CN114502188A - 人工免疫监视嵌合抗原受体及其表达细胞 - Google Patents
人工免疫监视嵌合抗原受体及其表达细胞 Download PDFInfo
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Abstract
一种非病毒载体，其包含，从5'至3'，侧翼为两个转座子末端反向重复序列、诱导型启动子、包含基因的特定组合的第一编码区，所述基因的表达定位于肿瘤微环境，并且它们的功能是CAR持续性和抗肿瘤机制的介质，以刺激或增强患者的抗肿瘤应答；表达一种或多种人工免疫监视嵌合抗原受体(AI‑CAR)的第二启动子和编码区，以及截短的CD20或截短的EGFR安全靶。多顺反子mRNA由瞬时表达的抗肿瘤机制的特异性组合组成，所述抗肿瘤机制被设计为刺激患者的抗肿瘤应答，与AI‑CAR载体相同。
Description
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，2019年2月21日提交的美国临时申请序列第62/808,830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
嵌合抗原受体(CAR)是免疫疗法的中心部分，其将抗体直接靶向引入细胞免疫中以治疗癌症。产生的CAR具有与TCR和TCR共刺激蛋白的细胞内结构域连接的肿瘤抗原结合结构域。在改造患者的T或NK细胞以产生CAR并将其输注回患者之后，配备表达CAR的T细胞以杀死表达肿瘤抗原的癌细胞。前两种FDA批准的CART细胞疗法均靶向CD19，CD19是许多类型B-细胞癌症上的泛B-细胞表面分子。Kymriah(tisagenlecleucel)被批准用于治疗复发性/难治性B-细胞前体急性淋巴母细胞性白血病(ALL)，而Yescarta(axicabtageneciloleucel)被批准用于治疗复发性/难治性弥漫性大B-细胞淋巴瘤(DLBCL)。在临床试验中，Kymriah治疗后的结果显示3个月后所有类型的B-细胞ALL的缓解率为83％。然而，49％的ALL患者患有细胞因子释放综合征(CRS)，这是在临床试验中造成多次死亡的严重副作用。另外，至少10％的患者由于靶向CD19表位的丢失而复发。在CLL试验中，Kymriah治疗导致57％的总应答率(Boyiadzis 2018)。
多种因素可能导致CAR-T治疗的复发，例如CAR T细胞持续性不足(由于耗竭或宿主抗CART应答)、靶抗原丧失、缺乏有效宿主抗肿瘤应答的诱导，以及不能有效地定位淋巴瘤/实体瘤。CD19表达的丧失发生在B-细胞肿瘤中和在靶向CD19的免疫治疗后(Masir2006，Kimura 2007，Yu 2017)。肿瘤抗原的丢失可以通过靶向第二泛B细胞/肿瘤抗原，例如CD20和CD22来解决。在CD22的情况下，其在ALL胚细胞上广泛表达并且已经用免疫缀合物和单特异性CAR T细胞成功靶向(Boyiadzis 2018)。显著降低免疫逃逸机会的一种策略是使用双特异性CAR靶向CD22作为第二抗原。
抗-CD19x抗-CD22双特异性CAR的几个临床试验正在进行中(Boyiadzis 2018)。这些CAR的配置基于FDA批准的第二代CAR，其共同具有带有CD3ζ内结构域的单链。尽管使用了双重和双特异性的术语，但它们都是双特异性CAR。如果CRS的副作用是由于输注CAR所致，则抗CD22 scFv的添加将不会产生很大的差异。尽管如此，仍然不清楚在这些试验中有多少患者将经历CRS。
需要非病毒双特异性CAR表达构建体，其构成导致更完全和持久应答的组合疗法。以这种方式，提供细胞因子不仅用于增强CAR细胞毒性、存活和增殖，而且用于诱导宿主抗肿瘤应答。此外，细胞因子应答是局部的和瞬时的，因此避免了全身施用细胞因子时观察到的毒性。除了全身细胞因子治疗和肿瘤抗原损失的考虑之外，CAR细胞存活、持续性、耗竭和制造的问题也是相关的。为了建立完整和持久的应答，存在补充可溶性细胞因子生长因子、多次给药或激活细胞因子信号传导途径的方法，以便驱动扩增而没有末端分化。细胞因子处理可增强CAR的体内扩增和活性，而CAR细胞的产生可利用多种细胞因子进行扩增。这些问题可以通过响应靶抗原产生细胞因子的选择组合来解决。
发明内容
在一个方面，本申请提供双特异性嵌合抗原受体。在一个实施方案中，所述受体包含通过接头与细胞间结构域连接的细胞外结构域，其中所述细胞外结构域包含与第二scFv连接的第一scFv，其中所述第一scFv结构域和所述第二scFv结构域各自独立地对CD19或CD22具有亲和力，其中所述第一scFv结构域和所述第二scFv结构域对不同抗原具有亲和力，并且其中所述细胞内结构域包含共刺激内结构域和CD3ξ结构域。
在第二方面，本申请提供双特异性嵌合抗原受体复合物。在一个实施方案中，这样的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CD19或CD22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CD19或CD22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。第一scFv结构域和第二scFv结构域对不同肿瘤抗原具有亲和力。
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)依次包含编码其公开的蛋白质的核酸、编码核糖体跳跃序列的核酸和编码其公开的蛋白质的核酸。在一个实施方案中，开放阅读框(ORF)依次包含CD22 scFv、接头、CD22 scFv和嵌合抗原受体结构域。
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，这样的复合物包含结合至CD19抗原或CD22抗原的如其所公开的双特异性或双重嵌合抗原受体。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，本申请提供了非病毒载体。在一个实施方案中，所述非病毒载体包含，5'至3'侧翼为两个转座子、启动子、包含用于表达第一人工免疫监视嵌合抗原受体(AI-CAR)的基因的第一编码区、包含表达截短的CD20或截短的EGFR安全靶的基因的第四编码区，随后是polyA信号序列。
在一个实施方案中，第一启动子包含STAT、NFAT或NF-κB诱导型启动子。在一个实施方案中，第一编码区和第四编码区通过IRES连接。在一个实施方案中，第一AI-CAR包含CD19 CAR或CD22 CAR。
在一个实施方案中，所述非病毒载体还包含第二编码区，所述第二编码区包含用于表达第二AI-CAR的基因，介于所述第一编码区和所述第四编码区中间。在一个实施方案中，第一CAR包含CD19 CAR并且其中第二区域包含CD22 CAR或CD20 CAR。
在一个实施方案中，所述非病毒载体还包含第三编码区，所述第三编码区包含用于表达第三AI-CAR的基因，基于所述第二编码区和所述第四编码区中间。在一个实施例中，第一CAR包含CD19 scFv，其中第二CAR包含CD22 scFv或CD20 scFv，并且其中第一CAR通过连接子连接到第二CAR。
在另一方面，本申请提供分离的核酸。在一个实施方案中，分离的核酸编码蛋白质、受体、生物分子或其生物分子复合物。
在进一步的方面，本申请提供表达载体。在一个实施方案中，所述表达载体包含如其所公开的分离的核酸。在一个实施方案中，所述表达载体包含编码细胞因子表达的核酸及其公开的ORF。在一个实施方案中，载体可在细胞中表达。
在进一步的方面，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或表达载体。在一个实施方案中，宿主细胞是原核细胞或真核细胞。
在另外的方面，本申请提供CAR-T或CAR-NK细胞。在一个实施方案中，这样的细胞表达如其所公开的嵌合抗原受体或嵌合抗原受体复合物。
在另一方面，本申请提供哺乳动物细胞。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或嵌合抗原受体复合物。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。
在另一方面，本申请提供用于治疗受试者的肿瘤的方法。在一个实施方案中，所述方法包含向受试者施用足够量的如公开的CAR-T或CAR-NK细胞或非病毒载体
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显示了在编码靶向CD19、CD22和/或CD20的单特异性、双重或双特异性CAR的非病毒DNA构建体中的AI-CAR表达盒(A-C)，其还能够诱导在AI-CAR载体内编码的蛋白的表达，所述蛋白支持CAR细胞持续性和额外的抗肿瘤活性机制；
图2描绘了体外转录的mRNA，其编码靶向CD19、CD22和/或CD20的单特异性、双重或双特异性CAR以及具有抗肿瘤活性的另外的治疗性蛋白质；
图3描述了在非病毒载体中靶向CD19和CD22或CD20的双重和双特异性AI-CAR诱导由相同的整合AI-CAR表达盒编码的基因(例如细胞因子和/或双特异性抗体)的表达的机制；
图4显示了在电穿孔后第1天，针对人源化抗-CD19scFv-Fc和抗-CD22scFv-Fc的特异性结合，表达CD19和CD22两者的SW480细胞的流式细胞分析结果；
图5显示了CD19和CD22双特异性和双特异性CAR-T细胞与重组人类抗CD19-Fc和抗CD22-Fc结合的流式细胞术分析结果。通过电穿孔质粒混合物或作为单独的质粒产生双特异性CAR细胞，然后汇集单特异性CAR细胞；
图6显示了在IL-15扩增的T细胞上，电穿孔后一天(蛋白质-L；A)，和与rhCD19hFc(B)和rhCD22hFc(C)结合的双重和双特异性CAR表达的总结；
图7显示了表达单一、双重或双特异性抗CD19和/或抗CD22 CAR的CAR-T细胞的细胞毒性，如通过在24小时T细胞依赖性细胞毒性(TDCC)测定中表达CD19、CD22或两者的SW480结肠癌细胞的活力测量的；并且
图8显示了表达双重或双特异性抗CD19和抗CD22 CAR的CAR-T细胞的细胞毒性，如通过在24小时T细胞依赖性细胞毒性(TDCC)测定中表达CD19、CD22或两者的结肠癌细胞SW480的活力测量的。
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))。
术语“抗原或表位结合部分或片段”是指能够结合抗原(在此CD19、CD20和CD22)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。
为了解决CAR扩增、终末分化和耗竭中细胞因子信号传导途径的问题，本申请公开了使用人工免疫监测嵌合抗原受体(AI-CAR)调节宿主对CAR的应答的组合物和方法。该AI-CAR技术的进步旨在替代标准CAR制造并实现有效的护理治疗点。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能够在不存在用于增殖的组成型活性驱动物或用于持久抗肿瘤应答的多次CAR给药的情况下产生CAR细胞。
与标准CAR相比，AI-CAR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。
随后在体内肿瘤细胞的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，而不使其组成型表达。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，存在多个靶，例如CD19、CD20和CD22、CD9和CD38。靶向策略可涉及使用在非病毒DNA载体或瞬时表达的RNA-CAR中编码的双重、双特异性AI-CAR。以这种方式，AI-CAR可用于更大的持续性或作为移植的瞬时治疗桥。或者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。由于强烈的体内扩增，可以施用较少的DNA载体AI-CAR细胞。在本文中，编码一个或两个CAR以及多个诱导型基因的非病毒盒构建体是用于护理点治疗和刺激持久宿主抗肿瘤应答的新方法。CAR的这种配置使得能够在T细胞、NK细胞和其它免疫细胞中产生CAR，而不存在对于增殖或炎性细胞因子的潜在有毒的组成型活性驱动物，并且不存在对于持久的抗肿瘤应答的多重CAR给药。本申请中的双特异性CAR不仅靶向CD19和CD22以防止经由抗原丢失的肿瘤逃逸，而且能够诱导应答，例如细胞因子、趋化因子或双特异性抗体，其定位或限于肿瘤细胞接合。
实施例
实施例1.AI-CAR构建体
可以构建具有诱导型启动子的CAR载体以在肿瘤接合后诱导额外蛋白的表达，其具有不同的抗肿瘤活性机制以增强CAR活性。因此AI-CAR构成组合疗法。通过将信号肽、抗CD19 CAR scFv、CD8胞外域茎和跨膜结构域、CD137和CD3z内结构域融合至P2A核糖体跳跃序列或IRES然后融合至信号肽、用于CAR消除的靶例如截短的EGFR或截短的CD20和polyA信号，可以构建单特异性AI-CAR(图1A，SEQ ID1-5)。为产生双特异性AI-CAR，可将第二完整CAR序列插入第一CAR与安全靶之间，如图1B中所指示；SEQ ID 8。可通过将信号肽的编码区融合至CD19结合scFv和接头肽、CD22或CD20结合scFv、CD8铰链和跨膜结构域，以及CD137和CD3z内结构域，随后融合IRES或P2A序列信号序列安全靶序列和pol A信号序列来产生双特异性AI-CAR(图1C，SEQ ID6和7)。此外，AI-CAR载体包含具有转录因子如STAT、NFAT或NF-κB的转录因子应答元件(TF-RE)的诱导型启动子，随后是通过IRES或自身切割核糖体跳跃肽如T2A或P2A连接的一个或多个基因(例如SEQ ID 9、10、16、17)的编码区，随后是如图2A-C所示的polyA信号序列。两个编码区可以位于转座子或病毒末端重复序列(IR)之间以整合到T或NK细胞中。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(Eyquem 2017)。
实施例2.用于瞬时表达抗肿瘤活性的其它机制的mRNA CAR
或者，可从体外转录的(IVT)RNA表达具有抗肿瘤活性的其它机制的瞬时表达的AI-CAR(图2A-C，SEQ ID 11-15)。单特异性、双重或双特异性CAR的编码区如图1所示构建。mRNA AI-CAR是横向表达的，因此不需要CAR细胞消除的靶。用于额外抗肿瘤活性的瞬时表达的蛋白质包括IRES或P2A序列的3'融合体，例如细胞因子或双特异性抗体的编码区(SEQID 11-15)，其随后是polyA尾。mRNA AI-CAR构建在用于体外转录(IVT)的载体内。因此，编码区侧翼为T7启动子和polyA尾。用T7聚合酶转录mRNA，用标准方法纯化并电穿孔到T或NK细胞中。还可通过共转染其mRNA来共表达额外蛋白以增强抗肿瘤活性。
实施例3.AI-CAR设计的实施例
具有未分化记忆表型的CAR T细胞的特征在于体内持续性和最大的治疗潜力。为了选择性地扩增具有这种表型的CAR细胞和防止终末分化，已经利用了几种细胞因子，包括IL15、IL7和IL21。这些细胞因子还可以促进淋巴瘤的T细胞排斥(Markley 2010)。其它促炎性细胞因子可增强CAR细胞根除肿瘤如IL18或IL12的功效(Chmielewski 2017，Kueberuwa2018)。将这些细胞因子的组合掺入具有由CAR结合肿瘤细胞调节的表达的CAR载体具有几个优点，包括容易制造CAR细胞(即体外扩增)、实现护理点治疗、增强CAR细胞的活性和持续性以及潜在地诱导或增强患者抗肿瘤应答。
靶向CD19和CD22或CD20的两类CAR被设计为如图3所示。双特异性CAR复合物包含分别靶向CD19和CD22的两个独立配置的受体(图3A)。双特异性CAR可以是经典的第二代CAR，但含有结合CD19和CD22或CD20的两个scFv(图3B)。
在结合肿瘤靶抗原之后，AI-CAR可活化与整合CAR载体诱导型启动子结合的转录因子，以通过额外的抗肿瘤机制诱导支持AI-CAR细胞持续性、未分化记忆表型和功效的基因的表达(SEQ ID 9、10、16、17)。例如，这些活性可以通过某些细胞因子和通过细胞毒性双特异性抗体如抗-CD20xNKG2D来提供，以靶向对肿瘤细胞的NK细胞毒性。相对于组成性表达，额外细胞毒性机制的瞬时表达降低例如肿瘤外细胞毒性的风险。或者，抗肿瘤活性的其它机制也可以使用mRNA AI-CAR(SEQ ID 11-17)瞬时表达。
实施例4.人源化抗-CD19scFv-Fc和抗-CD22scFv-Fc特异性结合靶抗原
为了证明用于AI-CAR构建的人源化抗CD19scFv和抗CD22scFv的功能，将scFv与Fc融合并在HEK-293细胞中表达。抗CD19和抗CD22 scFv特异性结合已经用CD19或CD20 mRNA转染的SW480细胞。scFv不与模拟转染子或用CD20 mRNA转染的细胞结合。SW480电穿孔后1天测定与CD19、CD22和CD20 mRNA的结合。通过标准流式细胞荧光测定法测定结合。
实施例5.CD19和CD22与CAR T细胞结合
在T细胞中表达人源化双重和双特异性CAR以证明它们与CD19和CD22的结合。用编码不同CAR的mRNA电穿孔T细胞。使用每50×10^6细胞(双重)总共50或100μg的RNA，将CD19和CD22 CAR RNA的组合共同电穿孔到T细胞中。每50×10^6细胞使用25或50μg每种RNA将CD19和CD22 CAR RNA单独电穿孔到T细胞中。然后汇集个体或单特异性CAR细胞(双重个体)。电穿孔后1天，通过标准流式细胞术测定蛋白质-L的结合来证实CAR表达。可溶性重组CD19-Fc和CD22-Fc特异性结合双重和双特异性CAR而不模拟转染的T细胞。数据表明相对于单独电穿孔和汇集的CAR T细胞，更大百分比的双重或共同电穿孔的T细胞结合CD19和CD22。
实施例6.电穿孔后第1天IL-15扩增的T细胞上CAR表达的总结
图6总结了电穿孔后一天CD19-Fc和CD22-Fc与表达人源化CD19和CD22 RNA CAR的T细胞结合的百分比和水平(中值荧光强度)。T细胞用所示不同量的CAR RNA电穿孔。通过标准流式细胞仪测定的蛋白质-L的结合证明了CAR表达。
实施例7.单特异性、双重和双特异性CD19和CD22 CAR T细胞细胞毒性
测定了单特异性、双重和双特异性CD19和CD22 CAR细胞的细胞毒活性。T细胞用CAR RNA电穿孔，表达荧光素酶的SW480用CD19、CD22或两者的跨膜形式电穿孔。CD20也在SW480中表达，作为阴性对照。一天后，将CAR T细胞与靶细胞以0：1至20：1的效应细胞与靶细胞比共同孵育。通过使用多模式读板器测定残留的荧光素酶活性，在24小时测定细胞毒性。单特异性CD19 CAR显示最有效的杀伤，随后是双CD19、CD22 CAR细胞。然而，双CD19、CD22 CAR细胞显示模拟和CD20表达靶的最大背景杀伤。该非特异性活性可反映共电穿孔中较高水平的输入RNA，其为用于其它电穿孔的量的2倍(每50×10^6T细胞总共100μg)。这在随后的细胞毒性测定中解决(图8)。
实施例8.双重和双特异性CD19和CD22 CAR T细胞细胞毒性
测定双重和双特异性CD19和CD22 CAR细胞的细胞毒活性。T细胞用CAR RNA电穿孔，表达荧光素酶的SW480用CD19、CD22或两者的跨膜形式电穿孔。CD20也表达为阴性对照。一天后，将CAR T细胞与靶细胞以0：1至20：1的效应细胞与靶细胞比共同孵育。通过使用多模式读板器测定残留的荧光素酶活性，在24小时测定细胞毒性。该数据表明双重CAR与25μgCD19 RNA和25μg CD22 RNA共同电穿孔(每50×10^6细胞)相对于用2×更多RNA电穿孔的双重CAR具有更大的比活性。此外，所述双重CAR格式相对于所述双特异性CAR表现出更大的活性。
序列表
1.人源化CD19 CAR序列。将来自FMC63小鼠抗体((Nicholson 1997)的人源化CD19scFv融合至CD8茎/铰链、CD8跨膜结构域、CD137内结构域和CD3ζ内结构域。使用P2A肽融合安全靶。
SEQ ID NO:1
h1FM19C7tER
MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSETLSLTCTVSGGSIPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYGGSYAMDYWGQGTSLTVSSGGGGSGGGGSGGGSGDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFGGGTKVEITGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMNAKVVVVLVLVLTALCLSDGRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRR
SEQ ID NO:2
h2FM19C7tER
MKHLWFFLLLVAAPRWVLSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGGAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTFTISSLQQEDIATYYCQQGNTLPYTFGGGTKVEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSQTLSLTCTVSGVSLPDYGVSWIRQHPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYGGSYAMDYWGQGTLVTVSSGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMNAKVVVVLVLVLTALCLSDGRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRR
SEQ ID NO:3
h3FM19C7tER
MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSQTLSLTCTVSGVSIPDYGVSWIRQHPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTFTISSLQQEDIATYYCQQGNTLPYTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMNAKVVVVLVLVLTALCLSDGRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRR
2.人源化CD22 CAR序列。将来自RFB4小鼠抗体(Mansfeild 1997)的人源化CD22特异性scFv融合至CD8茎/铰链、CD8跨膜结构域、CD137内结构域和CD3ζ内结构域。
SEQ ID NO:4
h1RF22C7tER
MKHLWFFLLLVAAPRWVLSEVQLVESGGGLVQPGGSLRLSCAASGFAFSIYDMSWVRQAPGKGLEWVSYISSGGGTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHSGYGSSYGVLFAYWGQGTLVTVSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSILHSGVPSRFSGSGSGTDFTFTISSLQQEDIATYYCQQGNTLPWTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMNAKVVVVLVLVLTALCLSDGRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRR
SEQ ID NO:5
h2RF22C7tER
MKHLWFFLLLVAAPRWVLSEVQLVESGGGLVQPGGSLRLSCAASGFTFSIYDMSWVRQAPGKGLEWVSYISSGGGTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHSGYGSSYGVLFAYWGQGTLVTGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSILHSGVPSRFSGSGSGTDFTLTISSLQQEDFATYYCQQGNTLPWTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMNAKVVVVLVLVLTALCLSDGRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRR
3.人源化CD19和CD22双特异性CAR序列。靶向CD19和CD22的双特异性CAR可通过将CD19 scFv(具有前导)融合至接头序列，随后融合CD22 scFv、CD8茎/铰链、CD8跨膜结构域、CD137内结构域和CD3ζ内结构域而产生。
SEQ ID NO:6
hRC19hRF22C7tER
MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSQTLSLTCTVSGVSLPDYGVSWIRQHPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGGAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTFTISSLQQEDIATYYCQQGNTLPYTFGGGTKVEIKPAGGGEPKSSDKTHTGGASEVQLVESGGGLVQPGGSLRLSCAASGFAFSIYDMSWVRQAPGKGLEWVSYISSGGGTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHSGYGSSYGVLFAYWGQGTLVTVSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSILHSGVPSRFSGSGSGTDFTFTISSLQQEDIATYYCQQGNTLPWTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMNAKVVVVLVLVLTALCLSDGRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRR
SEQ ID NO:7
h3FM19h2RF22C7tER
MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSQTLSLTCTVSGVSIPDYGVSWIRQHPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTFTISSLQQEDIATYYCQQGNTLPYTFGGGTKVEIKPAGGGEPKSSDKTHTGGASEVQLVESGGGLVQPGGSLRLSCAASGFTFSIYDMSWVRQAPGKGLEWVSYISSGGGTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHSGYGSSYGVLFAYWGQGTLVTGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSILHSGVPSRFSGSGSGTDFTLTISSLQQEDFATYYCQQGNTLPWTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMNAKVVVVLVLVLTALCLSDGRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRR
4.人源化CD19和CD22双重CAR序列。靶向CD19和CD22的双重CAR可以通过将CD19CAR(具有前导)融合到核糖体跳跃肽，例如T2A或P2A，随后融合CD22 CAR来产生。
SEQ ID NO:8
h2FM19C7xh2RF22C7tER
MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSQTLSLTCTVSGVSLPDYGVSWIRQHPGKGLEWIGVIWGSETTYYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGGAPKLLIYHTSRLHSGVPSRFSGSGSGTDFTFTISSLQQEDIATYYCQQGNTLPYTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPEVQLVESGGGLVQPGGSLRLSCAASGFTFSIYDMSWVRQAPGKGLEWVSYISSGGGTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHSGYGSSYGVLFAYWGQGTLVTGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSILHSGVPSRFSGSGSGTDFTLTISSLQQEDFATYYCQQGNTLPWTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMNAKVVVVLVLVLTALCLSDGRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRR
5.在CAR细胞中组合表达细胞因子以增强抗肿瘤活性的实例。
IL7、IL15或IL21的组合可在CAR细胞中瞬时表达以激活CAR细胞或宿主T和NK细胞以诱导增殖和抗肿瘤细胞毒性。IL7、IL15和IL21的组合序列可以由信号肽、细胞因子、核糖体跳跃肽如P2A和另一种细胞因子组成。
SEQ ID NO:9
IL7 x IL21
MKHLWFFLLLVAAPRWVLSDCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEHPAGGGTKTESSSRGQGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS
SEQ ID NO:10
IL7 x IL15
MKHLWFFLLLVAAPRWVLSDCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEHPAGGGTKTESSSRGGIHVFILGCFSAGLPKTEANWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS
6.RNA CAR的实例：
SEQ ID NO:11
h5RM19C7-P2A-h2RF22U1(图2A)
MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSQTLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTISKDNSKSQVSLKMSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISSLQPEDIATYFCQQGNTLPYTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSIYDMSWVRQAPGKGLEWVSYISSGGGTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHSGYGSSYGVLFAYWGQGTLVTGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSILHSGVPSRFSGSGSGTDFTLTISSLQQEDFATYYCQQGNTLPWTFGGGTKVEIKPAGGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKP
SEQ ID NO:12
h5RM19C7-P2A-IL18(图2A)
MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSQTLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTISKDNSKSQVSLKMSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISSLQPEDIATYFCQQGNTLPYTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
SEQ ID NO:13
h5RM19C7-P2A-h2RF22C7-P2A-IL18(图2B)
MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSQTLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTISKDNSKSQVSLKMSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISSLQPEDIATYFCQQGNTLPYTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMKHLWFFLLLVAAPRWVLSEVQLVESGGGLVQPGGSLRLSCAASGFTFSIYDMSWVRQAPGKGLEWVSYISSGGGTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHSGYGSSYGVLFAYWGQGTLVTGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSILHSGVPSRFSGSGSGTDFTLTISSLQQEDFATYYCQQGNTLPWTFGGGTKVEIKPAGTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
SEQ ID NO:14
h5RM19C7-P2A-h2RF22C7-P2A-IL12B-IL12A(图2B)
MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSQTLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTISKDNSKSQVSLKMSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISSLQPEDIATYFCQQGNTLPYTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRASGSGATNFSLLKQAGDVEENPGPMKHLWFFLLLVAAPRWVLSEVQLVESGGGLVQPGGSLRLSCAASGFTFSIYDMSWVRQAPGKGLEWVSYISSGGGTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHSGYGSSYGVLFAYWGQGTLVTGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSILHSGVPSRFSGSGSGTDFTLTISSLQQEDFATYYCQQGNTLPWTFGGGTKVEIKPAGTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
SEQ ID NO:15
h5RM19scFv-linker-h2RF22C7-P2A-IL18(图2C)
MKHLWFFLLLVAAPRWVLSQVQLQESGPGLVKPSQTLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTISKDNSKSQVSLKMSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISSLQPEDIATYFCQQGNTLPYTFGGGTKVEIKPAGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSIYDMSWVRQAPGKGLEWVSYISSGGGTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHSGYGSSYGVLFAYWGQGTLVTGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSILHSGVPSRFSGSGSGTDFTLTISSLQQEDFATYYCQQGNTLPWTFGGGTKVEIKGAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
7.另外的诱导型基因的实例：
SEQ ID NO:16
h2RF22U1-P2A-IL18(图1；诱导型基因；抗CD19xCD3双特异性抗体和IL18)
MEFGLSWVFLVALLRGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSIYDMSWVRQAPGKGLEWVSYISSGGGTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHSGYGSSYGVLFAYWGQGTLVTGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSILHSGVPSRFSGSGSGTDFTLTISSLQQEDFATYYCQQGNTLPWTFGGGTKVEIKPAGGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKPGSGATNFSLLKQAGDVEENPGPMEFGLSWVFLVALLRGVQCYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
SEQ ID NO:17
IL12B-接头-IL12A(图1；诱导基因；融合IL12B和IL12A链)
MKHLWFFLLLVAAPRWVLSIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
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及其表达细胞
<130> AVAR1901PCT
<141> 2020-02-21
<150> 62/808,815
<151> 2019-02-21
<150> 62/808,823
<151> 2019-02-21
<150> 62/808,830
<151> 2019-02-21
<150> 62/808,833
<151> 2019-02-21
<160> 17
<170> SIPOSequenceListing 1.0
<210> 1
<211> 488
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 1
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 Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile
35 40 45
Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro 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 Ser Leu Thr Val Ser Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly 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 Lys 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 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 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 Thr 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 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
290 295 300
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
305 310 315 320
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly
325 330 335
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
340 345 350
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
355 360 365
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
370 375 380
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
385 390 395 400
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
405 410 415
Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu
420 425 430
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
435 440 445
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
450 455 460
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
465 470 475 480
His Met Gln Ala Leu Pro Pro Arg
485
<210> 2
<211> 488
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 2
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile
35 40 45
Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gly Ala Pro Lys
50 55 60
Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser
85 90 95
Leu Gln Gln Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr
100 105 110
Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln
130 135 140
Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr Leu Ser
145 150 155 160
Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser
165 170 175
Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly Val Ile
180 185 190
Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Val
195 200 205
Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser
210 215 220
Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Tyr
225 230 235 240
Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
245 250 255
Val Thr Val Ser Ser 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 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
290 295 300
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
305 310 315 320
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly
325 330 335
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
340 345 350
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
355 360 365
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
370 375 380
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
385 390 395 400
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
405 410 415
Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu
420 425 430
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
435 440 445
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
450 455 460
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
465 470 475 480
His Met Gln Ala Leu Pro Pro Arg
485
<210> 3
<211> 488
<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 Ile
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 Lys 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 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
290 295 300
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
305 310 315 320
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly
325 330 335
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
340 345 350
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
355 360 365
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
370 375 380
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
385 390 395 400
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
405 410 415
Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu
420 425 430
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
435 440 445
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
450 455 460
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
465 470 475 480
His Met Gln Ala Leu Pro Pro Arg
485
<210> 4
<211> 490
<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 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 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
290 295 300
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
305 310 315 320
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
325 330 335
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
340 345 350
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
355 360 365
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
370 375 380
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
385 390 395 400
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
405 410 415
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro
420 425 430
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
435 440 445
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
450 455 460
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
465 470 475 480
Ala Leu His Met Gln Ala Leu Pro Pro Arg
485 490
<210> 5
<211> 488
<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 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 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 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 Asn Tyr Leu Asn Trp Tyr Gln Gln
180 185 190
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Ile 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 Leu Thr Ile Ser Ser Leu Gln Gln Glu Asp Phe Ala Thr Tyr
225 230 235 240
Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp 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 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
290 295 300
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
305 310 315 320
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly
325 330 335
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
340 345 350
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
355 360 365
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
370 375 380
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
385 390 395 400
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
405 410 415
Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu
420 425 430
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
435 440 445
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
450 455 460
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
465 470 475 480
His Met Gln Ala Leu Pro Pro Arg
485
<210> 6
<211> 751
<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 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 Pro Ala Gly Gly Gly Glu Pro Lys Ser Ser Asp
260 265 270
Lys Thr His Thr Gly Gly Ala Ser Glu Val Gln Leu Val Glu Ser Gly
275 280 285
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
290 295 300
Ser Gly Phe Ala Phe Ser Ile Tyr Asp Met Ser Trp Val Arg Gln Ala
305 310 315 320
Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr Ile Ser Ser Gly Gly Gly
325 330 335
Thr Thr Tyr Tyr Pro Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg
340 345 350
Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
355 360 365
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Ser Gly Tyr Gly Ser
370 375 380
Ser Tyr Gly Val Leu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
385 390 395 400
Val Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
405 410 415
Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
420 425 430
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn
435 440 445
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
450 455 460
Ile Tyr Tyr Thr Ser Ile Leu His Ser Gly Val Pro Ser Arg Phe Ser
465 470 475 480
Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln
485 490 495
Gln Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro
500 505 510
Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Ala Pro Thr
515 520 525
Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser
530 535 540
Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly
545 550 555 560
Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp
565 570 575
Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile
580 585 590
Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
595 600 605
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
610 615 620
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
625 630 635 640
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
645 650 655
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
660 665 670
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln
675 680 685
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
690 695 700
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
705 710 715 720
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
725 730 735
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
740 745 750
<210> 7
<211> 749
<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 Ile
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 Lys 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 Pro Ala Gly Gly Gly Glu Pro Lys Ser Ser Asp
260 265 270
Lys Thr His Thr Gly Gly Ala Ser Glu Val Gln Leu Val Glu Ser Gly
275 280 285
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
290 295 300
Ser Gly Phe Thr Phe Ser Ile Tyr Asp Met Ser Trp Val Arg Gln Ala
305 310 315 320
Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr Ile Ser Ser Gly Gly Gly
325 330 335
Thr Thr Tyr Tyr Pro Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg
340 345 350
Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
355 360 365
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Ser Gly Tyr Gly Ser
370 375 380
Ser Tyr Gly Val Leu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
405 410 415
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
420 425 430
Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu
435 440 445
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
450 455 460
Tyr Thr Ser Ile Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
465 470 475 480
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Gln Glu
485 490 495
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr
500 505 510
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Ala Pro Thr Thr Thr
515 520 525
Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro
530 535 540
Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val
545 550 555 560
His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro
565 570 575
Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu
580 585 590
Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro
595 600 605
Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys
610 615 620
Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe
625 630 635 640
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
645 650 655
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
660 665 670
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
675 680 685
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
690 695 700
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
705 710 715 720
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
725 730 735
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
740 745
<210> 8
<211> 979
<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 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 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
290 295 300
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
305 310 315 320
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly
325 330 335
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
340 345 350
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
355 360 365
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
370 375 380
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
385 390 395 400
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
405 410 415
Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu
420 425 430
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
435 440 445
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
450 455 460
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
465 470 475 480
His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser
485 490 495
Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Glu Val
500 505 510
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
515 520 525
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Tyr Asp Met
530 535 540
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr
545 550 555 560
Ile Ser Ser Gly Gly Gly Thr Thr Tyr Tyr Pro Asp Thr Val Lys Gly
565 570 575
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln
580 585 590
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
595 600 605
His Ser Gly Tyr Gly Ser Ser Tyr Gly Val Leu Phe Ala Tyr Trp Gly
610 615 620
Gln Gly Thr Leu Val Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
625 630 635 640
Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
645 650 655
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
660 665 670
Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala
675 680 685
Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Ile Leu His Ser Gly Val Pro
690 695 700
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
705 710 715 720
Ser Ser Leu Gln Gln Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly
725 730 735
Asn Thr Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
740 745 750
Gly Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
755 760 765
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
770 775 780
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
785 790 795 800
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
805 810 815
Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu
820 825 830
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
835 840 845
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
850 855 860
Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln
865 870 875 880
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
885 890 895
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
900 905 910
Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
915 920 925
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
930 935 940
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
945 950 955 960
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
965 970 975
Pro Pro Arg
<210> 9
<211> 326
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 9
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser Asp Cys Asp Ile Glu Gly Lys Asp Gly Lys Gln Tyr Glu
20 25 30
Ser Val Leu Met Val Ser Ile Asp Gln Leu Leu Asp Ser Met Lys Glu
35 40 45
Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe Asn Phe Phe Lys Arg His
50 55 60
Ile Cys Asp Ala Asn Lys Glu Gly Met Phe Leu Phe Arg Ala Ala Arg
65 70 75 80
Lys Leu Arg Gln Phe Leu Lys Met Asn Ser Thr Gly Asp Phe Asp Leu
85 90 95
His Leu Leu Lys Val Ser Glu Gly Thr Thr Ile Leu Leu Asn Cys Thr
100 105 110
Gly Gln Val Lys Gly Arg Lys Pro Ala Ala Leu Gly Glu Ala Gln Pro
115 120 125
Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu Lys Glu Gln Lys Lys Leu
130 135 140
Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu Gln Glu Ile Lys Thr Cys
145 150 155 160
Trp Asn Lys Ile Leu Met Gly Thr Lys Glu His Gly Ser Gly Ala Thr
165 170 175
Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly
180 185 190
Pro Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp
195 200 205
Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe
210 215 220
Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe
225 230 235 240
Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn
245 250 255
Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro
260 265 270
Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser
275 280 285
Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe
290 295 300
Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr
305 310 315 320
His Gly Ser Glu Asp Ser
325
<210> 10
<211> 326
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 10
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser Asp Cys Asp Ile Glu Gly Lys Asp Gly Lys Gln Tyr Glu
20 25 30
Ser Val Leu Met Val Ser Ile Asp Gln Leu Leu Asp Ser Met Lys Glu
35 40 45
Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe Asn Phe Phe Lys Arg His
50 55 60
Ile Cys Asp Ala Asn Lys Glu Gly Met Phe Leu Phe Arg Ala Ala Arg
65 70 75 80
Lys Leu Arg Gln Phe Leu Lys Met Asn Ser Thr Gly Asp Phe Asp Leu
85 90 95
His Leu Leu Lys Val Ser Glu Gly Thr Thr Ile Leu Leu Asn Cys Thr
100 105 110
Gly Gln Val Lys Gly Arg Lys Pro Ala Ala Leu Gly Glu Ala Gln Pro
115 120 125
Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu Lys Glu Gln Lys Lys Leu
130 135 140
Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu Gln Glu Ile Lys Thr Cys
145 150 155 160
Trp Asn Lys Ile Leu Met Gly Thr Lys Glu His Gly Ser Gly Ala Thr
165 170 175
Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly
180 185 190
Pro Gly Ile His Val Phe Ile Leu Gly Cys Phe Ser Ala Gly Leu Pro
195 200 205
Lys Thr Glu Ala Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile
210 215 220
Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu
225 230 235 240
Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu
245 250 255
Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His
260 265 270
Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser
275 280 285
Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu
290 295 300
Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln
305 310 315 320
Met Phe Ile Asn Thr Ser
325
<210> 11
<211> 1026
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 11
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 Val Thr Cys Thr Val Ser Gly Val Ser Leu
35 40 45
Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu
50 55 60
Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser
65 70 75 80
Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln
85 90 95
Val Ser Leu Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
100 105 110
Tyr Cys Ala Lys 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 Asp Gly Thr Val 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
Tyr Ser Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr
225 230 235 240
Phe 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 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
290 295 300
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
305 310 315 320
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly
325 330 335
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
340 345 350
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
355 360 365
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
370 375 380
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
385 390 395 400
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
405 410 415
Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu
420 425 430
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
435 440 445
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
450 455 460
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
465 470 475 480
His Met Gln Ala Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn
485 490 495
Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro
500 505 510
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
515 520 525
Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
530 535 540
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
545 550 555 560
Ser Ile Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
565 570 575
Glu Trp Val Ser Tyr Ile Ser Ser Gly Gly Gly Thr Thr Tyr Tyr Pro
580 585 590
Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
595 600 605
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
610 615 620
Tyr Tyr Cys Ala Arg His Ser Gly Tyr Gly Ser Ser Tyr Gly Val Leu
625 630 635 640
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Gly Gly Gly Gly Ser
645 650 655
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln
660 665 670
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
675 680 685
Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln
690 695 700
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Ile Leu
705 710 715 720
His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
725 730 735
Phe Thr Leu Thr Ile Ser Ser Leu Gln Gln Glu Asp Phe Ala Thr Tyr
740 745 750
Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Gly Gly Thr
755 760 765
Lys Val Glu Ile Lys Pro Ala Gly Gly Gly Gly Gly Ser Glu Val Gln
770 775 780
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
785 790 795 800
Leu Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn
805 810 815
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Leu Ile
820 825 830
Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Arg
835 840 845
Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr Leu Gln Met
850 855 860
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser
865 870 875 880
Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly
885 890 895
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
900 905 910
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
915 920 925
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
930 935 940
Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
945 950 955 960
Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val
965 970 975
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr
980 985 990
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
995 1000 1005
Gly Asn Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
1010 1015 1020
Lys Pro
1025
<210> 12
<211> 688
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 12
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 Val Thr Cys Thr Val Ser Gly Val Ser Leu
35 40 45
Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu
50 55 60
Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser
65 70 75 80
Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln
85 90 95
Val Ser Leu Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
100 105 110
Tyr Cys Ala Lys 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 Asp Gly Thr Val 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
Tyr Ser Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr
225 230 235 240
Phe 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 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
290 295 300
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
305 310 315 320
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly
325 330 335
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
340 345 350
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
355 360 365
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
370 375 380
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
385 390 395 400
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
405 410 415
Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu
420 425 430
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
435 440 445
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
450 455 460
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
465 470 475 480
His Met Gln Ala Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn
485 490 495
Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro
500 505 510
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
515 520 525
Val Gln Cys Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg
530 535 540
Asn Leu Asn Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu
545 550 555 560
Phe Glu Asp Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr
565 570 575
Ile Phe Ile Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala
580 585 590
Val Thr Ile Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu
595 600 605
Asn Lys Ile Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys
610 615 620
Asp Thr Lys Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His
625 630 635 640
Asp Asn Lys Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu
645 650 655
Ala Cys Glu Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu
660 665 670
Asp Glu Leu Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp
675 680 685
<210> 13
<211> 1198
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 13
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 Val Thr Cys Thr Val Ser Gly Val Ser Leu
35 40 45
Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu
50 55 60
Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser
65 70 75 80
Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln
85 90 95
Val Ser Leu Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
100 105 110
Tyr Cys Ala Lys 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 Asp Gly Thr Val 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
Tyr Ser Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr
225 230 235 240
Phe 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 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
290 295 300
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
305 310 315 320
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly
325 330 335
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
340 345 350
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
355 360 365
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
370 375 380
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
385 390 395 400
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
405 410 415
Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu
420 425 430
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
435 440 445
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
450 455 460
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
465 470 475 480
His Met Gln Ala Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn
485 490 495
Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro
500 505 510
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
515 520 525
Val Leu Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
530 535 540
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
545 550 555 560
Ser Ile Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
565 570 575
Glu Trp Val Ser Tyr Ile Ser Ser Gly Gly Gly Thr Thr Tyr Tyr Pro
580 585 590
Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
595 600 605
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
610 615 620
Tyr Tyr Cys Ala Arg His Ser Gly Tyr Gly Ser Ser Tyr Gly Val Leu
625 630 635 640
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Gly Gly Gly Gly Ser
645 650 655
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln
660 665 670
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
675 680 685
Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln
690 695 700
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Ile Leu
705 710 715 720
His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
725 730 735
Phe Thr Leu Thr Ile Ser Ser Leu Gln Gln Glu Asp Phe Ala Thr Tyr
740 745 750
Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Gly Gly Thr
755 760 765
Lys Val Glu Ile Lys Pro Ala Gly Thr Thr Thr Pro Ala Pro Arg Pro
770 775 780
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
785 790 795 800
Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
805 810 815
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
820 825 830
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly
835 840 845
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
850 855 860
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
865 870 875 880
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
885 890 895
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
900 905 910
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
915 920 925
Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu
930 935 940
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
945 950 955 960
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
965 970 975
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
980 985 990
His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser
995 1000 1005
Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Glu
1010 1015 1020
Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln
1025 1030 1035 1040
Cys Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu
1045 1050 1055
Asn Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu
1060 1065 1070
Asp Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe
1075 1080 1085
Ile Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr
1090 1095 1100
Ile Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys
1105 1110 1115 1120
Ile Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr
1125 1130 1135
Lys Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn
1140 1145 1150
Lys Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys
1155 1160 1165
Glu Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu
1170 1175 1180
Leu Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp
1185 1190 1195
<210> 14
<211> 1554
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 14
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 Val Thr Cys Thr Val Ser Gly Val Ser Leu
35 40 45
Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu
50 55 60
Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser
65 70 75 80
Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln
85 90 95
Val Ser Leu Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
100 105 110
Tyr Cys Ala Lys 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 Asp Gly Thr Val 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
Tyr Ser Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr
225 230 235 240
Phe 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 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
290 295 300
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
305 310 315 320
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly
325 330 335
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
340 345 350
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
355 360 365
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
370 375 380
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
385 390 395 400
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
405 410 415
Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu
420 425 430
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
435 440 445
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
450 455 460
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
465 470 475 480
His Met Gln Ala Leu Pro Pro Arg Ala Ser Gly Ser Gly Ala Thr Asn
485 490 495
Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro
500 505 510
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
515 520 525
Val Leu Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
530 535 540
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
545 550 555 560
Ser Ile Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
565 570 575
Glu Trp Val Ser Tyr Ile Ser Ser Gly Gly Gly Thr Thr Tyr Tyr Pro
580 585 590
Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
595 600 605
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
610 615 620
Tyr Tyr Cys Ala Arg His Ser Gly Tyr Gly Ser Ser Tyr Gly Val Leu
625 630 635 640
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Gly Gly Gly Gly Ser
645 650 655
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln
660 665 670
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
675 680 685
Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln
690 695 700
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Ile Leu
705 710 715 720
His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
725 730 735
Phe Thr Leu Thr Ile Ser Ser Leu Gln Gln Glu Asp Phe Ala Thr Tyr
740 745 750
Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Gly Gly Thr
755 760 765
Lys Val Glu Ile Lys Pro Ala Gly Thr Thr Thr Pro Ala Pro Arg Pro
770 775 780
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
785 790 795 800
Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
805 810 815
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
820 825 830
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly
835 840 845
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
850 855 860
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
865 870 875 880
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
885 890 895
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
900 905 910
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
915 920 925
Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu
930 935 940
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
945 950 955 960
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
965 970 975
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
980 985 990
His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser
995 1000 1005
Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Glu
1010 1015 1020
Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly Val Gln
1025 1030 1035 1040
Cys Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp
1045 1050 1055
Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro
1060 1065 1070
Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu
1075 1080 1085
Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala
1090 1095 1100
Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu
1105 1110 1115 1120
Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu
1125 1130 1135
Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala
1140 1145 1150
Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser
1155 1160 1165
Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro
1170 1175 1180
Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg
1185 1190 1195 1200
Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser
1205 1210 1215
Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp
1220 1225 1230
Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile
1235 1240 1245
Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro
1250 1255 1260
Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr
1265 1270 1275 1280
Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val
1285 1290 1295
Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys
1300 1305 1310
Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg
1315 1320 1325
Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val
1330 1335 1340
Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg Asn Leu
1345 1350 1355 1360
Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu His His Ser
1365 1370 1375
Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys Ala Arg Gln
1380 1385 1390
Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp His Glu Asp
1395 1400 1405
Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu Pro Leu Glu
1410 1415 1420
Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr Ser Phe Ile
1425 1430 1435 1440
Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe Met Met Ala
1445 1450 1455
Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Val Glu
1460 1465 1470
Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys Arg Gln Ile
1475 1480 1485
Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu Met Gln Ala
1490 1495 1500
Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser Leu Glu Glu
1505 1510 1515 1520
Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu Leu His Ala
1525 1530 1535
Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met Ser Tyr Leu Asn
1540 1545 1550
Ala Ser
<210> 15
<211> 935
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 15
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 Val Thr Cys Thr Val Ser Gly Val Ser Leu
35 40 45
Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu
50 55 60
Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser
65 70 75 80
Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln
85 90 95
Val Ser Leu Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
100 105 110
Tyr Cys Ala Lys 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 Asp Gly Thr Val 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
Tyr Ser Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr
225 230 235 240
Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr
245 250 255
Lys Val Glu Ile Lys Pro Ala Gly Gly Gly Gly Ser Glu Val Gln Leu
260 265 270
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
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Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Tyr Asp Met Ser Trp
290 295 300
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr Ile Ser
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Ser Gly Gly Gly Thr Thr Tyr Tyr Pro Asp Thr Val Lys Gly Arg Phe
325 330 335
Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn
340 345 350
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Ser
355 360 365
Gly Tyr Gly Ser Ser Tyr Gly Val Leu Phe Ala Tyr Trp Gly Gln Gly
370 375 380
Thr Leu Val Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
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Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
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Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile
420 425 430
Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
435 440 445
Leu Leu Ile Tyr Tyr Thr Ser Ile Leu His Ser Gly Val Pro Ser Arg
450 455 460
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
465 470 475 480
Leu Gln Gln Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr
485 490 495
Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Ala
500 505 510
Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
515 520 525
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
530 535 540
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
545 550 555 560
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
565 570 575
Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile
580 585 590
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
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Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
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Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
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Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
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Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
660 665 670
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
675 680 685
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
690 695 700
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
705 710 715 720
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
725 730 735
Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp
740 745 750
Val Glu Glu Asn Pro Gly Pro Met Glu Phe Gly Leu Ser Trp Val Phe
755 760 765
Leu Val Ala Leu Leu Arg Gly Val Gln Cys Tyr Phe Gly Lys Leu Glu
770 775 780
Ser Lys Leu Ser Val Ile Arg Asn Leu Asn Asp Gln Val Leu Phe Ile
785 790 795 800
Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp Met Thr Asp Ser Asp Cys
805 810 815
Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile Ile Ser Met Tyr Lys Asp
820 825 830
Ser Gln Pro Arg Gly Met Ala Val Thr Ile Ser Val Lys Cys Glu Lys
835 840 845
Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile Ser Phe Lys Glu Met
850 855 860
Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys Ser Asp Ile Ile Phe Phe
865 870 875 880
Gln Arg Ser Val Pro Gly His Asp Asn Lys Met Gln Phe Glu Ser Ser
885 890 895
Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu Lys Glu Arg Asp Leu Phe
900 905 910
Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu Gly Asp Arg Ser Ile Met
915 920 925
Phe Thr Val Gln Asn Glu Asp
930 935
<210> 16
<211> 712
<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 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 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 Asn Tyr Leu Asn Trp Tyr Gln Gln
180 185 190
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Ile 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 Leu Thr Ile Ser Ser Leu Gln Gln Glu Asp Phe Ala Thr Tyr
225 230 235 240
Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Gly Gly Thr
245 250 255
Lys Val Glu Ile Lys Pro Ala Gly Gly Gly Gly Gly Ser Glu Val Gln
260 265 270
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
275 280 285
Leu Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn
290 295 300
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Leu Ile
305 310 315 320
Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe Lys Asp Arg
325 330 335
Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr Leu Gln Met
340 345 350
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser
355 360 365
Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly
370 375 380
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
385 390 395 400
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
405 410 415
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
420 425 430
Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
435 440 445
Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val
450 455 460
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr
465 470 475 480
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
485 490 495
Gly Asn Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
500 505 510
Lys Pro Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly
515 520 525
Asp Val Glu Glu Asn Pro Gly Pro Met Glu Phe Gly Leu Ser Trp Val
530 535 540
Phe Leu Val Ala Leu Leu Arg Gly Val Gln Cys Tyr Phe Gly Lys Leu
545 550 555 560
Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn Asp Gln Val Leu Phe
565 570 575
Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp Met Thr Asp Ser Asp
580 585 590
Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile Ile Ser Met Tyr Lys
595 600 605
Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile Ser Val Lys Cys Glu
610 615 620
Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile Ile Ser Phe Lys Glu
625 630 635 640
Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys Ser Asp Ile Ile Phe
645 650 655
Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys Met Gln Phe Glu Ser
660 665 670
Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu Lys Glu Arg Asp Leu
675 680 685
Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu Gly Asp Arg Ser Ile
690 695 700
Met Phe Thr Val Gln Asn Glu Asp
705 710
<210> 17
<211> 532
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 17
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu
20 25 30
Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp
35 40 45
Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu
50 55 60
Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly
65 70 75 80
Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His
85 90 95
Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp
100 105 110
Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys
115 120 125
Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr
130 135 140
Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser
145 150 155 160
Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg
165 170 175
Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu
180 185 190
Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met
195 200 205
Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe
210 215 220
Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu
225 230 235 240
Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro
245 250 255
Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val
260 265 270
Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr
275 280 285
Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser
290 295 300
Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala
305 310 315 320
Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg
325 330 335
Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu His
340 345 350
His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys Ala
355 360 365
Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp His
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Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu Pro
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Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys Arg
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Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu Met
465 470 475 480
Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser Leu
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Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu Leu
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Leu Asn Ala Ser
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Claims (30)
1.一种双特异性嵌合抗原受体，其包含通过接头与细胞间结构域连接的细胞外结构域，其中所述细胞外结构域包含与第二scFv连接的第一scFv，其中所述第一scFv结构域和所述第二scFv结构域各自独立地对CD19或CD22具有亲和力，其中所述第一scFv结构域和所述第二scFv结构域对不同抗原具有亲和力，并且其中所述细胞内结构域包含共刺激内结构域和CD3ξ结构域。
2.一种双特异性嵌合抗原受体复合物，其包含：
第一蛋白，其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CD19或CD22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，其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CD19或CD22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；
其中第一scFv结构域和第二scFv结构域对不同肿瘤抗原具有亲和力。
3.根据权利要求2所述的嵌合抗原受体复合物，其中所述第一细胞内结构域包含IL7Rα(CD127)。
4.根据权利要求2所述的嵌合抗原受体复合物，其中所述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。
5.根据权利要求2所述的嵌合抗原受体复合物，其中所述第一细胞内进一步包含连接至JAK1结合结构域的第一细胞毒性信号传导结构域。
6.根据权利要求5所述的嵌合抗原受体复合物，其中所述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。
7.根据权利要求2所述的嵌合抗原受体复合物，其中所述第一scFv结构域对CD19具有亲和力。
8.根据权利要求2所述的嵌合抗原受体复合物，其中所述第二scFv结构域对CD22具有亲和力。
9.根据权利要求2所述的嵌合抗原受体复合物，其中所述第二细胞内结构域包含γ(CD132)。
10.根据权利要求2所述的嵌合抗原受体复合物，其中所述第二细胞内结构域还包含连接至JAK3结合结构域的第二细胞毒性信号传导结构域。
11.根据权利要求2所述的嵌合抗原受体复合物，其中所述第二细胞毒性结构域包含CD28、CD3ζ、CD137、OX40、CD27、ICOS或其组合。
12.根据权利要求2所述的嵌合抗原受体复合物，其中所述第二细胞内结构域包含串联的γ(CD132)、JAK3结合结构域、CD28和CD3ζ。
13.根据权利要求2所述的嵌合抗原受体复合物，其中所述第一细胞内结构域被配置为与所述第二细胞内结构域二聚化。
14.根据权利要求2所述的嵌合抗原受体复合物，其中所述第一接头和所述第二接头独立地包含CD8。
15.根据权利要求2所述的嵌合抗原受体复合物，其中所述第一接头和所述第二接头独立地包含茎和跨膜结构域。
16.根据权利要求13所述的嵌合抗原受体复合物，其中所述茎包含CD8、Fc铰链，FcCH2-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。
17.根据权利要求13所述的嵌合抗原受体复合物，其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。
18.一种开放阅读框(ORF)，其依次包含编码权利要求2的第一蛋白质的核酸、编码核糖体跳跃序列的核酸和编码权利要求2的第二蛋白质的核酸。
19.一种开放阅读框(ORF)，其依次包含CD22 scFv、接头、CD22 scFv和嵌合抗原受体结构域。
20.一种生物分子复合物，其包含与CD19抗原或CD22抗原结合的权利要求1的双特异性或双重嵌合抗原受体。
21.根据权利要求22所述的生物分子复合物，其中所述第一细胞内结构域与所述第二细胞内结构域二聚化。
22.根据权利要求23所述的生物分子复合物，其中JAK1与JAK3二聚化。
23.一种非病毒载体，其包含5'至3'侧翼为两个转座子、启动子、包含用于表达第一人工免疫监视嵌合抗原受体(AI-CAR)的基因的第一编码区、包含表达截短的CD20或截短的EGFR安全靶的基因的第四编码区，随后是polyA信号序列。
24.根据权利要求25所述的非病毒载体，其中所述第一启动子包含STAT、NFAT或NF-kB诱导型启动子。
25.根据权利要求25所述的非病毒载体，其中所述第一编码区和所述第四编码区通过IRES连接。
26.根据权利要求25所述的非病毒载体，其中所述第一AI-CAR包含CD19 CAR或CD22CAR。
27.根据权利要求25所述的非病毒载体，其进一步包含第二编码区，所述第二编码区包含用于表达第二AI-CAR的基因，介于所述第一编码区与所述第四编码区中间。
28.根据权利要求29所述的非病毒载体，其中所述第一CAR包含CD19 CAR且其中所述第二区包含CD22 CAR或CD20 CAR。
29.根据权利要求30所述的非病毒载体，其进一步包含第三编码区，所述第三编码区包含用于表达第三AI-CAR的基因，介于所述第二编码区与所述第四编码区中间。
30.根据权利要求31所述的非病毒载体，其中所述第一CAR包含CD19scFv，其中所述第二CAR包含CD22 scFv或CD20 scFv，且其中所述第一CAR通过连接子连接到所述第二CAR。
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| WO2016130598A1 (en) * | 2015-02-09 | 2016-08-18 | University Of Florida Research Foundation, Inc. | Bi-specific chimeric antigen receptor and uses thereof |
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| WO2017075537A1 (en) * | 2015-10-30 | 2017-05-04 | Aleta Biotherapeutics Inc. | Compositions and methods for treatment of cancer |
| US20180111992A1 (en) * | 2015-03-19 | 2018-04-26 | The United States Of America, As Represented By The Secretary, Department Of Health And Human | Dual specific anti-cd22-anti-cd19 chimeric antigen receptors |
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| US20170107285A1 (en) * | 2012-02-13 | 2017-04-20 | Seattle Children's Hospital D/B/A Seattle Children's Research Institute | Bispecific chimeric antigen receptors and encoding polynucleotides thereof |
| WO2016130598A1 (en) * | 2015-02-09 | 2016-08-18 | University Of Florida Research Foundation, Inc. | Bi-specific chimeric antigen receptor and uses thereof |
| US20180111992A1 (en) * | 2015-03-19 | 2018-04-26 | The United States Of America, As Represented By The Secretary, Department Of Health And Human | Dual specific anti-cd22-anti-cd19 chimeric antigen receptors |
| WO2017075537A1 (en) * | 2015-10-30 | 2017-05-04 | Aleta Biotherapeutics Inc. | Compositions and methods for treatment of cancer |
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