至11中任一项所述的抗原结合蛋白,其为多特异性的。
13.根据权利要求1至12中任一项所述的抗原结合蛋白,其包含以下特性中的一者或多者:
在25℃下以约2.18nM到约13.9nM的KD或在37℃下以约4.25nM到约29.5nM的KD与人类IL36R(IL-1RL2)结合;
在25℃下以约7.87nM到约34.4nM的KD或在37℃下以约14.4nM到约58.2nM的KD与食蟹猴(Macaca fascicularis)IL36R(IL-1RL2)结合;
在25℃下以约173pM到约5.79nM的KD或在37℃下以约205pM到约28.7nM的KD和与小鼠IgG2a融合的人类IL36R(IL-1RL2)结合;
在25℃下以约212pM到约14nM的KD或在37℃下以约264pM到约40.9nM的KD与经表达具有小鼠IgG2a Fc标签的与IL1RAcP胞外结构域融合的人类IL36R(IL-1RL2)结合;
与H4H14699P2;H4H14700P2;H4H14706P2;H4H14708P2;H4H14709P;H4H14728P;H4H14731P;H4H14732P2;H4H14734P2;H4H14757P;H4H14758P或H4H14760P2竞争结合IL36R(IL-1RL2);任选地其限制条件为所述抗原结合蛋白不为APE6155或其抗原结合片段;
在IL-1RAcP和IL36R配位体存在的情况下阻断IL-36R(IL-1RL2)对在宿主细胞中与报告基因融合的一个或多个NFκB元件的激活;
在罹患皮肤炎症的个体中预防或改善皮肤炎症或降低皮肤厚度或总病理评分或降低促炎性细胞因子水平;
在罹患结肠炎或结肠炎症的个体中预防或改善这类结肠炎或炎症或降低LCN2多肽的粪便水平;
在结合时保护包含SEQ ID NO:227中所阐述的氨基酸序列的人类IL36R(IL-1RL2)的残基(a)113-119、113-122、116-119和/或116-122;和/或(b)264-271、267-271、268-271、268-276、268-277和/或271-276免受胃蛋白酶和/或蛋白酶XIII消化和/或在氘存在的情况下氘化的影响;
在残基113-119、113-122、116-119、116-122、264-271、267-271、268-271、268-276、268-277和/或271-276处与包含SEQ ID NO:227中所阐述的氨基酸序列的IL36R(IL-1RL2)结合;
结合IL36R(IL-1RL2)的结构域II;
结合包含氨基酸序列YKQILHLGKD(SEQ ID NO:229)(SEQ ID NO:227的氨基酸113-122)的多肽;
以约1-6nM的IC50抑制体外表皮角化细胞、肠道肌成纤维细胞和/或CD14+单核细胞中的IL36α、IL36β和/或IL36γ;和/或
竞争性地抑制IL36α、IL36β和/或IL36γ介导的IL36R对NFκB的激活。
14.一种复合物,其包含与IL36R多肽结合的根据权利要求1至13中任一项所述的抗原结合蛋白。
15.一种用于制备根据权利要求1至14中任一项所述的抗原结合蛋白或其免疫球蛋白链的方法,其包含:
(a)将编码所述抗原结合蛋白的免疫球蛋白链的一个或多个多核苷酸引入宿主细胞中;
(b)在有利于表达所述多核苷酸的条件下在培养基中培养所述宿主细胞;以及
(c)任选地,从所述宿主细胞和/或所述宿主细胞在其中生长的培养基中分离所述抗原结合蛋白或免疫球蛋白链。
16.根据权利要求15所述的方法,其中所述宿主细胞为中国仓鼠卵巢细胞。
17.一种抗原结合蛋白或免疫球蛋白链,其为根据权利要求15至16中任一项所述的方法的产物。
18.一种多肽,其包含:
(a)包含SEQ ID NO:2、18、34、50、66、82、98、114、130、138、154、170、180、184、188、192、196、200、204、208、212、216、220或224中所阐述的氨基酸序列的重链免疫球蛋白或其可变区的CDR-H1、CDR-H2和CDR-H3或其变体;和/或
(b)包含SEQ ID NO:10、26、42、58、74、90、106、122、146、162、182、186、190、194、198、202、206、210、214、218、222或226中所阐述的氨基酸序列的轻链免疫球蛋白或其可变区的CDR-L1、CDR-L2和CDR-L3或其变体;
或,
(c)选自由SEQ ID NO:1-226组成的群组的成员中所阐述的氨基酸序列或其变体。
19.一种多核苷酸,其编码根据权利要求18所述的多肽。
20.一种载体,其包含根据权利要求19所述的多核苷酸。
21.一种宿主细胞,其包含根据权利要求1至13、17、18、19或20中任一项所述的抗原结合蛋白或免疫球蛋白链或多肽或多核苷酸或载体。
22.一种组合物或试剂盒,其包含根据权利要求1至13和17中任一项所述的抗原结合蛋白中的一者或多者,任选地与另一种治疗剂结合。
23.一种药物组合物,其包含根据权利要求1至13和17中任一项所述的抗原结合蛋白和药学上可接受的载体以及任选的另一种治疗剂。
24.根据权利要求22至23中任一项所述的组合物或试剂盒,其与另一种治疗剂结合,所述另一种治疗剂为抗炎剂。
25.根据权利要求22至24中任一项所述的组合物或试剂盒,其中另一种治疗剂为选自由以下组成的群组的成员:抗TNFα抗体或其抗原结合片段、一种或多种与免疫球蛋白连接的人类TNF受体或其片段、IL17抑制剂、IL23p19抑制剂、IL12p40抑制剂、古塞库单抗(guselkumab)、优特克单抗(ustekinumab)、布罗达单抗(brodalumab)、依奇珠单抗(ixekizumab)、苏金单抗(secukinumab)、英利昔单抗(infliximab)、阿达木单抗(adalimumab)、依那西普(etanercept)、杜匹鲁单抗(dupilumab)、沙瑞卢单抗(sarilumab)、托珠单抗(tocilizumab)、戈利木单抗(golimumab)、阿巴西普(abatacept)、托法替尼(tofacitinib)、阿巴西普(abatacept)、非类固醇抗炎药(NSAID)、布洛芬(ibuprofen)、萘普生(naproxen)、对乙酰氨基酚(acetaminophen)、阿司匹林(aspirin)、塞内昔布(celecoxib)、环磷酰胺(cyclophosphamide)、甲氨蝶呤(methotrexate)、皮质类固醇(corticosteroid)、可的松(cortisone)和泼尼松(prednisone)。
26.一种容器或注射装置,其包含根据权利要求1至13、17或22至25中任一项所述的抗原结合蛋白或组合物。
27.一种用于治疗或预防有需要的个体的IL-36R介导的疾病的方法,其包含任选地与另一种治疗剂结合施用治疗有效量的根据权利要求1至13或17中任一项所述的抗原结合蛋白。
28.一种用于治疗或预防疾病的方法,所述疾病是:发炎性病症、自身免疫性病症、白细胞介素IL-36受体拮抗因子缺乏(DITRA)综合症、疱疹样脓疱病(impetigoherpetiformis)、肢端皮炎(acrodermatitis)、中性粒细胞脓疱型皮肤病、脓疱型疾病、牛皮癣(psoriasis)、泛发性脓疱型牛皮癣、寻常型牛皮癣、掌跖脓疱型牛皮癣、掌跖脓疱病、结肠炎、气道炎症、关节炎症、肾脏炎症、斑秃、皮肤炎症、棘皮症(acanthosis)、角化过度(hyperkeratosis)、金德勒氏综合症(kindler syndrome)、全身性红斑狼疮(systemiclupus erythematosus;SLE)、肾病综合症、抗中性粒细胞胞质抗体(anti-neutrophilcytoplasmic antibody;ANCA)相关血管病变、肾小管间质病变或肾小球肾炎;所述方法包含任选地与另一种治疗剂结合施用治疗有效量的根据权利要求1至13或17中任一项所述的抗原结合蛋白。
29.根据权利要求27至28中任一项所述的方法,其用于治疗或预防牛皮癣或发炎性肠病。
30.一种用于向个体体内施用根据权利要求1至13或17中任一项所述的抗原结合蛋白的方法,其包含任选地与另一种治疗剂结合向所述个体体内注射所述抗原结合蛋白。
31.根据权利要求30所述的方法,其中将所述抗原结合蛋白皮下、静脉内或肌肉内注射到所述个体体内。
32.根据权利要求27至31中任一项所述的方法,其中所述个体具有纯合或杂合IL36RN突变基因型。
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WO2024175031A1 (zh) * | 2023-02-21 | 2024-08-29 | 江苏恒瑞医药股份有限公司 | Il-36r结合蛋白及其医药用途 |
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WO2022026829A1 (en) | 2020-07-30 | 2022-02-03 | Anaptysbio, Inc. | Anti-interleukin 36 receptor (il-36r) therapy for skin toxicity |
AU2021319103A1 (en) | 2020-07-30 | 2023-02-09 | Anaptysbio, Inc. | Anti-interleukin 36 receptor (IL-36r) therapy for ichthyosis |
CN116685605A (zh) * | 2020-12-17 | 2023-09-01 | 上海华奥泰生物药业股份有限公司 | 靶向il-17a和il-36r的双特异性抗体及其应用 |
WO2022150644A1 (en) | 2021-01-08 | 2022-07-14 | Anaptysbio, Inc. | Anti-interleukin 36 receptor (il-36r) therapy for acne |
US20240084021A1 (en) | 2021-01-08 | 2024-03-14 | Anaptysbio, Inc. | Anti-interleukin 36 receptor (il-36r) therapy for hidradenitis suppurativa |
WO2022166977A1 (zh) * | 2021-02-08 | 2022-08-11 | 上海普铭生物科技有限公司 | 抗人il-36r抗体及其应用 |
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JP2024512384A (ja) | 2021-03-12 | 2024-03-19 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 汎発型膿疱性乾癬における抗il-36r抗体による処置に関連したバイオマーカー |
BR112023026429A2 (pt) * | 2021-06-18 | 2024-03-05 | Chia Tai Tianqing Pharmaceutical Group Co Ltd | Anticorpo anti-il-36r isolado ou um fragmento de ligação ao antígeno deste, imunoconjugado ou molécula multiespecífica, composição farmacêutica, método para inibir a transdução de sinal de il-36/il-36r e método para tratar doenças e condições relacionadas mediadas por il-36/il-36r em um sujeito em necessidade |
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AU2019306217A1 (en) | 2021-01-14 |
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WO2020018503A2 (en) | 2020-01-23 |
IL280013A (en) | 2021-03-01 |
BR112020027015A2 (pt) | 2021-04-06 |
EP3823989A2 (en) | 2021-05-26 |
CN112513091B (zh) | 2024-08-27 |
PH12020552178A1 (en) | 2021-06-28 |
KR20210032401A (ko) | 2021-03-24 |
WO2020018503A3 (en) | 2020-02-20 |
US20200017592A1 (en) | 2020-01-16 |
AU2019306217B2 (en) | 2024-01-25 |
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