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人工免疫监视嵌合抗原受体(ai-car)及其表达细胞

文档序号：491497 发布日期：2022-01-04 浏览：13次 >En<

阅读说明：本技术 人工免疫监视嵌合抗原受体(ai-car)及其表达细胞 (Artificial immune surveillance chimeric antigen receptor (AI-CAR) and cells expressing same ) 是由 陆满晴 唐纳德·E·斯汤顿 约翰·M·哈兰 于 2020-02-21 设计创作，主要内容包括：本申请提供了非病毒载体,其包含侧翼为两个转座子或病毒末端重复序列(IR)的人工免疫监视嵌合抗原受体(AI-CAR)表达盒,其中所述AI-CAR表达盒包含诱导型基因表达单元和CAR表达单元。(The present application provides a non-viral vector comprising an artificial immune surveillance chimeric antigen receptor (AI-CAR) expression cassette flanked by two transposons or viral terminal repeats (IR), wherein the AI-CAR expression cassette comprises an inducible gene expression unit and a CAR expression unit.)

人工免疫监视嵌合抗原受体(AI-CAR)及其表达细胞

相关申请的交叉引用

本申请要求于2019年2月21日提交的美国临时申请序列第62/808,815号，于2019年2月21日提交的美国临时申请序列第62/808,823号和根据35 U.S.C.119(e)于2019年2月21日提交的美国临时申请序列第62/808,833号的优先权，其全部公开内容通过引用并入本文。

技术领域

本发明涉及一种用于改善嵌合抗原受体(CAR)-T细胞或NK细胞的扩增、制造、存活和功效的技术。

背景技术

除非在此另外指出，否则本部分中描述的材料不是本申请中的权利要求的现有技术，并且不通过包括在本部分中而被认为是现有技术。

制造CAR细胞是费力的，并且可能由于需要人工抗原递呈细胞(aAPC)，TCR的抗体刺激和共刺激受体和/或多种细胞因子以在施用前扩增自体或异源CAR细胞而复杂化。例如，当电穿孔条件设定为高CAR表达百分比时，用CAR的DNA载体电穿孔T细胞、NK细胞、PBL或PBMC通常导致大部分细胞的细胞死亡。因此，在电穿孔之后，可以将细胞与经照射的aAPC、抗体和/或生长因子共培养，并且可以将CAR细胞群特异性地扩增多次以产生用于治疗用途的单剂量。目前，标准CAR载体(CAR)不表达通常在免疫抑制的肿瘤微环境中需要的能够诱导患者抗肿瘤免疫应答的基因。

理想地，施用后CAR细胞的功效应该与具有未分化记忆表型的T细胞相关，所述未分化记忆表型的特征在于体内持续性和最大治疗潜力。为了选择性地扩增具有这种表型的CAR细胞和/或防止终末分化，已经利用了几种细胞因子，包括IL15、IL7和IL21。已知IL15和IL7对于产生和支持早期记忆T细胞是关键的，这是由于它们指导从幼稚前体产生人记忆干细胞的能力(Cieri等人，2013；Boyman等人，2012；Gattinoni L等人，2011)。IL15和IL7可以是用于使T细胞(例如人CD8+记忆T细胞亚群)响应于抗原或体内平衡细胞因子而去分化的工具(Geginat 2003)。IL15是先天样T细胞免疫监视所必需的(Dadi S等人，2016)。可溶性和转运的IL15/IL-15Rα能够维持IL-15活性并有助于CD8记忆T细胞的长期存活(Sato等人，2007)。因此，具有未分化记忆表型的CART细胞表现出最大的体内持续性和治疗功效。

然而，由于每种组分的安全性评估，不能共同施用用于制造和维持具有高治疗潜能的此类CAR细胞的所有组分。然而，将这些组分构建到具有组成型表达的CAR载体中可能不是可行的实践，因为随时间毒性的可能性高。或者，如果CAR细胞扩增和未分化记忆表型的信号传导途径处于单一分子(例如靶肿瘤抗原)的控制下，那么其将不仅使成本大大降低而且使护理点治疗成为可能。以这种方式，CAR信号传导可以足以支持CAR细胞的扩增而没有终末分化。

从临床观点来看，多种因素导致治疗复发，包括CAR细胞持续性不足(耗竭或宿主抗-CAR)、靶抗原丧失、缺乏诱导宿主抗-肿瘤应答和/或不能有效地定位至淋巴瘤/实体瘤。几乎所有形式的CAR解决了通过靶向2种或更多种肿瘤抗原解决的肿瘤抗原损失。因此，非常需要通过在CAR载体/RNA中包含额外的基因而具有一种或多种CAR以及持久的宿主应答。

发明内容

在一个方面，本申请提供嵌合抗原受体复合体。在一个实施方案中，所述嵌合抗原受体复合物包含第一蛋白，所述第一蛋白包含通过第一接头与第一细胞间结构域连接的第一细胞外结构域，其中所述第一细胞外结构域包含对第一肿瘤表位具有亲和力的第一scFv，并且其中所述第一细胞间结构域包含JAK1结合结构域，和第二蛋白，所述第二蛋白包含通过第二接头与第二细胞间结构域连接的第二细胞外结构域，其中所述第二细胞外结构域包含对第二肿瘤表位具有亲和力的第二scFv，并且其中所述第二细胞间结构域包含JAK3结合结构域。所述第一肿瘤表位在第一肿瘤抗原上。所述第二肿瘤表位在第二肿瘤抗原上。

在一个实施方案中，第一细胞内结构域包含IL7Rα(CD127)。在一个实施方案中，第一细胞内结构域包含IL15Rβ(CD122)、IL21Rα(CD360)或其组合的细胞内结构域。在一个实施方案中，第一细胞内还包含连接至JAK1结合结构域的第一细胞毒性信号传导结构域。

在一个实施方案中，第一细胞毒性信号传导结构域包含CD28、CD3ζ、CD137、OX40、CD27、ICOS或其组合。

在一个实施方案中，第一scFv结构域或第二scFv结构域独立地对CD19或CD22具有亲和力。在一个实施方案中，第一scFv结构域对CD19具有亲和力。在一个实施方案中，第二scFV结构域对CD22具有亲和力。在一个实施方案中，第二细胞内结构域包含γ(CD132)。

在一个实施方案中，第二细胞内结构域进一步包含连接至JAK3结合结构域的第二细胞毒性信号传导结构域。在一个实施方案中，第二细胞毒性结构域包含CD28、CD3ζ、CD137、OX40、CD27、ICOS或其组合。在一个实施方案中，第二细胞内结构域包含串联γ(CD132)、JAK3结合结构域、CD28和CD3ζ。在一个实施方案中，第一细胞内结构域被配置为与第二细胞内结构域二聚化。

在一个实施方案中，第一和第二接头独立地包含CD8。在一个实施方案中，第一和第二接头独立地包含茎和跨膜结构域。

在一个实施方案中，茎包含CD8、Fc铰链，Fc CH2-CH3，TCRα、TCRβ、截短的IL7Rα(CD127)、截短的IL15Rβ(CD122)、IL15Rα(CD215)、截短的γ(CD132)、截短的IL21Rα(CD360)或其组合。

在一个实施方案中，所述跨膜结构域包含CD8、CD28、CD3ζ、CD3ε、CD3δ、CD3γ、CD3ζ、TCRα、TCRβ、IL15Rβ(CD122)、γ(CD132)、IL7Rα(CD127)、IL21Rα(CD360)、IL15Rα(CD215)或其组合。

在一个实施方案中，肿瘤抗原包含CDH17、TROP2、CD19、CD22、CD37、BCMA、CD48、EGFR、HER2、EpCAM、CEACAM5、PSMA、GD2、GPC3或其组合。

在另一方面，本申请提供开放阅读框(ORF)。在一个实施方案中，开放阅读框(ORF)依次包含CD19 scFv、茎跨膜区和IL7α内结构域。在一个实施方案中，开放阅读框(ORF)依次包含CD22 scFv、茎跨膜区、γ链内结构域、CD28内结构域和CD3ζ内结构域。在一个实施方案中，开放阅读框(ORF)依次包含PD-1scFv、CCL21和IL7。

在另一方面，本申请提供生物分子复合物。在一个实施方案中，所述生物分子复合物包含第一蛋白，所述第一蛋白包含通过第一接头与第一细胞间结构域连接的第一细胞外结构域，其中所述第一细胞外结构域包含对第一肿瘤表位具有亲和力的第一scFv，并且其中所述第一细胞间结构域包含JAK1结合结构域，第二蛋白，所述第一蛋白包含通过第二接头与第二细胞间结构域连接的第二细胞外结构域，其中所述第二细胞外结构域包含对第二肿瘤表位具有亲和力的第二scFv，并且其中所述第二细胞间结构域包含JAK3结构域、第一肿瘤抗原和第二肿瘤抗原。所述第一肿瘤表位结合第一肿瘤抗原。所述第二肿瘤表位与所述肿瘤抗原结合。

在一个实施方案中，第一细胞内结构域与第二细胞内结构域二聚化。在一个实施方案中，JAK1与JAK3二聚化。

在另一方面，本申请提供非病毒DNA构建体。在一个实施方案中，所述非病毒DNA构建体依次包含从5'至3'的诱导型启动子，其随后是第一ORF，其中所述第一ORF包含抗PD-1scFV、CLL21和IL7，各自以单一肽引导并以核糖体跳跃肽结束，第二ORF包含至少一种组成型嵌合抗原受体，和第三启动子，其随后是至少一种RNA序列。

在另一方面，本申请提供了嵌合抗原受体。在一个实施方案中，所述嵌合抗原受体依次包含细胞因子结构域、接头、截短的CD8结构域和信号传导内结构域。

在一个实施方案中，细胞因子结构域包括IL7、IL12、IL21或其组合。在一个实施方案中，截短的CD8结构域包含铰链、跨膜结构域和胞质结构域的至少一部分。在一个实施方案中，胞质结构域包含CD28/CD170、CD3ζ或其组合。

在一个实施方案中，嵌合抗原受体进一步包含在细胞因子结构域和截短的CD8结构域中间的肿瘤抗原结构域。

在一个实施方案中，本申请提供生物分子复合物，其包含与肿瘤抗原结合的如其所公开的嵌合抗原受体。

在另一方面，本申请提供了非病毒载体，其包含侧翼为两个转座子或病毒末端重复序列(IR)的人工免疫监视嵌合抗原受体(AI-CAR)表达盒，其中所述AI-CAR表达盒包含诱导型基因表达单元和CAR表达单元。

在一个实施方案中，所述诱导型基因表达单元包含STAT、NFAT或NF-κB诱导型启动子，通过IRES或自身切割核糖体跳跃肽连接的一个或多个基因的编码区，随后是第一polyA信号序列。在一个实施方案中，自身切割核糖体跳跃肽包含TA2。在一个实施方案中，诱导型基因表达单元包含用于表达至少两种不同细胞因子受体的基因。在一个实施方案中，诱导型基因表达单元包含用于表达抗原结合蛋白的基因。在一个实施方案中，诱导型基因表达单元包含用于表达抗-PD1 scFv的基因。在一个实施方案中，所述诱导型基因表达单元包含用于表达CCL21的基因。在一个实施方案中，诱导型基因表达单元包含用于表达IL7的基因。

在一个实施方案中，CAR表达单元包含用于表达抗-CDH17 scFv，抗-TROP2 scFv，和CAR的基因。在一个实施方案中，CAR表达单元包含启动子、一个或两个CAR基因，随后是第二polyA信号序列。在一个实施方案中，CAR表达单元还包含用于表达安全开关的基因。在一个实施方案中，安全开关包含截短的EGFR(tEGFR)或截短的CD20。在一个实施方案中，AI-CAR表达盒被配置为表达shRNA，其中所述shRNA被配置为抑制所述内源TCR。

在另一方面，本申请提供分离的核酸，其编码如其所公开的生物分子复合物、生物分子、抗原和蛋白质。

在另一方面，本申请提供表达载体，其包含如其所公开的分离的核酸。在一个实施方案中，表达载体包含如其所公开的ORF。在一个实施方案中，表达载体包含如其所公开的非病毒DNA构建体。所述表达载体可以是病毒的或非病毒的。该载体可以在细胞中表达。

在进一步的实施方案中，本申请提供宿主细胞。在一个实施方案中，宿主细胞包含如其所公开的分离的核酸和/或表达载体。在一个实施方案中，宿主细胞包含如其所公开的非病毒DNA构建体。在一个实施方案中，宿主细胞包含如其所公开的非病毒载体。

在另一个实施方案中，本申请提供哺乳动物细胞，其包含嵌合抗原受体复合物、生物分子复合物、生物分子、抗原和如其公开的蛋白质。在一个实施方案中，哺乳动物细胞包含如其所公开的嵌合抗原受体。在一个实施方案中，哺乳动物细胞包含如其所公开的生物分子复合物。

在进一步的实施方案中，本申请提供CAR-T或CAR-NK细胞。在一个实施方案中，CAR-T或CAR-NK细胞表达如其所公开的嵌合抗原受体复合物。在一个实施方案中，CAR-T或CAR-NK细胞表达如其所公开的嵌合抗原受体。

在另一个实施方案中，本申请提供用于治疗受试者中的肿瘤的方法，包括向受试者施用足够量的如其所公开的CAR-T或CAR-NK细胞。

在另一方面，本申请提供药物组合物。在一个实施方案中，药物组合物包含治疗有效量的如其所公开的载体、非病毒载体、CAR-T或CAR-NK细胞、蛋白质、生物分子或生物分子复合物。在一个实施方案中，所述药物组合物还包含药学上可接受的媒介物。

附图说明

结合附图，根据以下描述和所附权利要求书，本公开的前述和其他特征将变得更加完全清楚。应理解，这些附图仅描绘了根据本公开安排的若干实施方案并且因此不应被认为是对其范围的限制，将通过使用附图以额外的特性和细节来描述本公开，其中：

图1描述了在非病毒载体(pPI)中包含诱导型基因表达单元和CAR表达单元的AI-CAR基因表达盒，用于组成型表达一个或两个CAR以诱导用于宿主抗肿瘤应答的基因表达；

图2显示了AI-CAR的一般概念；

图3描绘了编码组成型表达的双重CAR的AI-CAR表达载体，该双重CAR在非病毒载体(pPI)中在诱导型启动子下靶向CDH17和TROP2以及抗PD1 scFv、CCL21和IL17基因盒，用于CAR诱导的宿主抗肿瘤应答；AI-CAR表达载体编码组成型表达的双重CAR，该双重CAR在非病毒载体(pPI)中在诱导型启动子下靶向CDH17和TROP2以及抗PD1 scFv、CCL21和IL17基因盒，用于CAR诱导的宿主抗肿瘤应答；

图4显示了整合的pPI抗-CDH17 AI-CAR载体基因的肿瘤抗原诱导；整合的pPI-抗-CDH17-AI-CAR载体基因的肿瘤抗原诱导。(A)通过响应于不同浓度的CDH17的T细胞(Jurkat)中的GFP水平来测量整合的pPI-抗-CDH17-AI-CAR载体的表达；(B)在结肠癌细胞中用重组CDH17诱导(SW480)；和(C)pPI-抗-CDH17-AI-CAR整合的T细胞对表达CDH17的SW480细胞的细胞毒性；

图5显示了pPI-抗-CDH17-TROP2 AI-CAR的表达和结合特异性；并且

图6描述了支持AI-CAR增殖和持续性的iPro变体。支持AI-CAR增殖和持续性的iPro变体。(A)iPro7表达的示例；(B)CD25 T细胞群增殖的诱导；以及(C)增加T细胞存活。

具体实施方式

在下面的详细描述中，参考了形成其一部分的附图。在附图中，类似的符号通常标识类似的部件，除非上下文另外指示。在详细描述、附图和权利要求中描述的说明性实施方案并不意味着是限制性的。可以利用其他实施方案，并且可以进行其他改变，而不偏离在此呈现的主题的精神或范围。将容易理解的是，如在此一般描述的以及在附图中示出的本公开的这些方面可以被安排、替代、组合、分离，以及设计成多种不同的配置，在此明确地考虑了所有这些配置。

在下面的详细描述中，参考了形成其一部分的附图。在附图中，类似的符号通常标识类似的部件，除非上下文另外指示。在详细描述、附图和权利要求中描述的说明性实施方案并不意味着是限制性的。可以利用其他实施方案，并且可以进行其他改变，而不偏离在此呈现的主题的精神或范围。将容易理解的是，如在此一般描述的以及在附图中示出的本公开的这些方面可以被安排、替代、组合、分离，以及设计成多种不同的配置，在此明确地考虑了所有这些配置。

本公开尤其提供分离的抗体、制备此类抗体的方法、由此类抗体或抗原结合片段组成的双特异性或多特异性分子、抗体-药物缀合物和/或免疫缀合物、含有所述抗体、双特异性或多特异性分子、抗体-药物缀合物和/或免疫缀合物的药物组合物、制备所述分子和组合物的方法，以及使用本文公开的分子和组合物治疗癌症的方法。

术语“抗体”以最广泛的含义使用，并且具体涵盖单一单克隆抗体(包括激动剂抗体和拮抗剂抗体)，具有多表位特异性的抗体组合物以及抗体片段(例如Fab、F(ab′)2和Fv)，只要它们表现出所需的生物学活性即可。在一些实施方案中，抗体可以是单克隆抗体、多克隆抗体、嵌合抗体、单链抗体、双特异性抗体或双有效抗体、模拟抗体、人抗体和人源化抗体及其活性片段。与已知抗原结合的分子的活性片段的实例包括Fab、F(ab′)2、scFv和Fv片段，包括Fab免疫球蛋白表达文库的产物和任何上述抗体和片段的表位结合片段。在一些实施方案中，抗体可包括免疫球蛋白分子和免疫球蛋白分子的免疫活性部分，即含有免疫特异性结合抗原的结合位点的分子。免疫球蛋白可以是任何类型(IgG、IgM、IgD、IgE、IgA和IgY)或类(IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或免疫球蛋白分子的亚类。在一个实施方案中，抗体可以是全抗体和衍生自全抗体的任何抗原结合片段。典型的抗体是指通常包含两条重(H)链和两条轻(L)链的异四聚体蛋白。每条重链由重链可变结构域(缩写为VH)和重链恒定结构域组成。每条轻链由轻链可变结构域(缩写为VL)和轻链恒定结构域组成。VH和VL区可以进一步细分为高变互补决定区(CDR)的结构域和更保守的称为构架区(FR)的区域。每个可变结构域(VH或VL)通常由三个CDR和四个FR组成，按以下顺序排列：从氨基末端到羧基末端的FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。在轻链和重链的可变结构域内有与抗原相互作用的结合区。

如本文所用，术语“单克隆抗体”是指从基本上均质的抗体群获得的抗体，即，包含所述群的各个抗体是相同的，除了可能以少量存在的可能的天然存在的突变。单克隆抗体是高度特异性的，针对单一抗原位点。此外，与通常包括针对不同决定簇(表位)的不同抗体的常规(多克隆)抗体制剂相反，每种单克隆抗体针对抗原上的单一决定簇。除了它们的特异性，单克隆抗体是有利的，因为它们是通过杂交瘤培养物合成的，没有被其它免疫球蛋白污染。修饰语“单克隆”表示抗体的特性是从基本上均质的抗体群获得的，并且不应被解释为需要通过任何特定方法产生抗体。例如，根据本公开使用的单克隆抗体可以通过Kohler&Milstein，Nature，256:495(1975)首次描述的杂交瘤方法制备，或者可以通过重组DNA方法制备(参见，例如美国专利第4,816,567号)。

单克隆抗体可以包括“嵌合”抗体(免疫球蛋白)，其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类或亚类的抗体中的相应序列相同或同源，而链的剩余部分与衍生自另一物种或属于另一抗体类或亚类的抗体以及此类抗体的片段中的相应序列相同或同源，只要它们表现出所需的生物学活性(美国专利第4,816,567号；和Morrison等人，Proc.Natl.Acad.Sci.USA，81:6851-6855[1984])。

单克隆抗体可以使用各种方法产生，包括小鼠杂交瘤或噬菌体展示(参见Siegel.Transfus.Clin.Biol.9:15-22(2002)综述)或直接从原代B细胞的抗体的分子克隆(参见Tiller.New Biotechnol.28:453-7(2011))。在本公开内容中，通过用人PD-L1蛋白和在细胞表面瞬时表达人PD-L1的细胞免疫兔子产生抗体。已知兔子产生高亲和力、多样性和特异性的抗体(Weber等人，Exp.Mol.Med.49:e305)。将来自免疫动物的B细胞体外培养并筛选抗PD-L1抗体的产生。使用重组DNA技术分离抗体可变基因，并重组表达所得抗体，并进一步筛选期望的特征，例如抑制PD-L1与PD-1结合的能力，与非灵长类PD-L1结合的能力和增强人T细胞活化的能力。这种抗体发现的一般方法类似于Seeber等人，PLOS One.9:e86184(2014)描述的方法。

术语“抗原或表位结合部分或片段”是指能够结合抗原(在这种情况下是CD19)的抗体片段。这些片段可以具有抗原结合功能和完整抗体的其它功能。结合片段的实例包括但不限于单链Fv片段(scFv)或Fab片段，所述单链Fv片段(scFv)由通过合成接头连接在单一多肽链中的抗体的单臂的VL和VH结构域组成，所述Fab片段是由VL、恒定轻链(CL)、VH和恒定重链1(CH1)结构域组成的单价片段。抗体片段可以是甚至更小的亚片段，并且可以由与单个CDR结构域一样小的结构域，特别是来自VL和/或VH结构域的CDR3区组成(例如参见Beiboer等人，J.Mol.Biol.296:833-49(2000))使用本领域技术人员已知的常规方法产生抗体片段。可以使用与完整抗体使用的相同技术筛选抗体片段的效用。

“抗原-或表位-结合片段”可以通过许多本领域已知的技术衍生自本公开的抗体。例如，纯化的单克隆抗体可以用酶例如胃蛋白酶切割，并进行HPLC凝胶过滤。然后通过膜过滤等收集并浓缩含有Fab片段的合适部分。关于分离抗体的活性片段的一般技术的进一步描述，参见例如Khaw,B.A.等人，J.Nucl.Med.23:1011-1019(1982)；Rousseaux等人，Methods Enzymology，121:663-69，Academic Press，1986。

抗体的木瓜蛋白酶消化产生两个相同的抗原结合片段，称为“Fab”片段，每个片段具有单个抗原结合位点，和残余的“Fc”片段，其名称反映了其容易结晶的能力。胃蛋白酶处理产生具有两个抗原结合位点并且仍然能够交联抗原的F(ab′)2片段。

Fab片段可以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片段的不同在于在重链CH1结构域的羧基端添加了几个残基，包括来自抗体铰链区的一个或多个半胱氨酸。Fab′-SH在本文中是指其中恒定结构域的半胱氨酸残基带有游离巯基的Fab′。F(ab′)2抗体片段最初作为Fab′片段对产生，Fab′片段之间具有铰链半胱氨酸。其它抗体片段的化学偶联也是已知的。

“Fv”是含有完整抗原识别和结合位点的最小抗体片段。该区域由一个重链和一个轻链可变结构域以紧密的，非共价缔合的二聚体组成。在这种配置中，每个可变结构域的三个CDR相互作用以在VH-VL二聚体的表面上限定抗原结合位点。6个CDR共同赋予抗体抗原结合特异性。然而，即使是单个可变结构域(或者仅包含三个对抗原特异的CDR的Fv的一半)也具有识别和结合抗原的能力，尽管亲和力低于整个结合位点。

来自任何脊椎动物物种的抗体(免疫球蛋白)的“轻链”可基于其恒定结构域的氨基酸序列而分配至称为κ和λ的两种明显不同类型中的一种。

根据免疫球蛋白重链恒定结构域的氨基酸序列，免疫球蛋白可分为不同的类别。有五种主要类型的免疫球蛋白：IgA、IgD、IgE、IgG和IgM，并且这些中的一些可以进一步分为亚类(同种型)，例如，IgG-1、IgG-2、IgG-3和IgG-4；IgA-1和IgA-2。对应于不同免疫球蛋白类别的重链恒定结构域分别称为α、δ、ε、γ和μ。不同类别免疫球蛋白的亚单位结构和三维配置是熟知的。

“人源化抗体”是指一类工程抗体，其CDR衍生自非人供体免疫球蛋白，分子的其余免疫球蛋白衍生部分衍生自一种(或多种)人免疫球蛋白。此外，可改变构架支持残基以保持结合亲和力。获得“人源化抗体”的方法是本领域技术人员熟知的。(参见，例如，Queen等人，Proc.Natl Acad Sci USA，86:10029-10032(1989)，Hodgson等人，Bio/Technology，9:421(1991))。

如本文所用，术语“多肽”、“肽”和“蛋白质”可互换并且定义为意指由通过肽键连接的氨基酸组成的生物分子。

如在此使用的术语“一个”、“一种”和“该”被定义为意指“一个或多个”并且包括复数，除非上下文不适当。

“分离的”是指不含其天然存在的至少一些组分的生物分子。“分离的”当用于描述本文公开的各种多肽时，意指已经从其表达的细胞或细胞培养物鉴定和分离和/或回收的多肽。通常，分离的多肽将通过至少一个纯化步骤制备。“分离的抗体”是指基本上不含具有不同抗原结合特异性的其它抗体的抗体。

“重组”意指使用重组核酸技术在外源宿主细胞中产生抗体。

术语“抗原”是指可以在生物体，特别是动物，更特别是哺乳动物(包括人)中诱导免疫应答的实体或其片段。该术语包括免疫原及其负责抗原性或抗原决定簇的区域。

此外，如本文所用，术语“免疫原性的”是指引起或增强针对免疫原性剂的抗体、T-细胞或其它反应性免疫细胞的产生并且有助于人或动物中的免疫应答的物质。当个体针对所施用的本公开的免疫原性组合物产生足够的抗体、T-细胞和其它反应性免疫细胞以减轻或缓解待治疗的病症时，发生免疫应答。

“特异性结合”或“特异性结合至”或“特异于”特定抗原或表位是指可测量地不同于非特异性相互作用的结合。特异性结合可以例如通过测定分子与对照分子的结合的结合来测量，所述对照分子通常是不具有结合活性的类似结构的分子。例如，特异性结合可以通过与类似于靶的对照分子竞争来测定。

例如，对特定抗原或表位的特异性结合可以由对抗原或表位具有至少约10-4M、至少约10-5M、至少约10-6M、至少约10-7M、至少约10-8M、至少约10-9M、或者至少约10-10M、至少约10-11M、至少约10-12M或更大KD的抗体来显示，其中KD指特定抗体-抗原相互作用的解离速率。通常，特异性结合抗原的抗体对于对照分子将具有相对于抗原或表位为20-、50-、100-、500-、1000-、5,000-、10,000-或更多倍的KD。

此外，例如，通过对于抗原或表位具有相对于对照为该表位的至少20-、50-、100-、500-、1000-、5,000-、10,000-或更多倍的KA或Ka的抗体，可以表现出对于特定抗原或表位的特异性结合，其中KA或Ka是指特定抗体-抗原相互作用的结合速率。

通过序列同一性确定两个序列之间的“同源性”。如果待比较的两个序列长度不同，则序列同一性优选是指与较长序列的核苷酸残基相同的较短序列的核苷酸残基的百分比。可以使用计算机程序常规地确定序列同一性。在给定序列与本公开的上述序列之间的比较中出现的偏差可以由例如添加、缺失、取代、插入或重组引起。

通过参考以下对本文包括的具体实施方案和实施例的详细描述，可以更容易地理解本公开。尽管已参考本公开的某些实施方案的特定细节描述了本公开，但并不希望此些细节应视为对本公开的范围的限制。

在先前的公开中，通过细胞因子信号传导途径解决CAR耗竭以驱动扩增而没有末端分化。本文所公开的组合物和使用方法涉及用于人工免疫监测嵌合抗原受体的AI-CAR载体。该AI-CAR技术的进步旨在替代标准CAR制造并实现有效的“组合”和护理点治疗。虽然其它CAR技术可能需要可溶性细胞因子生长因子的表达和/或持续活性的多次给药以产生完全且持久的应答，但AI-CAR载体掺入了这些活性并能够在不存在增殖的组成型活性驱动物或持久抗肿瘤应答的多次CAR给药的情况下产生有效且持续的CAR细胞。

第二，在保持与标准CAR相同功能的同时，AI-CAR信号传导增加了制造CAR细胞的效率。AI-CAR在体外和体内可能仅需要一种靶抗原以获得完全增殖和细胞毒活性。在本文中，由于标准CAR-T细胞的扩增通常需要使用生长因子和aAPC的组合来制造，所以AI-CAR可以显著降低制造成本。

第三，在体内肿瘤细胞的AI-CAR接合后，可以诱导由整合的AI-CAR载体编码的几种抗肿瘤基因的表达。这些内源基因的表达可以使患者产生更广泛地靶向不同肿瘤抗原例如新抗原的抗肿瘤应答。例如，STAT5报告系统用于在人T细胞中诱导STAT5响应性基因(Kanai等人，2014；Zeng等人，2016；Bednorz等人，2011；以及Fang等人，2008)。该特征是独特的，因为标准CAR构建体通常不能诱导基因表达。与这些辅助因子一起，AI-CAR将成为为癌症护理点治疗提供实用、经济和有效解决方案的平台技术。许多形式的癌症可以存在于免疫抑制的肿瘤环境中。AI-CAR将是高度合乎需要的，因为AI-CAR载体经设计以表达额外的抗癌基因，所述抗癌基因可降低肿瘤免疫抑制并激活患者的抗肿瘤免疫应答。AI-CAR的独特特征之一是其在肿瘤位点调节相关抗肿瘤基因的表达的能力，而不是使它们组成型表达，这可能是有毒的。另一特征是AI-CAR经设计以在施用时具有单剂量，接着具有其长期活性和较大功效。具有这些有利特征，AI-CAR对于市场上未得到满足的挑战是更好的解决方案，其预示治疗大多数(如果不是所有)类型的癌症的功效。

关于用于治疗血液癌症的CAR疗法，靶包括CD19和CD22、CD20、CD9、CD38，其可通过使用非病毒DNA载体或RNA-CAR(瞬时)的双重双特异性AI-CAR靶向。以这种方式，AI-CAR可用作移植或更持续性化的瞬时治疗桥。此外，AI-CAR可用作诱导针对新抗原的宿主抗肿瘤免疫应答的定点护理治疗。

此外，对于某些实体瘤，可以应用编码AI-CAR组合治疗的RNA。对于其他治疗失败的侵袭性肿瘤，由于RNA的高电穿孔效率，现成的RNA CAR可以有效且快速地制造。由RNAAI-CAR瞬时表达的多种抗肿瘤机制，如诱导的AI-CAR载体基因，应当能够实现更有效和更安全的抗肿瘤活性并潜在地诱导患者免疫应答。多剂量RNA AI-CAR可用作在用某些持续性AI-CAR细胞治疗之前测定功效的桥梁。

实施例

实施例1.用于持续和联合治疗的AI-CAR载体的构建

AI-CAR细胞的目的是通过在静止状态下持续、长期的免疫监视直至被肿瘤细胞刺激来提高癌症免疫治疗的功效。肿瘤刺激后，诱导型AI-CAR基因能够进行涉及抗肿瘤活性的其它机制的局部安全且更有效的“组合”治疗。对于更高频率的完全和持久应答，预期刺激患者的抗肿瘤应答。

通常，AI-CAR构建体由非病毒载体(pPI)如基于转座子的整合系统中的AI-CAR表达盒组成(Ivics和Izsvák，2010；Z Cooper等人，US9,629,877；Uckert等人，US20190071484A1)。如图1所示，AI-CAR载体包含诱导型基因表达单元和CAR表达单元，即侧翼为转座子末端反向重复(IR)的AI-CAR表达盒。可以用STAT、NFAT或NF-κB诱导型启动子，通过IRES或自身切割核糖体跳跃肽如P2A或T2A(例如SEQ ID 18-21)连接的一个或多个基因的编码区，以及随后的polyA信号序列构建AI-CAR表达盒。这之后可以是用于组成型表达一个或两个CAR的另一个启动子，其之后是另一个polyA信号。AI-CAR链对的实例参见SEQID 1和2、3和4、5和6、7和8、9和10。两个编码区可以位于两个转座子或用于整合的病毒末端重复序列(IR)之间。或者，AI-CAR构建体的编码区可使用锌指、TALEN或CRISPR/Cas9核酸酶整合在特定基因组位点(Eyquem2017)。

如图2所示，T细胞表面上一个或两个CAR的组成型表达在肿瘤处与肿瘤相关抗原结合。所述AI-CAR诱导诱导型基因的表达，实现抗肿瘤活性的安全且多重机制和宿主抗肿瘤应答的有效刺激。理想地，这些基因的表达将在AI-CAR与肿瘤抗原或肿瘤微环境(TME)内的抗原接合后被诱导。为了延伸这些基因的库，可以从第二载体表达第二AI-CAR链。

AI-CAR非病毒载体的组成至少有一些灵活性，例如piggyBac、Tol2和SleepingBeauty(Ivics和Izsvák，2010)。另外，AI-CAR可表达安全开关，例如截短的EGFR(tEGFR)，其可被FDA批准的抗体西妥昔单抗靶向用于消除。或者，安全靶可以是截短的CD20，其可被利妥昔单抗靶向用于CAR细胞消除。AI-CAR载体可表达shRNA，所述shRNA例如抑制内源TCR以使得能够产生通用AI-CAR细胞。

作为诱导型启动子的替代，AI-CAR可包括弱启动子，例如经修饰的PGK启动子，以安全表达其它抗肿瘤活性机制。

实施例2.单和双重AI-CAR设计

设计单或双重AI-CAR以通过细胞因子受体途径发信号以获得更大的CAR细胞持续性并诱导载体编码的基因以获得额外的抗肿瘤机制和增强的功效。此外，简单接合AI-CAR可促进有效的AI-CAR扩增，并且可用于制造以简化给药前的体外扩增。

用IL12、IL7、IL21或IL15细胞因子受体内结构域构建双重AI-CAR以使载体基因能够持续和诱导以用于额外的抗肿瘤机制。如表2所列，细胞因子内结构域融合至一个或多个TCR或TCR共刺激胞质区(也称为共刺激结构域)，例如CD3ζ、CD28、CD137、CD27、OX40和ICOS。例如，可以用由融合至茎和跨膜结构域以及IL12β1链的细胞内(内)结构域和CD3ζ的片段的肿瘤抗原特异性scFv组成的一种CAR构建双重AIL-CAR。第二CAR可由融合至茎和跨膜结构域的肿瘤抗原特异性scFv、共同β2链内结构域的片段和CD137共刺激内结构域组成。

AI-CAR可通过转录因子如STAT4诱导基因表达。IL12β1链具有Ty2k结合位点，而β2链具有JAK2结合位点。两条链的结合可以通过与邻近靶抗原或与相同肿瘤靶抗原的两个不同但邻近的表位结合来稳定。当CAR与肿瘤抗原结合时，Ty2k和JAK2将磷酸化β链并最终磷酸化STAT4，然后STAT4二聚化并转位至细胞核。然后STAT4可以与启动子转录因子(TF)应答元件结合并促进基因表达的诱导。可以将可通过STAT4调节的启动子和下游基因掺入到CAR转座子或病毒载体中。一旦整合，这些基因可以在CAR细胞接合肿瘤或TME抗原之后被诱导。STAT4诱导的内源基因也支持CAR细胞持续性(DeRenzo 2019)。

大多数双重AI-CAR组分是独立的功能单元，即抗肿瘤scFv、茎、跨膜结构域和内结构域，以及IL15、IL7和IL21链、CD3ζ和共刺激蛋白的不同片段，并且为了许多具体目的而进行替换。如表1和表2中所示的实例，可存在用于制造特定AI-CAR的许多组合。

可以构建单特异性AI-CAR，使得CAR细胞持续性由CAR载体内编码的诱导型基因支持。AI-CAR可由靶向肿瘤或TME相关抗原的scFv、茎、跨膜结构域和共刺激CD137和CD3ζ内结构域组成。在接合具有肿瘤抗原活性的NFAT后，将产生结合至整合CAR载体内的应答元件的NFAT，所述应答元件诱导支持持续性的一种或多种基因(例如IL15、IL12和IL7)的表达以及抗肿瘤活性的其它机制。

表2显示了编码具有持续性活性或抗肿瘤活性的蛋白质或miRNA的额外基因，例如抗免疫检查点抑制剂(ICI)、OX40激动剂、TLR激动剂、细胞因子、双特异性抗体、iPro、趋化因子和趋化因子受体，其可以被置于诱导型启动子的控制下。或者，编码这些蛋白(例如SEQID18-20)的mRNA可用AI-CAR载体共转染以瞬时表达。或者，编码CAR和这些蛋白的mRNA可用作瞬时、安全治疗的AI-CAR(SEQ ID 11-17)。瞬时表达这些基因的若干剂量的AI-CAR可足以降低肿瘤微环境中的免疫抑制并激活患者的抗肿瘤免疫应答。

实施例3.编码双特异性抗-CDH17和抗-TROP2 CAR的AI-CAR和用于持续性和增强 的抗肿瘤应答的诱导型基因

如图3所示，可以用NFAT诱导型启动子，由核糖体跳跃肽如T2A连接的一个或多个基因如抗PD-1、CCL21和IL7的编码区以及其后的polyA信号序列构建AI-CAR载体。这之后可以是靶向具有CD137和CD3ζ内结构域的CDH17和TROP2的单一双特异性CAR的启动子，之后是T2A、信号肽、tEGFR和polyA信号。两个编码区可以位于转座子或病毒末端重复序列(IR)之间用于整合。或者，可使用TALEN或CRISPR/Cas9(Eyquem2017)将AI-CAR表达盒整合在特定基因组位点处。

实施例4.肿瘤靶抗原的AI-CAR基因诱导

重组和细胞肿瘤靶抗原用于在整合到T细胞系中后诱导AI-CAR载体基因。将在NFAT诱导型启动子控制下表达GFP的pPI-抗-CDH17-AI-CAR构建体电穿孔入Jurkat T细胞系。将该pBac转座子构建体与转座酶表达载体共同电穿孔以进行AI-CAR载体整合。将具有整合的pPI抗-CDH17 AI-CAR载体的T细胞系(Jurkat)在用0、1.25、2.5、5、10或20μg/mlCDH17-Fc包被的微量滴定孔中孵育(37℃，5％CO2)2小时或14小时。pPI抗-CDH17 AI-CAR载体含有受NFAT诱导型启动子调节的GFP。在14小时时，通过流式细胞荧光测定法测定GFP表达水平。GFP表达的水平相对于免疫培养物处理14小时时最大诱导的水平(抗-CD3、CD28和CD2；干细胞)。仅暴露2小时的CDH17，通过流式细胞术检测到低水平的GFP，如图4A所示。14小时后，相对于免疫培养物，CDH17暴露后GFP以浓度依赖性方式增加至70％。在未刺激的细胞中存在可接受水平的GFP。通过用0、1.25、5、10或20μg CDH17 RNA(每10^7细胞)电穿孔，在SW480细胞中以不同水平表达CDH17。通过标准流式细胞荧光测定法测定CDH17的表达，如图4B所示。将整合有pPI抗CDH17 AI-CAR载体的Jurkat系与表达不同水平CDH17的单层SW480一起温育2或14小时。在14小时时，通过流式细胞荧光测定法测定GFP表达水平。GFP表达水平相对于免疫培养14小时的最大诱导水平。如图4C所示，将AI-CAR暴露于表达Sw480的CDH17 2或14小时后，检测到相似水平的GFP诱导(50-80％)。因此，表达靶抗原的肿瘤细胞似乎有效地诱导AI-CAR载体基因表达。因此，该AI-CAR构建体可用于在肿瘤位点表达具有抗肿瘤活性的蛋白以安全和增强肿瘤杀伤。

实施例5.双重AI-CAR的表达

显示了双链双重AI-CAR的表达和结合活性。在CHO细胞中表达双重AI-CAR，一个具有IL15β和CD28内结构域，另一个具有IL15γ和CD3ζ内结构域(SEQ ID 1和2)。并且如图5所示，通过用生物素化的蛋白质-L(对于scFv)染色测定单个链，pSh3C15b28和pSh3A4C15g3，或两个链的表达。也通过流式细胞术测定与肿瘤抗原，CDH17-Fc或TROP2-Fc的结合。使用抗生蛋白链菌素-藻红蛋白(对于蛋白质-L)和抗人IgG-Alexa647(对于CDH17和TROP2)测定表达和肿瘤抗原结合。这些结果表明可以容易地实现双重CAR的转染、表达和配体结合功能。

实施例6.支持AI-CAR增殖和持续性的iPro设计和表达

可在单一AI-CAR中诱导增殖诱导剂(iPro)以支持增殖和持续性。iPro可以用N-末端细胞因子或结合TME抗原的scFv，随后是接头、茎、跨膜结构域和具有JAK家族和STAT结合位点的内结构域来构建，如图6A所示。在N-末端结构域与细胞因子受体或肿瘤抗原接合后，iPro可通过STAT发信号以诱导T或NK细胞蛋白的表达，所述T或NK细胞蛋白支持和Tcm茎表型的存活和维持。具有N-末端细胞因子结构域，例如IL7、IL15或IL12。iPro可以支持双向由内向外和由外向内刺激，除了AI-CAR细胞外，其还激活患者T细胞和NK细胞。除了增强体内AI-CAR活性，iPro的表达可促进AI-CAR的内含子扩增以用于制造。

通过流式细胞术在24小时而不是48小时检测到通过电穿孔其体外转录的mRNA在PBMC中瞬时表达的具有N-末端IL7的iPro(iPro7；SEQ ID 19)(图6B，左图)。在第2天，通过流式细胞术证明IL2受体CD25的诱导表达(图6C，中间图)。在没有进一步刺激的情况下，T细胞计数在10天内保持稳定，而模拟对照T细胞计数显著减少(图6D，右图)。这些结果表明，可设计AI-CAR诱导基因(例如iPro)的变体以支持AI-CAR增殖和持续性。

参考文献

Rodríguez-Galán A,Fernández-Messina L,Sánchez-Madrid F.Control ofImmunoregulatory Molecules by miRNAs in T Cell Activation.FrontImmunol.2018Sep 25；9:2148.

Lykken EA,Li QJ.The MicroRNA miR-191Supports T Cell SurvivalFollowing CommonγChain Signaling.J Biol Chem.2016Nov 4；291(45):23532-23544.Epub 2016Sep 15.

Ivics,Z.,Izsvák,Z.The expanding universe of transposon technologiesfor gene and cell engineering.Mobile DNA 1,25(2010).

Cooper Lj,Torikai H,Zhang L,Huls H,Wang-Johanning F,Hurton L,OlivaresS,Krishnamurthy J.Human application of engineered chimeric antigen receptor(CAR)T-cells.US9629877B2.Uckert W,Bunse M,Clauss J,Izsvák Z.A transposon-based transfection system for primary cells US20190071484A1.

表

表1列出了AI-CAR组合物的实例。可使用编码不同功能性片段的不同基因的片段来构建AI-CAR，所述功能性片段包括抗肿瘤相关抗原(TAA)scFv、茎、跨膜结构域和内结构域。不同种类的内结构域可以例如在信号传导细胞因子受体增殖和存活应答或肿瘤细胞毒性应答中起作用。细胞因子受体，CD3ζ和共刺激内结构域可以以各种串联排列融合。

表2列出了可掺入AI-CAR载体中的诱导型基因的实例。可选择这些基因以增强CAR定位至肿瘤(例如淋巴瘤)，逆转肿瘤免疫抑制和刺激宿主免疫应答或用于直接抗肿瘤细胞活性。可将所述基因置于STAT5诱导型启动子的下游以避免长期组成型表达可能发生的任何毒性。或者，某些趋化因子和趋化因子受体基因和细胞因子，例如IL7可以位于弱启动子的下游。低水平的表达可以避免毒性。

序列表

SEQ ID NO:1

TROP2特异性AI-CAR(pSh3A4C15g3)

MEFGLSWVFLVALLRGVQCQVQLVQSGAEVKKPGASVKVSCKASGYTFTDFYMNWVRQAPGQGLEWMGRVNPSNGDTNYNQKFKGRVTSTRDTSISTAYMELSRLRSDDTAVYYCARERIYYGISWYFDVWDTGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKAPKLLLYNAKTLAEGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCHHYYSTPPTFGQGTKLEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDAVVISVGSMGLIISLLCVYFWLERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPETRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO:2

CDH17特异性AI-CAR(pSh3C15b28)

MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGSGGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIPWLGHLLVGLSGAFGFIILVYLLINCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLPDALEIEACQVYFRSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS P

SEQ ID NO:3

h2FM19AIg3z(CD19特异性AI-CAR-g3z)

MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSQTLSLTCTVSGVSLPDYGVSWIRQHPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGGAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTFTISSLQQEDIATYYCQQGNTLPYTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADAVVISVGSMGLIISLLCVYFWLERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPETRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO:4

hAT38AIa7(CD38特异性,AI-CAR-a7)

MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVRPSQTLSLTCTVSGFTFTSYGVHWVRQPPGRGLEWIGVMWRGGSTDYNAAFMSRVTMLVDTSKNQFSLRLSSVTAADTAVYYCAKSMITTGFVMDSWGQGSLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASEDIYNRLTWYQQKPGKAPKLLISGATSLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYWSNPYTFGQGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADPILLTISILSFFSVALLVILACVLWKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLEESEKQRLGGDVQSPNCPSEDVVITPESFGRDSSLTCLAGNVSACDAPILSSSRSLDCRESGKNGPHVYQDLLLSLGTTNSTLPPPFSLQSGILTLNPVAQGQPILTSLGSNQEEAYVTMSSFYQNQ

SEQ ID NO:5

h81AIaI7(CD81特异性,AI-CAR-a7)

MKHLWFFLLLVAAPRWVLSQVQLVQSGAEVKKPGASVKVSCKASGYTFSSSWMNWVRQAPGQRLEWMGRIYSGDGDAIYNGKFKGRVTITADTSASTAYMELSSLRSEDTAVYYCAREGKTGDLLLRSWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCRASKSVSTSIYSYMHWYQQKPGQPPKLLIYYASYLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCEHSREFPFTFGQGTKLEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADPILLTISILSFFSVALLVILACVLWKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLEESEKQRLGGDVQSPNCPSEDVVITPESFGRDSSLTCLAGNVSACDAPILSSSRSLDCRESGKNGPHVYQDLLLSLGTTNSTLPPPFSLQSGILTLNPVAQGQPILTSLGSNQEEAYVTMSSFYQNQSEQ ID NO:6

hRF22AIgC7(CD22特异性,AI-CAR-gC7)

MKHLWFFLLLVAAPRWVLSEVQLVESGGGLVQPGGSLRLSCAASGFAFSIYDMSWVRQAPGKGLEWVSYISSGGGTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHSGYGSSYGVLFAYWGQGTLVTVSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSILHSGVPSRFSGSGSGTDFTFTISSLQQEDIATYYCQQGNTLPWTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADIPWLGHLLVGLSGAFGFIILVYLLINCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLPDALEIEACQVYFRSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSP

SEQ ID NO:7

h2FM19b1AI3z(CD19特异性AI-CAR–IL12b1 CD137-CD3z)

MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSQTLSLTCTVSGVSLPDYGVSWIRQHPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGGAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTFTISSLQQEDIATYYCQQGNTLPYTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADWLIFFASLGSFLSILLVGVLGYLGLNRAARHLCPPLPTPCASSAIEFPGGKETWQWINPVDFQEEASLQEALVVEMSWDKGERTEPLEKTELPEGAPELALDTELSLEDGDRCKAKMKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO:8

hAT38bAI2(CD38特异性,AI-CAR–IL12b2)

MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVRPSQTLSLTCTVSGFTFTSYGVHWVRQPPGRGLEWIGVMWRGGSTDYNAAFMSRVTMLVDTSKNQFSLRLSSVTAADTAVYYCAKSMITTGFVMDSWGQGSLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASEDIYNRLTWYQQKPGKAPKLLISGATSLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYWSNPYTFGQGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADWMAFVAPSICIAIIMVGIFSTHYFQQKVFVLLAALRPQWCSREIPDPANSTCAKKYPIAEEKTQLPLDRLLIDWPTPEDPEPLVISEVLHQVTPVFRHPPCSNWPQREKGIQGHQASEKDMMHSASSPPPPRALQAESRQLVDLYKVLESRGSDPKPENPACPWTVLPAGDLPTHDGYLPSNIDDLPSHEAPLADSLEELEPQHISLSVFPSSSLHPLTFSCGDKLTLDQLKMRCDSLML

SEQ ID NO:9

h5AIg137.3z(CDH17特异性AI-CARγ/CD137/CD3z)

MEFGLSWVFLVALLRGVQCQVQLVQSGAEVKKPGASVKVSCKVSAYAFSSSWMNWVRQAPGKGLEWMGRIYPRDGDTNYNGKFKGRVTMTADTSTDTAYMELSSLRSEDTAVYYCAREGDGYYWYFDVWGQGTTVTVSSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSIRNYLHWYQQKPGEAPRLLIYYASQSISGIPARFSGSGSGTDFTLTISSLETEDFAMYYCQHSNSWPLTFGQGTKLEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADAVVISVGSMGLIISLLCVYFWLERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPETKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO:10

h10AIa7(CDH17特异性a7)

MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQTPGKGLEWVAVIDSNGGSTYYPDTVKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCSSYTNLGAYWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISGYLNWLQQKPGGAIKRLIYTTSTLDSGVPKRFSGSGSGTDFTLTISSLQSEDFATYYCLQYASSPFTFGGGTKVEIKGAPPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFAADPILLTISILSFFSVALLVILACVLWKKRIKPIVWPSLPDHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLEESEKQRLGGDVQSPNCPSEDVVITPESFGRDSSLTCLAGNVSACDAPILSSSRSLDCRESGKNGPHVYQDLLLSLGTTNSTLPPPFSLQSGILTLNPVAQGQPILTSLGSNQEEAYVTMSSFYQNQ

RNA AI-CAR的实例

SEQ ID NO:11

h10C7-P2A-IL18(CDH17 CAR-IL18)

MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQTPGKGLEWVAV IDSNGGSTYYPDTVKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCSSYTNLGAYWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISGYLNWLQQKPGGAIKRLIYTTSTLDSGVPKRFSGSGSGTDFTLTISSLQSEDFATYYCLQYASSPFTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED

SEQ ID NO:12

h10C7-P2A-INFg(CDH17 CAR-INFγ)

-MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQTPGKGLEWVAVIDSNGGSTYYPDTVKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCSSYTNLGAYWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISGYLNWLQQKPGGAIKRLIYTTSTLDSGVPKRFSGSGSGTDFTLTISSLQSEDFATYYCLQYASSPFTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMKHLWFFLLLVAAPRWVLSQDPYVKEAENLKKYFNAGHSDVADNGTLFLGILKNWKEESDRKIMQSQIVSFYFKLFKNFKDDQSIQKSVETIKEDMNVKFFNSNKKKRDDFEKLTNYSVTDLNVQRKAIHELIQVMAELSPAAKTGKRKRSQMLFRGRRASQ

SEQ ID NO:13

h10C7-P2A-IL18-pro-CCL21(CDH17 CAR-IL18-proCCL21)

MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQTPGKGLEWVAV IDSNGGSTYYPDTVKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCSSYTNLGAYWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISGYLNWLQQKPGGAIKRLIYTTSTLDSGVPKRFSGSGSGTDFTLTISSLQSEDFATYYCLQYASSPFTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNEDP AGGGTKTESSSRSDGGAQDCCLKYSQRKIPAKVVRSYRKQEPSLGCSIPAILFLPRKRSQAELCADPKELWVQQLMQHLDKTPSPQKPAQGCRKDRGASKTGKKGKGSKGCKRTERSQTPKGP

SEQ ID NO:14

h10C7-P2A-h8C7-P2A-IL18(CDH17 CAR-TROP2CAR-IL18)

MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQTPGKGLEWVAV IDSNGGSTYYPDTVKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCSSYTNLGAYWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISGYLNWLQQKPGGAIKRLIYTTSTLDSGVPKRFSGSGSGTDFTLTISSLQSEDFATYYCLQYASSPFTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYTMSWVRQTPAKGLVWVSTINSDGYNIYYSDSMKGRFTISRDNAKYTLYLQMNSLRAEDTAMYYCARCSYYSYDYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASENIDNYLAWYQQKQGKVPKLLIYAATNLADGMPSRFSGSGSGTDFTLTISSLQPEDVATYYCQHYYSNQLTFGQGTKLEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITL YCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED

SEQ ID NO:15

h10C7-P2A-h3U1(CDH17 CAR-双特异性抗体抗-CDH17xCD3)

MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQTPGKGLEWVAV IDSNGGSTYYPDTVKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCSSYTNLGAYWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISGYLNWLQQKPGGAIKRLIYTTSTLDSGVPKRFSGSGSGTDFTLTISSLQSEDFATYYCLQYASSPFTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGSGGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELKPAGGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK

SEQ ID NO:16

h10C7-P2A-h3U1-pro-IL18(CDH17 CAR-双特异性抗体抗-CDH17xCD3-pro-IL18)

MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQTPGKGLEWVAV IDSNGGSTYYPDTVKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCSSYTNLGAYWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISGYLNWLQQKPGGAIKRLIYTTSTLDSGVPKRFSGSGSGTDFTLTISSLQSEDFATYYCLQYASSPFTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGSGGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELKPAGGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKPAGGGTKTESSSRGYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED

SEQ ID NO:17

h10C7-P2A-h3U1-pro-IL18-pro-XCL1(CDH17 CAR-双特异性抗体抗-CDH17xCD3-proIL18-proXCL1)

MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQTPGKGLEWVAV IDSNGGSTYYPDTVKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCSSYTNLGAYWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISGYLNWLQQKPGGAIKRLIYTTSTLDSGVPKRFSGSGSGTDFTLTISSLQSEDFATYYCLQYASSPFTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGSGGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELKPAGGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKPAGGGTKTESSSRGYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNEDSGGGTKTESSSRGVGSEVSDKRTCVSLTTQRLPVSRIKTYTITEGSLRAVIFITKRGLKVCA

DPQATWVRDVVRSMDRKSNTRNNMIQTKPTGTQQSTNTAVTLTG

AI-CAR诱导型基因组合的实例

SEQ ID NO:18

h3U1–P2A-IL18(双特异性抗体抗-CDH17xCD3-IL18)

MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGSGGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELKPAGGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKASGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED

SEQ ID NO:19

iPro7(具有n-末端IL7的iPro)

MFHVSFRYIFGLPPLILVLLPVASSDCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEHGGGSGGGSGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKKPAGRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLNTDAYLSLQELQGQDP

SEQ ID NO:20

iPro7-P2A-h3U1–P2A-IL18(iProIL7-双特异性抗体抗-CDH17xCD3-IL18)

MFHVSFRYIFGLPPLILVLLPVASSDCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEHGGGSGGGSGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKKPAGRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLNTDAYLSLQELQGQDPASGSGATNFSLLKQAGDVEENPGPQVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGSGGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELKPAGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED

SEQ ID NO:21

iPro7-P2A-h3U1–P2A-IL18-pro-CCL21(iProIL7-双特异性抗体抗-CDH17xCD3-IL18-proCCL21)

MFHVSFRYIFGLPPLILVLLPVASSDCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEHGGGSGGGSGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKKPAGRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLNTDAYLSLQELQGQDPASGSGATNFSLLKQAGDVEENPGPQVQLVESGGGVVQPGRSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVASISFDGTYTYYTDRVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPAWFPYWGQGTLVTVSAGGGGSGGGGSGGGGSGDIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGAGTKLELKPAGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNEDGGGTKTESSSRSDGGAQDCCLKYSQRKIPAKVVRSYRKQEPSLGCSIPAILFLPRKRSQAELCADPKELWVQQLMQHLDKTPSPQKPAQGCRKDRGASKTGKKGKGSKGCKRTERSQTPKGP

序列表

<110> 艾贝乐医药科技有限公司

<120> 人工免疫监视嵌合抗原受体（AI-CAR）及其表达细胞

<130> ARTI917PCT

<141> 2020-02-21

<150> 62/808,815

<151> 2019-02-21

<150> 62/808,823

<151> 2019-02-21

<150> 62/808,833

<151> 2019-02-21

<160> 21

<170> SIPOSequenceListing 1.0

<210> 1

<211> 532

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 1

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

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

20 25 30

Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe

35 40 45

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

50 55 60

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

65 70 75 80

Gln Lys Phe Lys Gly Arg Val Thr Ser Thr Arg Asp Thr Ser Ile Ser

85 90 95

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

100 105 110

Tyr Tyr Cys Ala Arg Glu Arg Ile Tyr Tyr Gly Ile Ser Trp Tyr Phe

115 120 125

Asp Val Trp Asp Thr Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met

145 150 155 160

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

165 170 175

Ile Thr Cys Arg Ala Ser Gly Asn Ile His Asn Tyr Leu Ala Trp Tyr

180 185 190

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

195 200 205

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

210 215 220

Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

225 230 235 240

Thr Tyr Tyr Cys His His Tyr Tyr Ser Thr Pro Pro Thr Phe Gly Gln

245 250 255

Gly Thr Lys Leu Glu Ile Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ala Val Val Ile Ser Val Gly Ser Met

305 310 315 320

Gly Leu Ile Ile Ser Leu Leu Cys Val Tyr Phe Trp Leu Glu Arg Thr

325 330 335

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

340 345 350

Tyr His Gly Asn Phe Ser Ala Trp Ser Gly Val Ser Lys Gly Leu Ala

355 360 365

Glu Ser Leu Gln Pro Asp Tyr Ser Glu Arg Leu Cys Leu Val Ser Glu

370 375 380

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

385 390 395 400

Cys Asn Gln His Ser Pro Tyr Trp Ala Pro Pro Cys Tyr Thr Leu Lys

405 410 415

Pro Glu Thr Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

420 425 430

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

435 440 445

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

450 455 460

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

465 470 475 480

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

485 490 495

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

500 505 510

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

515 520 525

Leu Pro Pro Arg

530

<210> 2

<211> 496

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 2

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

20 25 30

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

35 40 45

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

50 55 60

Glu Trp Val Ala Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr Tyr Thr

65 70 75 80

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

85 90 95

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

100 105 110

Tyr Tyr Cys Ala Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp Gly Gln

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp

180 185 190

Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val

195 200 205

Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser

210 215 220

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

225 230 235 240

Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Leu Thr Phe Gly

245 250 255

Ala Gly Thr Lys Leu Glu Leu Lys Gly Ala Pro Thr Thr Thr Pro Ala

260 265 270

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

275 280 285

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

290 295 300

Arg Gly Leu Asp Phe Ala Cys Asp Ile Pro Trp Leu Gly His Leu Leu

305 310 315 320

Val Gly Leu Ser Gly Ala Phe Gly Phe Ile Ile Leu Val Tyr Leu Leu

325 330 335

Ile Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val Leu Lys Cys

340 345 350

Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser Ser Glu His

355 360 365

Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro Ser Ser Ser

370 375 380

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

385 390 395 400

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

405 410 415

Glu Pro Ala Ser Leu Ser Ser Asn His Ser Leu Thr Ser Cys Phe Thr

420 425 430

Asn Gln Gly Tyr Phe Phe Phe His Leu Pro Asp Ala Leu Glu Ile Glu

435 440 445

Ala Cys Gln Val Tyr Phe Arg Ser Lys Arg Ser Arg Gly Gly His Ser

450 455 460

Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His

465 470 475 480

Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Pro

485 490 495

<210> 3

<211> 530

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 3

Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp

1 5 10 15

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

20 25 30

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

35 40 45

Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu

50 55 60

Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser

65 70 75 80

Ala Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln

85 90 95

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

100 105 110

Tyr Cys Ala Arg His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln

145 150 155 160

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

165 170 175

Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln

180 185 190

Lys Pro Gly Gly Ala Pro Lys Leu Leu Ile Tyr His Thr Ser Arg Leu

195 200 205

His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

210 215 220

Phe Thr Phe Thr Ile Ser Ser Leu Gln Gln Glu Asp Ile Ala Thr Tyr

225 230 235 240

Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr

245 250 255

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

260 265 270

Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro

275 280 285

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

290 295 300

Asp Phe Ala Ala Asp Ala Val Val Ile Ser Val Gly Ser Met Gly Leu

305 310 315 320

Ile Ile Ser Leu Leu Cys Val Tyr Phe Trp Leu Glu Arg Thr Met Pro

325 330 335

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

340 345 350

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

355 360 365

Leu Gln Pro Asp Tyr Ser Glu Arg Leu Cys Leu Val Ser Glu Ile Pro

370 375 380

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

385 390 395 400

Gln His Ser Pro Tyr Trp Ala Pro Pro Cys Tyr Thr Leu Lys Pro Glu

405 410 415

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

420 425 430

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

435 440 445

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

450 455 460

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

465 470 475 480

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

485 490 495

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

500 505 510

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

515 520 525

Pro Arg

530

<210> 4

<211> 528

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 4

Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp

1 5 10 15

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

20 25 30

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

35 40 45

Thr Ser Tyr Gly Val His Trp Val Arg Gln Pro Pro Gly Arg Gly Leu

50 55 60

Glu Trp Ile Gly Val Met Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala

65 70 75 80

Ala Phe Met Ser Arg Val Thr Met Leu Val Asp Thr Ser Lys Asn Gln

85 90 95

Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr

100 105 110

Tyr Cys Ala Lys Ser Met Ile Thr Thr Gly Phe Val Met Asp Ser Trp

115 120 125

Gly Gln Gly Ser Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser

145 150 155 160

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

165 170 175

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

180 185 190

Pro Gly Lys Ala Pro Lys Leu Leu Ile Ser Gly Ala Thr Ser Leu Glu

195 200 205

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

210 215 220

Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

Phe Ala Ala Asp Pro Ile Leu Leu Thr Ile Ser Ile Leu Ser Phe Phe

305 310 315 320

Ser Val Ala Leu Leu Val Ile Leu Ala Cys Val Leu Trp Lys Lys Arg

325 330 335

Ile Lys Pro Ile Val Trp Pro Ser Leu Pro Asp His Lys Lys Thr Leu

340 345 350

Glu His Leu Cys Lys Lys Pro Arg Lys Asn Leu Asn Val Ser Phe Asn

355 360 365

Pro Glu Ser Phe Leu Asp Cys Gln Ile His Arg Val Asp Asp Ile Gln

370 375 380

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

385 390 395 400

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

405 410 415

Asn Cys Pro Ser Glu Asp Val Val Ile Thr Pro Glu Ser Phe Gly Arg

420 425 430

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

435 440 445

Pro Ile Leu Ser Ser Ser Arg Ser Leu Asp Cys Arg Glu Ser Gly Lys

450 455 460

Asn Gly Pro His Val Tyr Gln Asp Leu Leu Leu Ser Leu Gly Thr Thr

465 470 475 480

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

485 490 495

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

500 505 510

Asn Gln Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn Gln

515 520 525

<210> 5

<211> 533

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 5

Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp

1 5 10 15

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

20 25 30

Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe

35 40 45

Ser Ser Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu

50 55 60

Glu Trp Met Gly Arg Ile Tyr Ser Gly Asp Gly Asp Ala Ile Tyr Asn

65 70 75 80

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

85 90 95

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

100 105 110

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

115 120 125

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln

145 150 155 160

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

165 170 175

Cys Arg Ala Ser Lys Ser Val Ser Thr Ser Ile Tyr Ser Tyr Met His

180 185 190

Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Tyr

195 200 205

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

210 215 220

Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp

225 230 235 240

Val Ala Val Tyr Tyr Cys Glu His Ser Arg Glu Phe Pro Phe Thr Phe

245 250 255

Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Ala Pro Thr Thr Thr Pro

260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Leu Trp Lys Lys Arg Ile Lys Pro Ile Val Trp Pro Ser Leu Pro Asp

340 345 350

His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro Arg Lys Asn Leu

355 360 365

Asn Val Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys Gln Ile His Arg

370 375 380

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

385 390 395 400

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

405 410 415

Asp Val Gln Ser Pro Asn Cys Pro Ser Glu Asp Val Val Ile Thr Pro

420 425 430

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

435 440 445

Ser Ala Cys Asp Ala Pro Ile Leu Ser Ser Ser Arg Ser Leu Asp Cys

450 455 460

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

465 470 475 480

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

485 490 495

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

500 505 510

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

515 520 525

Phe Tyr Gln Asn Gln

530

<210> 6

<211> 495

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 6

Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp

1 5 10 15

Val Leu Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

20 25 30

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

35 40 45

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

50 55 60

Glu Trp Val Ser Tyr Ile Ser Ser Gly Gly Gly Thr Thr Tyr Tyr Pro

65 70 75 80

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

85 90 95

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

100 105 110

Tyr Tyr Cys Ala Arg His Ser Gly Tyr Gly Ser Ser Tyr Gly Val Leu

115 120 125

Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met

145 150 155 160

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

165 170 175

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr

180 185 190

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

195 200 205

Ile Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

210 215 220

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Gln Glu Asp Ile Ala

225 230 235 240

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Gly

245 250 255

Gly Thr Lys Val Glu Ile Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

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

290 295 300

Gly Leu Asp Phe Ala Ala Asp Ile Pro Trp Leu Gly His Leu Leu Val

305 310 315 320

Gly Leu Ser Gly Ala Phe Gly Phe Ile Ile Leu Val Tyr Leu Leu Ile

325 330 335

Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val Leu Lys Cys Asn

340 345 350

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

355 360 365

Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro Ser Ser Ser Phe

370 375 380

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

385 390 395 400

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

405 410 415

Pro Ala Ser Leu Ser Ser Asn His Ser Leu Thr Ser Cys Phe Thr Asn

420 425 430

Gln Gly Tyr Phe Phe Phe His Leu Pro Asp Ala Leu Glu Ile Glu Ala

435 440 445

Cys Gln Val Tyr Phe Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp

450 455 460

Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr

465 470 475 480

Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Pro

485 490 495

<210> 7

<211> 581

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 7

Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp

1 5 10 15

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

20 25 30

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

35 40 45

Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu

50 55 60

Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser

65 70 75 80

Ala Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln

85 90 95

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

100 105 110

Tyr Cys Ala Arg His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln

145 150 155 160

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

165 170 175

Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln

180 185 190

Lys Pro Gly Gly Ala Pro Lys Leu Leu Ile Tyr His Thr Ser Arg Leu

195 200 205

His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

210 215 220

Phe Thr Phe Thr Ile Ser Ser Leu Gln Gln Glu Asp Ile Ala Thr Tyr

225 230 235 240

Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr

245 250 255

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

260 265 270

Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro

275 280 285

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

290 295 300

Asp Phe Ala Ala Asp Trp Leu Ile Phe Phe Ala Ser Leu Gly Ser Phe

305 310 315 320

Leu Ser Ile Leu Leu Val Gly Val Leu Gly Tyr Leu Gly Leu Asn Arg

325 330 335

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

340 345 350

Ala Ile Glu Phe Pro Gly Gly Lys Glu Thr Trp Gln Trp Ile Asn Pro

355 360 365

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

370 375 380

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

385 390 395 400

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

405 410 415

Glu Asp Gly Asp Arg Cys Lys Ala Lys Met Lys Arg Gly Arg Lys Lys

420 425 430

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

435 440 445

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

450 455 460

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

465 470 475 480

Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

485 490 495

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

500 505 510

Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

515 520 525

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

530 535 540

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

545 550 555 560

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

565 570 575

Ala Leu Pro Pro Arg

580

<210> 8

<211> 548

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 8

Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp

1 5 10 15

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

20 25 30

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

35 40 45

Thr Ser Tyr Gly Val His Trp Val Arg Gln Pro Pro Gly Arg Gly Leu

50 55 60

Glu Trp Ile Gly Val Met Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala

65 70 75 80

Ala Phe Met Ser Arg Val Thr Met Leu Val Asp Thr Ser Lys Asn Gln

85 90 95

Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr

100 105 110

Tyr Cys Ala Lys Ser Met Ile Thr Thr Gly Phe Val Met Asp Ser Trp

115 120 125

Gly Gln Gly Ser Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser

145 150 155 160

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

165 170 175

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

180 185 190

Pro Gly Lys Ala Pro Lys Leu Leu Ile Ser Gly Ala Thr Ser Leu Glu

195 200 205

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

210 215 220

Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr

225 230 235 240

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

245 250 255

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

260 265 270

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

275 280 285

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

290 295 300

Phe Ala Ala Asp Trp Met Ala Phe Val Ala Pro Ser Ile Cys Ile Ala

305 310 315 320

Ile Ile Met Val Gly Ile Phe Ser Thr His Tyr Phe Gln Gln Lys Val

325 330 335

Phe Val Leu Leu Ala Ala Leu Arg Pro Gln Trp Cys Ser Arg Glu Ile

340 345 350

Pro Asp Pro Ala Asn Ser Thr Cys Ala Lys Lys Tyr Pro Ile Ala Glu

355 360 365

Glu Lys Thr Gln Leu Pro Leu Asp Arg Leu Leu Ile Asp Trp Pro Thr

370 375 380

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

385 390 395 400

Thr Pro Val Phe Arg His Pro Pro Cys Ser Asn Trp Pro Gln Arg Glu

405 410 415

Lys Gly Ile Gln Gly His Gln Ala Ser Glu Lys Asp Met Met His Ser

420 425 430

Ala Ser Ser Pro Pro Pro Pro Arg Ala Leu Gln Ala Glu Ser Arg Gln

435 440 445

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

450 455 460

Pro Glu Asn Pro Ala Cys Pro Trp Thr Val Leu Pro Ala Gly Asp Leu

465 470 475 480

Pro Thr His Asp Gly Tyr Leu Pro Ser Asn Ile Asp Asp Leu Pro Ser

485 490 495

His Glu Ala Pro Leu Ala Asp Ser Leu Glu Glu Leu Glu Pro Gln His

500 505 510

Ile Ser Leu Ser Val Phe Pro Ser Ser Ser Leu His Pro Leu Thr Phe

515 520 525

Ser Cys Gly Asp Lys Leu Thr Leu Asp Gln Leu Lys Met Arg Cys Asp

530 535 540

Ser Leu Met Leu

545

<210> 9

<211> 572

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 9

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

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

20 25 30

Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Ala Tyr Ala Phe

35 40 45

Ser Ser Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Met Gly Arg Ile Tyr Pro Arg Asp Gly Asp Thr Asn Tyr Asn

65 70 75 80

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

85 90 95

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

100 105 110

Tyr Tyr Cys Ala Arg Glu Gly Asp Gly Tyr Tyr Trp Tyr Phe Asp Val

115 120 125

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln

145 150 155 160

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

165 170 175

Cys Arg Ala Ser Gln Ser Ile Arg Asn Tyr Leu His Trp Tyr Gln Gln

180 185 190

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

195 200 205

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

210 215 220

Phe Thr Leu Thr Ile Ser Ser Leu Glu Thr Glu Asp Phe Ala Met Tyr

225 230 235 240

Tyr Cys Gln His Ser Asn Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr

245 250 255

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

260 265 270

Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro

275 280 285

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

290 295 300

Asp Phe Ala Ala Asp Ala Val Val Ile Ser Val Gly Ser Met Gly Leu

305 310 315 320

Ile Ile Ser Leu Leu Cys Val Tyr Phe Trp Leu Glu Arg Thr Met Pro

325 330 335

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

340 345 350

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

355 360 365

Leu Gln Pro Asp Tyr Ser Glu Arg Leu Cys Leu Val Ser Glu Ile Pro

370 375 380

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

385 390 395 400

Gln His Ser Pro Tyr Trp Ala Pro Pro Cys Tyr Thr Leu Lys Pro Glu

405 410 415

Thr Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

420 425 430

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

435 440 445

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

450 455 460

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

465 470 475 480

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

485 490 495

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys

500 505 510

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

515 520 525

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

530 535 540

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

545 550 555 560

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

565 570

<210> 10

<211> 526

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 10

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

20 25 30

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

35 40 45

Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro

65 70 75 80

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

85 90 95

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

100 105 110

Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly

115 120 125

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

130 135 140

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

145 150 155 160

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

165 170 175

Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly

180 185 190

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

195 200 205

Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

210 215 220

Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln

225 230 235 240

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

245 250 255

Lys Gly Ala Pro Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

260 265 270

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

275 280 285

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

290 295 300

Ala Asp Pro Ile Leu Leu Thr Ile Ser Ile Leu Ser Phe Phe Ser Val

305 310 315 320

Ala Leu Leu Val Ile Leu Ala Cys Val Leu Trp Lys Lys Arg Ile Lys

325 330 335

Pro Ile Val Trp Pro Ser Leu Pro Asp His Lys Lys Thr Leu Glu His

340 345 350

Leu Cys Lys Lys Pro Arg Lys Asn Leu Asn Val Ser Phe Asn Pro Glu

355 360 365

Ser Phe Leu Asp Cys Gln Ile His Arg Val Asp Asp Ile Gln Ala Arg

370 375 380

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

385 390 395 400

Glu Ser Glu Lys Gln Arg Leu Gly Gly Asp Val Gln Ser Pro Asn Cys

405 410 415

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

420 425 430

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

435 440 445

Leu Ser Ser Ser Arg Ser Leu Asp Cys Arg Glu Ser Gly Lys Asn Gly

450 455 460

Pro His Val Tyr Gln Asp Leu Leu Leu Ser Leu Gly Thr Thr Asn Ser

465 470 475 480

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

485 490 495

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

500 505 510

Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn Gln

515 520 525

<210> 11

<211> 684

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 11

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

20 25 30

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

35 40 45

Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro

65 70 75 80

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

85 90 95

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

100 105 110

Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly

115 120 125

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

130 135 140

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

145 150 155 160

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

165 170 175

Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly

180 185 190

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

195 200 205

Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

210 215 220

Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln

225 230 235 240

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

245 250 255

Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

260 265 270

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

275 280 285

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

290 295 300

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

305 310 315 320

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

325 330 335

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

340 345 350

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

355 360 365

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

370 375 380

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

385 390 395 400

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

405 410 415

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

420 425 430

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

435 440 445

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

450 455 460

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

465 470 475 480

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

485 490 495

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

500 505 510

Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln Cys Tyr

515 520 525

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

530 535 540

Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp Met

545 550 555 560

Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile Ile

565 570 575

Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile Ser

580 585 590

Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile

595 600 605

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

610 615 620

Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys Met

625 630 635 640

Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu Lys

645 650 655

Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu Gly

660 665 670

Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp

675 680

<210> 12

<211> 670

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 12

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

20 25 30

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

35 40 45

Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro

65 70 75 80

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

85 90 95

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

100 105 110

Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly

115 120 125

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

130 135 140

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

145 150 155 160

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

165 170 175

Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly

180 185 190

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

195 200 205

Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

210 215 220

Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln

225 230 235 240

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

245 250 255

Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

260 265 270

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

275 280 285

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

290 295 300

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

305 310 315 320

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

325 330 335

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

340 345 350

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

355 360 365

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

370 375 380

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

385 390 395 400

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

405 410 415

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

420 425 430

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

435 440 445

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

450 455 460

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

465 470 475 480

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

485 490 495

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

500 505 510

Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp Val Leu Ser Gln

515 520 525

Asp Pro Tyr Val Lys Glu Ala Glu Asn Leu Lys Lys Tyr Phe Asn Ala

530 535 540

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

545 550 555 560

Lys Asn Trp Lys Glu Glu Ser Asp Arg Lys Ile Met Gln Ser Gln Ile

565 570 575

Val Ser Phe Tyr Phe Lys Leu Phe Lys Asn Phe Lys Asp Asp Gln Ser

580 585 590

Ile Gln Lys Ser Val Glu Thr Ile Lys Glu Asp Met Asn Val Lys Phe

595 600 605

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

610 615 620

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

625 630 635 640

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

645 650 655

Lys Arg Ser Gln Met Leu Phe Arg Gly Arg Arg Ala Ser Gln

660 665 670

<210> 13

<211> 808

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 13

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

20 25 30

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

35 40 45

Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro

65 70 75 80

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

85 90 95

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

100 105 110

Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly

115 120 125

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

130 135 140

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

145 150 155 160

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

165 170 175

Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly

180 185 190

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

195 200 205

Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

210 215 220

Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln

225 230 235 240

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

245 250 255

Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

260 265 270

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

275 280 285

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

290 295 300

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

305 310 315 320

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

325 330 335

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

340 345 350

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

355 360 365

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

370 375 380

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

385 390 395 400

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

405 410 415

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

420 425 430

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

435 440 445

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

450 455 460

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

465 470 475 480

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

485 490 495

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

500 505 510

Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln Cys Tyr

515 520 525

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

530 535 540

Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp Met

545 550 555 560

Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile Ile

565 570 575

Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile Ser

580 585 590

Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile

595 600 605

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

610 615 620

Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys Met

625 630 635 640

Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu Lys

645 650 655

Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu Gly

660 665 670

Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp Pro Ala Gly Gly

675 680 685

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

690 695 700

Cys Cys Leu Lys Tyr Ser Gln Arg Lys Ile Pro Ala Lys Val Val Arg

705 710 715 720

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

725 730 735

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

740 745 750

Lys Glu Leu Trp Val Gln Gln Leu Met Gln His Leu Asp Lys Thr Pro

755 760 765

Ser Pro Gln Lys Pro Ala Gln Gly Cys Arg Lys Asp Arg Gly Ala Ser

770 775 780

Lys Thr Gly Lys Lys Gly Lys Gly Ser Lys Gly Cys Lys Arg Thr Glu

785 790 795 800

Arg Ser Gln Thr Pro Lys Gly Pro

805

<210> 14

<211> 1119

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 14

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

1 5 10 15

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

20 25 30

Thr Ala Val Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp

35 40 45

Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly

50 55 60

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser

65 70 75 80

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

85 90 95

Arg Ala Ser Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys

100 105 110

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

115 120 125

Ser Gly Val Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

130 135 140

Thr Leu Thr Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr

145 150 155 160

Cys Leu Gln Tyr Ala Ser Ser Pro Phe Thr Phe Gly Gly Gly Thr Lys

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

225 230 235 240

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

245 250 255

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

260 265 270

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

275 280 285

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

290 295 300

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

305 310 315 320

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

325 330 335

Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly

340 345 350

Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu

355 360 365

Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu

370 375 380

Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His

385 390 395 400

Met Gln Ala Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn Phe

405 410 415

Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met

420 425 430

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

435 440 445

Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro

450 455 460

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

465 470 475 480

Thr Tyr Thr Met Ser Trp Val Arg Gln Thr Pro Ala Lys Gly Leu Val

485 490 495

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

500 505 510

Ser Met Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Tyr Thr

515 520 525

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr

530 535 540

Tyr Cys Ala Arg Cys Ser Tyr Tyr Ser Tyr Asp Tyr Phe Asp Tyr Trp

545 550 555 560

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

565 570 575

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser

580 585 590

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

595 600 605

Arg Ala Ser Glu Asn Ile Asp Asn Tyr Leu Ala Trp Tyr Gln Gln Lys

610 615 620

Gln Gly Lys Val Pro Lys Leu Leu Ile Tyr Ala Ala Thr Asn Leu Ala

625 630 635 640

Asp Gly Met Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

645 650 655

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

660 665 670

Cys Gln His Tyr Tyr Ser Asn Gln Leu Thr Phe Gly Gln Gly Thr Lys

675 680 685

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

690 695 700

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

705 710 715 720

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

725 730 735

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

740 745 750

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

755 760 765

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

770 775 780

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

785 790 795 800

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

805 810 815

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

820 825 830

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

835 840 845

Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly

850 855 860

Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu

865 870 875 880

Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu

885 890 895

Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His

900 905 910

Met Gln Ala Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn Phe

915 920 925

Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met

930 935 940

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

945 950 955 960

Gln Cys Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn

965 970 975

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

980 985 990

Glu Asp Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile

995 1000 1005

Phe Ile Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val

1010 1015 1020

Thr Ile Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn

1025 1030 1035 1040

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

1045 1050 1055

Thr Lys Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp

1060 1065 1070

Asn Lys Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala

1075 1080 1085

Cys Glu Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp

1090 1095 1100

Glu Leu Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp

1105 1110 1115

<210> 15

<211> 1024

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 15

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

20 25 30

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

35 40 45

Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro

65 70 75 80

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

85 90 95

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

100 105 110

Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly

115 120 125

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

130 135 140

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

145 150 155 160

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

165 170 175

Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly

180 185 190

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

195 200 205

Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

210 215 220

Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln

225 230 235 240

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

245 250 255

Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

260 265 270

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

275 280 285

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

290 295 300

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

305 310 315 320

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

325 330 335

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

340 345 350

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

355 360 365

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

370 375 380

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

385 390 395 400

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

405 410 415

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

420 425 430

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

435 440 445

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

450 455 460

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

465 470 475 480

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

485 490 495

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

500 505 510

Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln Cys Gln

515 520 525

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

530 535 540

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr

545 550 555 560

Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala

565 570 575

Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr Tyr Thr Asp Arg Val Lys

580 585 590

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

595 600 605

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

610 615 620

Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val

625 630 635 640

Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

645 650 655

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

660 665 670

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

675 680 685

Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys

690 695 700

Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe

705 710 715 720

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

725 730 735

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

740 745 750

Cys Phe Gln Gly Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys

755 760 765

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

770 775 780

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

785 790 795 800

Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp

805 810 815

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

820 825 830

Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Arg Phe

835 840 845

Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn

850 855 860

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

865 870 875 880

Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr

885 890 895

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

900 905 910

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

915 920 925

Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln

930 935 940

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

945 950 955 960

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

965 970 975

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile

980 985 990

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly

995 1000 1005

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

1010 1015 1020

<210> 16

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 16

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

20 25 30

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

35 40 45

Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro

65 70 75 80

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

85 90 95

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

100 105 110

Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly

115 120 125

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

130 135 140

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

145 150 155 160

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

165 170 175

Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly

180 185 190

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

195 200 205

Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

210 215 220

Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln

225 230 235 240

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

245 250 255

Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

260 265 270

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

275 280 285

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

290 295 300

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

305 310 315 320

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

325 330 335

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

340 345 350

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

355 360 365

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

370 375 380

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

385 390 395 400

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

405 410 415

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

420 425 430

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

435 440 445

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

450 455 460

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

465 470 475 480

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

485 490 495

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

500 505 510

Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln Cys Gln

515 520 525

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

530 535 540

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr

545 550 555 560

Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala

565 570 575

Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr Tyr Thr Asp Arg Val Lys

580 585 590

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

595 600 605

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

610 615 620

Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val

625 630 635 640

Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

645 650 655

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

660 665 670

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

675 680 685

Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys

690 695 700

Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe

705 710 715 720

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

725 730 735

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

740 745 750

Cys Phe Gln Gly Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys

755 760 765

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

770 775 780

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

785 790 795 800

Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp

805 810 815

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

820 825 830

Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Arg Phe

835 840 845

Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn

850 855 860

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

865 870 875 880

Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr

885 890 895

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

900 905 910

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

915 920 925

Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln

930 935 940

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

945 950 955 960

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

965 970 975

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile

980 985 990

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly

995 1000 1005

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

1010 1015 1020

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

1025 1030 1035 1040

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

1045 1050 1055

Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp Met Thr

1060 1065 1070

Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile Ile Ser

1075 1080 1085

Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile Ser Val

1090 1095 1100

Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile Ser

1105 1110 1115 1120

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

1125 1130 1135

Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys Met Gln

1140 1145 1150

Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu Lys Glu

1155 1160 1165

Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu Gly Asp

1170 1175 1180

Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp

1185 1190 1195

<210> 17

<211> 1301

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 17

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

20 25 30

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

35 40 45

Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ala Val Ile Asp Ser Asn Gly Gly Ser Thr Tyr Tyr Pro

65 70 75 80

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

85 90 95

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

100 105 110

Tyr Tyr Cys Ser Ser Tyr Thr Asn Leu Gly Ala Tyr Trp Gly Gln Gly

115 120 125

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

130 135 140

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

145 150 155 160

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

165 170 175

Gln Asp Ile Ser Gly Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Gly

180 185 190

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

195 200 205

Pro Lys Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

210 215 220

Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln

225 230 235 240

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

245 250 255

Lys Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

260 265 270

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

275 280 285

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

290 295 300

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

305 310 315 320

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

325 330 335

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

340 345 350

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

355 360 365

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

370 375 380

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

385 390 395 400

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

405 410 415

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

420 425 430

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

435 440 445

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

450 455 460

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

465 470 475 480

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

485 490 495

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

500 505 510

Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln Cys Gln

515 520 525

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

530 535 540

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr

545 550 555 560

Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala

565 570 575

Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr Tyr Thr Asp Arg Val Lys

580 585 590

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

595 600 605

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

610 615 620

Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val

625 630 635 640

Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

645 650 655

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

660 665 670

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

675 680 685

Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys

690 695 700

Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe

705 710 715 720

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

725 730 735

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

740 745 750

Cys Phe Gln Gly Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys

755 760 765

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

770 775 780

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

785 790 795 800

Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp

805 810 815

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

820 825 830

Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Arg Phe

835 840 845

Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn

850 855 860

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

865 870 875 880

Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr

885 890 895

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

900 905 910

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

915 920 925

Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln

930 935 940

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

945 950 955 960

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

965 970 975

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile

980 985 990

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly

995 1000 1005

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

1010 1015 1020

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

1025 1030 1035 1040

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

1045 1050 1055

Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp Met Thr

1060 1065 1070

Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile Ile Ser

1075 1080 1085

Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile Ser Val

1090 1095 1100

Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile Ser

1105 1110 1115 1120

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

1125 1130 1135

Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys Met Gln

1140 1145 1150

Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu Lys Glu

1155 1160 1165

Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu Gly Asp

1170 1175 1180

Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp Ser Gly Gly Gly Thr

1185 1190 1195 1200

Lys Thr Glu Ser Ser Ser Arg Gly Val Gly Ser Glu Val Ser Asp Lys

1205 1210 1215

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

1220 1225 1230

Lys Thr Tyr Thr Ile Thr Glu Gly Ser Leu Arg Ala Val Ile Phe Ile

1235 1240 1245

Thr Lys Arg Gly Leu Lys Val Cys Ala Asp Pro Gln Ala Thr Trp Val

1250 1255 1260

Arg Asp Val Val Arg Ser Met Asp Arg Lys Ser Asn Thr Arg Asn Asn

1265 1270 1275 1280

Met Ile Gln Thr Lys Pro Thr Gly Thr Gln Gln Ser Thr Asn Thr Ala

1285 1290 1295

Val Thr Leu Thr Gly

1300

<210> 18

<211> 716

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 18

Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly

1 5 10 15

Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln

20 25 30

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

35 40 45

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

50 55 60

Glu Trp Val Ala Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr Tyr Thr

65 70 75 80

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

85 90 95

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

100 105 110

Tyr Tyr Cys Ala Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp Gly Gln

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp

180 185 190

Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val

195 200 205

Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser

210 215 220

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

225 230 235 240

Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Leu Thr Phe Gly

245 250 255

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

260 265 270

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

275 280 285

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

290 295 300

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

305 310 315 320

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

325 330 335

Lys Asp Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr

340 345 350

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

355 360 365

Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp

370 375 380

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

385 390 395 400

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser

405 410 415

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

420 425 430

Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys

435 440 445

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

450 455 460

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

465 470 475 480

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr

485 490 495

Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys

500 505 510

Val Glu Ile Lys Ala Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu

515 520 525

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

530 535 540

Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln Cys Tyr

545 550 555 560

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

565 570 575

Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp Met

580 585 590

Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile Ile

595 600 605

Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile Ser

610 615 620

Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile

625 630 635 640

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

645 650 655

Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys Met

660 665 670

Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu Lys

675 680 685

Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu Gly

690 695 700

Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp

705 710 715

<210> 19

<211> 349

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 19

Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile

1 5 10 15

Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys

20 25 30

Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu

35 40 45

Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe

50 55 60

Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe

65 70 75 80

Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser

85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu

145 150 155 160

Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu

165 170 175

His Gly Gly Gly Ser Gly Gly Gly Ser Gly Ala Pro Thr Thr Thr Pro

180 185 190

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

195 200 205

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

210 215 220

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

225 230 235 240

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

245 250 255

Cys Lys Lys Pro Ala Gly Arg Asn Thr Gly Pro Trp Leu Lys Lys Val

260 265 270

Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser

275 280 285

Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro

290 295 300

Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu

305 310 315 320

Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Leu Asn Thr Asp

325 330 335

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

340 345

<210> 20

<211> 818

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 20

Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile

1 5 10 15

Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys

20 25 30

Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu

35 40 45

Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe

50 55 60

Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe

65 70 75 80

Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser

85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu

145 150 155 160

Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu

165 170 175

His Gly Gly Gly Ser Gly Gly Gly Ser Gly Ala Pro Thr Thr Thr Pro

180 185 190

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

195 200 205

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

210 215 220

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

225 230 235 240

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

245 250 255

Cys Lys Lys Pro Ala Gly Arg Asn Thr Gly Pro Trp Leu Lys Lys Val

260 265 270

Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser

275 280 285

Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro

290 295 300

Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu

305 310 315 320

Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Leu Asn Thr Asp

325 330 335

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

340 345 350

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

355 360 365

Glu Asn Pro Gly Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val

370 375 380

Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

385 390 395 400

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

405 410 415

Gly Leu Glu Trp Val Ala Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr

420 425 430

Tyr Thr Asp Arg Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

435 440 445

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

450 455 460

Ala Val Tyr Tyr Cys Ala Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp

465 470 475 480

Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly

485 490 495

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Asp Ile Val Met Thr Gln

500 505 510

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

515 520 525

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

530 535 540

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

545 550 555 560

Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser

565 570 575

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

580 585 590

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

595 600 605

Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Pro Ala Gly Ser Gly Ala

610 615 620

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

625 630 635 640

Gly Pro Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu

645 650 655

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

660 665 670

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

675 680 685

Pro Leu Phe Glu Asp Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro

690 695 700

Arg Thr Ile Phe Ile Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly

705 710 715 720

Met Ala Val Thr Ile Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser

725 730 735

Cys Glu Asn Lys Ile Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn

740 745 750

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

755 760 765

Gly His Asp Asn Lys Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr

770 775 780

Phe Leu Ala Cys Glu Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys

785 790 795 800

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

805 810 815

Glu Asp

<210> 21

<211> 940

<212> PRT

<213> Artificial Sequence

<220>

<223> synthesized

<400> 21

Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile

1 5 10 15

Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys

20 25 30

Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu

35 40 45

Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe

50 55 60

Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe

65 70 75 80

Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser

85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu

145 150 155 160

Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu

165 170 175

His Gly Gly Gly Ser Gly Gly Gly Ser Gly Ala Pro Thr Thr Thr Pro

180 185 190

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

195 200 205

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

210 215 220

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

225 230 235 240

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

245 250 255

Cys Lys Lys Pro Ala Gly Arg Asn Thr Gly Pro Trp Leu Lys Lys Val

260 265 270

Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser

275 280 285

Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro

290 295 300

Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu

305 310 315 320

Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Leu Asn Thr Asp

325 330 335

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

340 345 350

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

355 360 365

Glu Asn Pro Gly Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val

370 375 380

Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

385 390 395 400

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

405 410 415

Gly Leu Glu Trp Val Ala Ser Ile Ser Phe Asp Gly Thr Tyr Thr Tyr

420 425 430

Tyr Thr Asp Arg Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

435 440 445

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

450 455 460

Ala Val Tyr Tyr Cys Ala Arg Asp Arg Pro Ala Trp Phe Pro Tyr Trp

465 470 475 480

Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly

485 490 495

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Asp Ile Val Met Thr Gln

500 505 510

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

515 520 525

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

530 535 540

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

545 550 555 560

Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser

565 570 575

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

580 585 590

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

595 600 605

Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Pro Ala Gly Ser Gly Ala

610 615 620

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

625 630 635 640

Gly Pro Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu

645 650 655

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

660 665 670

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

675 680 685

Pro Leu Phe Glu Asp Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro

690 695 700

Arg Thr Ile Phe Ile Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly

705 710 715 720

Met Ala Val Thr Ile Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser

725 730 735

Cys Glu Asn Lys Ile Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn

740 745 750

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

755 760 765

Gly His Asp Asn Lys Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr

770 775 780

Phe Leu Ala Cys Glu Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys

785 790 795 800

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

805 810 815

Glu Asp Gly Gly Gly Thr Lys Thr Glu Ser Ser Ser Arg Ser Asp Gly

820 825 830

Gly Ala Gln Asp Cys Cys Leu Lys Tyr Ser Gln Arg Lys Ile Pro Ala

835 840 845

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

850 855 860

Ile Pro Ala Ile Leu Phe Leu Pro Arg Lys Arg Ser Gln Ala Glu Leu

865 870 875 880

Cys Ala Asp Pro Lys Glu Leu Trp Val Gln Gln Leu Met Gln His Leu

885 890 895

Asp Lys Thr Pro Ser Pro Gln Lys Pro Ala Gln Gly Cys Arg Lys Asp

900 905 910

Arg Gly Ala Ser Lys Thr Gly Lys Lys Gly Lys Gly Ser Lys Gly Cys

915 920 925

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

930 935 940
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