CN112979802B - 抗人il-33单克隆抗体及其应用 - Google Patents
抗人il-33单克隆抗体及其应用 Download PDFInfo
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Abstract
本公开提供一种抗人IL‑33单克隆抗体及其应用。以重组人IL‑33作为免疫原，通过杂交瘤技术制备鼠源抗人IL‑33单克隆抗体，对鼠源抗体进行结合活性分析、对IL‑33与ST2结合的阻断活性分析、测序，构建人‑鼠嵌合抗人IL‑33单克隆抗体，检测嵌合抗体的动力学参数。在鼠源抗体、嵌合抗体性能分析的基础上，采用CDRs移植技术、CDR区突变设计构建人源化抗人IL‑33单克隆抗体，检测人源化抗体的动力学参数、亲和力、以及阻断IL33诱导的细胞因子释放。所述抗人IL‑33单克隆抗体对IL‑33具有较高的亲和力、能有效阻断IL‑33与其受体ST2的结合、抑制IL‑33/ST2通路相关的免疫应答，在哮喘、炎症性疾病、糖尿病、自身免疫性疾病的治疗中具有良好的应用前景。
Description
技术领域
本发明属于抗体工程领域，具体涉及一种抗人IL-33单克隆抗体及其应用，特别是涉及一种阻断人IL-33与ST2的结合、抑制IL-33诱导的细胞因子分泌的单克隆抗体及其应用。
背景技术
白介素33（IL-33）是白介素1（IL-1）家族成员，其基因位于9号染色体（9p24.1），它编码的蛋白质是由270个氨基酸残基组成的多肽，分子量约18kDa，其氨基端存在螺旋-转角-螺旋的结构模式，含有染色质结合区及核定位序列，是一种具有转录抑制功能的染色质相关因子；其羧基端具有IL-1类分子特有的结构域，是IL-33与其受体的结合部位。IL-33常表达于屏障组织细胞，如皮肤、肠、肺等，当这些细胞发生损伤时，全长IL-33（1-270）在胞外经中性粒细胞丝氨酸蛋白酶、组织蛋白酶G和弹性蛋白酶酶切，产生3种活性形式，分别是IL-33（95-270），IL-33（99-270）和IL-33（109-270）。
IL-33具有双重作用，既可以作为核内定位的分子结合核染色粒调节基因表达，起到转录因子的作用；又可以作为可溶性细胞因子起到调节Th2型免疫应答的作用。IL-33可促进Th2细胞产生和释放IL-5、IL-13等Th2型细胞因子。由于IL-33的受体(ST2)选择性地表达在Th2细胞上(Thl细胞不表达)，从而增强了Th2型免疫应答。IL-33对肥大细胞的作用是通过诱导其产生趋化因子和细胞因子而增强炎症反应。IL-33对其他细胞(嗜酸粒细胞、嗜碱粒细胞、树突细胞)的作用也是通过诱导产生Th2型细胞因子和趋化因子，上调细胞黏附分子的表达而促进炎症反应。
与IL-33 相关的疾病可以归为三类：变态反应性疾病，如哮喘，过敏性疾病等; 自身免疫病，如风湿性关节炎、系统性红斑狼疮等；心肺疾病，如心衰、扩心病等。
过敏性疾病发病过程中与多种细胞因子有关，其中IL-33与多种过敏性疾病密切相关，通过IL-33与其受体ST2的结合，激活Th2细胞、肥大细胞、嗜酸粒细胞、嗜碱粒细胞，产生IL-4、IL-5、IL-13等Th2型细胞因子，加重炎症反应。阻断IL-33/ST2信号通路有望为过敏性疾病的诊断、预防和治疗带来新的希望。IL-4 、IL-5和IL-13在2型免疫中发挥多种重要作用，协同调控2型炎症通路的激活，呈现出2型炎症通路的典型特征：高浓度IgE和嗜酸性粒细胞。目前认为IL-4、IL-5和IL-13是2型炎症通路的关键驱动因子，是特异性治疗严重过敏性疾病（包括特异性皮炎、哮喘、特发性荨麻疹、慢性鼻窦炎鼻息肉以及食物过敏等）颇具吸引力的一类靶点。
重组IL-33以ST2依赖性方式作用于多种靶细胞，包括肥大细胞、不同亚群的CD T细胞、嗜酸粒细胞、嗜碱粒细胞、单核细胞、巨噬细胞、自然杀伤细胞、恒定的自然杀伤T细胞(invariant nature killer T，iNKT)和中性粒细胞。在此过程中，IL-33诱导细胞激活、分化、极化、趋化及不同细胞因子和化学因子的产生。ST2可表达在一些Th2型免疫相关的细胞，因此体内应用重组IL-33可在不同的小鼠模型(包括哮喘和寄生虫感染)诱导或扩增Th2反应。此外，与体外IL-33可诱导不同细胞产生前炎性因子相一致，IL-33也可引起模型动物产生炎症效应。 IL-33定位于静止细胞的细胞核，通过H2A-H2B组蛋白复合体结合到染色质；IL-33与异染色质的关系研究表明，其具有转录抑制和染色质凝缩的特性。在胰腺星型细胞的核内存在IL-33的表达，通过RNA干扰IL-33的表达可减少这种细胞的增殖。
IL-33与皮肤炎症研究表明，与正常皮肤相比过敏性皮炎和银屑病患者的皮肤IL-33表达量明显增高，同时在皮肤炎症模型小鼠的研究中IL-33能诱导IL-13介导的皮肤纤维化。此外AxelJ.Hueber发现牛皮癣患者皮肤IL-33和ST2的表达也显著增多。IL-33通过触发肥大细胞、中性粒细胞的激活而导致牛皮癣的形成。
IL-33与过敏性哮喘过敏性哮喘是由肥大细胞、嗜酸粒细胞和T淋巴细胞等多种炎性细胞浸润呼吸道，并以Th2型免疫应答为主，以气道变应性炎症和气道高反应为主要特征的过敏性疾病。目前普遍认为哮喘的发病机制是：Thl／Th2的亚群比例和功能的失衡，即Thl型细胞数目和功能相对减弱，而Th2型免疫应答占优势。而IL-33正是加强Th2型免疫应答的一种细胞因子，它作用的靶细胞也正是上述各类炎性细胞。目前认为过敏性哮喘的发病过程是由于暴露于空气中的过敏原、污染、呼吸道病毒等造成肺上皮细胞的损害，可激活上皮细胞模式识别受体(如Toll样受体4，TLR4)]，激活的TLR4信号通路可促进IL-33的表达，从而引起一系列级联反应，主要是通过激活以下几种细胞发挥作用：①通过招募大量的树突状细胞从而激活过敏原特异性Th2应答，促使Th2产生大量的IL-4、IL-5和IL-13；②通过促进嗜酸粒细胞的聚集、成熟和存活；③通过作用于肥大细胞和IL一13诱导气道对过敏原产生高反应性。目前，国内外关于IL-33在哮喘的发病机制中所起的作用的研究已取得了一定的成果，IL-33主要通过作用于T淋巴细胞而加重哮喘的有关证据：在哮喘发病过程中，浸润到呼吸道的淋巴细胞主要为Th2细胞。而IL-33的受体也主要表达于Th2细胞上，通过它的信号转导通路促进了Th2型细胞因子的产生，引起炎症。IL-33是Th2细胞的趋化因子，它促使Th2细胞在淋巴结和组织中募集。在大规模哮喘病的研究中，已得出IL-33与ST2基因均是哮喘的易感因素。巩芷娟等发现在人类Th2细胞中ST2选择性表达，并且在支气管哮喘患者外周血单个核细胞中ST2 mRNA水平明显升高。Pr6fontaine等研究证实人气道上皮细胞、平滑肌细胞和血管内皮细胞组成型表达IL-33mRNA，哮喘可使其表达升高。麻晓燕等研究外周血IL-33水平，与正常健康者相比，在中重度患者明显提高，在轻度患者无明显差异。Besnard等研究结果发现在用卵白蛋白诱发哮喘模型中，IL-33可诱导募集肺部抗原提呈细胞DC，并活化DC，进而影响Th2型应答导致过敏性气道炎性反应。总之，可以推断IL-33作用于Th2细胞的过程是通过其触发一系列级联反应，最终激活Th2细胞并且诱导产生大量Th2型细胞因子形成慢性炎症。最新动物实验结果表明，应用抗ST2L单克隆抗体能阻止IL-33与ST2L结合，并下调IL-33诱导核因子NF-KB信号，可减轻Th2型为主的免疫应答。
IL-33与过敏性鼻炎过敏性鼻炎是指特应性个体接触变应原后主要由IgE介导的组胺等介质释放，并有多种免疫活性细胞和细胞因子参与的鼻黏膜非感染性炎性疾病。过敏性鼻炎的发病机制目前认为是由细胞因子失衡引起的。有研究报道，日本学者研究发现在花粉症患者血清中有高水平的IL-33检出。之后，有研究证实血清中IL 33的水平不仅是Th2型细胞介导的过敏反应的标志，更是过敏性鼻炎严重程度的标志。在过敏性鼻炎的发病机制中，起最主要作用的是肥大细胞，IL-33诱导肥大细胞产生趋化因子和Th2型细胞因子加重了炎症反应。
IL-33与过敏性肠炎过敏性肠炎是由于触发了体内一系列失调的细胞因子产物而引起的一类慢性肠道疾病。对于过敏性肠炎的发病机制至今还不是很清楚。传统观点认为过敏性肠炎是IL-4、IL-5、IL-13等介导的Th2型炎症反应。最新资料表示，IL-33不但是肠粘膜Th2细胞强效的化学诱导剂，促使Th2相关细胞因子(如IL-4、IL-5和IL-13)的表达，而且能促进肥大细胞表达促炎症因子和趋化蛋白。IL-33在正常人的结肠黏膜层的上皮细胞具有较高水平表达，参与调控固有免疫和适应性免疫的启动阶段。Carriere等在正常人小肠派氏集合淋巴结的小静脉高内皮细胞中也检出IL-33的表达。Sponheim等的研究发现，过敏性肠炎的肠道组织中IL-33mRNA表达水平较正常人高2-6倍，对病变部位活检组织标本进行免疫组化检测发现黏膜上皮下肌纤维母细胞IL-33呈阳性高表达。研究发现，其实IL-33在过敏性肠炎的发病机制中是通过以下三种方式发挥作用的：①作为核因子抑制转录阻遏促炎症基因表达；②通过参与调控肠黏膜淋巴细胞Th2型免疫应答；③通过促进肠黏膜肥大细胞表达促炎性因子。
IL-33与过敏性肺炎：过敏性肺炎是由于吸入各种抗原性有机物质所引起的一种间质性肺病。由于IL-33在呼吸道等与外界接触的黏膜系统中是高表达的，最终引起嗜酸粒细胞水平的升高而产生大量的IL-4、IL-5、IL-13等细胞因子。已有研究表明：当用不同浓度的IL-33作用小鼠时，IL-33浓度越高，小鼠体内产生的IL-4、IL-5、IL-13也就越多。主要病理表现体现在肺部血管和呼吸道的变化上：①肺部血管的变化：在血管内皮下、血管壁内以及血管附近会有嗜酸粒细胞和单核细胞的浸润；②在呼吸道的变化：主要表现在支气管和较大的细支气管黏膜上皮肿胀，管腔内充满粘液。这可能与IL-33有效地介导嗜酸粒细胞活性，并能上调嗜酸粒细胞表面的V6细胞间黏附分子1(ICAM-1)的表达量，并诱导其产生IL-6、IL-8等细胞因子而加重炎症反应有关。
截至目前针对IL-33的抗体药物研发有四种进入临床阶段。再生元与赛诺菲联合研制的Itepekimab (REGN-3500; SAR440340)完成了部分II期临床试验（NCT03546907），用于治疗过敏性哮喘、慢性阻塞性肺病。AnaptysBio公司推出的Etokimab（ANB020）也进入了II期临床试验阶段（NCT02920021、NCT03469934、NCT03533751），用于治疗特应性皮炎、过敏症、鼻窦炎、哮喘。礼来公司研发的LY3375880也初步完成了特异性皮炎的II期临床评估（NCT03831191）。另外，辉瑞公司研发的PF-06817024进入了I期临床阶段（NCT02743871）。
尽管机理明确、研究方向清楚，但是由于抗体药物研发过程中的诸多不可控因素，导致抗IL-33抗体作为临床用药物仍有待深入研究。目前临床试验进展最快的是赛诺菲和再生元开发的全人源抗IL-33单抗Itepekimab，然而其在哮喘、特异性皮炎、慢性阻塞性肺炎等的临床应用前景方面仍不明朗。此外，全人源抗体Itepekimab在临床上导致不良反应率较高，单独使用Itepekimab的不良事件（aes）发生率为61.6%。其它关于抗IL-33抗体药物的研究在人源化程度、亲和力强度、影响细胞因子分泌等方面产生的效果均存在不足。
发明内容
本公开提供一种抗人IL-33单克隆抗体及其应用。以重组人IL-33作为免疫原，通过杂交瘤技术制备鼠源抗人IL-33单克隆抗体，对鼠源抗体进行结合活性分析、对IL-33与ST2结合的阻断活性分析、测序，构建人-鼠嵌合抗人IL-33单克隆抗体，检测嵌合抗体的动力学参数。在鼠源抗体、嵌合抗体性能分析的基础上，采用CDRs移植技术、CDR区突变设计构建人源化抗人IL-33单克隆抗体，检测人源化抗体的动力学参数、亲和力、以及阻断IL33诱导的细胞因子释放。所述抗人IL-33单克隆抗体对IL-33具有较高的亲和力、能有效阻断IL-33与其受体ST2的结合、抑制IL-33/ST2通路相关的免疫应答，在哮喘、炎症性疾病、糖尿病、自身免疫性疾病的治疗中具有良好的应用前景。
具体而言：
一方面，本发明提供一种抗人IL-33单克隆抗体或其片段，其特征在于所述抗体或其片段特异性结合于人IL-33上与ST2受体结合的位点，并且其与IL-33结合的KD<1×10-8。
优选的，抗人IL-33单克隆抗体或其片段与IL-33结合的KD值小于1×10-8、5×10-9、1×10-9、5×10-10、1×10-10、5×10-11、1×10-11。
进一步，如本发明所述抗人IL-33单克隆抗体或其片段，其特征在于所述抗体或其片段通过阻断人IL-33与ST2的结合，抑制IL-33诱导的细胞因子分泌。
进一步，如本发明所述的抗人IL-33单克隆抗体或其片段，其特征在于所述抗体或其片段通过阻断人IL-33与ST2的结合，抑制IL-33诱导的淋巴细胞分泌IL-5。
进一步，如本发明前述任一项所述抗人IL-33单克隆抗体或其片段，其特征在于所述抗体或其片段来自鼠源抗体、兔源抗体、人源抗体、嵌合抗体、人源化抗体。
进一步，如本发明前述任一项所述抗人IL-33单克隆抗体或其片段，其特征在于所述抗体或其片段包括：
重链可变区，具有选自以下重链可变区序列的3个CDRs：SEQ ID NO: 2、5、20、22、25、42；
和
轻链可变区，具有选自以下轻链可变区序列的3个CDRs：SEQ ID NO: 48、51、66、68、71、88。
进一步，如本发明前述任一项所述的抗人IL-33单克隆抗体或其片段，其中：
所述抗体的重链可变区选自：SEQ ID NO: 2、5、20、22、25、42；
所述抗体的轻链可变区选自：SEQ ID NO: 48、51、66、68、71、88。
进一步，如本发明前述任一项所述的人源化抗人IL-33单克隆抗体或其片段，其特征在于：所述抗体部分包括Fab、Fab’、F(ab’)2、Fv、scFv、dAb等。
第二方面，本发明提供一种人源化抗人IL-33单克隆抗体或其片段，其是在本发明前述任一项所述抗人IL-33单克隆抗体或其片段的基础上，采用CDRs移植技术、CDR区突变设计构建的人源化抗人IL-33单克隆抗体。
进一步，如本发明所述的人源化抗人IL-33单克隆抗体或其片段，其特征在于：
重链可变区，具有选自SEQ ID NO: 93-108中任一重链可变区序列的3个CDRs；
和
轻链可变区，具有选自SEQ ID NO: 109-118中任一轻链可变区序列的3个CDRs。
进一步，如本发明所述的人源化抗人IL-33单克隆抗体或其片段，其特征在于：
所述抗体的重链可变区选自：SEQ ID NO: 93-108；
所述抗体的轻链可变区选自：SEQ ID NO: 109-118。
进一步，如本发明前述任一项所述的人源化抗人IL-33单克隆抗体或其片段，其特征在于：所述抗体部分包括Fab、Fab’、F(ab’)2、Fv、scFv、dAb等。
第三方面，本发明提供一种多核苷酸，其编码本发明前述任一项所述抗人IL-33单克隆抗体或其片段、或人源化抗人IL-33单克隆抗体或其片段。
第四方面，本发明提供一种核酸构建体，其包含本发明前述的多核苷酸。
第五方面，本发明提供一种宿主细胞，其包含本发明前述的多核苷酸或本发明前述的核酸构建体。
第六方面，本发明提供一种组合物，其包含本发明前述任一项所述抗人IL-33单克隆抗体或其片段/人源化抗人IL-33单克隆抗体或其片段、前述多核苷酸、前述核酸构建体、和/或前述宿主细胞，以及可选的药学上可接受的辅料。
第七方面，本发明提供一种制备抗人IL-33单克隆抗体或其片段的方法，包括：
（1）在合适的条件下，培养前述述的宿主细胞；
（2）分离回收抗人IL-33单克隆抗体或其片段或者人源化抗人IL-33单克隆抗体或其片段。
第八方面，本发明提供前述任一项所述抗人IL-33单克隆抗体或其片段/人源化抗人IL-33单克隆抗体或其片段、前述多核苷酸、前述核酸构建体、前述宿主细胞、和/或前述组合物在制备治疗IL-33/ST2信号通路相关疾病的药物中的用途。
进一步，本发明所述的用途，其中IL-33/ST2信号通路相关疾病包括变态反应性疾病，如哮喘，过敏性疾病等; 自身免疫病，如风湿性关节炎、系统性红斑狼疮等；心肺疾病，如心衰、扩心病等。
为更好理解本发明，首先定义一些术语。其他定义则贯穿具体实施方式部分而列出。
术语“IL-33”是2005年薪发现的一种白细胞介素，其分子量约18kDa，具有270个氨基酸，包含一个N末端核定位信号、螺旋-转角-螺旋的motif和C段与IL-1同源的结构，属于IL-1家族，常表达于屏障组织细胞，如皮肤、肠、肺等。当这些细胞发生损伤时，IL-33的胞外域能够被中性粒细胞丝氨酸蛋白酶、组织蛋白酶G和弹性蛋白酶酶切，产生活性形式的酶切片段，激活肥大细胞、淋巴细胞、嗜酸性粒细胞从而产生Th2类细胞因子。IL-33在炎症、感染、自身免疫性疾病中发挥着十分重要的作用。
术语“特异性”是指在蛋白和/或其他生物异质群体中确定是否存在所述蛋白，例如本发明所述单抗与hIL-33的结合反应。因此，在所指定的条件下，特定的配体/抗原与特定的受体/抗体结合，并且并不以显著的量与样本中存在的其它蛋白结合。
本文中的术语“抗体”意在包括全长抗体及其任何抗原结合片段(即，抗原结合部分)或单链。全长抗体是包含至少两条重(H)链和两条轻(L)链的糖蛋白，重链和轻链由二硫键连接。各重链由重链可变区(简称VH)和重链恒定区构成。重链恒定区由三个结构域构成，即CH1、CH2和CH3。各轻链由轻链可变区(简称VL)和轻链恒定区构成。轻链恒定区由一个结构域CL构成。VH和VL区还可以划分为称作互补决定区(CDR)的高变区，其由较为保守的框架区(FR)区分隔开。各VH和VL由三个CDR以及四个FR构成，从氨基端到羧基端以FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4的顺序排布。重链和轻链的可变区包含与抗原相互作用的结合域。抗体的恒定区可以介导免疫球蛋白与宿主组织或因子的结合，包括多种免疫系统细胞(例如，效应细胞)和传统补体系统的第一组分(C1q)。
术语“单克隆抗体”或“单抗”或“单克隆抗体组成”是指单一分子组成的抗体分子制品。单克隆抗体组成呈现出对于特定表位的单一结合特异性和亲和力。
本文中的术语，抗体的“抗原结合片段”(或简称为抗体部分)，是指抗体的保持有特异结合抗原能力的一个或多个片段。已证实，抗体的抗原结合功能可以通过全长抗体的片段来实施。包含在抗体的“抗原结合部分”中的结合片段的例子包括(i)Fab片段，由VL、VH、CL和CH1构成的单价片段；(ii)F(ab′)2片段，包含铰链区二硫桥连接的两个Fab片段的二价片段；(iii)由VH和CH1构成的Fd片段；(iv)由抗体单臂VL和VH构成的Fv片段；(v)由VH构成的dAb片段(Ward et al.，(1989)Nature 341：544-546)；(vi)分离的互补决定区(CDR)；以及(vii)纳米抗体，一种包含单可变结构域和两个恒定结构域的重链可变区。此外，尽管Fv片段的两个结构域VL和VH由不同的基因编码，它们可以通过重组法经由使两者成为单蛋白链的合成接头而连接，其中VL和VH区配对形成单价分子(称为单链Fc(scFv)；参见例如Bird et al.，(1988)Science 242：423-426；and Huston et al.，(1988)Proc.Natl.Acad.Sci.USA 85：5879-5883)。这些单链抗体也意在包括在术语涵义中。这些抗体片段可以通过本领域技术人员已知的常用技术而得到，且片段可以通过与完整抗体相同的方式进行功能筛选。
本发明的抗原结合片段包括能够特异性结合IL-33的那些。抗体结合片段的实例包括例如但不限于Fab、Fab'、F（ab'）2、Fv片段、单链Fv（scFv）片段和单结构域片段。
Fab片段含有轻链的恒定结构域和重链的第一恒定结构域（CH1）。Fab'片段与Fab片段的不同之处在于在重链CH1结构域的羧基末端处的少数残基的添加，包括来自抗体铰链区的一个或多个半胱氨酸。通过切割在F（ab'）2胃蛋白酶消化产物的铰链半胱氨酸处的二硫键产生Fab'片段。抗体片段的另外化学偶联是本领域普通技术人员已知的。Fab和F（ab'）2片段缺乏完整抗体的片段可结晶（Fc）区，从动物的循环中更快速地清除，并且可能具有比完整抗体更少的非特异性组织结合（参见例如，Wahl等人，1983，J. Nucl. Med. 24:316）。
如本领域通常理解的，“Fc”区是不包含抗原特异性结合区的抗体的片段可结晶恒定区。在IgG、IgA和IgD抗体同种型中，Fc区由两个相同的蛋白质片段组成，衍生自抗体的两条重链的第二和第三恒定结构域（分别为CH2和CH3结构域）。IgM和IgE Fc区在每条多肽链中含有三个重链恒定结构域（CH2、CH3和CH4结构域）。
“Fv”片段是含有完整靶识别和结合位点的抗体的最小片段。该区域由以紧密的非共价结合的一个重链和一个轻链可变结构域的二聚体（VH-VL二聚体）组成。在该构型中，每个可变结构域的三个CDR相互作用，以限定在VH-VL二聚体的表面上的靶结合位点。通常，六个CDR对抗体赋予靶结合特异性。然而，在一些情况下，甚至单个可变结构域（或仅包含对于靶特异性的三个CDR的Fv的一半）可以具有识别且结合靶的能力，尽管其亲和力低于整个结合位点。
“单链Fv”或“scFv”抗体结合片段包含抗体的VH和VL结构域，其中这些结构域存在于单条多肽链中。一般地，Fv多肽进一步包含在VH和VL结构域之间的多肽接头，其致使scFv能够形成有利于靶结合的结构。
“单结构域片段”由对IL-33显示出足够亲和力的单个VH或VL结构域组成。在一个具体实施方案中，单结构域片段是骆驼化的（参见例如，Riechmann，1999，JournalofImmunological Methods 231:25–38）。
本发明的抗hIL-33的抗体包括衍生化抗体。例如，衍生化抗体通常通过糖基化、乙酰化、聚乙二醇化、磷酸化、酰胺化、通过已知保护/封闭基团的衍生化、蛋白酶解切割、与细胞配体或其它蛋白质的连接来修饰。可以通过已知技术进行众多化学修饰中的任一种，所述技术包括但不限于特定的化学切割、乙酰化、甲酰化、衣霉素的代谢合成等。另外，衍生物可以含有一种或多种非天然氨基酸，例如，使用ambrx技术（参见例如，Wolfson，2006，Chem.Biol. 13（10）:1011-2）。
术语“识别抗原的抗体”以及“对抗原特异的抗体”在本文中与术语“特异结合抗原的抗体”交替使用。
术语“IC50”，又叫半抑制浓度，是指对指定的生物过程或该生物过程中的某个组份（例如酶、受体、细胞等）抑制一半时所需的药物或抑制剂的浓度。在竞争ELISA中是表征竞争抑制能力的一个重要指标。
术语“载体”、“核酸构建体”是指能够运输与其连接的另一种核酸的核酸分子。一种类型的载体是“质粒”，其是指其中可以连接另外的DNA区段的环状双链DNA环。另一种类型的载体是病毒载体，其中额外的DNA区段可以连接到病毒基因组中。某些载体能够在它们被导入的宿主细胞中自主复制(例如，具有细菌复制起点和游离型哺乳动物载体的细菌载体)。其他载体(例如非附加型哺乳动物载体)可以在导入宿主细胞后整合到宿主细胞的基因组中，并由此与宿主基因组一起复制。此外，某些载体能够指导它们有效连接的基因的表达。这种载体在本文中被称为“重组表达载体”(或简称为“表达载体”)。通常，在重组DNA技术中有用的表达载体通常以质粒的形式存在。然而，也包括其他形式的表达载体，如病毒载体(例如，复制缺陷型逆转录病毒，腺病毒和腺伴随病毒)，其起到等同的功能。
术语“核酸分子”旨在包括DNA分子和RNA分子。核酸分子可以是单链或双链的，并且可以是cDNA。
术语“多肽”是指包含至少两个连续连接的氨基酸残基的链，对链的长度没有上限。蛋白质中的一个或多个氨基酸残基可含有修饰，例如但不限于糖基化，磷酸化或二硫键。“蛋白质”可以包含一种或多种多肽。
术语“宿主细胞”在其中载体可以增殖并且其DNA可以表达的细胞，所述细胞可以是原核细胞或者真核细胞。该术语还包括受试宿主细胞的任何后代。应理解，并不是所有的后代都与亲本细胞相同，因为在复制过程中可能会发生突变，这类后代被包括在内。
本发明所述抗体具有较高的抗IL-33结合能力，亲和力常数KD值小于1×10-8、5×10-9、1×10-9、5×10-10、1×10-10、5×10-11、1×10-11。为了克服将鼠源抗体通过CDRs移植技术人源化带来的抗体分子结构不稳定的问题，还进一步对人源化抗人IL-33进行了可变区突变，以提高人源化抗体的稳定性、确保其体内生物活性。
附图说明
通过阅读下文优选实施方式的详细描述，各种其他的优点和益处对于本领域普通技术人员将变得清楚明了。附图仅用于示出优选实施方式的目的，而并不认为是对本发明的限制。而且在整个附图中，用相同的参考符号表示相同的部件。在附图中：
图1：抗人IL33鼠源单克隆抗体与人IL33的结合活性。
图2：抗人IL33抗体阻断IL-33与人ST2的结合。
图3A：抗人抗体IL33抗体H02-8F11与人IL33蛋白的亲和力。
图3B：抗人抗体IL33抗体H05-19E1与人IL33蛋白的亲和力。
图3C：抗人抗体IL33抗体H22-38E11与人IL33蛋白的亲和力。
图3D：抗人抗体IL33抗体A02-21E12与人IL33蛋白的亲和力。
图3E：抗人抗体IL33抗体A02-hz02与人IL33蛋白的亲和力。
图3F：抗人抗体IL33抗体A02-hz22与人IL33蛋白的亲和力。
图3G：抗人抗体IL33抗体A02-hz11与人IL33蛋白的亲和力。
图3H：抗人抗体IL33抗体A02-hz12与人IL33蛋白的亲和力。
图4A：抗人IL33抗体A02-21E12 xiIgG、A02-21E12 Hz10、A02-21E12 Hz11、A02-21E12 Hz12对IL-33诱导KU812分泌IL-5的抑制。
图4B：抗人IL33抗体H02-8F11 xiIgG、H05-19E1 xiIgG、H22-38E11 xiIgG对IL-33诱导KU812分泌IL-5的抑制。
图4C：抗人IL33抗体：H22-38E11 Hz00、H22-38E11 Hz10、H22-38E11 Hz20、H02-8F11 Hz00、H02-8F11 Hz01、H02-8F11 Hz10、H02-8F11 Hz11对IL-33诱导KU812分泌IL-5的抑制。
具体实施方式
下面将参照附图更详细地描述本公开的示例性实施方式。虽然附图中显示了本公开的示例性实施方式，然而应当理解，可以以各种形式实现本公开而不应被这里阐述的实施方式所限制。相反，提供这些实施方式是为了能够更透彻地理解本公开，并且能够将本公开的范围完整的传达给本领域的技术人员。
实施例1：抗人IL-33抗体鼠杂交瘤细胞的制备
人白介素33（Ser112-Thr270）抗原购自近岸蛋白质科技有限公司（Novoprotein，货号C091），选取8周龄Balb/c小鼠作为免疫动物，免疫前采血作为阴性对照。将人IL33蛋白在弗氏佐剂中乳化后进行皮下注射免疫，共三次，每次间隔2周，第三次免疫后一周尾静脉采血，测血清的抗体效价，选取效价高的小鼠在融合前3天进行冲刺免疫。
取免疫小鼠的脾脏和淋巴结无菌分离脾细胞和淋巴细胞，用电融合和PEG的方法与状态良好的SP20骨髓瘤细胞进行融合，8~10天进行阳性杂交瘤筛选。取杂交瘤细胞培养上清用ELISA进行分析，筛选得到若干能够结合人白介素33的杂交瘤细胞系。通过有限稀释法将筛选到的阳性孔单细胞化，待连续两次亚克隆的阳性都为100%时结束亚克隆，一般三到四轮亚克隆即可达到要求，这时得到的杂交瘤细胞株只分泌一个抗体。
实施例2：杂交瘤细胞株分泌抗人IL33单克隆抗体与人IL33的结合活性
取融合后8~10天的杂交瘤细胞上清液，用ELISA的方法，筛选能够分泌抗人IL33抗体的阳性杂交瘤母克隆。
具体方法如下：将0.5ug/ml的人IL-33蛋白，30µl/孔，包被384孔板（greiner bio-one 781097）4℃孵育过夜；次日用PBST洗板，样品孔中加入60µl的含1% BSA的PBST，37℃封闭2h；然后用PBST洗板，并甩干孔中水分。向孔板中加入20µl待测样品，室温孵育1 h。然后用PBST洗板后每孔加入30ul 1:30000稀释的二抗羊抗鼠IgG偶联辣根过氧化物酶（Jackson,cat#:115-035-164），并置于室温孵育1h。用PBST洗板，每孔加入30µl TMB显色液（life technologies,cat#:002023），于室温孵育10 min后于酶标仪（M5e，MolecularDevice）650nm波长处检测吸光度。较高的650nM读值表明该孔中杂交瘤细胞分泌的小鼠抗人白介素33蛋白抗体与人IL-33蛋白的结合活性较高。部分高结合活性的小鼠抗人白介素33蛋白抗体如图1所示。
图1的结果数据表明本发明得到的鼠杂交瘤细胞株培养上清里含有以高亲和力结合人IL33蛋白的小鼠抗体。
实施例3：鼠源抗人IL33抗体阻断IL-33与人ST2的结合
将与人IL33蛋白结合的阳性克隆从384孔板转到96孔板，用ELISA方法进行阻断实验，具体方法如下：用hST2-hFc蛋白（Acro,#IL1-H5250）包被96孔板，1ug/ml,每孔50ul,4℃孵育过夜；次日用PBST洗板3次，样品孔中加入200µl的含1% BSA的PBST，37℃封闭2h；然后用PBST洗板，并甩干孔中水分。向孔板中加入50ul预孵育待测样品（biotin hIL-33蛋白和杂交瘤克隆上清液），室温孵育1 h。然后用PBST洗板后每孔加入50ul 1:5000稀释的二抗StrepTactin-HRP Conjugate（Bio-rad, #1610380），并置于室温孵育1h。用PBST洗板，每孔加入50µl TMB显色液（life technologies,cat#:002023），于室温孵育10 min后加入50ul/well 2N HCl终止反应，最后于酶标仪（M5e）450nm波长处检测吸光度。能有效阻断人IL33与人ST2结合的鼠抗如图2所示。
图2的数据表明本发明得到的鼠杂交瘤细胞株培养上清里含有能在体外有效阻断人IL33蛋白与其受体ST2结合的小鼠抗体。
实施例4：鼠单克隆抗体的序列测定
将实施例2-3中得到的分泌抗人IL33抗体且有阻断与ST2结合活性的杂交瘤母克隆扩大培养后，按照RNeasy mini kit试剂盒（Qiagen ，#74104）提取细胞总RNA；利用SuperScript™ IV VILO™ Master Mix（Invitrogen，#11756050）将杂交瘤细胞总RNA反转录成cDNA；使用简并引物和Extaq PCR试剂（Takara，#RR001A）扩增抗体轻链可变区IgVL(κ)和重链可变区VH序列；利用胶回收试剂盒纯化PCR产物（MN，#740609）；按照pMD-19T SimpleVector Kit（Takara）将PCR产物连接至T载体并转化大肠杆菌感受态细胞，菌株扩增、抽提质粒后进行DNA测序获得单克隆抗体可变区序列。获取鼠源抗体（以克隆编号命名）的可变区序列并分析，重链可变区的氨基酸序列如表1所示（SEQ ID NO:1-46）；轻链可变区的氨基酸序列如表2所示（SEQ ID NO:47-92）。
表1：鼠源抗人IL33抗体重链可变区的氨基酸序列
表2：鼠源抗人IL33抗体轻链可变区的氨基酸序列
实施例5：抗人IL33嵌合抗体的制备
将鼠源抗人IL33单克隆抗体的重链可变区和轻链可变区序列克隆进入哺乳动物细胞表达载体中，重链恒定区选用公开发表的人单克隆抗体IgG1序列，轻链恒定区选用公开发表的人单克隆抗体κ亚类的序列。构建好的抗人IL33嵌合抗体的重链质粒和轻链质粒比例为1:1.5配对混合，使用聚乙烯亚胺（PEIPolysciences,#24885-2））转染HEK293细胞，约7天后收集细胞上清，使用Mabselect纯化得到抗人IL33嵌合抗体蛋白。
实施例6：抗人IL33嵌合抗体与IL33的动力学参数测定
利用Fortebio (BLITZ pro1.1.0.28)仪器，分析嵌合抗体与抗原IL33的结合动力学参数。测定前先将NTA传感器浸泡在缓冲液（PBS+0.1% BSA+0.02%Tween 20，pH7.4）中10分钟；然后将NTA传感器先捕获浓度为100nM的带有组氨酸标签的IL33抗原，进一步将传感器与100nM嵌合抗体进行结合反应，之后转移至上述缓冲液中进行解离反应。实验完毕，扣除空白亲本响应值，用软件进行1：1 Langmuir结合模式拟合，计算抗原抗体结合的动力学常数（部分结果如表3）。表3的数据表明本发明得到的不同抗体能以高亲和力结合人IL33蛋白。
表3. 抗人IL33嵌合抗体的动力学参数分析
实施例7：抗人IL33嵌合抗体的人源化
对抗人IL33的鼠源抗体序列进行人源化改造，根据Kabat、Chothia的抗体编码方案，确定鼠源抗体的重链和轻链的6个抗原互补决定簇（CDR）的氨基酸序列区域及支撑抗体保守三维构象的框架区域（framework region）。随后通过分析搜索已知人源抗体序列，选择与鼠源抗体最为相似接近的人源抗体重链可变区序列，选择其抗体框架区序列作为模板，将鼠源抗体重链CDR与人源抗体框架区结合，最终生成人源化抗体重链可变区序列。同样过程，生成人源化抗体轻链可变区序列。随后，对可能参与抗原抗体结合的鼠源框架区个别氨基酸位点进行回复突变，同时检查是否有一些潜在的翻译后修饰位点，如N（天冬酰胺）糖基化位点、N脱酰胺化位点、D（天冬氨酸）异构化位点等。生成人源化抗体重链序列（版本1，2，3）。同样过程，生成人源化抗体轻链序列（版本0，1，2……）。将设计好的人源化抗体轻重链序列构建到哺乳动物细胞表达载体中，然后轻重链质粒使用PEI共转染HEK293细胞，使用Mabselect纯化得到人源化抗体蛋白。人源化抗体（版本命名方式例如：重链版本0+轻链版本0共表达，即为hz00）。人源化抗体的重链可变区及CDR区序列如表4所示；人源化抗体的轻链可变区及CDR区序列如表5所示。
表4. 人源化抗体的重链可变区及CDR区序列
表5. 人源化抗体的轻链可变区及CDR区序列
实施例8：人源化抗人IL33抗体与人IL33蛋白结合的动力学参数测定
采用Fortebio公司Octet RED 96仪器分析人源化抗体的亲和力。同样参照实施例6进行，人源化抗体也为100nM的检测浓度。结果见表6。表6的数据表明本发明得到的不同人源化抗体能以高亲和力结合人IL33蛋白。
表6.人源化抗体的动力学参数分析
| 人源化抗体 | KD (M) | kon(1/Ms) | kdis(1/s) |
| A02-21E12 Hz01 | 1.62E-09 | 2.62E+04 | 4.23E-05 |
| A02-21E12 Hz02 | <1.0E-12 | 2.24E+04 | <1.0E-07 |
| A02-21E12 Hz10 | <1.0E-12 | 6.46E+04 | <1.0E-07 |
| A02-21E12 Hz11 | <1.0E-12 | 1.62E+04 | <1.0E-07 |
| A02-21E12 Hz12 | <1.0E-12 | 1.66E+04 | <1.0E-07 |
| A02-21E12 Hz21 | 5.03E-10 | 2.68E+04 | 1.35E-05 |
| A02-21E12 Hz22 | <1.0E-12 | 2.09E+04 | <1.0E-07 |
| D02-3P1 Hz00 | 1.53E-08 | 1.62E+05 | 2.48E-03 |
| D02-3P1 Hz01 | 5.10E-09 | 1.29E+05 | 6.56E-04 |
| D02-3P1 Hz10 | 1.79E-08 | 1.68E+05 | 3.01E-03 |
| D02-3P1 Hz11 | 7.43E-09 | 1.27E+05 | 9.40E-04 |
| D02-3P1 Hz20 | 1.74E-08 | 1.58E+05 | 2.74E-03 |
| D02-3P1 Hz21 | 4.88E-09 | 1.49E+05 | 7.27E-04 |
| D02-3P1 Hz30 | 1.53E-08 | 1.98E+05 | 3.02E-03 |
| D02-3P1 Hz31 | 6.41E-09 | 1.41E+05 | 9.06E-04 |
| D02-3P1 Hz40 | 1.55E-08 | 2.12E+05 | 3.29E-03 |
| D02-3P1 Hz41 | 8.91E-09 | 1.35E+05 | 1.20E-03 |
| E01-14O9 Hz00 | 1.59E-08 | 1.34E+05 | 2.13E-03 |
| E01-14O9 Hz01 | 1.68E-08 | 1.30E+05 | 2.17E-03 |
| E01-14O9 Hz10 | 6.61E-09 | 1.38E+05 | 9.13E-04 |
| E01-14O9 Hz11 | 6.92E-09 | 1.35E+05 | 9.30E-04 |
| E01-14O9 Hz20 | 1.16E-08 | 2.62E+05 | 3.04E-03 |
| E01-14O9 Hz21 | 1.32E-08 | 2.47E+05 | 3.26E-03 |
| H02-8F11 Hz00 | 3.84E-08 | 3.51E+04 | 1.35E-03 |
| H02-8F11 Hz01 | 1.14E-08 | 3.47E+04 | 3.95E-04 |
| H02-8F11 Hz10 | 4.74E-08 | 3.15E+04 | 1.49E-03 |
| H02-8F11 Hz11 | 1.68E-08 | 3.21E+04 | 5.38E-04 |
| H22-38E11 Hz00 | 2.34E-07 | 3.23E+04 | 7.54E-03 |
| H22-38E11 Hz10 | 9.23E-09 | 3.04E+04 | 2.80E-04 |
| H22-38E11 Hz20 | 1.09E-08 | 2.86E+04 | 3.13E-04 |
实施例9：嵌合/人源化抗IL33抗体与人IL33蛋白结合的亲和力的分析
采用GE公司BIAcore仪器S200测定抗体抗原相互作用力。将anti-human IgGantibody偶联到CM5芯片上,使用HBS-EP+作为实验缓冲液，每个循环包括捕获抗体、不同浓度抗原的进样及再生。将抗体以固定的流速注入样品通道，使其通过anti-human IgGantibody捕获在该通道表面。将稀释后的hIL33-His抗原（novoprotein, #C233）依次以不同的浓度梯度注入芯片参比通道和样品通道。使用Biacore S200分析软件（Biacore S200Evaluation Software Version:1.1，General Electric Company）对数据进行分析。分析所用模型为1:1binding, 最终得到抗体的结合常数Kon和解离常数Koff，以及亲和力常数KD。结果如表7和图3所示。表7和图3的数据表明本发明得到嵌合/人源化抗IL-33抗体能以高亲和力结合人IL33蛋白。
表7. 抗人IL33抗体与人IL33蛋白的亲和力分析
| 抗体 | ka (M-1s-1) | kd (s-1) | KD (M) |
| xiIgG H02-8F11 | 5.15E+05 | 3.00E-04 | 5.83E-10 |
| xiIgG H05-19E1 | 5.23E+05 | 2.80E-04 | 5.35E-10 |
| xiIgG H22-38E11 | 1.31E+05 | 3.06E-04 | 2.34E-09 |
| xiIgG A02-21E12 | 3.62E+04 | 4.19E-04 | 1.16E-08 |
| A02-21E12 Hz02 | 9.25E+04 | 2.83E-03 | 3.06E-08 |
| A02-21E12 Hz11 | 8.50E+03 | 4.53E-02 | 5.33E-06 |
| A02-21E12 Hz12 | 6.48E+02 | 3.18E-04 | 4.92E-07 |
| A02-21E12 Hz22 | 1.06E+05 | 3.98E-03 | 3.77E-08 |
实施例10：嵌合/人源化抗人IL33抗体阻断经人IL33诱导的细胞因子释放
KU812细胞经IL33刺激分泌IL-5，抗IL33抗体能抑制此信号通路中IL-5的释放，可以通过测定IL5的释放来评估IL33抗体的体外活性。具体方法如下：KU812细胞培养于RPMI1640+10%FBS培养基中，调整细胞状态至活力达95%以上。实验当日，将KU812细胞密度调整至2000000个/mL，50μL/孔加入透明96孔板中；IL33抗体稀释至200μg/mL起始，5倍稀释，设置8个梯度点，将各样品梯度点按50μL/孔加入上述铺有细胞的透明96孔板中，37℃孵育30分钟；将IL33蛋白稀释至60ng/mL，按50μL/孔加入上述铺有细胞和抗体的透明96孔板中，37℃继续孵育48小时；取上述细胞培养液100μL/孔进行ELISA测试，使用IL-5 DuosetELISA（R&D）试剂盒检测，OD值使用MD酶标仪读取，最后使用Prism软件进行四参数拟合得到样品IC50值。结果见表8和图4。表8和图4的结果表明本发明得到的嵌合/人源化抗IL-33抗体能以剂量依赖的方式在体外阻断人IL33介导的KU812细胞中IL-5的释放。
表8. 嵌合/人源化抗IL33抗体阻断IL33介导的KU812细胞IL-5释放
| 抗体名称 | IC50 [nM] |
| H05-19E1 xiIgG | 22.18 |
| A02-21E12 xiIgG | 149.2 |
| A02-21E12 Hz10 | N/A |
| A02-21E12 Hz11 | N/A |
| A02-21E12 Hz12 | N/A |
| H02-8F11 xiIgG | 23.62 |
| H02-8F11Hz00 | 36.77 |
| H02-8F11Hz01 | 32.46 |
| H02-8F11Hz10 | 50.80 |
| H02-8F11Hz11 | 25.99 |
| H22-38E11 xiIgG | 20.17 |
| H22-38E11 Hz00 | 4.560 |
| H22-38E11 Hz10 | 5.260 |
| H22-38E11 Hz20 | 8.920 |
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应以所述权利要求的保护范围为准。
序列表
<110> 上海普铭生物科技有限公司
<120> 抗人IL-33单克隆抗体及其应用
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Ala Phe Ile Ser Asn Leu Ala His Ser Ile Tyr Tyr Ala Asp Thr Val
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Ala Arg Ile Tyr Gly Tyr Phe Tyr Ala Met Asp Asp Trp Gly Lys Gly
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Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
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Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
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Ala Phe Ile Ser Asn Leu Ala His Ser Ile Tyr Tyr Ala Asp Thr Val
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Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Ser
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Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Ser
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Ala Ser Ile Tyr Tyr Gly Asn Ser Phe Tyr Thr Met Asp Tyr Trp Gly
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Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Ser
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Ala Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val
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Ala Thr Ile Ser Ser Gly Gly Gly Lys Thr Tyr Tyr Pro Asp Ser Val
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Ala Ser Ile Tyr Tyr Gly Asn Ser Phe Tyr Thr Met Asp Tyr Trp Gly
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<213> 小鼠(Mus musculus)
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Glu Val Met Leu Val Glu Ser Gly Gly Asp Leu Val Asn Pro Gly Gly
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Ala Thr Ile Ser Ser Gly Gly Gly Lys Thr Tyr Tyr Pro Asp Ser Val
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Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Asn Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Gly Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Ser Ile Tyr Tyr Gly Asn Ser Phe Tyr Thr Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 19
<211> 121
<212> PRT
<213> 小鼠(Mus musculus)
<400> 19
Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Tyr Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Gly Lys Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Asn Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Ser Ile Tyr Tyr Gly Asn Ser Phe Ser Ser Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Ala Val Ser Ser
115 120
<210> 20
<211> 122
<212> PRT
<213> 小鼠(Mus musculus)
<400> 20
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Phe Ile Arg Asn Lys Val Asn Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Gln Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Ser Ala Thr Tyr
85 90 95
Tyr Cys Ala Arg Pro Tyr Tyr Gly Asn Tyr Gly Trp Phe Pro Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 21
<211> 121
<212> PRT
<213> 小鼠(Mus musculus)
<400> 21
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ser Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Leu Met Asn Trp Val Met Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Ile Ser Pro Tyr Asn Gly Glu Thr Phe Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala His
65 70 75 80
Met Glu Leu Arg Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Met Ile Thr Thr Gly Arg Pro Trp Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 22
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 22
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile Gln Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Gly Trp Ile
35 40 45
Gly Glu Ile Phe Pro Gly Thr Gly Thr Ser Tyr Tyr Ser Glu Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Ile Asp Thr Ser Ser Ala Thr Ala Tyr
65 70 75 80
Met Gln Leu Thr Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Lys His Arg Gly Tyr Gly Tyr Gly Gly Ala Trp Ile Ala Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 23
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 23
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Val Asn Pro Ser Asn Gly Gly Thr Ser Tyr Asn Gln Phe Phe
50 55 60
Lys Gly Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Gly Ser Ser Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 24
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 24
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Val Asn Pro Ser Asn Gly Gly Thr Ser Tyr Asn Gln Phe Phe
50 55 60
Lys Gly Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Gly Ser Ser Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 25
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 25
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Asn Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Gly Trp Ile
35 40 45
Gly Glu Ile Phe Pro Gly Thr Gly Thr Ser Tyr Phe Ser Glu Arg Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Ile Asp Thr Ser Ser Asp Thr Ala Tyr
65 70 75 80
Met His Leu Thr Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Lys His Arg Gly Tyr Gly Tyr Gly Gly Ala Trp Ile Ala Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 26
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 26
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Val Asn Pro Ser Asn Gly Gly Thr Ser Tyr Asn Gln Phe Phe
50 55 60
Lys Gly Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Gly Ser Ser Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 27
<211> 121
<212> PRT
<213> 小鼠(Mus musculus)
<400> 27
Asp Ile Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Thr
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ser Ser Gly Asn Ser Phe Thr Gly Asp
20 25 30
Leu Met Asn Trp Val Met Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Ile Ser Pro Tyr Asn Gly Glu Thr Phe Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala His
65 70 75 80
Met Glu Leu Arg Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Met Ile Thr Thr Gly Arg Pro Tyr Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 28
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 28
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Val Asn Pro Ser Asn Gly Gly Thr Ser Tyr Asn Gln Phe Phe
50 55 60
Lys Gly Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Gly Ser Ser Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 29
<211> 121
<212> PRT
<213> 小鼠(Mus musculus)
<400> 29
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Arg Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Pro Leu Tyr Tyr Gly Asn Ser Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 30
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 30
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Val Asn Pro Ser Asn Gly Gly Thr Ser Tyr Asn Gln Phe Phe
50 55 60
Lys Gly Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Gly Ser Ser Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 31
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 31
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Val Asn Pro Ser Asn Gly Gly Thr Ser Tyr Asn Gln Phe Phe
50 55 60
Lys Gly Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Gly Ser Ser Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 32
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 32
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Val Asn Pro Ser Asn Gly Gly Thr Ser Tyr Asn Gln Phe Phe
50 55 60
Lys Gly Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Gly Ser Ser Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 33
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 33
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Val Asn Pro Ser Asn Gly Gly Thr Ser Tyr Asn Gln Phe Phe
50 55 60
Lys Gly Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Gly Ser Ser Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 34
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 34
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Val Asn Pro Ser Asn Gly Gly Thr Ser Tyr Asn Gln Phe Phe
50 55 60
Lys Gly Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Gly Ser Ser Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 35
<211> 119
<212> PRT
<213> 小鼠(Mus musculus)
<400> 35
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Thr Gly Tyr Thr Phe Ser Ser Tyr
20 25 30
Trp Ile Glu Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Leu Pro Gly Ser Val Ser Thr Lys Cys Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Ser Phe Thr Ala Asp Thr Ser Ser Asn Thr Ala Phe
65 70 75 80
Met Gln Leu Ile Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Ser Tyr Gly Arg Trp Tyr Phe Asp Val Trp Gly Ala Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 36
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 36
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Val Asn Pro Ser Asn Gly Gly Thr Ser Tyr Asn Gln Phe Phe
50 55 60
Lys Gly Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Gly Ser Ser Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 37
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 37
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Val Asn Pro Ser Asn Gly Gly Thr Ser Tyr Asn Gln Phe Phe
50 55 60
Lys Gly Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Gly Ser Ser Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 38
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 38
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Arg Leu Ala Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Thr Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Phe Pro Gly Thr Gly Thr Thr His Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Arg Ala Thr Leu Thr Ile Asp Thr Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Lys Asn Arg Gly Tyr Gly Tyr Gly Gly Ala Trp Ile Ala Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 39
<211> 121
<212> PRT
<213> 小鼠(Mus musculus)
<400> 39
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ser Ser Gly Phe Ser Phe Thr Ala Tyr
20 25 30
Leu Met Ser Trp Val Met Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Ile Ser Pro Tyr Asn Gly Glu Thr Phe Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala His
65 70 75 80
Met Glu Leu Arg Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Met Ile Thr Thr Gly Arg Pro Trp Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 40
<211> 121
<212> PRT
<213> 小鼠(Mus musculus)
<400> 40
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ser Ser Gly Tyr Ser Phe Thr Ala Tyr
20 25 30
Leu Met Asn Trp Val Met Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Ile Ser Pro Tyr Asn Gly Glu Thr Phe Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala His
65 70 75 80
Met Glu Leu Arg Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Asp Met Ile Thr Thr Gly Arg Pro Trp Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 41
<211> 118
<212> PRT
<213> 小鼠(Mus musculus)
<400> 41
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser His Val Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asn Pro Tyr Asn Gly Ala Thr Ser Tyr Asn Gln Asn Phe
50 55 60
Lys Asp Lys Ala Ser Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Phe Tyr Gly Ser Asn Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Pro Leu Thr Val Ser Ser
115
<210> 42
<211> 121
<212> PRT
<213> 小鼠(Mus musculus)
<400> 42
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Thr Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ser Ser Gly Tyr Ser Phe Thr Ala Tyr
20 25 30
Leu Met Asn Trp Val Met Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Ile Ser Pro Tyr Asn Gly Glu Thr Leu Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Val His
65 70 75 80
Met Glu Leu Arg Ser Leu Ala Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Asp Met Ile Thr Thr Gly Arg Pro Trp Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ala
115 120
<210> 43
<211> 120
<212> PRT
<213> 小鼠(Mus musculus)
<400> 43
Glu Val Gln Leu Gln Gln Ser Gly Thr Val Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Ala Thr Thr Ala Tyr
65 70 75 80
Val Glu Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Arg Tyr Gly Asn Tyr His Arg Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 44
<211> 121
<212> PRT
<213> 小鼠(Mus musculus)
<400> 44
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg His Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met
65 70 75 80
Leu Tyr Leu Gln Met Asn Asn Leu Gln Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Ser Tyr Gly His Trp Tyr Phe Asp Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 45
<211> 120
<212> PRT
<213> 小鼠(Mus musculus)
<400> 45
Glu Val Gln Leu Gln Gln Ser Gly Thr Val Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Ala Thr Thr Ala Tyr
65 70 75 80
Val Glu Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Arg Tyr Gly Asn Tyr His Arg Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 46
<211> 121
<212> PRT
<213> 小鼠(Mus musculus)
<400> 46
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Gly Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met
65 70 75 80
Leu Tyr Leu Gln Met Asn Asn Leu Gln Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Ser Tyr Gly His Trp Tyr Phe Asp Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 47
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 47
Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Met Ser Val Gly
1 5 10 15
Glu Arg Val Thr Leu Arg Cys Lys Ala Ser Glu Asn Val Gly Thr His
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Glu Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Thr Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Ala Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Asp Tyr His Cys Gly Gln Ser Tyr Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 48
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 48
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Arg
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Arg Ile Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ser Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 49
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 49
Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly
1 5 10 15
Glu Ser Val Ser Ile Ser Cys Arg Ser Thr Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Val
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 50
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 50
Asp Ile Val Met Thr Gln Val Ala Pro Ser Val Pro Val Ser Pro Gly
1 5 10 15
Glu Ala Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Val
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 51
<211> 111
<212> PRT
<213> 小鼠(Mus musculus)
<400> 51
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 52
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 52
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Arg Ile Ser Asp Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ser Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Thr Val Glu Pro
65 70 75 80
Glu Asp Val Gly Val Tyr Tyr Cys Gln His Gly His Ser Phe Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 53
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 53
Asp Ile Val Met Thr Gln Val Ala Pro Ser Leu Pro Val Ser Pro Gly
1 5 10 15
Glu Ala Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro His Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 54
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 54
Asp Ile Val Met Thr Gln Val Ala Pro Ser Val Pro Val Ser Pro Gly
1 5 10 15
Glu Ala Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 55
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 55
Asp Ile Val Met Thr Gln Val Ala Pro Ser Val Pro Val Ser Pro Gly
1 5 10 15
Glu Ala Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Val
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 56
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 56
Asp Ile Val Met Thr Gln Val Ala Pro Ser Val Pro Val Ser Pro Gly
1 5 10 15
Glu Ala Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Val
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 57
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 57
Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly
1 5 10 15
Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 58
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 58
Asp Ile Val Met Thr Gln Val Ala Pro Ser Val Pro Val Ser Pro Gly
1 5 10 15
Glu Ala Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 59
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 59
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Arg Ile Ser Asp Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ser Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Thr Val Glu Pro
65 70 75 80
Glu Asp Val Gly Val Tyr Tyr Cys Gln His Gly His Ser Phe Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 60
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 60
Asp Ile Val Met Thr Gln Val Ala Pro Ser Val Pro Val Ser Pro Gly
1 5 10 15
Glu Ala Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Asp Ile Lys
100 105 110
<210> 61
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 61
Asp Ile Val Met Thr Gln Val Ala Pro Ser Val Pro Val Ser Pro Gly
1 5 10 15
Glu Ala Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Asp Ile Lys
100 105 110
<210> 62
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 62
Asp Ile Val Met Thr Gln Val Ala Pro Ser Val Pro Val Ser Pro Gly
1 5 10 15
Glu Ala Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Val
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 63
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 63
Asp Ile Val Met Thr Gln Val Ala Pro Ser Val Pro Val Ser Pro Gly
1 5 10 15
Glu Ala Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 64
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 64
Asp Ile Val Met Thr Gln Val Ala Pro Ser Val Pro Val Ser Pro Gly
1 5 10 15
Glu Ala Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 65
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 65
Asn Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly
1 5 10 15
Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Asn Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 66
<211> 111
<212> PRT
<213> 小鼠(Mus musculus)
<400> 66
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 67
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 67
Asp Val Val Val Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Phe Gly
1 5 10 15
Asp Gln Val Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Ala Asn Ser
20 25 30
Tyr Gly Asn Thr Tyr Leu Ser Trp Tyr Leu His Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gly Ile Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Thr Ile Lys Pro Glu Asp Leu Gly Met Tyr Tyr Cys Leu Gln Gly
85 90 95
Thr His Gln Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 68
<211> 105
<212> PRT
<213> 小鼠(Mus musculus)
<400> 68
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly
1 5 10 15
Glu Glu Ile Thr Leu Asn Cys Ser Ala Thr Ser Ser Val Ser Ser Met
20 25 30
His Trp His Gln Gln Lys Ser Gly Thr Ser Pro Lys Leu Leu Ile Tyr
35 40 45
Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Phe Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Asp Tyr Tyr Cys His Gln Trp Ser Ser Tyr Pro Thr Phe
85 90 95
Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 69
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 69
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Leu Asn Tyr Met
20 25 30
His Trp Tyr Arg Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln His Trp Ser Ser Asn Pro Pro Ile
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 70
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 70
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Arg Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln His Trp Ser Ser Asn Pro Pro Ile
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 71
<211> 105
<212> PRT
<213> 小鼠(Mus musculus)
<400> 71
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly
1 5 10 15
Glu Glu Ile Thr Leu Asn Cys Ser Ala Ser Ser Ser Val Ser Ser Met
20 25 30
His Trp His Gln Gln Lys Ser Gly Thr Ser Pro Lys Leu Leu Ile Tyr
35 40 45
Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Phe Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Asp Tyr Tyr Cys His Gln Trp Ser Ser Tyr Pro Thr Phe
85 90 95
Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 72
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 72
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Leu Asn Tyr Met
20 25 30
His Trp Tyr Arg Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln His Trp Ser Ser Asn Pro Pro Ile
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 73
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 73
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Ala Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Tyr Asn Leu Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 74
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 74
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Leu Asn Tyr Met
20 25 30
His Trp Tyr Arg Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln His Trp Ser Ser Asn Pro Pro Ile
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 75
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 75
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Arg Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln His Trp Ser Ser Asn Pro Pro Ile
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 76
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 76
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Arg Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln His Trp Ser Ser Asn Pro Pro Ile
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 77
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 77
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Arg Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln His Trp Ser Ser Asn Pro Pro Ile
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 78
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 78
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Leu Asn Tyr Met
20 25 30
His Trp Tyr Arg Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln His Trp Ser Ser Asn Pro Pro Ile
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 79
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 79
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Leu Asn Tyr Met
20 25 30
His Trp Tyr Arg Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln His Trp Ser Ser Asn Pro Pro Ile
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 80
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 80
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Leu Asn Tyr Met
20 25 30
His Trp Tyr Arg Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln His Trp Ser Ser Asn Pro Pro Ile
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 81
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 81
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Asn Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Val Ile
35 40 45
Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Asp Arg Phe Ile Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Cys Asn Ile Tyr Pro Leu
85 90 95
Thr Phe Ala Ala Gly Thr Lys Leu Gly Leu Lys
100 105
<210> 82
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 82
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Leu Asn Tyr Met
20 25 30
His Trp Tyr Arg Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln His Trp Ser Ser Asn Pro Pro Ile
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 83
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 83
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Arg Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln His Trp Ser Ser Asn Pro Pro Ile
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 84
<211> 105
<212> PRT
<213> 小鼠(Mus musculus)
<400> 84
Gln Val Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly
1 5 10 15
Glu Glu Ile Thr Leu Thr Cys Ser Thr Ser Ser Ser Ile Ser Ser Ile
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Leu Leu Ile Tyr
35 40 45
Arg Thr Phe Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Phe Tyr Ser Leu Thr Ile Thr Ser Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Asp Tyr Tyr Cys His Gln Cys Asn Ser Phe Pro Thr Phe
85 90 95
Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 85
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 85
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Asn Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Ala Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Tyr Asn Leu Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 86
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 86
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Ile Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Ala Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Tyr Asn Leu Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 87
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 87
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Ala Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Thr Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Tyr Asn Leu Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 88
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 88
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Ala Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Ala Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Ser Tyr Asn Leu Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 89
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 89
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Asp Thr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 90
<211> 111
<212> PRT
<213> 小鼠(Mus musculus)
<400> 90
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Leu Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 91
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 91
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Asp Thr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 92
<211> 111
<212> PRT
<213> 小鼠(Mus musculus)
<400> 92
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Leu Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 93
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 93
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Thr Glu Thr Val Glu Pro Lys Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asp Phe Trp Trp Lys Phe Asp Phe Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 94
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 94
Glu Ile Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Thr Glu Thr Val Glu Pro Lys Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Leu Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asp Phe Trp Trp Lys Phe Asp Phe Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 95
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 95
Glu Ile Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Thr Glu Thr Val Glu Pro Lys Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asp Phe Trp Trp Lys Phe Asp Phe Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 96
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 96
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 Ser Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val
35 40 45
Ser Ala Ile Asn Ser Asn Gly Gly Ser Thr Tyr Tyr Pro Asp Thr 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 Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Ser Tyr Gly Asn Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 97
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 97
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 Ser Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val
35 40 45
Ser Ala Ile Asn Ser Asn Gly Gly Ser Thr Tyr Tyr Pro Asp Thr 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 Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Ser Tyr Gly Asn Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 98
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 98
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 Ser Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val
35 40 45
Ser Ala Ile Ser Ser Asn Gly Gly Ser Thr Tyr Tyr Pro Asp Thr 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 Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Ser Tyr Gly Asn Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 99
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 99
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 Ser Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val
35 40 45
Ser Ala Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Thr 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 Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Ser Tyr Gly Asn Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 100
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 100
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 Ser Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val
35 40 45
Ser Ala Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Ser Tyr Gly Asn Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 101
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 101
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 Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Phe Ile Arg Asn Lys Val Asn Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Thr Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Pro Tyr Tyr Gly Asn Tyr Gly Trp Phe Pro Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 102
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 102
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 Thr Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Phe Ile Arg Asn Lys Val Asn Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Pro Tyr Tyr Gly Asn Tyr Gly Trp Phe Pro Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 103
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 103
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 Thr Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Phe Ile Arg Asn Lys Val Ser Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Pro Tyr Tyr Gly Asn Tyr Gly Trp Phe Pro Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 104
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 104
Glu 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 Ile Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Gly Thr Gly Thr Ser Tyr Tyr Ser Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Lys His Arg Gly Tyr Gly Tyr Gly Gly Ala Trp Ile Ala Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 105
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 105
Glu 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 Thr Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Gly Thr Gly Thr Ser Tyr Tyr Ser Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ile Asp Thr Ser Thr Ala Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Lys His Arg Gly Tyr Gly Tyr Gly Gly Ala Trp Ile Ala Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 106
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 106
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Ser Phe Thr Ala Tyr
20 25 30
Leu Met Asn Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ser Pro Tyr Asn Gly Glu Thr Leu Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asp Met Ile Thr Thr Gly Arg Pro Trp Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 107
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 107
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ser Ser Gly Tyr Ser Phe Thr Ala Tyr
20 25 30
Leu Met Asn Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ser Pro Tyr Asn Gly Glu Thr Leu Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Val His
65 70 75 80
Met Glu Leu Arg Ser Leu Ala Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Asp Met Ile Thr Thr Gly Arg Pro Trp Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 108
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 108
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ser Ser Gly Tyr Ser Phe Thr Ala Tyr
20 25 30
Leu Met Asn Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ser Pro Tyr Thr Gly Glu Thr Leu Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Val His
65 70 75 80
Met Glu Leu Arg Ser Leu Ala Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Asp Met Ile Thr Thr Gly Arg Pro Trp Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 109
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 109
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Arg
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Arg Ile Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 110
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 110
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Arg
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Arg Ile Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 111
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 111
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Arg
20 25 30
Ser Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Arg Ile Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 112
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 112
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 113
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 113
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 114
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 114
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 115
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 115
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 116
<211> 105
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 116
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Ser Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys His Gln Trp Ser Ser Tyr Pro Thr Phe
85 90 95
Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 117
<211> 105
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 117
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Ser Met
20 25 30
His Trp His Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys His Gln Trp Ser Ser Tyr Pro Thr Phe
85 90 95
Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 118
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 118
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Ser Tyr Asn Leu Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Claims (20)
1.一种抗人IL-33单克隆抗体或其片段，其包括重链可变区和轻链可变区，分别具有选自以下重链可变区序列和轻链可变区序列组合的3个CDRs：
(1) 如SEQ ID NO: 2的重链可变区序列，和如SEQ ID NO: 48的轻链可变区序列；
(2) 如SEQ ID NO: 5的重链可变区序列，和如SEQ ID NO: 51的轻链可变区序列；
(3) 如SEQ ID NO: 20的重链可变区序列，和如SEQ ID NO: 66的轻链可变区序列；
(4) 如SEQ ID NO: 22的重链可变区序列，和如SEQ ID NO: 68的轻链可变区序列；
(5) 如SEQ ID NO: 25的重链可变区序列，和如SEQ ID NO: 71的轻链可变区序列；
(6) 如SEQ ID NO: 42的重链可变区序列，和如SEQ ID NO: 88的轻链可变区序列。
2.一种抗人IL-33单克隆抗体或其片段，其中所述抗体的重链可变区（VH）和轻链可变区（VL）分别选自以下组合：
(1) 如SEQ ID NO: 2的重链可变区序列，和如SEQ ID NO: 48的轻链可变区序列；
(2) 如SEQ ID NO: 5的重链可变区序列，和如SEQ ID NO: 51的轻链可变区序列；
(3) 如SEQ ID NO: 20的重链可变区序列，和如SEQ ID NO: 66的轻链可变区序列；
(4) 如SEQ ID NO: 22的重链可变区序列，和如SEQ ID NO: 68的轻链可变区序列；
(5) 如SEQ ID NO: 25的重链可变区序列，和如SEQ ID NO: 71的轻链可变区序列；
(6) 如SEQ ID NO: 42的重链可变区序列，和如SEQ ID NO: 88的轻链可变区序列。
3.如权利要求1或2所述抗人IL-33单克隆抗体或其片段，其特征在于所述抗体或其片段特异性结合于人IL-33上与ST2受体结合的位点，并且其与IL-33结合的KD<1×10-8。
4.如权利要求1或2所述抗人IL-33单克隆抗体或其片段，其特征在于所述抗体或其片段通过阻断人IL-33与ST2的结合，抑制IL-33诱导的细胞因子分泌。
5.如权利要求1或2所述抗人IL-33单克隆抗体或其片段，其特征在于所述抗体或其片段通过阻断人IL-33与ST2的结合，抑制IL-33诱导的淋巴细胞分泌IL-5。
6.如权利要求1或2所述抗人IL-33单克隆抗体或其片段，其特征在于所述抗体或其片段来自鼠源抗体、兔源抗体、人源抗体、嵌合抗体、人源化抗体。
7.如权利要求1或2所述抗人IL-33单克隆抗体或其片段，其特征在于所述抗体片段包括Fab、Fab’、F(ab’)2、Fv、scFv、dAb。
8.一种人源化抗人IL-33单克隆抗体或其片段，其是在权利要求1-2中任一项所述抗人IL-33单克隆抗体或其片段的基础上，采用CDRs移植技术、CDR区突变设计构建的人源化抗人IL-33单克隆抗体。
9.如权利要求8所述的人源化抗人IL-33单克隆抗体或其片段，其特征在于：
重链可变区，具有选自SEQ ID NO: 93-108中任一重链可变区序列的3个CDRs；
和
轻链可变区，具有选自SEQ ID NO: 109-118中任一轻链可变区序列的3个CDRs。
10.如权利要求8-9中任一项所述的人源化抗人IL-33单克隆抗体或其片段，其特征在于：所述抗体部分包括Fab、Fab’、F(ab’)2、Fv、scFv、dAb。
11.一种多核苷酸，其编码权利要求 1-10 中任一项所述抗人 IL-33 单克隆抗体或其片段。
12.核酸构建体，其包含权利要求 11 所述的多核苷酸。
13.宿主细胞，其包含
（1）权利要求 11 所述的多核苷酸
或
（2）权利要求 12 所述的核酸构建体。
14.一种制备抗人 IL-33 单克隆抗体或其片段的方法，包括：
（1）在合适的条件下，培养权利要求 13 所述的宿主细胞；
（2）分离回收抗人 IL-33 单克隆抗体或其片段或者人源化抗人 IL-33 单克隆抗体或其片段。
15.一种组合物，其包含
（1）权利要求 1-10 中任一项所述抗人 IL-33 单克隆抗体或其片段、
（2）权利要求 11 所述多核苷酸、
（3）权利要求 12 所述核酸构建体
和/或
（4）权利要求 13 所述宿主细胞；
以及药学上可接受的辅料。
16.如下产品在制备治疗 IL-33/ST2 信号通路相关疾病的药物中的用途，
（1）权利要求 1-10 中任一项所述抗人 IL-33 单克隆抗体或其片段、
（2）权利要求 11 所述多核苷酸、
（3）权利要求 12 所述核酸构建体、
（4）权利要求 13 所述宿主细胞
和/或
（5）权利要求 15 所述组合物。
17.如权利要求16所述产品在制备治疗 IL-33/ST2 信号通路相关疾病的药物中的用途，其中IL-33/ST2 信号通路相关疾病包括变态反应性疾病。
18.如权利要求 17 所述用途，其特征在于所述变态反应性疾病，包括哮喘，过敏性疾病，自身免疫病，和心肺疾病。
19.如权利要求 18所述用途，其特征在于所述自身免疫病，包括风湿性关节炎、系统性红斑狼疮。
20.如权利要求 18所述用途，其特征在于所述心肺疾病，包括心衰、扩心病。
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| CN113234157B (zh) * | 2021-07-09 | 2021-09-21 | 上海普铭生物科技有限公司 | 亲和力成熟的人源化抗人il-33单克隆抗体及其应用 |
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| CN118339187A (zh) * | 2021-12-31 | 2024-07-12 | 上海宏成药业有限公司 | 抗pd-1抗体及其用途 |
| CN115109161B (zh) * | 2022-06-28 | 2023-08-11 | 广东赛尔生物科技有限公司 | 含有间充质干细胞的减肥药物组合物 |
| CN115960226B (zh) * | 2022-09-20 | 2023-06-16 | 北京科跃中楷生物技术有限公司 | 一种磁微粒免疫层析快速反应方法及检测试剂盒 |
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