CN117321077A - 双特异性分子及相关的组合物和方法 - Google Patents

双特异性分子及相关的组合物和方法 Download PDF

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CN117321077A
CN117321077A CN202280035165.5A CN202280035165A CN117321077A CN 117321077 A CN117321077 A CN 117321077A CN 202280035165 A CN202280035165 A CN 202280035165A CN 117321077 A CN117321077 A CN 117321077A
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卡洛琳·R·贝尔托齐
杰西卡·斯塔克
梅利莎·格雷
西蒙·维斯诺夫斯基
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Abstract

本公开的方面包括双特异性分子。所述双特异性分子包含细胞靶向部分和聚糖结合部分。根据一些实施方案，所述细胞靶向部分是癌细胞靶向部分或免疫细胞靶向部分。在某些实施方案中，所述聚糖结合部分包含凝集素的唾液酸聚糖结合结构域，凝集素的非限制性示例是唾液酸结合免疫球蛋白样凝集素(Siglec)。所述双特异性分子可以采取多种形式，包括异二聚体分子、融合蛋白、缀合物等。还提供了使用所述双官能分子例如用于治疗目的的组合物、试剂盒和方法。

Description

双特异性分子及相关的组合物和方法
相关申请的交叉引用
本申请要求于2021年4月2日提交的美国临时专利申请号63/170,297的权益，该申请以全文引用的方式并入本文。
政府支持声明
本发明是在国立卫生研究院授予的合同CA226051、CA250324和GM058867下受政府支持完成的。美国政府享有本发明的一定权利。
通过参考作为文本文件提供的序列表并入
序列表以文本文件(S21-091_STAN-1838WO_SEQ_LIST_ST25)随附提供，该文本文件创建于2022年4月1日并且文件大小为425,000字节。该文本文件的内容以全文引用的方式并入本文。
背景技术
尽管在选定病例中观察到癌症免疫疗法的显著益处，但许多肿瘤仍对现有治疗无反应。因此，对于靶向另外的驱动癌症进展的免疫检查点的疗法存在未满足的需要。细胞表面上唾液酸单糖的高唾液酸化(hypersialylation)或上调是已确定与增加的侵袭性和转移速率相关的癌症标志。新出现的证据表明高唾液酸化允许肿瘤与免疫细胞上称为Siglec的抑制性聚糖结合受体接合。Siglec受体由每一类免疫细胞表达，并且八个Siglec家族成员的胞内结构域与已确定的PD-1免疫检查点具有同源性。这些研究已经确定Siglec和它们的唾液酸聚糖配体是促成癌症进展的免疫检查点。
Siglec-唾液酸聚糖免疫检查点的发现和表征激发了对靶向Siglec受体以阻断检查点的兴趣。然而，迄今为止，具有高亲和力和选择性的聚糖结合试剂的缺乏已经阻止了针对阻断检查点的肿瘤相关唾液酸聚糖配体的靶向。哺乳动物聚糖结构的弱免疫原性在历史上已经阻碍了抗聚糖抗体的开发。即使聚糖结合抗体是可获得的，肿瘤用于接合Siglec的唾液酸聚糖的特性也没有被完全了解，排除了它们作为靶标的用途。已经证实可溶性Siglec-Fc嵌合体会维持天然唾液酸聚糖结合特异性，但它们的结合亲和力太低而不能用作诱饵-受体治疗剂。因此需要有效靶向肿瘤相关唾液酸聚糖以阻断检查点的试剂。
发明内容
本公开的方面包括双特异性分子。所述双特异性分子包含细胞靶向部分和聚糖结合部分。根据一些实施方案，所述细胞靶向部分是癌细胞靶向部分或免疫细胞靶向部分。在某些实施方案中，所述聚糖结合部分包含凝集素的唾液酸聚糖结合结构域，凝集素的非限制性示例是唾液酸结合免疫球蛋白样凝集素(Siglec)。所述双特异性分子可以采取多种形式，包括异二聚体分子、融合蛋白、缀合物等。还提供了使用所述双官能分子例如用于治疗目的的组合物、试剂盒和方法。
附图说明
图1a-图1e：证明双特异性抗体-凝集素(AbLec)能够将凝集素诱饵受体用于检查点阻断的示意图和数据。
图2a-图2f：证明AbLec阻断靶向的聚糖结合免疫受体的结合的示意图和数据。
图3a-图3e：证明AbLec增强抗体依赖性细胞吞噬作用和体外细胞毒性的示意图和数据。
图4：证明体外ADCP的AbLec增强依赖于靶向的抗原(在该示例中，是由曲妥珠单抗(trastuzumab)臂靶向的HER2)的表达。
图5：证明AbLec与人肿瘤细胞系结合并阻断Siglec受体结合的数据。
图6a-图6d：证明AbLec经由Siglec依赖性增强体外抗肿瘤免疫应答优于组合免疫疗法的示意图和数据。
图7a-图7d：证明AbLec平台能够阻断各种糖免疫检查点靶标的示意图和数据。
图8：证明与利妥昔单抗(rituximab)相比，R7 AbLec增强CD20+Raji细胞的ADCC。
图9：证明各种AbLec分子表达的示意图和数据。
图10：AbLec作为靶向聚糖免疫检查点的模块试剂的示意图。
图11：示例利妥昔单抗-Siglec-7 AbLec异二聚体(“Ritux-Sig7AbLec”)的氨基酸序列，包括杵臼结构(knobs-into-holes)修饰的CH3结构域以促进异二聚体形成，如通过质谱法所证实的。
图12：示例利妥昔单抗-Siglec-9 AbLec异二聚体(“Ritux-Sig9AbLec”)的氨基酸序列，包括杵臼结构修饰的CH3结构域以促进异二聚体形成，如通过质谱法所证实的。
图13：示例曲妥珠单抗-Siglec-9 AbLec异二聚体(“Tras-Sig9AbLec”)的氨基酸序列，包括杵臼结构修饰的CH3结构域以促进异二聚体形成，如通过质谱法所证实的。
图14：示例曲妥珠单抗-Siglec-7 AbLec异二聚体(“Tras-Sig7AbLec”)的氨基酸序列，包括杵臼结构修饰的CH3结构域以促进异二聚体形成，如通过质谱法所证实的。
具体实施方式
在更详细地描述本公开的双特异性分子、组合物和方法之前，应理解双特异性分子、组合物和方法不限于所描述的特定实施方案，因此当然可以对其进行改变。还应理解，本文使用的术语仅用于描述特定实施方案，并不旨在限制，因为双特异性分子、组合物和方法的范围仅受所附权利要求的限制。
在提供值的范围的情况下，应理解的是，除非上下文另有明确规定，否则在该范围的上限和下限之间的每个中间值，至下限单位的十分之一和所述范围内的任何其它所述或中间值均涵盖在双特异性分子、组合物和方法中。这些较小范围的上限和下限可以独立地包括在较小范围内，并且还涵盖在双特异性分子、组合物和方法中，受所述范围内的任何具体排除的界限。在所述范围包括一个或两个界限的情况下，排除那些包括的界限之一或两者的范围也包括在双特异性分子、组合物和方法中。
某些范围在本文以前面出现术语“约”的数值呈现。术语“约”在本文用于为其后面出现的精确数值以及接近或靠近术语后面的数值的数提供文字性支持。在确定一个数字是否接近或近似一个具体列举的数字时，接近或近似的未列举的数字可以是在其出现的上下文中提供该具体列举的数字的实质等同物的数字。
除非另外定义，否则本文使用的所有技术和科学术语均具有与双特异性分子、组合物和方法所属领域的普通技术人员通常理解的含义相同的含义。尽管任何与本文所述那些相似或等同的双特异性分子、组合物和方法也可用于双特异性分子、组合物和方法的实践或测试，但现在描述代表性的示例性双特异性分子、组合物和方法。
在本说明书中引用的所有公开和专利通过引用并入本文，如同每个单独的公开或专利被具体和单独地指示通过引用并入并且通过引用并入本文以公开和描述与所引用的公开有关的材料和/或方法。任何出版物的引用均为其在申请日之前的公开，并且不应被解释为承认本双特异性分子、组合物和方法无权先于此类出版物，因为所提供的出版日期可能与可能需要独立确认的实际出版日期不同。
应注意，如本文中和所附权利要求书中所用，除非上下文另外清楚指示，否则单数形式“一个”、“一种”和“所述”包括多个指示物。另外注意，权利要求可以撰写为排除任何可选的要素。因此，本声明旨在用作使用与权利要求要素的叙述有关的诸如“单独”、“仅”等排他性术语或使用“否定”限制的在先基础。
应理解，为了清楚起见，在单独的实施方案的上下文中描述的双特异性分子、组合物和方法的某些特征也可以以组合形式提供在单个实施方案中。相反，为了简洁起见，在单个实施方案的上下文中描述的双特异性分子、组合物和方法的各种特征也可以单独提供或以任何合适的子组合提供。本发明具体包含实施方案的所有组合，并在本文中公开，如同单独且明确地公开了每个组合一样，只要这些组合包含可操作的过程和/或组合物。另外，描述这种变量的实施方案中列出的所有子组合也由本双特异性分子、组合物和方法具体包括，并且在本文中公开，就好像每一个这种子组合在本文中单独和明确地公开。
本领域技术人员在阅读本公开时将理解，本文描述和示例的每个单独实施方案具有离散的组件和特征，其可以容易地与任何其他几个实施方案的特征分离或组合而不脱离本方法的范围或精神。任何叙述的方法可以以所叙述事件的顺序或以逻辑上可能的任何其他顺序进行。
双特异性分子
本公开提供了双特异性分子。双特异性分子包含细胞靶向部分(例如，癌细胞靶向部分或免疫细胞靶向部分)和聚糖结合部分。在某些实施方案中，所述聚糖结合部分包含凝集素的唾液酸聚糖结合结构域，凝集素的非限制性示例是唾液酸结合免疫球蛋白样凝集素(Siglec)。所述双特异性分子可以采取多种形式，包括异二聚体分子、融合蛋白、缀合物等。如本文所证明的，包含癌细胞靶向部分和聚糖结合部分的本公开的双特异性分子在增强抗肿瘤免疫应答中是有效的，例如，通过增强的抗体依赖性细胞吞噬作用(ADCP)和/或细胞毒性(ADCC)。此外，该增强需要双特异性形式，并且结果证明由将肿瘤细胞靶向臂和聚糖结合臂组合成单个双特异性分子产生的治疗协同作用。如本文所用，关于由两种或更多种单独组分产生的效应的“协同作用”或“协同效应”是指这样的现象，其中当组合使用时(这里，以单个双特异性分子存在)，由这些组分产生的总效应大于每种组分单独作用的单独效应的总和。现在将描述关于根据本公开的实施方案的双特异性分子的进一步细节。
细胞靶向部分
多种细胞靶向部分可用于本公开的双特异性分子中。在某些实施方案中，细胞靶向部分是癌细胞靶向部分。“癌细胞”意指表现出赘生性细胞表型的细胞，其特征可在于以下示例性特征中的一个或多个：异常细胞生长、异常细胞增殖、密度依赖性生长抑制的丧失、不依赖固着的生长潜力、在免疫受损的非人动物模型中促进肿瘤生长和/或发育的能力、和/或任何适当的细胞转化指标。“癌细胞(cancer cell)”在本文中可以与“肿瘤细胞”、“恶性细胞”或“癌细胞(cancerous cell)”互换使用，并且涵盖实体瘤、半实体瘤、恶性血液肿瘤(例如，白血病细胞、淋巴瘤细胞、骨髓瘤细胞等)、原发性肿瘤、转移性肿瘤等的癌细胞。
在某些实施方案中，当细胞靶向部分是癌细胞靶向部分时，癌细胞靶向部分与癌细胞表面上表达的分子(例如，蛋白质)特异性结合。癌细胞靶向部分可以特异性结合的癌细胞表面分子的非限制性示例包括5T4、AXL受体酪氨酸激酶(AXL)、B细胞成熟抗原(BCMA)、c-MET、C4.4a、碳酸酐酶6(CA6)、碳酸酐酶9(CA9)、钙粘蛋白6、CD19、CD22、CD25、CD27L、CD30、CD33、CD37、CD44v6、CD56、CD70、CD74、CD79b、CD123、CD138、癌胚抗原(CEA)、cKit、Cripto蛋白、CS1、δ样规范Notch配体3(DLL3)、内皮素受体B型(EDNRB)、肝配蛋白(ephrin)A4(EFNA4)、表皮生长因子受体(EGFR)、EGFRvIII、外切核苷酸焦磷酸酶/磷酸二酯酶3(ENPP3)、EPH受体A2(EPHA2)、成纤维细胞生长因子受体2(FGFR2)、成纤维细胞生长因子受体3(FGFR3)、FMS样酪氨酸激酶3(FLT3)、叶酸受体1(FOLR1)、非转移性糖蛋白B(GPNMB)、鸟苷酸环化酶2C(GUCY2C)、人表皮生长因子受体2(HER2)、人表皮生长因子受体3(HER3)、整联蛋白α、溶酶体相关膜蛋白1(LAMP-1)、Lewis Y、LIV-1、富含亮氨酸重复蛋白15(LRRC15)、间皮素(MSLN)、粘蛋白1(MUC1)、粘蛋白16(MUC16)、钠依赖性磷酸盐转运蛋白2B(NaPi2b)、连接素4、NMB、NOTCH3、p-钙粘蛋白(p-CAD)、前列腺特异性膜抗原(PSMA)、蛋白质酪氨酸激酶7(PTK7)、溶质载体家族44成员4(SLC44A4)、SLIT样家族成员6(SLITRK6)、STEAP家族成员1(STEAP1)、组织因子(TF)、T细胞免疫球蛋白和粘蛋白蛋白1(TIM-1)、滋养层细胞表面抗原(TROP-2)和Wilms肿瘤1(WT1)。
根据一些实施方案，细胞靶向部分是免疫细胞靶向部分。在某些实施方案中，当细胞靶向部分是免疫细胞靶向部分时，该免疫细胞靶向部分与免疫细胞表面上表达的分子(例如，蛋白质)特异性结合。可选择免疫细胞靶向部分以靶向任何期望的免疫细胞，免疫细胞的非限制性示例包括T细胞、B细胞、天然杀伤(NK)细胞、巨噬细胞、单核细胞、嗜中性粒细胞、树突细胞、肥大细胞、嗜碱细胞和嗜曙红细胞。在一些实施方案中，免疫细胞是T细胞。示例性T细胞类型包括原初T细胞(TN)、细胞毒性T细胞(TCTL)、记忆T细胞(TMEM)、T记忆干细胞(TSCM)、中央记忆T细胞(TCM)、效应记忆T细胞(TEM)、组织驻留记忆T细胞(TRM)、效应T细胞(TEFF)、调节性T细胞(TREGs)、辅助T细胞(TH、TH1、TH2、TH17)、CD4+T细胞、CD8+T细胞、病毒特异性T细胞、αβT细胞(Tαβ)和γδT细胞(Tγδ)。
免疫细胞靶向部分可特异性结合的免疫细胞表面分子的非限制性示例包括PD-1、PD-L1、PD-L2、CLTA-4、VISTA、LAG-3、TIM-3、CD24、CD47、SIRPα、CD3、CD8、CD4、CD28、CD80、CD86、CD19、ICOS、OX40、OX40L、GD3神经节苷脂、TIGIT、Siglec-2、Siglec-3、Siglec-7、Siglec-8、Siglec-9、Siglec-10、Siglec-15、半乳凝素-9、B7-H3、B7-H4、CD40、CD40L、B7RP1、CD70、CD27、BTLA、HVEM、KIR、4-1BB、4-1BBL、CD226、CD155、CD112、GITR、GITRL、A2aR、CD137、CD137L、CD45、CD206、CD163、TRAIL、NKG2D、CD16和TGF-β。
根据一些实施方案，细胞靶向部分包含与靶细胞上的细胞表面分子结合的小分子。“小分子”是指分子量为1000原子质量单位(amu)或更小的化合物。在某些实施方案中，小分子为750amu或更低、500amu或更低、400amu或更低、300amu或更低、或者200amu或更低。根据一些实施方案，小分子不是由重复的分子单元(诸如存在于聚合物中)制成的。在某些实施方案中，靶细胞表面分子是其配体是小分子的受体，并且细胞靶向部分的小分子是受体的小分子配体(或其衍生物)。已知可用于将缀合物靶向感兴趣的靶细胞的小分子。仅作为一个示例，已显示叶酸(FA)衍生物通过与叶酸受体结合而有效地靶向某些类型的癌细胞，叶酸受体例如在许多上皮肿瘤中过表达。参见例如Vergote等人(2015)Ther.Adv.Med.Oncol.7(4):206-218。在另一个示例中，小分子σ-2已被证明在靶向癌细胞方面是有效的。参见例如Hashim等人(2014)Molecular Oncology 8(5):956-967。σ-2是σ-2受体的小分子配体，其在许多增殖性肿瘤细胞(包括胰腺癌细胞)中过表达。在某些方面，本公开的双特异性分子的细胞靶向部分包含小分子，其中已经在小分子药物缀合物(SMDC)的背景下证明小分子通过与靶细胞上的细胞表面分子结合而有效地将缀合物靶向感兴趣的靶细胞。
根据某些实施方案，细胞靶向部分包含配体。如本文所用，“配体”是与生物分子形成复合物以用于生物学目的的物质。配体可以是选自循环因子、分泌因子、细胞因子、生长因子、激素、肽、多肽、小分子和核酸的物质，其与靶细胞表面上的细胞表面分子形成复合物。在某些实施方案中，当细胞靶向部分包含配体时，配体以如下方式被修饰：发生与细胞表面分子形成复合物，但是不发生这种复合物形成的正常生物学结果。在某些方面，配体是靶细胞上存在的细胞表面受体的配体。
在某些实施方案中，细胞靶向部分包含适体。“适体”是指对靶细胞表面分子具有特异性结合亲和力的核酸(例如，寡核苷酸)。适体对于靶向递送双特异性分子表现出某些期望的性质，诸如易于选择和合成、高结合亲和力和特异性、低免疫原性和通用合成可及性。与细胞表面分子结合的适体是已知的，并且包括例如TTA1(细胞外基质蛋白肌腱蛋白-C的肿瘤靶向适体)。可用于本公开的双特异性分子的适体包括在Zhu等人(2015)ChemMedChem 10(1):39-45；Sun等人(2014)Mol.Ther.Nucleic Acids 3:e182；和Zhang等人(2011)Curr.Med.Chem.18(27):4185-4194中描述的那些。
根据一些实施方案，细胞靶向部分包含纳米颗粒。如本文所用，“纳米颗粒”是具有至少一个在1nm至1000nm，20nm至750nm，50nm至500nm，包括100nm至300nm，例如，120-200nm范围内的尺寸的颗粒。纳米颗粒可具有任何合适的形状，包括但不限于球形、球体、棒形、盘形、金字塔形、立方体形、圆柱形、纳米螺旋状、纳米弹簧形、纳米环形、箭头形、泪滴形、四脚形、棱柱形或任何其它合适的几何或非几何形状。在某些实施方案中，纳米颗粒在其表面上包括一种或多种本文所述的其它靶向部分，例如抗体、配体、适体、小分子等。可用于本公开的双特异性分子的纳米颗粒包括在Wang等人(2010)Pharmacol.Res.62(2):90-99；Rao等人(2015)ACS Nano 9(6):5725-5740；和Byrne等人(2008)Adv.Drug Deliv.Rev.60(15):1615-1626中描述的那些。
在一些实施方案中，细胞靶向部分特异性结合在靶细胞表面上表达的受体。这种细胞靶向部分可包含例如特异性结合受体的抗体的抗原结合结构域，或受体的配体。这种细胞表面受体的非限制性示例包括干细胞受体、免疫细胞受体(例如，T细胞受体、B细胞受体等)、生长因子受体、细胞因子受体、激素受体、受体酪氨酸激酶、免疫受体(如CD28、CD80、ICOS、CTLA4、PD1、PD-L1、BTLA、HVEM、CD27、4-1BB、4-1BBL、OX40、OX40L、DR3、GITR、CD30、SLAM、CD2、2B4、TIM1、TIM2、TIM3、TIGIT、CD226、CD160、LAG3、LAIR1、B7-1、B7-H1和B7-H3)、I型细胞因子受体(如白介素1受体、白介素2受体、白介素3受体、白介素4受体、白介素5受体、白介素6受体、白介素7受体、白介素9受体、白介素11受体、白介素12受体、白介素13受体、白介素15受体、白介素18受体、白介素21受体、白介素23受体、白介素27受体)、促红细胞生成素受体、GM-CSF受体、G-CSF受体、生长激素受体、催乳素受体、瘦素受体、制瘤素M受体、白血病抑制因子、II型细胞因子受体(如干扰素α/β受体、干扰素γ受体、干扰素III型受体、白介素10受体、白介素20受体、白介素22受体、白介素28受体)、肿瘤坏死因子受体超家族中的受体(如肿瘤坏死因子受体2(1B)、肿瘤坏死因子受体1)、淋巴毒素β受体、OX40、CD40、Fas受体、诱饵受体3、CD27、CD30、4-1BB、诱饵受体2、诱饵受体1、死亡受体5、死亡受体4、RANK、骨保护素、TWEAK受体、TACI、BAFF受体、疱疹病毒进入介质、神经生长因子受体、B细胞成熟抗原、糖皮质激素诱导的TNFR相关受体、TROY、死亡受体6、死亡受体3、外异蛋白(Ectodysplasin)A2受体、趋化因子受体(如CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、CXCR6、CX3CR1、XCR1、ACKR1、ACKR2、ACKR3、ACKR4、CCRL2)、表皮生长因子受体(EGFR)家族中的受体、成纤维细胞生长因子受体(FGFR)家族中的受体、血管内皮生长因子受体(VEGFR)家族中的受体、转染期间重排(RET)受体家族中的受体、Eph受体家族中的受体、可诱导细胞分化的受体(例如，Notch受体)、细胞粘附分子(CAM)、粘附受体(如整联蛋白受体)、钙粘蛋白、选择素、以及盘状结构域受体(DDR)家族中的受体、转化生长因子β受体1和转化生长因子β受体2。在一些实施方案中，这样的受体是选自以下的免疫细胞受体：T细胞受体、B细胞受体、天然杀伤(NK)细胞受体、巨噬细胞受体、单核细胞受体、嗜中性粒细胞受体、树突细胞受体、肥大细胞受体、嗜碱性粒细胞受体和嗜酸性粒细胞受体。
在某些实施方案中，细胞靶向部分包含抗体的抗原结合结构域。“抗体”意指任何同种型的抗体或免疫球蛋白(例如IgG(例如IgG1、IgG2、IgG3或IgG4)、IgE、IgD、IgA、IgM等)、全抗体(例如由四聚体组成的抗体，该四聚体又由重链和轻链多肽的两个二聚体组成)；单链抗体(例如，scFv)；保持与靶细胞的细胞表面分子的特异性结合的抗体片段(例如，全抗体或单链抗体的片段)，包括但不限于单链Fv(scFv)、Fab、(Fab')2、(scFv')2和双链抗体；嵌合抗体；单克隆抗体、人抗体、人源化抗体(例如，人源化全抗体、人源化半抗体或人源化抗体片段(例如人源化scFv))；以及包含抗体的抗原结合部分和非抗体蛋白的融合蛋白。在某些实施方案中，抗体选自IgG、Fv、单链抗体、scFv、Fab、F(ab')2或Fab'。抗体可以被可检测地标记，例如，被体内显像剂、放射性同位素、产生可检测产物的酶、荧光蛋白等标记。抗体可以进一步与其它部分缀合，例如特异性结合对的成员，例如生物素(生物素-亲和素特异性结合对的成员)等。
根据一些实施方案中，当细胞靶向部分包含抗体的抗原结合结构域时，抗体的抗原结合结构域是由美国食品和药品管理局(United States Food and DrugAdministration)和/或欧洲药品管理局(European Medicines Agency，EMA)批准用作治疗性抗体(例如用于诱导患者中某些疾病相关细胞的抗体依赖性细胞毒性(ADCC)，包括抗体依赖性细胞吞噬作用(ADCP)和/或类似作用)的抗体。可以用于本公开的双特异性分子中的抗原结合结构域的非限制性示例包括来自选自以下的抗体的那些：阿德木单抗(Adecatumumab)、阿伐苏单抗(Ascrinvacumab)、西妥木单抗(Cixutumumab)、可那木单抗(Conatumumab)、达雷木单抗(Daratumumab)、曲齐妥单抗(Drozitumab)、杜利妥单抗(Duligotumab)、德瓦鲁单抗(Durvalumab)、杜斯吉妥单抗(Dusigitumab)、恩诺单抗(Enfortumab)、依诺苏单抗(Enoticumab)、芬妥木单抗(Figitumumab)、加尼妥单抗(Ganitumab)、格巴妥木单抗(Glembatumumab)、英妥木单抗(Intetumumab)、伊匹木单抗、伊妥木单抗(Iratumumab)、艾芦库单抗(Icrucumab)、来沙木单抗(Lexatumumab)、鲁卡木单抗(Lucatumumab)、马帕木单抗(Mapatumumab)、那呐妥单抗(Narnatumab)、奈昔木单抗(Necitumumab)、奈弗库单抗(Nesvacumab)、奥法木单抗(Ofatumumab)、奥拉单抗(Olaratumab)、帕木单抗(Panitumumab)、帕曲妥单抗(Patritumab)、普立木单抗(Pritumumab)、达雷妥尤单抗(Radretumab)、雷莫芦单抗(Ramucirumab)、利妥木单抗(Rilotumumab)、罗妥木单抗(Robatumumab)、塞巴坦单抗(Seribantumab)、他瑞妥单抗(Tarextumab)、替妥木单抗(Teprotumumab)、托维妥单抗(Tovetumab)、万替妥单抗(Vantictumab)、维森库单抗(Vesencumab)、伏妥木单抗(Votumumab)、扎芦木单抗(Zalutumumab)、法兰妥单抗(Flanvotumab)、阿妥莫单抗(Altumomab)、安那妥莫单抗(Anatumomab)、阿西莫单抗(Arcitumomab)、贝妥莫单抗(Bectumomab)、兰妥莫单抗(Blinatumomab)、地莫单抗(Detumomab)、替伊莫单抗(Ibritumomab)、明瑞莫单抗(Minretumomab)、米妥莫单抗(Mitumomab)、莫塞妥莫单抗(Moxetumomab)、那普妥莫单抗(Naptumomab)、诺非单抗(Nofetumomab)、培妥莫单抗(Pemtumomab)、帕尼单抗(Pintumomab)、雷妥莫单抗(Racotumomab)、沙妥莫单抗(Satumomab)、索利托单抗(Solitomab)、他利妥莫单抗(Taplitumomab)、替妥莫单抗(Tenatumomab)、托西莫单抗(Tositumomab)、曲美木单抗(Tremelimumab)、阿巴伏单抗(Abagovomab)、伊戈伏单抗(Igovomab)、奥戈伏单抗(Oregovomab)、卡罗单抗(Capromab)、依屈洛单抗(Edrecolomab)、纳可洛单抗(Nacolomab)、阿麦妥昔单抗(Amatuximab)、巴维昔单抗(Bavituximab)、本妥昔单抗(Brentuximab)、西妥昔单抗(cetuximab)、德尔罗妥单抗(Derlotuximab)、地努图希单抗(Dinutuximab)、恩妥昔单抗(Ensituximab)、伏妥昔单抗(Futuximab)、吉瑞昔单抗(Girentuximab)、英达妥昔单抗(Indatuximab)、伊沙妥昔单抗(Isatuximab)、马格妥昔单抗(Margetuximab)、利妥昔单抗、司妥昔单抗(Siltuximab)、乌妥昔单抗(Ublituximab)、依美昔单抗(Ecromeximab)、阿比妥珠单抗(Abituzumab)、阿仑珠单抗(Alemtuzumab)、贝伐珠单抗(Bevacizumab)、比伐珠单抗(Bivatuzumab)、布隆妥珠单抗(Brontictuzumab)、坎妥珠单抗(Cantuzumab)、坎妥珠单抗、西他珠单抗(Citatuzumab)、克利伐珠单抗(Clivatuzumab)、达西珠单抗(Dacetuzumab)、登赛珠单抗(Demcizumab)、达洛珠单抗(Dalotuzumab)、地宁妥珠单抗(Denintuzumab)、埃罗妥珠单抗(Elotuzumab)、艾玛曲单抗(Emactuzumab)、艾米贝妥珠单抗(Emibetuzumab)、依诺妥珠单抗(Enoblituzumab)、埃达珠单抗(Etaracizumab)、法利珠单抗(Farletuzumab)、非克拉珠单抗(Ficlatuzumab)、吉妥珠单抗(Gemtuzumab)、伊马珠单抗(Imgatuzumab)、英妥珠单抗(Inotuzumab)、拉贝珠单抗(Labetuzumab)、利法妥珠单抗(Lifastuzumab)、林妥珠单抗(Lintuzumab)、洛沃妥珠单抗(Lorvotuzumab)、鲁妥珠单抗(Lumretuzumab)、马妥珠单抗(Matuzumab)、米拉珠单抗(Milatuzumab)、尼妥珠单抗(Nimotuzumab)、奥比妥珠单抗(Obinutuzumab)、奥卡珠单抗(Ocaratuzumab)、奥乐妥珠单抗(Otlertuzumab)、奥纳妥珠单抗(Onartuzumab)、奥泼妥珠单抗(Oportuzumab)、帕沙妥珠单抗(Parsatuzumab)、培妥珠单抗(Pertuzumab)、匹那妥珠单抗(Pinatuzumab)、泊洛妥珠单抗(Polatuzumab)、西罗珠单抗(Sibrotuzumab)、辛妥珠单抗(Simtuzumab)、他珠单抗(Tacatuzumab)、替加珠单抗(Tigatuzumab)、曲妥珠单抗(Trastuzumab)、西莫白介素单抗(Tucotuzumab)、万多妥珠单抗(Vandortuzumab)、伐努赛珠单抗(Vanucizumab)、维妥珠单抗(Veltuzumab)、沃瑟妥珠单抗(Vorsetuzumab)、索非妥珠单抗(Sofituzumab)、卡妥索单抗(Catumaxomab)、厄马索单抗(Ertumaxomab)、达妥昔单抗(Depatuxizumab)、昂妥昔珠单抗(Ontuxizumab)、布隆妥维单抗(Blontuvetmab)、坦妥维单抗(Tamtuvetmab)、或它们的抗原结合变体，例如单链形式(例如，scFv形式)。
在某些实施方案中，细胞靶向部分包含抗体重链，该抗体重链包含γ、α、δ、ε或μ抗体重链或其片段。根据一些实施方案，抗体重链或其片段是IgG重链或其片段，例如人IgG1重链或其片段。在某些实施方案中，抗体重链或其片段包含重链可变区(VH)。这种抗体重链或其片段还可包括重链恒定区或其片段。例如，当细胞靶向部分中包括重链恒定区或其片段时，抗体重链恒定区或其片段可包括CH1结构域、CH2结构域和/或CH3结构域中的一种或多种。根据一些实施方案，细胞靶向部分包含全长抗体重链，即，包括VH、CH1结构域、CH2结构域和CH3结构域的抗体重链。
在某些实施方案中，细胞靶向部分包含抗体轻链或其片段。根据一些实施方案中，抗体轻链或其片段包括kappa(κ)轻链或其片段或lambda(λ)轻链或其片段。根据一些实施方案，抗体轻链或其片段包括轻链可变区(VL)。这种抗体轻链或其片段可进一步包括抗体轻链恒定区(CL)或其片段。在某些实施方案中，细胞靶向部分包含全长抗体轻链，即，包括VL和CL的抗体轻链。
根据一些实施方案，细胞靶向部分包含抗体重链和抗体轻链，该抗体重链包含可变重链(VH)区，该抗体轻链包含可变轻链(VL)区。在某些实施方案中，细胞靶向部分包含CH1结构域、铰链区、CH2结构域、CH3结构域或它们的任何组合。例如，细胞靶向部分可包含抗体重链，该抗体重链包含CH2结构域、CH3结构域或两者。这种细胞靶向部分的示例包括包含片段可结晶(Fc)区的那些。
本公开的双特异性分子的细胞靶向部分和/或聚糖结合部分可以与它们各自的靶标特异性结合。如本文所用，如果细胞靶向部分或聚糖结合部分以比该细胞靶向部分或聚糖结合部分与(例如，样品中和/或体内的)其他物质结合更大的亲和力、亲合力、更容易地和/或以更长的持续时间结合靶标，则该细胞靶向部分或聚糖结合部分“特异性结合”或“优先结合”该靶标。在某些实施方案中，如果细胞靶向部分或聚糖结合部分以例如大于或等于约104M-1的亲和力或Ka(即，以1/M为单位的特定结合相互作用的缔合速率常数)结合或缔合靶标，则该细胞靶向部分或聚糖结合部分“特异性结合”该靶标。替代地，亲和力可以定义为以M为单位(例如，10-5M至10-13M，或更小)进行的特定结合相互作用的平衡解离常数(KD)。在某些方面中，特异性结合意指细胞靶向部分或聚糖结合部分与靶标结合的KD小于或等于约10-5M、小于或等于约10-6M、小于或等于约10-7M、小于或等于约10-8M，或小于或等于约10-9M、10-10M、10-11M、或10-12M或更小。细胞靶向部分或聚糖结合部分与靶标的结合亲和力可以使用常规技术容易地确定，例如，通过竞争性ELISA(酶联免疫吸附测定)、平衡透析、通过使用表面等离子体共振(SPR)技术(例如，BIAcore 2000或BIAcore T200仪器，使用制造商所概述的一般工序)；通过放射免疫测定；等等。
聚糖结合部分
多种聚糖结合部分可用于本公开的双特异性分子中。在某些实施方案中，聚糖结合部分包含凝集素的聚糖结合结构域。例如，聚糖结合部分可以包含唾液酸聚糖结合凝集素的唾液酸聚糖结合结构域。唾液酸聚糖结合部分的非限制性示例包括那些包含唾液酸结合免疫球蛋白样凝集素(Siglec)的唾液酸聚糖结合结构域的部分。
Siglec是免疫调节受体家族，其功能由其聚糖配体调控。Siglec家族由15个人家族成员组成，这些家族成员在造血谱系中的一组受限细胞上表达，已知的例外情况包括少突胶质细胞和许旺细胞上的Siglec-4(MAG)和胎盘滋养层上的Siglec-6。Siglec通过其最外面的N末端V-set结构域以独特但重叠的特异性识别糖蛋白和糖脂上的含唾液酸的聚糖配体。其配体的识别可通过其细胞质尾部上的基于免疫受体酪氨酸的抑制基序(ITIM)影响细胞信号传导。对于大多数Siglec，这些ITIM具有募集磷酸酶的能力，因此，这些成员被称为抑制型Siglec。例外情况包括缺乏这种基序的Siglec-1和MAG，以及激活型Siglec(Siglec-14至Siglec-16)，它们通过其跨膜区中的正电荷氨基酸与带有免疫受体酪氨酸基激活基序(ITAM)的衔接蛋白缔合。
基于它们在哺乳动物物种中的遗传同源性，Siglec可以分成两组。第一组存在于所有哺乳动物中并由Siglec-1(唾液酸粘附素)、Siglec-2(CD22)、Siglec-4和Siglec-15组成。第二组由CD33相关的Siglec组成，其包括Siglec-3(CD33)、Siglec-5、Siglec-6、Siglec-7、Siglec-8、Siglec-9、Siglec-10、Siglec-11、Siglec-14和Siglec-16。单核细胞，单核细胞源的巨噬细胞和单核细胞源的树突细胞具有基本相同的Siglec谱，即Siglec-3、Siglec-7、Siglec-9的高表达、Siglec-10的低表达，以及在用IFN-α刺激后，Siglec-1的表达。相比之下，巨噬细胞主要表达Siglec-1、Siglec-3、Siglec-8、Siglec-9、Siglec-11、Siglec-15和Siglec-16，这取决于它们的分化状态。常规树突细胞表达Siglec-3、Siglec-7和Siglec-9，类似于单核细胞源的树突细胞，但另外还表达低水平的Siglec-2和Siglec-15。浆细胞样树突细胞表达Siglec-1和Siglec-5。在用LPS刺激48小时后观察到单核细胞源的树突细胞上的Siglec-7和Siglec-9表达下调，然而，在单核细胞源的巨噬细胞上，在LPS触发后Siglec表达没有改变。Siglec也存在于其它免疫细胞上，诸如B细胞、嗜碱性粒细胞、中性粒细胞和NK细胞。关于Siglec的进一步细节可见于例如Angata等人(2015)TrendsPharmacol Sci.36(10):645–660；Lübbers等人(2018)Front.Immunol.9:2807；Bochner等人(2016)J Allergy Clin Immunol.135(3):598–608；和Duan等人(2020)Annu.Rev.Immunol.38(1):365–395；上述文献的公开内容出于所有目的通过引用整体并入本文。
聚糖结合部分可以包含15个人Siglec家族成员中的任一个的唾液酸聚糖结合结构域。在某些实施方案中，聚糖结合部分包含CD33相关Siglec的唾液酸聚糖结合结构域。根据一些实施方案，CD33相关Siglec是Siglec-7(UniProtKB-Q9Y286)。在一些实施方案中，聚糖结合部分与Siglec-7配体结合，其中聚糖结合部分包含SEQ ID NO:15中所示的氨基酸序列，或其Siglec-7配体结合变体，或其保留结合Siglec-7配体能力的片段，该变体与SEQ IDNO:15中所示的氨基酸序列具有70％或更高、75％或更高、80％或更高、85％或更高、90％或更高、95％或更高、96％或更高、97％或更高、98％或更高、或99％或更高的氨基酸序列同一性。在某些实施方案中，CD33相关Siglec是Siglec-9(UniProtKB-Q9Y336)。在一些实施方案中，聚糖结合部分与Siglec-9配体结合，其中聚糖结合部分包含SEQ ID NO:21中所示的氨基酸序列，或其Siglec-9配体结合变体，或其保留结合Siglec-9配体能力的片段，该变体与SEQ ID NO:21中所示的氨基酸序列具有70％或更高、75％或更高、80％或更高、85％或更高、90％或更高、95％或更高、96％或更高、97％或更高、98％或更高、或99％或更高的氨基酸序列同一性。根据一些实施方案，CD33相关Siglec是Siglec-10(UniProtKB-Q96LC7)。在某些实施方案中，聚糖结合部分包含Siglec-15(UniProtKB-Q6ZMC9)的唾液酸聚糖结合结构域。根据一些实施方案，聚糖结合部分包含Siglec样粘附素的唾液酸聚糖结合结构域。参见，例如Deng等人(2014)PLoS Pathog 10(12):e1004540，和Bensing等人(2018)Glycobiology28(8):601-611，其公开内容出于所有目的以全文引用的方式并入本文中。
在某些实施方案中，聚糖结合部分包含C型凝集素的聚糖结合结构域。C型凝集素是由至少一个C型凝集素样结构域(CTLD)的存在所定义，并且识别广泛的配体组库并调控不同范围的生理功能的蛋白质超家族。大多数研究关注集中于C型凝集素在先天和适应性抗微生物免疫应答中发挥作用的能力，但是这些蛋白质越来越多地被认为在自身免疫疾病中具有主要作用并且促成多细胞存在的许多其它方面。引入术语C型凝集素是为了区分Ca2+依赖性和Ca2+非依赖性碳水化合物结合凝集素。C型凝集素共有至少一个碳水化合物识别结构域，该碳水化合物识别结构域是含有保守残基基序的紧凑结构模块并且决定CLR的碳水化合物特异性。定位于基因的天然杀伤簇的端粒区的Dectin-1和Dectin-2家族的基因，对于它们在联合先天免疫和适应性免疫中的作用特别感兴趣。这两组C-型凝集素主要由髓系细胞诸如单核细胞、巨噬细胞、树突细胞(DC)和嗜中性粒细胞表达。C型凝集素不仅充当抗原摄取受体进行内化和呈递至T细胞，而且触发导致NF-κB、I型干扰素(IFN)和/或炎性小体活化的多个信号传导途径。这又导致促炎和抗炎细胞因子和趋化因子的产生，随后精细调节适应性免疫应答。关于C型凝集素的进一步细节可以在例如Zelensky等人(2005)FEBSJ.272:6179-6217；Geijtenbeek&Grinhuis(2009)Nature Reviews Immunology 9:465-479；Brown等人(2018)Nature Reviews Immunology18:374-389；Dambuza和Brown(2015)Curr.Opin.Immunol.32:21-7；及Chiffoleau(2018)Front.Immunol.9:227中找到；上述文献的公开内容出于所有目的通过引用整体并入本文。根据一些实施方案，聚糖结合部分包含选自以下的C型凝集素的聚糖结合结构域：DECTIN-1、凝集素样氧化低密度脂蛋白受体-1(LOX-1)、C型凝集素样受体-1(CLEC-1)、C型凝集素样受体2(CLEC-2)、髓样抑制性C型凝集素样受体(MICL)、CLEC9A、DC免疫受体(DCIR)、DECTIN-2、血液DC抗原-2(BDCA-2)、巨噬细胞诱导型C型凝集素(MINCLE)、巨噬细胞半乳糖凝集素(MGL)和无唾液酸糖蛋白受体(ASGPR)。
在某些实施方案中，聚糖结合部分包含选择素的聚糖结合结构域。选择素是介导白细胞运输以及白细胞、血小板和内皮细胞与肿瘤细胞的特异性粘附相互作用的C型跨膜凝集素。这些凝集素存在于内皮细胞(E-选择素)、白细胞(L-选择素)和血小板(P-选择素)上，并优先结合含有SLeX和SLeA糖表位的聚糖，这些聚糖在几种肿瘤类型中大量表达。在TME中，选择素在白细胞募集、肿瘤促进炎症和获取转移潜力方面是功能相关的。P-选择素(CD62P)参与肿瘤生长和转移，因为它介导活化的血小板和癌细胞之间的相互作用，促成肿瘤发生。E-选择素(CD62E)还在转移级联的不同事件时癌细胞粘附性中起主要作用，促进肿瘤细胞外渗。最后，在白细胞上组成性表达的L-选择素(CD62L)调控肿瘤-白细胞相互作用并通过有利于栓子形成而促进细胞粘附和血行转移。关于选择素的进一步细节可见于例如Cagnoni等人(2016)Front Oncol.6:109；Barthel等人(2007)Expert Opin Ther Targets11(11):1473-91；以及Chen和Geng(2006)Arch Immunol Ther Exp 54(2):75-84；上述文献的公开内容出于所有目的通过引用整体并入本文。根据一些实施方案，聚糖结合部分包含选自P-选择素(CD62P)、E-选择素(CD62E)和L-选择素(CD62L)的选择素的聚糖结合结构域。
根据一些实施方案，聚糖结合部分包含半乳凝素的聚糖结合结构域。半乳凝素是高度保守的结合聚糖的可溶性凝集素家族，由保守碳水化合物识别结构域(CRD)和常见结构折叠限定。Vasta GR(2012)Adv Exp Med Biol 946:21-36。基于结构特征，已将哺乳动物半乳凝素分类为三种类型：原型半乳凝素(Gal-1、Gal-2、Gal-5、Gal-7、Gal-10、Gal-11、Gal-13、Gal-14和Gal-15，其含有一个CRD并且作为单体存在或通过非共价相互作用二聚化)；串联重复型半乳凝素(Gal-4、Gal-6、Gal-8、Gal-9和Gal-12)，其作为含有通过接头肽连接的两个不同CRD的二价半乳凝素存在；以及最后Gal-3，半乳凝素家族的唯一嵌合型成员。半乳凝素调节肿瘤发生和转移中的不同事件。半乳凝素通过效应T细胞的凋亡、克隆扩增的调控、调控性T细胞(Treg)的功能和细胞因子分泌的控制而促成免疫耐受和逃避。一些半乳凝素的表达水平在恶性转化期间也改变，证实了它们在癌症进展中的作用。几乎所有恶性肿瘤细胞大量分泌的Gal-1已被表征为免疫阻遏性原致癌基因微环境的主要促进剂。Gal-3，该家族的另一个成员，已经在多种肿瘤中显示出显著的原致癌基因作用。类似于Gal-1，Gal-3信号传导通过与特定聚糖相互作用并削弱抗肿瘤应答而促使平衡向免疫阻遏TME倾斜。在这点上，已经证实Gal-3会促进肿瘤浸润性淋巴细胞(TIL)的无变应性。根据一些实施方案，聚糖结合部分包含选自Gal-1、Gal-2、Gal-3、Gal-4、Gal-5、Gal-6、Gal-7、Gal-8、Gal-9、Gal-10、Gal-11、Gal-12、Gal-13、Gal-14和Gal-15的半乳凝素的聚糖结合结构域。在某些实施方案中，聚糖结合部分包含Gal-1的聚糖结合结构域。根据一些实施方案，聚糖结合部分包含Gal-3的聚糖结合结构域。
所谓凝集素的“聚糖结合结构域”或“唾液酸聚糖结合结构域”意指负责与相应聚糖结合的凝集素或其聚糖/唾液酸聚糖结合变体(例如，聚糖/唾液酸聚糖结合片段)的结构域。例如，Siglec包含负责唾液酸苷配体结合的胞外N端V-set Ig(Ig-V)结构域。在某些实施方案中，本公开的任何多肽或其结构域的“变体”含有一个或多个氨基酸取代。根据一些实施方案，该一个或多个氨基酸取代是保守取代。“保守取代”是其中一个氨基酸被具有相似性质的另一氨基酸取代的取代，使得肽化学领域的技术人员预期多肽的二级结构和亲水性质基本上不变。可以对特定实施方案中考虑的多核苷酸和多肽的结构中进行修饰，多肽包括具有至少约并且仍然获得编码具有所需特性的变体或衍生多肽的功能性分子的多肽。当需要改变多肽的氨基酸序列以产生等同或甚至改进的变体多肽时，本领域技术人员例如可以改变编码DNA序列的一个或多个密码子。
除了凝集素的聚糖结合结构域之外，聚糖结合部分可以包含凝集素的一个或多个另外的结构域或其变体(例如，片段)。举例而言，在Siglec的情况下，除了Siglec的唾液酸聚糖结合结构域(例如，Siglec-7、Siglec-9、Siglec-10、Siglec-15等)之外，聚糖结合部分还可以包含Siglec的一个或多个(例如，1、2、3个或更多个)Ig样结构域或其片段。Siglec和其他凝集素的氨基酸序列和结构域(例如，胞外结构域)是已知的，并且根据需要和/或有用，任何这样的结构域都可以包括在聚糖结合部分中。
在某些实施方案中，聚糖结合部分包含抗体重链，该抗体重链包含γ、α、δ、ε或μ抗体重链或其片段。根据一些实施方案，抗体重链或其片段是IgG重链或其片段，例如人IgG1重链或其片段。在某些实施方案中，抗体重链或其片段包含重链恒定区或其片段。例如，当聚糖结合部分中包括重链恒定区或其片段时，抗体重链恒定区或其片段可包括CH1结构域、CH2结构域和/或CH3结构域中的一种或多种，例如CH2结构域和CH3结构域。根据一些实施方案，聚糖结合部分包含CH1结构域、CH2结构域和CH3结构域。根据一些实施方案，聚糖结合部分包含片段可结晶(Fc)区。根据一些实施方案，细胞靶向部分和聚糖结合部分各自包含CH2结构域和/或CH3结构域(例如，Fc区)，并且双特异性分子是包含杵臼结构修饰的结构域(例如经修饰的CH3结构域)的异二聚体。本公开的这种双特异性分子的非限制性示例在图14-图17中示意性地说明(含氨基酸序列)。
“杵臼结构”策略(其非限制性示例例如在WO 2006/028936中有描述)可用于促进双特异性分子的部分的异二聚化。简而言之，可以在影响CH3结构域相互作用的位置突变形成人IgG中CH3结构域界面的选定氨基酸，以促进异二聚体形成。具有小侧链(臼)的氨基酸被引入特异性结合第一靶标的部分的重链中，具有大侧链(杵)的氨基酸被引入特异性结合第二靶标的部分的重链。两种部分共表达后，由于带有“臼”的重链与带有“杵”的重链优先相互作用而形成异二聚体。形成杵和臼的示例性CH3取代对是(表示为第一重链的第一CH3结构域中的修饰位置/第二重链的第二CH3结构域中的修饰位置)：T366Y7F405A、T366W/F405W、F405W/Y407A、T394W/Y407T、T3945/Y407A、T366W/T394S、F405W/T394S和T366W/T366S_L368A_Y407V。
可以使用其他策略，例如通过在一个CH3表面取代带正电荷的残基和在第二个CH3表面取代带负电荷的残基，使用静电相互作用促进重链异二聚化，如US2010/0015133；US2009/0182127；US2010/028637或US2011/0123532中所述。在其他策略中，异二聚化可以通过以下取代(表示为第一重链的第一CH3结构域中的修饰位置/第二重链的第二CH3结构域中的修饰位置)促进：L351 Y_F405A_Y407V T394W、T366I_K392M_T394W/F405A_Y407V、T366L_K392M_T394W/F405A_Y407V、L351 Y_Y407A'T366A_K409F、L351Y_Y407A/T366V_K409F、Y407A/T366A_K409F、或T350V_L351Y_F405A_Y407V/T350V_T366L_K392L_T394W，如在US2012/0149876或US2013/0195849中所述。
根据一些实施方案，本公开的双特异性分子是包含与聚糖结合部分融合的细胞靶向部分的融合蛋白。当双特异性分子是融合蛋白时，细胞靶向部分可以直接与聚糖结合部分融合(例如，在聚糖结合部分的N端或C端)，或者细胞靶向部分可以经由接头间接地与聚糖结合部分融合。可以采用任何有用的接头，包括但不限于丝氨酸-甘氨酸接头等。在特定的实施方案中，接头的长度为约1个至约25个氨基酸、约5个至约20个氨基酸、或约10个至约20个氨基酸、或任何氨基酸插入长度。在一些实施方案中，接头为1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个、20个、21个、22个、23个、24个、25个或更多个氨基酸长。还提供了编码本公开的融合蛋白的核酸，以及包含此类核酸的表达载体，及包含此类核酸和/或表达载体的宿主细胞。
在某些实施方案中，本公开的双特异性分子是包含经由接头与聚糖结合部分缀合的细胞靶向部分的缀合物。可用于本公开的缀合物中的接头的非限制性示例包括酯类接头、酰胺接头、马来酰亚胺或基于马来酰亚胺的接头；缬氨酸-瓜氨酸接头；腙接头；N-琥珀酰亚胺基-4-(2-吡啶基二硫代)丁酸酯(SPDB)接头；琥珀酰亚胺基-4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯(SMCC)接头；基于乙烯基砜的接头；包括聚乙二醇(PEG)(诸如但不限于四乙二醇)的接头；包括丙酸的接头；包括己酸的接头和包括它们的任何组合的接头。在某些方面，该接头是化学不稳定接头，诸如在中性pH(血流pH 7.3-7.5)下稳定但在内化到弱酸性胞内体(pH 5.0-6.5)以及靶细胞(例如，癌细胞)的溶酶体(pH 4.5-5.0)中时发生水解的酸可裂解接头。化学不稳定接头包括但不限于腙基接头、肟基接头、碳酸酯基接头、酯基接头等。根据某些实施方案，该接头是酶不稳定接头，诸如这样一种酶不稳定接头，其在血流中是稳定的，但在内化到靶细胞中时进行酶切(例如，通过靶细胞(例如，癌细胞)的溶酶体中的溶酶体蛋白酶(诸如组织蛋白酶或纤溶酶))。酶不稳定接头包括但不限于包括肽键的接头，例如，二肽基接头，诸如缬氨酸-瓜氨酸接头，诸如马来酰亚胺己酰基-缬氨酸-瓜氨酸-对氨基苄基(MC-vc-PAB)接头、缬氨酰-丙氨酰基-对氨基苄氧基(Val-Ala-PAB)接头等。化学不稳定接头、酶不稳定的和不可切割的接头是已知的并且详细描述于例如Ducry&Stump(2010)Bioconjugate Chem.21:5-13中。
在某些实施方案中，本公开的缀合物包括接头，该接头包括缬氨酸-瓜氨酸二肽、缬氨酸-丙氨酸二肽或两者。根据一些实施方案，接头是缬氨酸-瓜氨酸-对氨基苄氧基(Val-Cit-PAB)接头。在某些实施方案中，接头是缬氨酰丙氨酰对氨基苄氧基(Val-Ala-PAB)接头。
细胞靶向部分可以使用任何方便的方法缀合至聚糖结合部分。例如，缀合可以包括将聚糖结合部分位点特异性地缀合到细胞靶向部分的预先选择的氨基酸上(或反之亦然)。在某些方面，预先选择的氨基酸位于细胞靶向部分的N端或C端。在其他方面，预先选择的氨基酸在细胞靶向部分的内部——即，在细胞靶向部分的N端和C端氨基酸之间。在一些实施方案中，预先选择的氨基酸是非天然氨基酸。可以提供给细胞靶向部分(或聚糖结合部分)以促进缀合的非天然氨基酸的非限制性示例包括具有选自以下的官能团的那些：叠氮化物、炔烃、烯烃、氨基-氧基、肼、醛(例如，甲酰甘氨酸，例如，来自Catalent PharmaSolutions的SMARTagTM技术)、硝酮、氧化腈、环丙烯、降冰片烯、异氰化物、芳基卤化物和硼酸官能团。可以掺入和选择以提供目标官能团的非天然氨基酸是已知的并且描述于例如Maza等人(2015)Bioconjug.Chem.26(9):1884-9；Patterson等人(2014)ACS Chem.Biol.9:592-605；Adumeau等人(2016)Mol.Imaging Biol.(2):153-65；以及其他文献中。
许多策略可用于通过接头缀合细胞靶向部分和聚糖结合部分。例如，可以通过将接头共价附接至聚糖结合部分来衍生聚糖结合部分，其中接头具有能够与细胞靶向部分上的“化学柄”反应的官能团。又例如，细胞靶向部分可以通过将接头共价附接至细胞靶向部分而衍生，其中接头具有能够与聚糖结合部分上的“化学柄”反应的官能团。接头上的官能团可以变化，并且可以基于与细胞靶向部分或聚糖结合部分上的化学柄的相容性来选择。根据一个实施方案，通过将具有化学柄的非天然氨基酸掺入细胞靶向部分或聚糖结合部分中来提供化学柄。在一些实施方案中，通过无铜、应变促进的环加成、炔-叠氮化物环加成等将细胞靶向部分与聚糖结合部分缀合。
使用本文提供的信息，本公开的细胞靶向部分与聚糖结合部分和融合蛋白可以使用本领域技术人员熟知的标准技术制备。例如，编码本公开的双特异性分子的细胞靶向部分和聚糖结合部分的氨基酸序列的核酸序列可用于表达细胞靶向部分和聚糖结合部分。根据本领域技术人员已知的标准方法，可以优化核酸序列以反映各种表达系统的特定密码子“偏好”。使用提供的序列信息，可以根据本领域技术人员已知的多种标准方法合成核酸。
一旦合成了编码主题细胞靶向部分和/或聚糖结合部分的核酸，就可以根据标准方法对其进行扩增和/或克隆。实现这些目的的分子克隆技术是本领域已知的。适用于构建重组核酸的多种克隆和体外扩增方法是本领域技术人员已知的并且是许多教科书和实验室手册的主题。
编码本公开的细胞靶向部分和/或聚糖结合部分的天然或合成核酸的表达可以通过将编码细胞靶向部分和/或聚糖结合部分的核酸可操作地连接至启动子(其是组成型的或诱导型的)并将构建体掺入表达载体中以产生重组表达载体来实现。载体可适用于原核生物、真核生物或两者中的复制和整合。典型的克隆载体包含功能上适当定向的转录和翻译终止子、起始序列和可用于调控编码细胞靶向部分和/或聚糖结合部分的核酸的表达的启动子。载体任选地包含含有至少一个独立终止子序列的通用表达盒、允许所述盒在真核生物和原核生物中复制的序列，例如在穿梭载体中发现的，以及用于原核和真核系统二者的选择标记。
为了获得克隆核酸的高水平表达，通常构建表达质粒，该质粒通常包含指导转录的强启动子、用于翻译起始的核糖体结合位点和转录/翻译终止子，每个都功能取向于彼此和蛋白质编码序列。在大肠杆菌中适用于此目的的调控区的例子是大肠杆菌色氨酸生物合成途径的启动子和操纵子区——噬菌体λ的左侧启动子(PL)和L-阿拉伯糖(araBAD)操纵子。在大肠杆菌中转化的DNA载体中包含选择标记也是有用的。此类标记的示例包括指定对氨苄青霉素、四环素或氯霉素抗性的基因。使用例如大肠杆菌、芽孢杆菌属和沙门氏菌，用于表达抗体的表达系统是可用的。也可以使用大肠杆菌系统。
还可以将细胞靶向部分和/或聚糖结合部分基因亚克隆到允许在细胞靶向部分和/或聚糖结合部分的C端或N端添加标签(例如FLAG、六组氨酸等)的表达载体中以促进纯化。在哺乳动物细胞中转染和表达基因的方法是本领域已知的。用核酸转导细胞可以包括，例如，将含有核酸的脂质微粒与细胞温育或将含有核酸的病毒载体与载体宿主范围内的细胞温育。本公开中使用的细胞培养物，包括来自组织(例如，肿瘤)或血液样品的细胞系和培养的细胞，是本领域已知的。
一旦分离并克隆了编码主题细胞靶向部分和/或聚糖结合部分的核酸，就可以在本领域技术人员已知的各种重组工程细胞中表达该核酸。此类细胞的示例包括细菌、酵母、丝状真菌、昆虫(例如使用杆状病毒载体的那些)和哺乳动物细胞。
可以根据本领域已知的方法完成主题细胞靶向部分和/或聚糖结合部分的分离和纯化。例如，可以通过免疫亲和纯化(或使用蛋白质L或A沉淀)，洗涤以去除非-特异性结合的材料，并洗脱特异性结合的细胞靶向部分和/或聚糖结合部分，从经基因修饰以组成型和/或诱导表达蛋白质的细胞的裂解物中，或从合成反应混合物中，分离蛋白质。分离的细胞靶向部分和/或聚糖结合部分可以通过透析和其他通常用于蛋白质纯化方法的方法进一步纯化。在一个实施方案中，可以使用金属螯合层析方法分离细胞靶向部分和/或聚糖结合部分。本公开的细胞靶向部分和/或聚糖结合部分可以包含修饰以促进分离，如上所述。
可以以基本上纯的形式或分离的形式(例如，不含其他多肽)制备细胞靶向部分和/或聚糖结合部分。蛋白质可以存在于相对于可能存在的其他组分(例如，其他多肽或其他宿主细胞组分)富含多肽的组合物中。可以提供纯化的细胞靶向部分和/或聚糖结合部分，使得细胞靶向部分和/或聚糖结合部分存在于基本上不含其他表达蛋白的组合物中，例如组合物的低于90％，通常低于60％，更通常低于50％由其他表达的蛋白组成。
原核细胞产生的细胞靶向部分和/或聚糖结合部分可能需要暴露于离液剂以便正确折叠。例如，在从大肠杆菌中纯化期间，表达的蛋白质可以任选地变性然后复性。这可以例如通过将细菌产生的细胞靶向部分和/或聚糖结合部分溶解在离液剂诸如盐酸胍中来实现。然后通过缓慢透析或通过凝胶过滤使细胞靶向部分和/或聚糖结合部分复性。或者，编码细胞靶向部分和/或聚糖结合部分的核酸可以与分泌信号序列诸如pelB可操作地连接，使得细胞靶向部分和/或聚糖结合部分以正确折叠的形式分泌到周质中。
核酸、表达载体和细胞
鉴于以上关于产生本公开的双特异性分子的细胞靶向部分和/或聚糖结合部分的方法的小节，应理解本公开还提供核酸、表达载体和细胞。
在某些实施方案中，提供了编码本公开的双特异性分子的任何细胞靶向部分、本公开的双特异性分子的任何聚糖结合部分或两者的核酸。编码根据本公开的实施方案的双特异性分子的细胞靶向部分和聚糖结合部分的核苷酸序列的非限制性示例在以下实验部分中提供。
还提供了包含本公开的任何核酸的表达载体。编码细胞靶向部分和/或聚糖结合部分的天然或合成核酸的表达可以通过将编码细胞靶向部分和/或聚糖结合部分的核酸可操作地连接至启动子(其是组成型的或诱导型的)并将构建体掺入表达载体中以产生重组表达载体来实现。载体可适用于原核生物、真核生物或两者中的复制和整合。典型的克隆载体包含功能上适当定向的转录和翻译终止子、起始序列和可用于调控编码细胞靶向部分和/或聚糖结合部分的核酸的表达的启动子。载体任选地包含含有至少一个独立终止子序列的通用表达盒、允许所述盒在真核生物和原核生物中复制的序列，例如在穿梭载体中发现的，以及用于原核和真核系统二者的选择标记。
还提供了包含本公开的任何核酸和/或表达载体的细胞。根据一些实施方案，本公开的细胞包含编码本公开的双特异性分子的任何细胞靶向部分、本公开的双特异性分子的任何聚糖结合部分或两者的核酸。在某些此类实施方案中，双特异性分子是融合蛋白(如上所述)并且核酸编码该融合蛋白。根据一些实施方案，提供了一种细胞，该细胞包含编码本公开的双特异性分子的任何细胞靶向部分的第一核酸，以及编码本公开的双特异性分子的任何聚糖结合部分的第二核酸。在某些实施方案中，此类细胞包括包含第一核酸的第一表达载体和包含第二核酸的第二表达载体。
还提供了制备本公开的双特异性分子的方法，这些方法包括在适于本公开的细胞表达细胞靶向部分和/或聚糖结合部分的条件下培养该细胞，其中产生细胞靶向部分和/或聚糖结合部分。用于培养细胞使得细胞靶向部分和/或聚糖结合部分表达的条件可以变化。此类条件可包括在合适的容器(例如，细胞培养板或其孔)中、在合适的培养基(例如细胞培养基，诸如DMEM、RPMI、MEM、IMDM、DMEM/F-12等)中、在合适的温度(例如，32℃-42℃，例如37℃)和pH(例如，pH 7.0-7.7，例如pH 7.4)下、在具有合适CO2百分比(例如3％到10％，诸如5％)的环境中培养细胞。
另外的双特异性分子
本公开还提供了如本文别处描述的双特异性分子，但其中第二部分与除聚糖以外的靶标结合。即，在本公开的益处下，将理解本公开的AbLec提供了该技术可应用于聚糖结合背景以外的背景的概念的证据。在某些实施方案中，提供了包含与Fc区融合的细胞靶向部分(例如，本文别处描述的任何细胞靶向部分)和包含受体的配体结合结构域的部分的双特异性分子，其中包含受体的配体结合结构域的部分也与Fc区融合。在某些实施方案中，两个部分经由Fc区异二聚化。在一些实施方案中，经由Fc区的异二聚化是经由如本文别处所述的杵臼结构策略。
在一些实施方案中，包含受体的配体结合结构域的部分包含与细胞表面配体结合的受体的配体结合结构域。即，配体结合结构域与细胞表面配体结合。在某些实施方案中，细胞表面配体存在于也展示细胞靶向部分的靶标的细胞表面上，使得细胞靶向部分和第二部分(包含受体的配体结合结构域的部分)与同一细胞表面上存在的不同类型的分子结合。
在某些实施方案中，包含受体的配体结合结构域的部分包括以下的配体结合结构域：干细胞受体、免疫细胞受体、生长因子受体、细胞因子受体、激素受体、受体酪氨酸激酶、表皮生长因子受体(EGFR)家族中的受体(例如，HER2(人表皮生长因子受体2)等)、成纤维细胞生长因子受体(FGFR)家族中的受体、血管内皮生长因子受体(VEGFR)家族中的受体、血小板衍生的生长因子受体中的受体(PDGFR)家族中的受体、转染过程中重排(RET)受体家族中的受体、Eph受体家族中的受体、盘状结构域受体(DDR)家族中的受体以及粘蛋白(例如，MUC1)。在一些实施方案中，包含受体的配体结合结构域的部分包含CD71(转铁蛋白受体)的配体结合结构域。在某些实施方案中，包含受体的配体结合结构域的部分包含免疫细胞受体的配体结合结构域，免疫细胞受体的非限制性示例包括T细胞受体、B细胞受体、天然杀伤(NK)细胞受体、巨噬细胞受体、单核细胞受体、嗜中性粒细胞受体、树突细胞受体、肥大细胞受体、嗜碱性粒细胞受体和嗜酸性粒细胞受体。
组合物
本公开的方面还包括组合物。根据一些实施方案，本公开的组合物包括本公开的双特异性分子。例如，双特异性分子可以是上文双特异性分子部分中描述的任何双特异性分子，出于简洁的目的，将描述并入但本文不再重复。
在某些方面，本公开的组合物包含存在于液体介质中的双特异性分子。液体介质可以是水性液体介质，例如水、缓冲溶液等。一种或多种添加剂，诸如盐(例如NaCl、MgCl2、KCl、MgSO4)、缓冲剂(Tris缓冲剂、N-(2-羟乙基)哌嗪-N'-(2-乙磺酸)(HEPES)、2-(N-吗啉)乙磺酸(MES)、2-(N-吗啉)乙磺酸钠盐(MES)、3-(N-吗啉)丙磺酸(MOPS)、N-三[羟基甲基]甲基-3-氨基丙磺酸(TAPS)等)、增溶剂、洗涤剂(例如，非离子型洗涤剂，诸如吐温(Tween)-20等)、核酸酶抑制剂、蛋白酶抑制剂、甘油、螯合剂等可以存在于此类组合物中。
本公开的方面还包括药物组合物。在一些实施方案中，本公开的药物组合物包含本公开的双特异性分子和药学上可接受的载剂。
双特异性分子可以掺入各种用于治疗性施用的制剂中。更特别地，双特异性分子可以通过与适当的药学上可接受的赋形剂或稀释剂组合配制成药物组合物，并且可以配制成固体、半固体、液体或气体形式的制剂，诸如片剂、胶囊剂、粉剂、颗粒剂、软膏、溶液剂、注射剂、吸入剂和喷雾剂。
用于向个体施用(例如，适于人施用)的双特异性分子制剂通常是无菌的，并且可以进一步不含可检测的热原或根据所选择的施用途径禁忌用于向患者施用的其它污染物。
在药物剂型中，双特异性分子可以其药学上可接受的盐的形式施用，或者它们也可以单独使用或与其它药学活性化合物适当联合以及组合使用。以下方法和载剂/赋形剂仅仅是示例，而决不是限制性的。
对于口服制剂，双特异性分子可单独使用或与制备片剂、粉剂、颗粒剂或胶囊剂的适当添加剂组合使用，例如与常规添加剂诸如乳糖、甘露醇、玉米淀粉或马铃薯淀粉组合使用；与粘合剂，诸如结晶纤维素、纤维素衍生物、阿拉伯胶、玉米淀粉或明胶组合使用；与崩解剂，诸如玉米淀粉、马铃薯淀粉或羧甲基纤维素钠组合使用；与润滑剂，诸如滑石或硬脂酸镁组合使用；以及如果需要，与稀释剂、缓冲剂、润湿剂、防腐剂和调味剂组合使用。
可配制双特异性分子剂用于肠胃外(例如，静脉内、动脉内、骨内、肌肉内、脑内，侧脑室内、鞘内、皮下等)施用。在某些方面，通过将双特异性分子溶解、悬浮或乳化于水性或非水性溶剂，诸如植物油或其它类似的油、合成脂族酸甘油酯、高级脂族酸的酯或丙二醇中来配制双特异性分子用于注射；并且如果需要，与常规添加剂，诸如增溶剂、等渗剂、悬浮剂、乳化剂、稳定剂和防腐剂一起配制。
包括双特异性分子的药物组合物可通过将具有所需纯度的双特异性分子与任选的生理上可接受的载剂、赋形剂、稳定剂、表面活性剂、缓冲剂和/或张力剂混合来制备。可接受的载剂、赋形剂和/或稳定剂在所采用的剂量和浓度下对接受者是无毒的，并且包括缓冲剂，诸如磷酸盐、柠檬酸盐和其它有机酸；抗氧化剂，包括抗坏血酸、谷胱甘肽、半胱氨酸、甲硫氨酸和柠檬酸；防腐剂(诸如乙醇、苄醇、苯酚、间甲酚、对氯间甲酚、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯、苯扎氯铵或它们的组合)；氨基酸诸如精氨酸、甘氨酸、鸟氨酸、赖氨酸、组氨酸、谷氨酸、天冬氨酸、异亮氨酸、亮氨酸、丙氨酸、苯丙氨酸、酪氨酸、色氨酸、甲硫氨酸、丝氨酸、脯氨酸及它们的组合；单糖、二糖和其它碳水化合物；低分子量(少于约10个残基)多肽；蛋白质，诸如明胶或血清白蛋白；螯合剂，诸如EDTA；糖，诸如海藻糖、蔗糖、乳糖、葡萄糖、甘露糖、麦芽糖、半乳糖、果糖、山梨糖、棉子糖、葡糖胺、N-甲基葡糖胺、半乳糖胺和神经氨酸；和/或非离子表面活性剂诸如吐温、Brij Pluronic、Triton-X或聚乙二醇(PEG)。
药物组合物可以是液体形式、冻干形式或从冻干形式重构的液体形式，其中在施用之前用无菌溶液重构冻干制剂。重构冻干组合物的标准程序是回加一定体积的纯水(通常等于冻干期间去除的体积)；然而，包含抗菌剂的溶液可用于产生供肠胃外施用的药物组合物。
双特异性分子的水性制剂可在pH缓冲溶液中制备，例如在约4.0至约7.0，或约5.0至约6.0，或可替代地约5.5的pH范围内。适于此范围内的pH的缓冲剂的示例包括磷酸盐缓冲剂、组氨酸缓冲剂、柠檬酸盐缓冲剂、琥珀酸盐缓冲剂、乙酸盐缓冲剂和其他有机酸缓冲剂。缓冲液浓度可以为约1mM到约100mM或约5mM到约50mM，这取决于例如缓冲液和制剂的所需张力。
可以包含张力剂来调节制剂的张力。张力剂示例包括氯化钠、氯化钾、甘油和来自氨基酸、糖以及其组合的群组的任何组分。在一些实施方案中，水性制剂是等渗的，尽管高渗或低渗溶液可能是合适的。术语“等渗”表示具有与其比较的一些其它溶液相同的张力的溶液，诸如生理盐溶液或血清。可以以约5mM到约350mM的量使用张力剂，例如以100mM到350mM的量使用。
还可以将表面活性剂添加到制剂中以减少聚集和/或使所述制剂中颗粒的形成最小化和/或减少吸附。表面活性剂示例包含聚氧乙烯山梨糖醇酐脂肪酸酯(Tween)、聚氧乙烯烷基醚(Brij)、烷基苯基聚氧乙烯醚(Triton-X)、聚氧乙烯-聚氧丙烯共聚物(泊洛沙姆，Pluronic)和十二烷基硫酸钠(SDS)。合适的聚氧乙烯山梨糖醇酐-脂肪酸酯的示例是聚山梨醇酯20(以商标吐温20TM销售)和聚山梨醇酯80(以商标吐温80TM销售)。合适的聚乙烯-聚丙烯共聚物的示例是以名称F68或Poloxamer 188TM销售的聚乙烯-聚丙烯共聚物。合适的聚氧乙烯烷基醚的示例是以商标BrijTM销售的聚氧乙烯烷基醚。表面活性剂的示例浓度范围可以为约0.001％到约1％w/v。
也可添加冻干保护剂以保护双特异性分子在冻干过程中不受不稳定条件的影响。例如，已知的冻干保护剂包括糖(包括葡萄糖和蔗糖)；多元醇(包括甘露糖醇、山梨糖醇和甘油)；氨基酸(包括丙氨酸、甘氨酸和谷氨酸)。可以包含例如约10mM至500nM的量的冻干保护剂。
在一些实施方案中，药物组合物包括双特异性分子和上述鉴定的组分(例如，表面活性剂、缓冲剂、稳定剂、张力剂)中的一种或多种组分并且基本上不含一种或多种防腐剂，诸如乙醇、苯甲醇、苯酚、间甲酚、对氯间甲酚、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯、苯扎氯铵以及其组合。在其他实施方案中，制剂中包含防腐剂，例如，以约0.001到约2％(w/v)的浓度范围。
试剂盒
本公开的方面还包括试剂盒。在某些实施方案中，试剂盒可用于实践本公开的方法，例如包括向个体施用本公开的药物组合物以增强个体中的抗肿瘤免疫，向个体施用本公开的药物组合物以增强或阻遏个体中的免疫应答等的方法。
因此，在某些实施方案中，本公开的试剂盒包含一个或多个剂量的本公开的药物组合物，以及向有需要的个体施用该药物组合物的说明书。试剂盒中包括的药物组合物可包括本公开内容的任何双特异性分子，例如上文所述的任何双特异性分子，为了简洁的目的，本文不再重复。
本公开的试剂盒可包含以单位剂量(例如，安瓿)或多剂量形式存在的一定量的组合物。因此，在某些实施方案中，试剂盒可包含一个或多个(例如，两个或更多个)单位剂量(例如，安瓿)的组合物，该组合物包含本公开的双特异性分子。如本文中所使用的，术语“单位剂量”是指适合作为用于人和动物受试者的单位剂量的物理上离散的单位，每个单位包含按足以产生期望效果的量计算的预定量的组合物。单位剂量的量取决于各种因素，诸如在受试者中所采用的特定双特异性分子、要实现的效果以及与双特异性分子相关联的药效学。在又其它实施方案中，试剂盒可以包含单个多剂量的组合物。
在某些实施方案中，本公开的试剂盒包含将一个或多个单位剂量的药物组合物施用于需要增强抗肿瘤免疫的个体的说明书。根据一些实施方案，本公开的试剂盒包含将一个或多个单位剂量的药物组合物施用于需要增强或阻遏免疫应答的个体的说明书。
试剂盒中包含的说明书(例如，使用说明书(IFU))可以记录在合适的记录介质上。例如，说明书可以印刷在如纸或塑料等基材上。因此，说明书可以作为包装插页存在于试剂盒中、存在于试剂盒的容器或其组分的标签中(即，与包装或次包装有关联)等。在其它实施方案中，说明书作为存在于合适的计算机可读存储介质(例如，便携式闪存驱动器、DVD、CD-ROM、软盘等)上的电子存储数据文件存在。在又其它实施方案中，试剂盒中不存在实际说明书，但是提供了用于从远程源，例如通过因特网，获得说明书的手段。该实施方案的一个示例是包括网址的试剂盒，可以在所述网址中查看说明书和/或可以从所述网址下载说明书。与说明书一样，用于获得说明书的方式被记录在合适的基材上。
方法
本公开的方面包括使用本公开的双特异性分子的方法。所述方法可用于多种环境，包括体外和/或体内研究和/或临床应用中。
在某些方面，提供了增强有需要的个体的抗肿瘤免疫的方法。此类方法包括向个体施用有效量的本公开的药物组合物，例如包含本公开的双特异性分子的药物组合物，该双特异性分子包含癌细胞靶向部分和聚糖结合部分。在某些实施方案中，这些方法用于增强个体中的抗体依赖性细胞吞噬作用(ADCP)和/或细胞毒性(ADCC)。
在某些方面，提供了增强或阻遏有需要的个体的免疫应答的方法。此类方法包括向个体施用有效量的本公开的药物组合物，例如包含本公开的双特异性分子的药物组合物，该双特异性分子包含免疫细胞靶向部分和聚糖结合部分。
有需要的个体可能患有细胞增殖性病症。“细胞增殖性疾病”意指其中多细胞生物中的一个或多个细胞亚群发生不希望的细胞增殖，从而导致伤害(例如，疼痛或生物体预期寿命缩短)的疾病。细胞增殖性疾病包含但不限于癌症、癌症前期、良性肿瘤、血管增殖性疾病(例如，关节炎、再狭窄等)、纤维化疾病(例如，肝硬化、动脉粥样硬化等)、银屑病、表皮囊肿和皮样囊肿、脂肪瘤、腺瘤、毛细血管瘤和皮肤血管瘤、淋巴管瘤、痣病变、畸胎瘤、肾瘤、肌纤维瘤病、成骨肿瘤、发育不良性肿块、系膜细胞增殖性疾病等。
在一些实施方案中，个体患有癌症。本主题的方法可以用于治疗多种癌症。如本文所用，“肿瘤”是指所有肿瘤细胞的生长和增殖，无论是恶性的还是良性的，以及所有癌前和癌性细胞和组织。术语“癌症”和“癌性”是指或描述哺乳动物中通常表征为不受调节的细胞生长/增殖的生理状况。可以使用本主题方法治疗的癌症的示例包含但不限于癌、淋巴瘤、母细胞瘤和肉瘤。此类癌症的更具体的示例包含鳞状细胞癌、小细胞肺癌、非小细胞肺癌、肺腺癌、肺鳞状细胞癌、腹膜癌、肝细胞癌、胃肠癌、胰腺癌、胶质母细胞瘤、宫颈癌、卵巢癌、肝癌、胆管癌、膀胱癌、肝瘤、乳腺癌、结肠癌、结直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、肝癌、各种类型的头颈癌等。在某些实施方案中，个体患有选自以下的癌症：实体瘤、复发性多形性成胶质细胞瘤(GBM)、非小细胞肺癌、转移性黑素瘤、黑素瘤、腹膜癌、上皮性卵巢癌、多形性成胶质细胞瘤(GBM)、转移性结直肠癌、结直肠癌、胰腺导管腺癌、鳞状细胞癌、食管癌、胃癌、神经母细胞瘤、输卵管癌、膀胱癌、转移性乳腺癌、胰腺癌、软组织肉瘤、复发性头颈癌、鳞状细胞癌、头颈癌、间变性星形细胞瘤、恶性胸膜间皮瘤、乳腺癌、鳞状非小细胞肺癌、横纹肌肉瘤、转移性肾细胞癌、基底细胞癌(基底细胞上皮瘤)和胶质肉瘤。在某些方面，个体患有选自以下的癌症：黑素瘤、霍奇金淋巴瘤、肾细胞癌(RCC)、膀胱癌、非小细胞肺癌(NSCLC)和头颈鳞状细胞癌(HNSCC)。
本公开的双特异性分子可以通过选自以下的施用途径来施用：口服(例如，以片剂形式、胶囊形式、液体形式等)、肠胃外(例如，通过静脉内、动脉内、皮下、肌内或硬膜外注射)、局部、鼻内或肿瘤内施用。
本公开的双特异性分子可以治疗有效量在药物组合物中施用。“治疗有效量”意指足以产生期望结果的剂量，例如，与对照相比，足以实现有益或期望的治疗(包含预防)结果(诸如使癌症和/或免疫病症的症状减轻)的量。关于癌症，在一些实施方案中，治疗有效量足以减慢肿瘤的生长、减小肿瘤的大小等。可以以一次或多次施用的方式来施用有效量。
本公开的方面包括用于治疗个体的癌症和/或免疫病症的方法。治疗意指至少改善一种或多种与个体的癌症和/或免疫病症相关联的症状，其中改善以广义使用以指至少降低与所治疗的癌症和/或免疫病症相关联的参数(例如，症状)的幅度。因此，治疗还包括完全抑制癌症和/或免疫病症或与其相关联的至少一种或多种症状的情况，例如，防止癌症和/或免疫病症或与其相关联的至少一种或多种症状发生或停止(例如，终止)该癌症和/或免疫病症或与其相关联的至少一种或多种症状，使得个体不再患有该癌症和/或免疫病症，或者至少不再患有表征该癌症和/或免疫病症的症状。
本公开的双特异性分子可单独或与第二试剂组合施用于个体。感兴趣的第二试剂包括但不限于经美国食品和药物管理局和/或欧洲药品管理局(EMA)批准用于治疗癌症的试剂。在一些实施方案中，第二试剂是免疫检查点抑制剂。感兴趣的免疫检查点抑制剂包括但不限于细胞毒性T淋巴细胞相关抗原4(CTLA-4)抑制剂、程序性细胞死亡-1(PD-1)抑制剂、程序性细胞死亡配体-1(PD-L1)抑制剂、淋巴细胞激活基因-3(LAG-3)抑制剂、T细胞免疫球蛋白结构域和粘蛋白结构域-3(TIM-3)抑制剂、吲哚胺(2,3)-双加氧酶(IDO)抑制剂、具有Ig和ITIM结构域的T细胞免疫受体(TIGIT)抑制剂、T细胞激活的V结构域Ig抑制物(VISTA)抑制剂、B7-H3抑制剂，以及它们的任何组合。
当本公开的双特异性分子与第二试剂一起施用时，该双特异性分子和第二试剂可以根据任何合适的施用方案施用于个体。根据某些实施方案，根据批准用于个体使用的给药方案施用双特异性分子和第二试剂。在一些实施方案中，与在不施用双特异性分子的情况下施用第二试剂时所使用的给药方案相比，施用双特异性分子允许根据涉及一种或多种较低和/或较少频率的剂量和/或减少的周期数的给药方案来施用第二试剂。在某些方面中，与在不施用第二试剂的情况下施用双特异性分子时所使用的给药方案相比，施用第二试剂允许根据涉及一种或多种较低和/或较少频率的剂量和/或减少的周期数的给药方案来施用双特异性分子。
在一些实施方案中，将一个或多个剂量的双特异性分子和第二试剂同时施用于个体。“同时”意指双特异性分子和第二试剂存在于同一药物组合物中，或双特异性分子和第二试剂在1小时或更短、30分钟或更短、或15分钟或更短内作为单独的药物组合物施用。
在一些实施方案中，将一个或多个剂量的双特异性分子和第二试剂连续施用于个体。
在一些实施方案中，双特异性分子和第二试剂以不同组合物和/或在不同时间施用于个体。例如，可以在施用第二试剂之前，例如在特定周期中施用双特异性分子。可替代地，可以在施用双特异性分子之前，例如在特定周期中施用第二试剂。待施用的第二试剂可以施用一段时间，该时间在待施用的第一试剂施用至少1小时、3小时、6小时、12小时、24小时、48小时、72小时或高达5天或更久之后开始。
在一个示例中，在施用双特异性分子之前，将第二试剂施用给个体达期望的时间段。在某些方面，当个体患有癌症时，此类方案“引发”癌细胞以增强双特异性分子的抗癌作用。将施用第二试剂的步骤与施用双特异性分子的步骤分开的这种时间段具有足够的时长以允许引发癌细胞，理想地使得双特异性分子的抗癌作用增加。
在一些实施方案中，相对于其他试剂的施用，对一种试剂的施用进行具体地定时。例如，在一些实施方案中，施用双特异性分子，以便观察到特定效果(或预期观察到特定效果，例如基于示出给定的给药方案与感兴趣的特定效果之间的相关性的群体研究)。
在某些方面，组合施用的试剂的期望的相对给药方案可根据经验评估或确定，例如使用离体、体内和/或体外模型；在一些实施方案中，此类评估或经验确定在患者群体体内进行(例如，以便建立相关性)，或者可替代地在感兴趣的特定个体中进行。
在一些实施方案中，根据包含至少两个周期的间歇性给药方案施用双特异性分子和第二试剂。当两种或超过两种试剂组合施用且每种试剂通过这种间歇的周期性方案施用时，不同试剂的单独剂量可以彼此相互交叉。在某些方面中，在第一试剂的剂量之后某一时间段施用一个或多个剂量的第二试剂。在一些实施方案中，在第一试剂的一个剂量之后的一段时间施用第二试剂的每个剂量。在某些方面，在施用第二试剂的一个剂量一段时间之后，接着施用第一试剂的每个剂量。在一些实施方案中，在至少一对剂量的第二试剂之间施用两个或更多个剂量的第一试剂。在某些方面，在至少一对剂量的第一试剂之间施用两个或更多个剂量的第二试剂。在一些实施方案中，相同试剂的不同剂量由共同的时间间隔隔开；在一些实施方案中，相同试剂的不同剂量之间的时间间隔不同。在某些方面，不同剂量的双特异性分子和第二试剂被共同的时间间隔彼此隔开；在一些实施方案中，不同试剂的不同剂量被不同的时间间隔彼此隔开。
用于交错两个间歇、循环给药方案的一个示例性方案可包括：(a)第一给药期，在此期间向个体施用治疗有效量的双特异性分子；(b)第一休息期；(c)第二给药期，在此期间向个体施用治疗有效量的第二试剂；和(d)第二休息期。用于交错两个间歇、循环给药方案的第二示例性方案可包括：(a)第一给药期，在此期间向个体施用治疗有效量的第二试剂；(b)第一休息期；(c)第二给药期，在此期间向个体施用治疗有效量的双特异性分子；和(d)第二休息期。
在一些实施方案中，第一休息期和第二休息期可以对应于相同的小时数或天数。可替代地，在一些实施方案中，第一休息期和第二休息期是不同的，第一休息期比第二休息期长，或者反之亦然。在一些实施方案中，休息期中的每一个对应于120小时、96小时、72小时、48小时、24小时、12小时、6小时、30小时、1小时或更短时间。在一些实施方案中，如果第二休息期长于第一休息期，则可以将其定义为数天或数周而不是数小时(例如1天、3天、5天、1周、2周、4周或更长时间)。
如果第一休息期的时长是由特定的生物学事件或治疗事件的存在或发展确定的，则第二休息期的时长可以单独或组合地根据不同因素来确定。示例性的此类因素可包括对其施用该疗法的癌症的类型和/或阶段；双特异性分子的性质(例如药代动力学性质)，和/或患者对用双特异性分子的疗法的应答的一个或多个特征。在一些实施方案中，可以根据所施用的试剂中的一种或另一种试剂的药代动力学特性(例如，如经由血浆浓度水平评定的)来调节一个或两个休息期的时长。例如，当相关试剂的血浆浓度低于预定水平时，任选地在对个体响应的一个或多个特征进行评估或其它考虑时，可以认为相关的休息期完成了。
在某些方面中，可以凭经验确定施用特定试剂的周期数。而且，在一些实施方案中，与一个或多个其它周期相比，一个或多个周期所遵循的精确方案(例如，剂量的数量、剂量的间隔(例如，相对于彼此或相对于另一个事件，如施用另一种疗法)、剂量的量等)可以是不同的。
双特异性分子和第二试剂可以通过任何合适的施用途径一起或独立地施用。可以通过独立地选自口服、肠胃外(例如，通过静脉内、动脉内、皮下、肌内或硬膜外注射)、局部或鼻腔施用的施用途径施用双特异性分子和第二试剂。根据某些实施方案，双特异性分子和第二试剂均同时(在相同的药物组合物或单独的药物组合物中)或连续地口服施用(例如，以片剂形式、胶囊形式、液体形式等)。
尽管有所附权利要求，但本公开还由以下实施方案定义：
1.一种双特异性分子，所述双特异性分子包含：
细胞靶向部分；以及
聚糖结合部分。
2.根据实施方案1所述的双特异性分子，其中所述细胞靶向部分是癌细胞靶向部分。
3.根据实施方案2所述的双特异性分子，其中所述癌细胞靶向部分与选自由以下组成的组的癌细胞表面分子结合：5T4、AXL受体酪氨酸激酶(AXL)、B细胞成熟抗原(BCMA)、c-MET、C4.4a、碳酸酐酶6(CA6)、碳酸酐酶9(CA9)、钙粘蛋白6、CD19、CD20、CD22、CD25、CD27L、CD30、CD33、CD37、CD44、CD44v6、CD56、CD70、CD74、CD79b、CD123、CD138、癌胚抗原(CEA)、cKit、Cripto蛋白、CS1、δ样规范Notch配体3(DLL3)、内皮素受体B型(EDNRB)、肝配蛋白A4(EFNA4)、表皮生长因子受体(EGFR)、EGFRvIII、外切核苷酸焦磷酸酶/磷酸二酯酶3(ENPP3)、EPH受体A2(EPHA2)、成纤维细胞生长因子受体2(FGFR2)、成纤维细胞生长因子受体3(FGFR3)、FMS样酪氨酸激酶3(FLT3)、叶酸受体1(FOLR1)、GD2神经节苷脂、非转移性糖蛋白B(GPNMB)、鸟苷酸环化酶2C(GUCY2C)、人表皮生长因子受体2(HER2)、人表皮生长因子受体3(HER3)、整联蛋白α、溶酶体相关膜蛋白1(LAMP-1)、Lewis Y、LIV-1、富含亮氨酸重复蛋白15(LRRC15)、间皮素(MSLN)、粘蛋白1
(MUC1)、粘蛋白16(MUC16)、钠依赖性磷酸盐转运蛋白2B(NaPi2b)、连接素4、NMB、NOTCH3、p-钙粘蛋白(p-CAD)、程序性细胞死亡受体配体1(PD-L1)、程序性细胞死亡受体配体2(PD-L2)、前列腺特异性膜抗原(PSMA)、蛋白质酪氨酸激酶7(PTK7)、溶质载体家族44成员4(SLC44A4)、SLIT样家族成员6(SLITRK6)、STEAP家族成员1
(STEAP1)、组织因子(TF)、T细胞免疫球蛋白和粘蛋白蛋白1(TIM-1)、Tn抗原、滋养层细胞表面抗原(TROP-2)和Wilms肿瘤1(WT1)。
4.根据实施方案1所述的双特异性分子，其中所述细胞靶向部分是免疫细胞靶向部分。
5.根据实施方案4所述的双特异性分子，其中所述免疫细胞靶向部分与选自由以下组成的组的免疫细胞表面分子结合：PD-1、PD-L1、PD-L2、CLTA-4、VISTA、LAG-3、TIM-3、CD24、CD47、SIRPα、CD3、CD8、CD4、CD28、CD80、CD86、CD19、ICOS、OX40、OX40L、GD3神经节苷脂、TIGIT、Siglec-2、Siglec-3、Siglec-7、Siglec-8、Siglec-9、Siglec-10、Siglec-15、半乳凝素-9、B7-H3、B7-H4、CD40、CD40L、B7RP1、CD70、CD27、BTLA、HVEM、KIR、4-1BB、4-1BBL、CD226、CD155、CD112、GITR、GITRL、A2aR、CD137、CD137L、CD45、CD206、CD163、TRAIL、NKG2D、CD16和TGF-β。
6.根据实施方案1至5中任一项所述的双特异性分子，其中所述聚糖结合部分包括唾液酸聚糖结合部分。
7.根据实施方案6所述的双特异性分子，其中所述唾液酸聚糖结合部分包含凝集素的唾液酸聚糖结合结构域。
8.根据实施方案7所述的双特异性分子，其中所述凝集素是唾液酸结合免疫球蛋白样凝集素(Siglec)。
9.根据实施方案8所述的双特异性分子，其中所述Siglec是CD33相关Siglec。
10.根据实施方案9所述的双特异性分子，其中所述CD33相关Siglec选自由以下组成的组：Siglec-7、Siglec-9和Siglec-10。
11.根据实施方案10所述的双特异性分子，其中所述CD33相关Siglec是Siglec-7。
12.根据实施方案10所述的双特异性分子，其中所述CD33相关Siglec是Siglec-9。
13.根据实施方案8所述的双特异性分子，其中所述Siglec是Siglec-15。
14.根据实施方案6所述的双特异性分子，其中所述唾液酸聚糖结合部分包含Siglec样粘附素的唾液酸聚糖结合结构域。
15.根据实施方案1至5中任一项所述的双特异性分子，其中所述聚糖结合部分包含C型凝集素的聚糖结合结构域。
16.根据实施方案15所述的双特异性分子，其中所述C型凝集素是DECTIN-1、凝集素样氧化低密度脂蛋白受体-1(LOX-1)、C型凝集素样受体-1(CLEC-1)、C型凝集素样受体2(CLEC-2)、髓样抑制性C型凝集素样受体(MICL)、CLEC9A、DC免疫受体(DCIR)、DECTIN-2、血液DC抗原-2(BDCA-2)、巨噬细胞诱导型C型凝集素(MINCLE)、巨噬细胞半乳糖凝集素(MGL)或无唾液酸糖蛋白受体(ASGPR)。
17.根据实施方案1至5中任一项所述的双特异性分子，其中所述聚糖结合部分包含半乳凝素的聚糖结合结构域。
18.根据实施方案17所述的双特异性分子，其中所述半乳凝素是Gal-1、Gal-2、Gal-3、Gal-4、Gal-5、Gal-6、Gal-7、Gal-8、Gal-9、Gal-10、Gal-11、Gal-12、Gal-13、Gal-14或Gal-15。
19.根据实施方案17所述的双特异性分子，其中所述半乳凝素是Gal-1。
20.根据实施方案17所述的双特异性分子，其中所述半乳凝素是Gal-3。
21.根据实施方案1至5中任一项所述的双特异性分子，其中所述聚糖结合部分包含选择素的聚糖结合结构域。
22.根据实施方案21所述的双特异性分子，其中所述选择素是P-选择素(CD62P)、E-选择素(CD62E)或L-选择素(CD62L)。
23.根据实施方案1至22中任一项所述的双特异性分子，其中所述细胞靶向部分包含靶细胞表面上受体的配体，或与靶细胞上的细胞表面分子结合的小分子。
24.根据实施方案1至22中任一项所述的双特异性分子，其中所述细胞靶向部分包含抗体的抗原结合结构域。
25.根据实施方案1至22中任一项所述的双特异性分子，其中所述细胞靶向部分包含抗体重链和抗体轻链，所述抗体重链包含可变重链(VH)区，所述抗体轻链包含可变轻链(VL)区。
26.根据实施方案25所述的双特异性分子，其中所述抗体重链包含CH1结构域、铰链区、CH2结构域、CH3结构域或它们的任何组合。
27.根据实施方案25或实施方案26所述的双特异性分子，其中所述抗体重链包含CH2结构域、CH3结构域或两者。
28.根据实施方案25至27中任一项所述的双特异性分子，其中所述抗体重链包含片段可结晶(Fc)区。
29.根据实施方案1至28中任一项所述的双特异性分子，其中所述聚糖结合部分包含抗体重链结构域。
30.根据实施方案29所述的双特异性分子，其中所述聚糖结合部分的所述抗体重链结构域包含CH1结构域、铰链区、CH2结构域、CH3结构域或它们的任何组合。
31.根据实施方案29或实施方案30所述的双特异性分子，其中所述聚糖结合部分的所述抗体重链结构域包含CH2结构域、CH3结构域或两者。
32.根据实施方案29至31中任一项所述的双特异性分子，其中所述聚糖结合部分的所述抗体重链结构域包含片段可结晶(Fc)区。
33.根据实施方案31或实施方案32所述的双特异性分子，其中所述细胞靶向部分包含含有CH3结构域的抗体重链，并且其中所述双特异性分子是包含杵臼结构修饰的CH3结构域的异二聚体。
34.根据实施方案1至32中任一项所述的双特异性分子，其中所述双特异性分子是包含所述细胞靶向部分与所述聚糖结合部分融合的融合蛋白。
35.根据实施方案34所述的双特异性分子，其中所述细胞靶向部分直接与所述聚糖结合部分融合。
36.根据实施方案34所述的双特异性分子，其中所述细胞靶向部分经由接头间接地与所述聚糖结合部分融合。
37.根据实施方案1至32中任一项所述的双特异性分子，其中所述双特异性分子是包含所述细胞靶向部分与所述聚糖结合部分缀合的缀合物。
38.一种核酸，所述核酸编码：
根据实施方案1至36中任一项所述的双特异性分子的细胞靶向部分；
根据实施方案1至36中任一项所述的双特异性分子的聚糖结合部分；或
两者。
39.一种表达载体，所述表达载体包含根据实施方案38所述的核酸。
40.一种药物组合物，所述药物组合物包含：
根据实施方案1至37中任一项所述的双特异性分子；以及
药学上可接受的载剂。
41.根据实施方案40所述的药物组合物，其中所述细胞靶向部分是癌细胞靶向部分。
42.根据实施方案40所述的药物组合物，其中所述细胞靶向部分是免疫细胞靶向部分。
43.一种试剂盒，所述试剂盒包含：
一个或多个单位剂量的根据实施方案40至42中任一项所述的药物组合物；以及
用于向有需要的个体施用所述一个或多个单位剂量的所述药物组合物的说明书。
44.根据实施方案43所述的试剂盒，所述试剂盒包含两个或更多个单位剂量的所述药物组合物。
45.根据实施方案43或实施方案44所述的试剂盒，其中所述细胞靶向部分是癌细胞靶向部分，并且其中所述说明书包括将所述一个或多个单位剂量的所述药物组合物施用于需要增强抗肿瘤免疫的个体的说明书。
46.根据实施方案43或实施方案44所述的试剂盒，其中所述细胞靶向部分是免疫细胞靶向部分，并且其中所述说明书包括将所述一个或多个单位剂量的所述药物组合物施用于需要增强或阻遏免疫应答的个体的说明书。
47.一种增强有需要的个体的抗肿瘤免疫的方法，所述方法包括：
向所述个体施用有效量的根据实施方案41所述的药物组合物。
48.一种增强或阻遏有需要的个体的免疫应答的方法，所述方法包括：
向所述个体施用有效量的根据实施方案42所述的药物组合物。
49.根据实施方案47或实施方案48所述的方法，其中所述施用是通过肠胃外施用进行。
50.一种双特异性分子，所述双特异性分子包含：
与Fc区融合的细胞靶向部分；以及
与Fc区融合的包含受体的配体结合结构域的部分，
其中所述细胞靶向部分和包含受体的配体结合结构域的所述部分经由Fc区异二聚化。
51.根据实施方案50所述的双特异性分子，其中所述细胞靶向部分如实施方案2至5中任一项限定。
52.根据实施方案50或实施方案51所述的双特异性分子，其中包含受体的配体结合结构域的所述部分包含与细胞表面配体结合的受体的配体结合结构域。
53.根据实施方案50至52中任一项所述的双特异性分子，其中所述双特异性分子是包含杵臼结构修饰的CH3结构域的异二聚体。
以下实施例以说明性方式而不是以限制性方式提供。
实验
实施例1-使用包含癌细胞靶向部分和聚糖结合部分的双特异性分子增强抗肿瘤 免疫应答
本文描述了包含细胞靶向部分和聚糖结合部分的双特异性分子，并且证明此类分子对于增强抗肿瘤免疫应答是有效的，例如通过增强的抗体依赖性细胞吞噬作用(ADCP)和/或细胞毒性(ADCC)。
作为原理论证，本文描述了一类新的靶向肿瘤相关唾液酸聚糖进行检查点阻断的抗体-凝集素双特异性分子(本文有时称为“AbLec”)。在这种方法中，具有唾液酸聚糖结合特异性的重组Siglec结合结构域与高亲和力肿瘤靶向抗体结合结构域偶联。预期AbLec在癌细胞表面上以高有效摩尔浓度累积，从而允许其他低亲和力重组Siglec以治疗相关浓度结合细胞表面唾液酸聚糖。
作为初始的概念论证，使用杵臼结构方法生成一组重组Siglec-7和Siglec-9-Fc嵌合体，这些嵌合体与衍生自FDA批准的抗体(曲妥珠单抗和利妥昔单抗)的单价抗体链二聚化，这些抗体分别靶向常见癌抗原HER2和CD20。在图11-图14中示意性地说明了这些构建体，并提供了它们的氨基酸序列。
在图1a-图1e中提供了证明双特异性抗体-凝集素(AbLec)能够将凝集素诱饵受体用于检查点阻断的示意图和数据。(a)AbLec将单克隆抗体的有益性质(对期望的肿瘤、免疫细胞或组织靶标的高亲和力和选择性)与凝集素诱饵受体的有益性质(对同源糖缀合物配体的选择性和特异性)组合，同时克服了每种平台的限制。(b)AbLec使用IgG1抗体框架，使用修饰的杵臼结构策略设计AbLec。(c)曲妥珠单抗重链和轻链与Siglec-7-Fc或Siglec-9-Fc链在Expi293细胞中的共表达导致单一蛋白产物的表达。还原性SDS-PAGE分析显示这些产物由与Siglec-Fc链以及曲妥珠单抗重链和轻链的分子量一致的3条二硫键键合的蛋白链组成。分别针对Siglec-Fc和抗体重链上的HA和His6标签的蛋白质印迹进一步证明全长蛋白质产物由抗体和诱饵受体臂两者组成。总的来说，这一证据表明AbLec是由抗体臂和诱饵臂两者组成的双官能异二聚体。(d)曲妥珠单抗×Siglec-7(T7)和曲妥珠单抗×Siglec-9 AbLec的离解常数(KD)值通过经由流式细胞术定量在不同浓度下与SK-BR-3细胞的结合来测量。通过流式细胞术确定，SK-BR-3细胞表达由曲妥珠单抗结合的HER2抗原以及Siglec-7和Siglec-9的配体。(e)诱饵受体分子(Siglec-7/9-Fc)仅以低水平结合SK-BR-3细胞，甚至在最高测试浓度(200nM)下也是如此，并且尽管事实是SK-BR-3细胞表达Siglec-7和Siglec-9配体(图1d)。然而，通过将诱饵受体臂与高亲和力曲妥珠单抗臂组合，AbLec可在治疗相关浓度下与SK-BR-3细胞结合(左)。AbLec表现出类似于亲本抗体曲妥珠单抗的低nM KD值(右)。进一步地，AbLec结合是协作性的。通过将Siglec-Fc结合位点中的保守精氨酸突变为丙氨酸，产生具有Siglec-Fc臂的T7A和T9A AbLec突变体，这些突变体表现出对Siglec配体显著降低的亲和力，如先前报道的。突变AbLec表现出与SK-BR-3细胞的结合降低(中)，并且导致表观KD与WT AbLec相比增加～2-3倍(右)。这表明尽管Siglec-Fc诱饵受体分子的亲和力低，但当其借助于高亲和力抗体-抗原相互作用在细胞表面上以高局部浓度累积时，它可与Siglec配体结合。所观察到的Siglec-Fc臂对结合的贡献可以解释为什么尽管仅具有一个抗体臂，AbLec离解常数与二价亲本抗体曲妥珠单抗具有相同的数量级。
实施例2-AbLec阻断靶向聚糖-结合免疫受体的结合
在该实施例中证明，AbLec阻断靶向聚糖-结合免疫受体的结合。在图2a-图2f和图5中提供了示意图和数据。(a)假设如果AbLec能够通过阻断肿瘤细胞上的Siglec配体以及经由抗体效应子功能募集免疫细胞来减轻经由Siglec轴的抑制性信号传导，则它们与亲本单克隆抗体相比具有增强抗肿瘤免疫应答的潜力。(b)曲妥珠单抗/Siglec-7(T7)和曲妥珠单抗/Siglec-9AbLec的离解常数(KD)值通过经由流式细胞术定量在不同浓度下与SK-BR-3细胞的结合来测量。通过流式细胞术确定，SK-BR-3细胞表达由曲妥珠单抗结合的HER2抗原以及Siglec-7和Siglec-9的配体。测试了T7和T9AbLec与AF647标记的Siglec-Fc试剂竞争结合HER2+K562细胞的能力，这些细胞表达靶向的HER2以及Siglec-7和Siglec-9的配体。通过流式细胞术观察到，用递增浓度的T7或T9 AbLec处理细胞分别增强了我们阻断Siglec-7-Fc-AF647(c)或Siglec-9-Fc-AF647(d)结合的能力。AbLec使Siglec-Fc结合几乎降低至唾液酸酶对照的水平，表明它们能够阻断Siglec受体与细胞绝大多数的唾液酸依赖性结合。(e)AbLec还似乎仅阻断靶向的Siglec的结合。在所有测试浓度下，与用曲妥珠单抗或非同源T9 AbLec处理相比，用T7 AbLec处理能够以更大程度阻断同源Siglec-7-Fc的结合。(f)AbLec结合并阻断由内源受体结合的相同表位。测试了AbLec与抗CD43抗体MEM59竞争结合HER2+K562细胞的能力。先前已证实，K562细胞上表达的Siglec-7的主要配体是粘蛋白糖蛋白CD43，并且MEM59可阻断Siglec-7与CD43上的唾液酸化表位的结合。观察到T7 AbLec能够阻断MEM59的结合，表明T7 AbLec结合并阻断内源Siglec-7免疫受体结合的相同的CD43表位。此外，与曲妥珠单抗或非同源T9 AbLec相比，T7 AbLec能够以更大程度阻断MEM59的结合。
图5显示曲妥珠单抗杂交AbLec与不同的HER2+人肿瘤细胞系结合并阻断Siglec受体的结合。该图左侧的图显示T7 AbLec与HCC-1954、SK-BR-3、BT-20和ZR-75-1细胞系结合，这些细胞系表达不同水平的靶向的HER2抗原和Siglec-7配体。该图右侧的图表显示，当我们用递增浓度的T7 AbLec处理SK-BR-3细胞时，增强了我们阻断Siglec-7-Fc-AF647与细胞结合的能力。T7 AbLec使Siglec-Fc结合几乎降低至唾液酸酶对照的水平，表明AbLec能够阻断Siglec受体与细胞绝大多数的唾液酸依赖性结合。
实施例3-AbLec增强抗体依赖性细胞吞噬作用和体外细胞毒性
在该实施例中证明，AbLec增强抗体依赖性细胞吞噬作用和体外细胞毒性。在图3a-图3e和图4中提供了示意图和数据。(a)使用从健康供体外周血分离和分化的人巨噬细胞进行体外抗体依赖性细胞吞噬作用(ADCP)测定。在测定时，巨噬细胞表达Siglec-7和Siglec-9。用pHrodo红标记SK-BR-3靶细胞以使得能够使用Incucyte仪器经由延时荧光显微镜术定量ADCP。(b)温育5小时后巨噬细胞/SK-BR-3共培养实验的图像显示红色荧光水平作为吞噬作用的指标。(c)在n＝3个独特供体中，与单独的曲妥珠单抗或Siglec-Fc相比，T7和T9 AbLec显著增强SK-BR-3细胞的ADCP。(d)使用从健康供体外周血分离的人NK细胞进行体外抗体依赖性细胞毒性(ADCC)测定。在测定时，NK细胞表达Siglec-7。将SK-BR-3靶细胞用celltracker红标记并在Sytox绿的存在下与NK细胞共培养，以使得能够通过流式细胞术定量靶细胞死亡来评估ADCC活性。(e)在n＝3个独特供体中，与单独的曲妥珠单抗或Siglec-7-Fc相比，T7 AbLec显著增强SK-BR-3细胞的ADCC。
图4显示AbLec介导的ADCP增强依赖于靶向的抗原(例如，HER2)的表达。在n＝3个独特供体中，与单独的曲妥珠单抗或Siglec-7/9-Fc相比，T7和T9 AbLec显著增强HER2+K562细胞的ADCP。然而，对于不表达HER2的WT K562细胞，我们用曲妥珠单抗或AbLec没有观察到ADCP活性。这表明AbLec免疫疗法可以特异性地针对表达感兴趣的抗原(例如，肿瘤抗原、免疫细胞标志物等)的细胞。
实施例4-AbLec经由Siglec依赖性增强体外抗肿瘤免疫应答优于组合免疫疗法
在该实施例中证明，AbLec经由Siglec依赖性增强体外抗肿瘤免疫应答优于组合免疫疗法。在图6a-图6d中提供了示意图和数据。(a)在n＝3个独特供体中，与曲妥珠单抗和Siglec-7-Fc、Siglec-9-Fc或霍乱弧菌(V.cholerae)唾液酸酶的组合相比，T7和T9 AbLec引起HER2+K562细胞的增强的ADCP。在n＝3个独特供体中，与曲妥珠单抗和Siglec-7或Siglec-9拮抗抗体或霍乱弧菌唾液酸酶的组合相比，T7和T9 AbLec引起SK-BR-3细胞的增强的ADCP(b)和ADCC(c)。(d)AbLec介导的ADCP和ADCC增强是Siglec依赖性的。如果在与SK-BR-3细胞共培养之前将巨噬细胞(顶部)或NK细胞(底部)与Siglec-7或Siglec-9拮抗抗体一起温育，在免疫细胞中基本上起到Siglec-7/9敲除的作用，则在AbLec处理时观察到的ADCP或ADCC水平降低至与曲妥珠单抗处理时观察到的水平类似的水平。然而，如果Siglec免疫受体未被阻断，则AbLec增强体外ADCP和ADCC。在n＝3个独特供体中观察到这种Siglec依赖性，表明用AbLec处理时观察到的ADCP和ADCC的增强是靶向的Siglec轴的阻断的结果。
实施例5-AbLec平台能够阻断各种糖免疫检查点靶标
在该实施例中证明，AbLec平台能够阻断各种糖免疫检查点靶标。在图7a-图7d和图8中提供了示意图和数据。(a)由于用于制备AbLec的杵臼结构双特异性支架的模块结构，可以容易地交换抗体和诱饵受体组分以产生另外的检查点抑制剂。(b)具有不同作用机制的另外的AbLec候选物的SDS-PAGE表征。莫洛利单抗(magrolimab)×Siglec-7 AbLec设计用于肿瘤细胞上CD47和Siglec-7配体的双重检查点阻断。莫洛利单抗是一种抗CD47抗体(Liu等人2015)，目前处于针对血液癌症的III期临床试验(Garcia-Manero等人2021)。帕博利珠单抗(pembrolizumab)×半乳凝素-9AbLec设计用于耗竭T细胞上PD-1和半乳凝素-9配体的双重检查点阻断。已证实半乳凝素-9通过结合T细胞上的TIM-3检查点并促成T细胞耗竭而促成免疫逃避(Yang等人2021)。曲妥珠单抗×Siglec-10 AbLec设计用于同时靶向HER2+肿瘤并阻断Siglec-10免疫检查点，最近证实其在乳腺癌和卵巢癌的免疫逃避中发挥作用(Barkal等人2019)。利妥昔单抗×Siglec-7(R7)和西妥昔单抗×Siglec-7(C7)AbLec的功能表征证明了AbLec平台在不同肿瘤类型中用于组合肿瘤靶向和糖免疫检查点阻断的效用。在n＝3个独特供体中，与单独的亲本抗体或Siglec-7-Fc相比，R7(c)和C7(d)AbLec显著增强了CD20+Ramos细胞或EGFR+K562细胞的ADCP。
图8显示，在n＝3个独特供体中，与利妥昔单抗相比，R7 AbLec也增强CD20+Raji细胞的ADCC(左)。ADCC的增强是唾液酸依赖性作用，因为在用唾液酸酶处理之后，与利妥昔单抗相比，用R7 AbLec没有显著增强ADCC(右)。
实施例6-不同AbLec分子的表达
图9中示出了不同AbLec分子的还原和非还原性SDS-PAGE和蛋白质印记(Westernblot)分析。还原性SDS-PAGE证明显示每种AbLec由与诱饵受体链以及抗体重链和轻链的分子量一致的3条二硫键键合的蛋白链组成。分别针对诱饵受体和抗体重链上的HA和His6标签的蛋白质印迹进一步证明全长AbLec由抗体和诱饵受体臂两者组成。
材料和方法
质粒和蛋白质序列
所有AbLec质粒均由Twist Bioscience生成。DNA序列列于表1中并且蛋白序列列于表2中。使用XhoI和NheI切割位点将AbLec序列插入到Twist Bioscience载体pTwist CMVβ珠蛋白中。本论文中使用的曲妥珠单抗是从我们先前工作中描述的pCDNA3.1载体表达的(Gray等人2020)。利妥昔单抗和西妥昔单抗抗体可变序列通过IDT生成，并通过使用In-Fusion克隆试剂盒(Takara)根据制造商的方案克隆到VRC01抗体质粒载体(来自斯坦福的Kim实验室的慷慨礼物)的可变区中。
蛋白表达和纯化
使抗体和AbLec在Expi293F系统(Thermo Fisher)中表达，并根据建立的制造商方案表达。对于利妥昔单抗和西妥昔单抗抗体，使用1:1重量比的重链与轻链质粒。对于AbLec，使用2:1:1比率的凝集素:重链:轻链。曲妥珠单抗抗体重链和轻链从单个质粒共表达。表达七天后，通过以300×g使细胞沉淀5分钟，随后以3700×g离心40分钟澄清，并通过0.2μm尼龙过滤器(Fisher Scientific 0974025A)过滤，从上清液收集蛋白质。通过使用蛋白A琼脂糖(Fisher Scientific 20333)的手动重力柱，通过使澄清的上清液流过该柱2次，在室温(rt)处用2μM ST唾液酸酶在珠粒上进行唾液酸酶处理0.5-2小时，然后用5×柱体积的PBS洗涤，并且一次用100mM甘氨酸缓冲液pH 2.8洗脱5mL到用150μL 1M Tris pH 8预平衡的管中来纯化抗体。使用PD-10柱(GE)将抗体缓冲液交换到PBS中。通过使用镍-NTA琼脂糖树脂(Qiagen 30210)的手动重力柱纯化AbLec。简言之，将AbLec上清液与树脂膜(在PBS中预平衡)在4℃处温育～1小时。然后将珠粒和上清液上样到色谱柱(BioRad 7321010)上，用2μM ST唾液酸酶在珠粒上进行唾液酸酶处理2小时，用20×柱体积的PBS+20mM咪唑洗涤，并用5×柱体积的PBS+250mM咪唑洗脱两次。使用PD-10脱盐柱将AbLec缓冲液交换到PBS中。
生物缀合以制备Siglec-Fc-AF647试剂
Siglec-Fc DNA序列在共表达用于醛标记的稳定的人FGE蛋白的Expi293F细胞中表达。根据来自Thermo Fisher的Expi293方案使细胞在黑暗中表达，然后通过0.2μm滤器过滤并上样到含有蛋白A琼脂糖珠粒的柱上。将蛋白质在柱上进行唾液酸酶处理2小时(2μM鼠伤寒沙门氏菌(Salmonella typhimurium)唾液酸酶，室温)。随后用PBS洗涤并用10mL100mM甘氨酸(pH 2.8)洗脱到缓冲的Tris pH 8溶液中。根据Gray等人的方案，将Siglec缓冲液交换到酸性缓冲液中，浓缩并与HIPS-叠氮化物缀合(Gray等人2020)。然后取Siglec-Fc-叠氮化物，不进行进一步表征，缓冲液交换到PBS中，并添加100×摩尔当量在DMSO中的的DBCO-AF647(Click Chemistry Tools，1302-1)，并将反应在黑暗中在室温处以500rpm混合2小时。在Amicon柱(30kDa MWCO)上在PBS中通过6次离心对Siglec进行缓冲液交换，并且通过使用NanoDrop分光光度计在
650nm处对AF647染料(消光系数239,000)和在280nm处对蛋白(使用由Expasy计算的每种Sigleec的消光系数)确认AF647添加。18
AbLec凝胶表征
对于SDS-PAGE凝胶，将2μg蛋白与单独的SDS染料(非还原条件)或在95℃加热5分钟的SDS染料+1Mβ巯基乙醇(还原条件)上样到Bis-Tris 4％-12％ CriterionTM XT Bis-Tris蛋白凝胶，18孔，(Bio-Rad 3450124)上，并用XT-MES缓冲液在180V运行40分钟。用Aquastain(Bulldog Bio AS001000)将蛋白质染色10分钟，随后在水中脱色10分钟。对于AbLec的蛋白质印迹，将0.2μg蛋白上样到SDS-PAGE凝胶上并如上所述运行，然后使用TransTurboTM RTA Midi硝酸纤维素转移试剂盒(Bio-Rad 1704271)在25V下将凝胶转移到硝化纤维素膜上14分钟。将膜在封闭缓冲液(PBS+0.5％ BSA)中在室温处封闭1小时，然后用Invitrogen HA标签多克隆抗体(SG77)(Thermo Fisher Scientific 71-5500)和纯化的抗His标签抗体(BioLegend 652502)在封闭缓冲液中在室温处染色1小时。将膜在PBST(PBS+0.1％吐温)中洗涤3次，随后在PBST中用二次抗体/>800CW山羊抗小鼠和/>680RD山羊抗兔(LI-COR)在室温处振荡染色15分钟，随后在PBST中再洗涤3次。所有凝胶在CLx成像系统(LI-COR)上成像。
AbLec熔融温度表征
将SYPRO橙染料(Thermo Fisher)稀释成25×储备液，并将5μL(含抗体，最终5×浓度)添加到20μL在PBS中0.2mg/mL的AbLec、Siglec-Fc或抗体中，以在96孔qPCR板中每孔得到25μL。在qPCR的FRET荧光通道中通过每1分钟0.5℃使温度从25℃增加到95℃来分析蛋白质的变性。
AbLec质谱表征
用胰蛋白酶消化溶解在PBS中的各4微克AbLec用于蛋白质组分析。将样品与5mM二硫苏糖醇在55℃处温育18分钟，随后与15mM碘乙酰胺在室温处在黑暗中温育30分钟。以1:20w:w的比率添加胰蛋白酶(Promega)并在室温处进行消化过夜。第二天早晨，通过首先用甲酸猝灭消化至最终pH为～2，随后在聚苯乙烯-二乙烯基苯固相萃取(PS-DVB SPE)盒(Phenomenex,Torrance,CA)上脱盐来将样品脱盐。脱盐后真空离心干燥样品，并以0.5μg/μL重悬于0.2％甲酸的水溶液中。
每次分析注射大约1μg肽，其中在25cm EasySpray反相LC柱(75μm内径，填充有2μm、PepMap C18颗粒，Thermo Fisher Scientific)上分离肽。通过Dionex Ultimate3000RPLC纳米系统(Thermo Fisher Scientific)驱动和控制流动相(A：含0.2％甲酸的水和B：含0.2％甲酸的乙腈)。以300nL/分钟进行梯度洗脱。流动相B在6分钟内保持在0％，随后在7分钟时增加至5％，在66分钟时增加至25％，在70分钟时升至90％B，并且在90％ B下洗涤5分钟。然后在75.1分钟时将流速回升至0％B，并将柱在0％ B下再平衡15分钟，总共分析时间为90分钟。在Orbitrap Fusion Tribrid MS系统(Thermo Fisher Scientific)上分析洗脱的肽。使用相比于地保持在+2.2kV的EASY-Spray电离源(Thermo FisherScientific)使前体电离，并且将柱保持在40℃。入口毛细管温度保持在275℃。在Orbitrap中从350-1350m/z收集肽前体的调查扫描，AGC靶标为1,000,000，最大注射时间为50ms，并且在200m/z的分辨率为60,000。能够对肽同位素分布进行单一同位素前体选择，选择z＝2-5的前体用于2秒循环时间的数据依赖性MS/MS扫描，并且动态排除设置为30秒，其中在前体单一同位素周围设置±10ppm窗口。使用1m/z的分离窗口来选择具有四极子的前体离子。使用HCD以30归一化碰撞能量(nce)收集MS/MS扫描，AGC靶标为100,000且最大注射时间为54ms。在Orbitrap中在200m/z下以30,000的分辨率进行质量分析，并且设定扫描范围以自动计算。
使用Byonic19，版本MaxQuant版本3.11.3处理原始数据。将甲硫氨酸(+15.994915)的氧化设定为常见的20可变修饰，将蛋白N端乙酰化(+42.010565)和天冬酰胺脱氨基化(+0.984016)指定为罕见的1可变修饰，并且将半胱氨酸(+57.021464)的脲甲基化设定为固定修饰。容许多达三种常见修饰和两种罕见修饰。使用10ppm的前体离子搜索公差和20ppm的子离子(product ion)质量公差进行搜索，并且对于完全胰蛋白酶特异性允许三个缺失的裂解。针对定制的FASTA序列文件进行肽谱匹配(PSM)，该FASTA序列文件含有Siglec-7和Siglec-9臼以及曲妥珠单抗/利妥昔单抗杵和轻链的适当组合。将肽过滤达到1％假发现率(FDR)，并根据靶-诱饵方法应用1％蛋白FDR。2手动检查所有肽鉴定，并且仅从验证的肽鉴定计算序列覆盖率。序列覆盖百分比从通过肽鉴定解释的氨基酸相对于氨基酸总数的比例得到。
细胞培养
所有细胞系均购自美国模式培养物保藏中心(American Type CultureCollection，ATCC)。将SK-BR-3、HCC-1954、K562、Raji和Ramos在没有抗生素选择的情况下在RPMI+10％热灭活胎牛血清(FBS)中培养。Expi293F细胞是来自斯坦福的Kim实验室的礼物，并根据Thermo Fisher Scientific的用户指导进行培养。根据制造商的方案，使用预包装的慢病毒颗粒(G&P Biosciences)用EGFR转染K562，并通过在1μg/mL嘌呤霉素(InVivoGen)中培养来针对EGFR表达进行选择。根据制造商的方案，使用预包装的慢病毒颗粒(G&P Biosciences LTV-CD20)用CD20转染K562，并在FACS仪器上使用利妥昔单抗和BV421标记的抗人二次抗体(Biolegend)作为染色试剂针对CD20表达进行分选。HER2 WT是来自Mien-Chie Hung的礼物(Addgene质粒#16257)并且按照它们的方案产生稳定的HER2+细胞系，21通过流式细胞术验证蛋白质表达。在ATCC提供的特性之外，不独立地鉴别细胞系。细胞系在5％ CO2和37℃下在加湿培养箱中培养，并且使用基于PCR的测定每季测试为支原体阴性。
定量AbLec KD
HER2+K562和SK-BR-3细胞分别从细胞培养上清液分离或经由用TrypLE(Gibco)离解分离，用1×PBS洗涤，并重悬于封闭缓冲液中。然后将60,000个细胞分配到96孔V形底板(Corning)的孔中。将不同浓度(200-0.4nM)的曲妥珠单抗、Siglec-Fc或AbLec以等体积添加到细胞中，并与细胞在4℃处温育1小时，同时定期用移液管混合。将细胞在封闭缓冲液中洗涤三次，通过在洗涤间期在4℃处以300g离心5分钟进行沉淀。细胞在封闭缓冲液中的AF647山羊抗人(BioLegend)中在4℃处重悬30分钟。将细胞进一步洗涤两次并重悬于封闭缓冲液中，并通过流式细胞术(BD LSR II)分析荧光。使用FlowJo v.10.0软件(Tree Star)进行门控以消除碎片并分离单细胞。将细胞群体的平均荧光强度(MFI)针对来自每个实验重复的用50nM曲妥珠单抗染色的细胞的MFI进行归一化。使用GraphPad Prism 9将MFI值拟合为单位点总结合曲线，其按照实现半最大结合量所需的抗体浓度计算KD值。
与Siglec-Fc-AF647试剂的竞争性结合
HER2+K562和SK-BR-3细胞分别从细胞培养上清液分离或经由用TrypLE(Gibco)离解分离，用1×PBS洗涤，并重悬于封闭缓冲液中。将细胞等分，在37℃处用100nM霍乱弧菌唾液酸酶在封闭缓冲液中进行唾液酸酶处理30分钟。然后将60,000个未处理的细胞或经唾液酸酶处理的细胞分配到96孔V形底板(Corning)的孔中。将不同浓度(100-0.4nM)的曲妥珠单抗或AbLec与200nM Siglec-Fc-AF647试剂以等体积添加到细胞中，并与细胞在4℃处温育2-3小时，同时定期用移液管混合。将细胞洗涤三次并重悬于封闭缓冲液中，通过在洗涤间期在4℃处以300g离心5分钟进行沉淀，并通过流式细胞术(BD LSR II)分析荧光。使用FlowJo v.10.0软件(Tree Star)进行门控以消除碎片并分离单细胞。将细胞群体的平均荧光强度(MFI)针对来自每个实验重复的用200nM无抗体的Siglec-Fc-AF647或AbLec染色的细胞的MFI进行归一化。使用GraphPad Prism 9将MFI值拟合为单位点总结合曲线，其按照实现半最大结合量所需的抗体浓度计算KD值。
供体NK细胞的分离
如上所述从LRS腔室中分离PBMC，在90％热灭活的FBS+10％DMSO中制备2-4×107个细胞的储备液，并储存在液氮蒸气中直至使用。在使用前一天解冻储备液，使用EasySepNK分离试剂盒(StemCell Technologies 17955)分离NK细胞，并将细胞与0.5μg/mL重组IL-2(Biolegend 589106)在RPMI+10％热灭活的FBS中培养过夜直至使用。
NK细胞流式细胞术
用IL-2活化24小时后，从培养上清液中收集NK细胞，用1×PBS洗涤并重悬于封闭缓冲液中。在分析的当天，用抗CD16、Siglec-7和同种型对照在封闭缓冲液中在4℃处染色巨噬细胞30分钟。在PBS中洗涤2次后，通过流式细胞术(BD LSR II)分析NK细胞，并使用FlowJo v10对CD16阳性细胞进行门控。通过流式细胞术分析，NK细胞纯度>85％。
NK细胞杀伤测定
根据制造商的方案，将靶细胞用celltracker深红染料提起染色。将NK细胞和靶细胞以4:1的效应物与靶标(E/T)比率混合，并以100nM添加Sytox Green(Thermo)。通过流式细胞术，通过选择红色(FL4-A+)细胞并按照Sytox Green+/总红细胞计算死亡百分比来分析细胞死亡。在Prism9.0(GraphPad Software,Inc)中对来自三个独特的血液供体的重复进行作图。
供体巨噬细胞的分离和分化
从健康匿名血库供体获得LRS腔室并使用Ficoll-Paque(GE Healthcare LifeSciences，GE)密度梯度分离对PBMC进行分离。通过将～1×108个PBMC平板接种在无血清RPMI的T75烧瓶中1-2小时，随后用PBS+Ca+Mg剧烈洗涤3次以去除非粘附细胞来分离单核细胞。然后用含有10％人AB血清(Gemini)的IMDM替换培养基，以在巨噬细胞用于吞噬作用或流式细胞术实验之前使巨噬细胞分化7-9天。
巨噬细胞流式细胞术
将第7-9天的巨噬细胞从如上所述的板上提起，然后用4％甲醛(Thermo)的PBS溶液固定15分钟，并且用PBS洗涤3次并在4℃处储存2-7天直至分析。在分析的当天，用CD11b、CD14、Siglec-7、Siglec-9、Siglec-10和同种型对照在封闭缓冲液中在4℃处染色巨噬细胞30分钟。在PBS中洗涤2次后，在LSR II仪器上通过流式细胞术分析巨噬细胞，并使用FlowJov10对CD11b和CD14双阳性细胞进行门控。通过流式细胞术分析，巨噬细胞纯度>85％。
吞噬作用测定
用PBS洗涤巨噬细胞，并通过在37℃处与10mL TrypLE(Thermo)温育20分钟来提起巨噬细胞。添加RPMI+10％ HI FBS达到等体积，以300×g离心5分钟使巨噬细胞沉淀并且重悬于IncuCyte培养基(不含酚红的RPMI+10％ HI FBS)中。将巨噬细胞(10,000个细胞，100μL)添加到96孔平底板(Corning)中，并在37℃处在潮湿培养箱中温育1小时。同时，用PBS洗涤靶细胞1次，然后用1:80,000稀释的pHRodo红琥珀酰胺酯染料(Thermo Fisher)在PBS中在37℃处理30分钟，洗涤1次并重悬于IncuCyte培养基中。最后，向巨噬细胞中添加10μL的20×抗体或AbLec储备液的PBS溶液，随后添加pHRodo红染色的靶细胞(90μL，20,000个细胞)。通过温和离心(50×g，2分钟)将细胞平板接种。每孔以1小时间隔获取两张图像，直至达到最大信号(对于乳腺癌细胞系和K562细胞为5小时，对于Raji细胞和Ramos细胞为2小时)。基于它们的背景荧光和大小,针对每种细胞系的吞噬作用,经验性地优化pHRodo红色荧光的定量。对K562进行分析，阈值为0.8，边缘灵敏度为-70，并且以介于300和2000RCU×μm2/张图像之间的积分强度将面积门控为100μm2至2000μm2之间。对HCC-1954进行分析，阈值为1.5，边缘灵敏度为-45，且面积为30μm2至2000μm2之间。SK-BR-3分析的阈值为1，边缘灵敏度为-55，最小积分强度为60，且最大面积和偏心率分别为3000和0.96。使用1.5的阈值、-45的边缘灵敏度以及100μm2至2000μm2之间的面积来限定Ramos和Raji门控。对每张图像取总红色物体积分强度(RCU×μm2/张图像)。对于每个实验，将通过pHRodo红测量的最大吞噬作用归一化至1，然后对于每个生物重复取三份技术孔重复的平均值。在Prism 9.0(GraphPadSoftware,Inc)中对来自三个独特的血液供体的重复进行作图。
IncuCyte图像的获取
对于吞噬作用和毒性测定，使用S3活细胞分析系统(EssenBioScience)在Thermo Fisher Scientific组织培养箱内保持在37℃和5％ CO2下随时间获得图像。从相差的10×物镜、绿色荧光通道(激发波长：460±20，发射波长：524±20，获取时间：300ms)以及从红色荧光通道(激发波长：585±20，发射波长：665±40，获取时间：400ms)获取数据。每孔间隔获取两张图像。除非另有说明，否则所有细胞以100μm半径、边缘分裂、孔填充：0μm2通过Top-Hat分割进行分析。
细胞生长和毒性测定
将GFP+SK-BR-3、HER2+K562和HCC-1954细胞用2mL胰蛋白酶在37℃下提起5分钟，用8mL正常生长培养基冲洗，并通过以300×g离心使细胞沉淀，重悬于不含酚红的生长培养基中，该培养基含有用于GFP阳性SK-BR-3系的50nM Sytox绿色死细胞染剂(Thermo Fisher)或5nM Sytox红色死细胞染剂(Thermo Fisher)以测量细胞毒性。将细胞平板接种于平底96孔板上(每孔10,000个细胞，95μL)，然后添加5μL AbLec、Siglec或抗体的PBS溶液并混合，随后以30×g离心1分钟。每2小时获取图像，持续3天。对SK-BR-3细胞进行相分析，分割调整＝1且最小面积为200μm2，使用0.3RCU的阈值，以-50的边缘灵敏度和介于50至1000平方微米之间的面积通过红色荧光对细胞死亡进行定量。HCC-1954细胞具有0.9分割调整、300平方微米孔填充和200平方微米的最小面积。以1的阈值、-45的边缘灵敏度和介于100-3000平方微米之间的面积检测Sytox绿色死亡事件。K562相分割调整为0.2，没有孔填充且最小面积为60微米。在绿色荧光通道中，阈值为2，边缘灵敏度为-45且面积介于50至800微米之间，偏心率和积分强度分别小于0.95和40000。
统计分析
所有统计分析均在Prism(版本9)中执行。对于结合曲线，使用单位点特异性结合曲线来计算抗体和AbLec的离解常数。在结合测定、NK细胞的细胞毒性实验、吞噬作用实验和Siglec表达分析中，用Tukey多重比较检验进行普通单因素方差分析(one-way ANOVA)以比较处理组。在每种情况下，星号*指示p<0.05，**指示p<0.01，***指示p<0.001，并且****指示p<0.0001。
氨基酸序列
本文采用的AbLec和抗体的氨基酸序列示于下表中。斜体氨基酸表示最终纯化分子中不存在的信号输出序列。HA-标签和六组氨酸标签加下划线或加粗，且终止密码子用星号*表示。
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核苷酸序列
编码本文采用的AbLec和抗体的核苷酸序列示于下表中。序列包括输出信号肽、肽标签(诸如六组氨酸标签和HA标签)以及终止密码子。
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参考文献
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因此，以上仅说明本公开的原理。应当理解的是，本领域技术人员能够设计各种布置，尽管未在本文明确描述或示出，但所述各种布置体现了本发明的原理并且包括在本发明的精神和范围内。此外，本文列举的所有示例和条件性语言主要旨在帮助读者理解本发明的原理和发明人为促进本领域的发展而贡献的概念，并且被解释为不限于这些具体列举的示例和条件。此外，本文叙述本发明的原理、方面和实施方案以及其具体示例的所有陈述旨在涵盖其结构和功能等同物。另外，预期此类等同物包括当前已知的等同物以及未来开发的等同物，即，开发的不论结构如何执行相同功能的任何要素。因此，本发明的范围并不旨在限于本文示出和描述的示范性实施方案。
序列表
<110> 小利兰·斯坦福大学理事会（The Board of Trustees of the LelandStanford Junior University）
卡洛琳·R·贝尔托齐（Bertozzi, Carolyn R.）
杰西卡·斯塔克（Stark, Jessica）
梅利莎·格雷（Gray, Melissa）
西蒙·维斯诺夫斯基（Wisnovsky, Simon）
<120> 双特异性分子及相关的组合物和方法
<130> STAN-1838WO
<150> US 63/170,297
<151> 2021-04-02
<160> 137
<170> PatentIn 3.5版
<210> 1
<211> 475
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 1
Met Gly Trp Ser Leu Ile Leu Leu Phe Leu Val Ala Val Ala Thr Arg
1 5 10 15
Val His 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 Asn Ile
35 40 45
Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
85 90 95
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
225 230 235 240
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
245 250 255
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
260 265 270
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
275 280 285
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
290 295 300
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
305 310 315 320
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
325 330 335
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
340 345 350
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
355 360 365
Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln
370 375 380
Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly Gly His His His His His His
465 470 475
<210> 2
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 2
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Gly
450
<210> 3
<211> 234
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 3
Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp
35 40 45
Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
50 55 60
Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr
100 105 110
Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 4
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 4
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 5
<211> 476
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 5
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu
50 55 60
Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn
115 120 125
Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
145 150 155 160
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
210 215 220
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro
225 230 235 240
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn
370 375 380
Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Gly His His His His His His
465 470 475
<210> 6
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 6
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Gly
450
<210> 7
<211> 232
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 7
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala
20 25 30
Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val
35 40 45
Ser Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro
50 55 60
Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe
65 70 75 80
Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val
85 90 95
Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn
100 105 110
Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val
115 120 125
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
130 135 140
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
145 150 155 160
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
165 170 175
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
180 185 190
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
195 200 205
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
210 215 220
Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 8
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 8
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 9
<211> 474
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 9
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln
20 25 30
Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu
35 40 45
Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu
50 55 60
Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr
65 70 75 80
Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln
85 90 95
Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr
100 105 110
Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro
130 135 140
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
145 150 155 160
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
165 170 175
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
180 185 190
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
195 200 205
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
210 215 220
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
225 230 235 240
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
245 250 255
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
260 265 270
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
275 280 285
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
290 295 300
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
305 310 315 320
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
340 345 350
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
355 360 365
Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val
370 375 380
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
385 390 395 400
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
405 410 415
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
420 425 430
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
435 440 445
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
450 455 460
Ser Pro Gly Gly His His His His His His
465 470
<210> 10
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 10
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Gly
<210> 11
<211> 233
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 11
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val
20 25 30
Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile
35 40 45
Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg
50 55 60
Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser
85 90 95
Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn
100 105 110
Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr
115 120 125
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
130 135 140
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
145 150 155 160
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
165 170 175
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
180 185 190
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
195 200 205
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
210 215 220
Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 12
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 12
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 13
<211> 595
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 13
Met Leu Leu Leu Leu Leu Leu Pro Leu Leu Trp Gly Arg Glu Arg Val
1 5 10 15
Glu Gly Gln Lys Ser Asn Arg Lys Asp Tyr Ser Leu Thr Met Gln Ser
20 25 30
Ser Val Thr Val Gln Glu Gly Met Cys Val His Val Arg Cys Ser Phe
35 40 45
Ser Tyr Pro Val Asp Ser Gln Thr Asp Ser Asp Pro Val His Gly Tyr
50 55 60
Trp Phe Arg Ala Gly Asn Asp Ile Ser Trp Lys Ala Pro Val Ala Thr
65 70 75 80
Asn Asn Pro Ala Trp Ala Val Gln Glu Glu Thr Arg Asp Arg Phe His
85 90 95
Leu Leu Gly Asp Pro Gln Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp
100 105 110
Ala Arg Met Ser Asp Ala Gly Arg Tyr Phe Phe Arg Met Glu Lys Gly
115 120 125
Asn Ile Lys Trp Asn Tyr Lys Tyr Asp Gln Leu Ser Val Asn Val Thr
130 135 140
Ala Leu Thr His Arg Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser
145 150 155 160
Gly Cys Phe Gln Asn Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln
165 170 175
Gly Thr Pro Pro Met Ile Ser Trp Met Gly Thr Ser Val Ser Pro Leu
180 185 190
His Pro Ser Thr Thr Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro
195 200 205
Gln His His Gly Thr Ser Leu Thr Cys Gln Val Thr Leu Pro Gly Ala
210 215 220
Gly Val Thr Thr Asn Arg Thr Ile Gln Leu Asn Val Ser Tyr Pro Pro
225 230 235 240
Gln Asn Leu Thr Val Thr Val Phe Gln Gly Glu Gly Thr Ala Ser Thr
245 250 255
Ala Leu Gly Asn Ser Ser Ser Leu Ser Val Leu Glu Gly Gln Ser Leu
260 265 270
Arg Leu Val Cys Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Trp
275 280 285
Thr Trp Arg Ser Leu Thr Leu Tyr Pro Ser Gln Pro Ser Asn Pro Leu
290 295 300
Val Leu Glu Leu Gln Val His Leu Gly Asp Glu Gly Glu Phe Thr Cys
305 310 315 320
Arg Ala Gln Asn Ser Leu Gly Ser Gln His Val Ser Leu Asn Leu Ser
325 330 335
Leu Gln Gln Glu Tyr Thr Gly Lys Met Arg Pro Val Ser Gly Gly Gly
340 345 350
Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
355 360 365
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
370 375 380
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
385 390 395 400
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
405 410 415
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
420 425 430
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
435 440 445
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
450 455 460
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
465 470 475 480
Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu
485 490 495
Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr
500 505 510
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
515 520 525
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
530 535 540
Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
545 550 555 560
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
565 570 575
Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Tyr Pro Tyr Asp Val Pro
580 585 590
Asp Tyr Ala
595
<210> 14
<211> 568
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 14
Gln Lys Ser Asn Arg Lys Asp Tyr Ser Leu Thr Met Gln Ser Ser Val
1 5 10 15
Thr Val Gln Glu Gly Met Cys Val His Val Arg Cys Ser Phe Ser Tyr
20 25 30
Pro Val Asp Ser Gln Thr Asp Ser Asp Pro Val His Gly Tyr Trp Phe
35 40 45
Arg Ala Gly Asn Asp Ile Ser Trp Lys Ala Pro Val Ala Thr Asn Asn
50 55 60
Pro Ala Trp Ala Val Gln Glu Glu Thr Arg Asp Arg Phe His Leu Leu
65 70 75 80
Gly Asp Pro Gln Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp Ala Arg
85 90 95
Met Ser Asp Ala Gly Arg Tyr Phe Phe Arg Met Glu Lys Gly Asn Ile
100 105 110
Lys Trp Asn Tyr Lys Tyr Asp Gln Leu Ser Val Asn Val Thr Ala Leu
115 120 125
Thr His Arg Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys
130 135 140
Phe Gln Asn Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr
145 150 155 160
Pro Pro Met Ile Ser Trp Met Gly Thr Ser Val Ser Pro Leu His Pro
165 170 175
Ser Thr Thr Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro Gln His
180 185 190
His Gly Thr Ser Leu Thr Cys Gln Val Thr Leu Pro Gly Ala Gly Val
195 200 205
Thr Thr Asn Arg Thr Ile Gln Leu Asn Val Ser Tyr Pro Pro Gln Asn
210 215 220
Leu Thr Val Thr Val Phe Gln Gly Glu Gly Thr Ala Ser Thr Ala Leu
225 230 235 240
Gly Asn Ser Ser Ser Leu Ser Val Leu Glu Gly Gln Ser Leu Arg Leu
245 250 255
Val Cys Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Trp Thr Trp
260 265 270
Arg Ser Leu Thr Leu Tyr Pro Ser Gln Pro Ser Asn Pro Leu Val Leu
275 280 285
Glu Leu Gln Val His Leu Gly Asp Glu Gly Glu Phe Thr Cys Arg Ala
290 295 300
Gln Asn Ser Leu Gly Ser Gln His Val Ser Leu Asn Leu Ser Leu Gln
305 310 315 320
Gln Glu Tyr Thr Gly Lys Met Arg Pro Val Ser Gly Gly Gly Gly Gly
325 330 335
Gly Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
340 345 350
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
355 360 365
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
370 375 380
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
385 390 395 400
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
405 410 415
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
420 425 430
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
435 440 445
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
450 455 460
Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
465 470 475 480
Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser
485 490 495
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
500 505 510
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val
515 520 525
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
530 535 540
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
545 550 555 560
Ser Leu Ser Leu Ser Pro Gly Gly
565
<210> 15
<211> 331
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 15
Gln Lys Ser Asn Arg Lys Asp Tyr Ser Leu Thr Met Gln Ser Ser Val
1 5 10 15
Thr Val Gln Glu Gly Met Cys Val His Val Arg Cys Ser Phe Ser Tyr
20 25 30
Pro Val Asp Ser Gln Thr Asp Ser Asp Pro Val His Gly Tyr Trp Phe
35 40 45
Arg Ala Gly Asn Asp Ile Ser Trp Lys Ala Pro Val Ala Thr Asn Asn
50 55 60
Pro Ala Trp Ala Val Gln Glu Glu Thr Arg Asp Arg Phe His Leu Leu
65 70 75 80
Gly Asp Pro Gln Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp Ala Arg
85 90 95
Met Ser Asp Ala Gly Arg Tyr Phe Phe Arg Met Glu Lys Gly Asn Ile
100 105 110
Lys Trp Asn Tyr Lys Tyr Asp Gln Leu Ser Val Asn Val Thr Ala Leu
115 120 125
Thr His Arg Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys
130 135 140
Phe Gln Asn Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr
145 150 155 160
Pro Pro Met Ile Ser Trp Met Gly Thr Ser Val Ser Pro Leu His Pro
165 170 175
Ser Thr Thr Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro Gln His
180 185 190
His Gly Thr Ser Leu Thr Cys Gln Val Thr Leu Pro Gly Ala Gly Val
195 200 205
Thr Thr Asn Arg Thr Ile Gln Leu Asn Val Ser Tyr Pro Pro Gln Asn
210 215 220
Leu Thr Val Thr Val Phe Gln Gly Glu Gly Thr Ala Ser Thr Ala Leu
225 230 235 240
Gly Asn Ser Ser Ser Leu Ser Val Leu Glu Gly Gln Ser Leu Arg Leu
245 250 255
Val Cys Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Trp Thr Trp
260 265 270
Arg Ser Leu Thr Leu Tyr Pro Ser Gln Pro Ser Asn Pro Leu Val Leu
275 280 285
Glu Leu Gln Val His Leu Gly Asp Glu Gly Glu Phe Thr Cys Arg Ala
290 295 300
Gln Asn Ser Leu Gly Ser Gln His Val Ser Leu Asn Leu Ser Leu Gln
305 310 315 320
Gln Glu Tyr Thr Gly Lys Met Arg Pro Val Ser
325 330
<210> 16
<211> 594
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 16
Met Leu Leu Leu Leu Leu Leu Pro Leu Leu Trp Gly Arg Glu Arg Val
1 5 10 15
Glu Gly Gln Lys Ser Asn Arg Lys Asp Tyr Ser Leu Thr Met Gln Ser
20 25 30
Ser Val Thr Val Gln Glu Gly Met Cys Val His Val Arg Cys Ser Phe
35 40 45
Ser Tyr Pro Val Asp Ser Gln Thr Asp Ser Asp Pro Val His Gly Tyr
50 55 60
Trp Phe Arg Ala Gly Asn Asp Ile Ser Trp Lys Ala Pro Val Ala Thr
65 70 75 80
Asn Asn Pro Ala Trp Ala Val Gln Glu Glu Thr Arg Asp Arg Phe His
85 90 95
Leu Leu Gly Asp Pro Gln Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp
100 105 110
Ala Arg Met Ser Asp Ala Gly Arg Tyr Phe Phe Ala Met Glu Lys Gly
115 120 125
Asn Ile Lys Trp Asn Tyr Lys Tyr Asp Gln Leu Ser Val Asn Val Thr
130 135 140
Ala Leu Thr His Arg Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser
145 150 155 160
Gly Cys Phe Gln Asn Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln
165 170 175
Gly Thr Pro Pro Met Ile Ser Trp Met Gly Thr Ser Val Ser Pro Leu
180 185 190
His Pro Ser Thr Thr Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro
195 200 205
Gln His His Gly Thr Ser Leu Thr Cys Gln Val Thr Leu Pro Gly Ala
210 215 220
Gly Val Thr Thr Asn Arg Thr Ile Gln Leu Asn Val Ser Tyr Pro Pro
225 230 235 240
Gln Asn Leu Thr Val Thr Val Phe Gln Gly Glu Gly Thr Ala Ser Thr
245 250 255
Ala Leu Gly Asn Ser Ser Ser Leu Ser Val Leu Glu Gly Gln Ser Leu
260 265 270
Arg Leu Val Cys Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Trp
275 280 285
Thr Trp Arg Ser Leu Thr Leu Tyr Pro Ser Gln Pro Ser Asn Pro Leu
290 295 300
Val Leu Glu Leu Gln Val His Leu Gly Asp Glu Gly Glu Phe Thr Cys
305 310 315 320
Arg Ala Gln Asn Ser Leu Gly Ser Gln His Val Ser Leu Asn Leu Ser
325 330 335
Leu Gln Gln Glu Tyr Thr Gly Lys Met Arg Pro Val Ser Gly Gly Gly
340 345 350
Gly Gly Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
355 360 365
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
370 375 380
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
385 390 395 400
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
405 410 415
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
420 425 430
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
435 440 445
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
450 455 460
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
465 470 475 480
Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu
485 490 495
Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro
500 505 510
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
515 520 525
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
530 535 540
Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
545 550 555 560
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
565 570 575
Lys Ser Leu Ser Leu Ser Pro Gly Gly Tyr Pro Tyr Asp Val Pro Asp
580 585 590
Tyr Ala
<210> 17
<211> 567
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 17
Gln Lys Ser Asn Arg Lys Asp Tyr Ser Leu Thr Met Gln Ser Ser Val
1 5 10 15
Thr Val Gln Glu Gly Met Cys Val His Val Arg Cys Ser Phe Ser Tyr
20 25 30
Pro Val Asp Ser Gln Thr Asp Ser Asp Pro Val His Gly Tyr Trp Phe
35 40 45
Arg Ala Gly Asn Asp Ile Ser Trp Lys Ala Pro Val Ala Thr Asn Asn
50 55 60
Pro Ala Trp Ala Val Gln Glu Glu Thr Arg Asp Arg Phe His Leu Leu
65 70 75 80
Gly Asp Pro Gln Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp Ala Arg
85 90 95
Met Ser Asp Ala Gly Arg Tyr Phe Phe Ala Met Glu Lys Gly Asn Ile
100 105 110
Lys Trp Asn Tyr Lys Tyr Asp Gln Leu Ser Val Asn Val Thr Ala Leu
115 120 125
Thr His Arg Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys
130 135 140
Phe Gln Asn Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr
145 150 155 160
Pro Pro Met Ile Ser Trp Met Gly Thr Ser Val Ser Pro Leu His Pro
165 170 175
Ser Thr Thr Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro Gln His
180 185 190
His Gly Thr Ser Leu Thr Cys Gln Val Thr Leu Pro Gly Ala Gly Val
195 200 205
Thr Thr Asn Arg Thr Ile Gln Leu Asn Val Ser Tyr Pro Pro Gln Asn
210 215 220
Leu Thr Val Thr Val Phe Gln Gly Glu Gly Thr Ala Ser Thr Ala Leu
225 230 235 240
Gly Asn Ser Ser Ser Leu Ser Val Leu Glu Gly Gln Ser Leu Arg Leu
245 250 255
Val Cys Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Trp Thr Trp
260 265 270
Arg Ser Leu Thr Leu Tyr Pro Ser Gln Pro Ser Asn Pro Leu Val Leu
275 280 285
Glu Leu Gln Val His Leu Gly Asp Glu Gly Glu Phe Thr Cys Arg Ala
290 295 300
Gln Asn Ser Leu Gly Ser Gln His Val Ser Leu Asn Leu Ser Leu Gln
305 310 315 320
Gln Glu Tyr Thr Gly Lys Met Arg Pro Val Ser Gly Gly Gly Gly Gly
325 330 335
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
340 345 350
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
355 360 365
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
370 375 380
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
385 390 395 400
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
405 410 415
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
420 425 430
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
435 440 445
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
450 455 460
Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
465 470 475 480
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
485 490 495
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
500 505 510
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
515 520 525
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
530 535 540
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
545 550 555 560
Leu Ser Leu Ser Pro Gly Gly
565
<210> 18
<211> 331
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 18
Gln Lys Ser Asn Arg Lys Asp Tyr Ser Leu Thr Met Gln Ser Ser Val
1 5 10 15
Thr Val Gln Glu Gly Met Cys Val His Val Arg Cys Ser Phe Ser Tyr
20 25 30
Pro Val Asp Ser Gln Thr Asp Ser Asp Pro Val His Gly Tyr Trp Phe
35 40 45
Arg Ala Gly Asn Asp Ile Ser Trp Lys Ala Pro Val Ala Thr Asn Asn
50 55 60
Pro Ala Trp Ala Val Gln Glu Glu Thr Arg Asp Arg Phe His Leu Leu
65 70 75 80
Gly Asp Pro Gln Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp Ala Arg
85 90 95
Met Ser Asp Ala Gly Arg Tyr Phe Phe Ala Met Glu Lys Gly Asn Ile
100 105 110
Lys Trp Asn Tyr Lys Tyr Asp Gln Leu Ser Val Asn Val Thr Ala Leu
115 120 125
Thr His Arg Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys
130 135 140
Phe Gln Asn Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr
145 150 155 160
Pro Pro Met Ile Ser Trp Met Gly Thr Ser Val Ser Pro Leu His Pro
165 170 175
Ser Thr Thr Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro Gln His
180 185 190
His Gly Thr Ser Leu Thr Cys Gln Val Thr Leu Pro Gly Ala Gly Val
195 200 205
Thr Thr Asn Arg Thr Ile Gln Leu Asn Val Ser Tyr Pro Pro Gln Asn
210 215 220
Leu Thr Val Thr Val Phe Gln Gly Glu Gly Thr Ala Ser Thr Ala Leu
225 230 235 240
Gly Asn Ser Ser Ser Leu Ser Val Leu Glu Gly Gln Ser Leu Arg Leu
245 250 255
Val Cys Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Trp Thr Trp
260 265 270
Arg Ser Leu Thr Leu Tyr Pro Ser Gln Pro Ser Asn Pro Leu Val Leu
275 280 285
Glu Leu Gln Val His Leu Gly Asp Glu Gly Glu Phe Thr Cys Arg Ala
290 295 300
Gln Asn Ser Leu Gly Ser Gln His Val Ser Leu Asn Leu Ser Leu Gln
305 310 315 320
Gln Glu Tyr Thr Gly Lys Met Arg Pro Val Ser
325 330
<210> 19
<211> 588
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 19
Met Leu Leu Leu Leu Leu Pro Leu Leu Trp Gly Arg Glu Arg Ala Glu
1 5 10 15
Gly Gln Thr Ser Lys Leu Leu Thr Met Gln Ser Ser Val Thr Val Gln
20 25 30
Glu Gly Leu Cys Val His Val Pro Cys Ser Phe Ser Tyr Pro Ser His
35 40 45
Gly Trp Ile Tyr Pro Gly Pro Val Val His Gly Tyr Trp Phe Arg Glu
50 55 60
Gly Ala Asn Thr Asp Gln Asp Ala Pro Val Ala Thr Asn Asn Pro Ala
65 70 75 80
Arg Ala Val Trp Glu Glu Thr Arg Asp Arg Phe His Leu Leu Gly Asp
85 90 95
Pro His Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp Ala Arg Arg Ser
100 105 110
Asp Ala Gly Arg Tyr Phe Phe Arg Met Glu Lys Gly Ser Ile Lys Trp
115 120 125
Asn Tyr Lys His His Arg Leu Ser Val Asn Val Thr Ala Leu Thr His
130 135 140
Arg Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys Pro Gln
145 150 155 160
Asn Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr Pro Pro
165 170 175
Met Ile Ser Trp Ile Gly Thr Ser Val Ser Pro Leu Asp Pro Ser Thr
180 185 190
Thr Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro Gln Asp His Gly
195 200 205
Thr Ser Leu Thr Cys Gln Val Thr Phe Pro Gly Ala Ser Val Thr Thr
210 215 220
Asn Lys Thr Val His Leu Asn Val Ser Tyr Pro Pro Gln Asn Leu Thr
225 230 235 240
Met Thr Val Phe Gln Gly Asp Gly Thr Val Ser Thr Val Leu Gly Asn
245 250 255
Gly Ser Ser Leu Ser Leu Pro Glu Gly Gln Ser Leu Arg Leu Val Cys
260 265 270
Ala Val Asp Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Leu Ser
275 280 285
Trp Arg Gly Leu Thr Leu Cys Pro Ser Gln Pro Ser Asn Pro Gly Val
290 295 300
Leu Glu Leu Pro Trp Val His Leu Arg Asp Ala Ala Glu Phe Thr Cys
305 310 315 320
Arg Ala Gln Asn Pro Leu Gly Ser Gln Gln Val Tyr Leu Asn Val Ser
325 330 335
Leu Gln Ser Lys Ala Thr Ser Gly Gly Gly Gly Gly Pro Lys Ser Cys
340 345 350
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
355 360 365
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
370 375 380
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
385 390 395 400
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
405 410 415
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
420 425 430
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
435 440 445
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
450 455 460
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
465 470 475 480
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
485 490 495
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
500 505 510
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
515 520 525
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
530 535 540
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
545 550 555 560
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
565 570 575
Pro Gly Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
580 585
<210> 20
<211> 571
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 20
Gln Thr Ser Lys Leu Leu Thr Met Gln Ser Ser Val Thr Val Gln Glu
1 5 10 15
Gly Leu Cys Val His Val Pro Cys Ser Phe Ser Tyr Pro Ser His Gly
20 25 30
Trp Ile Tyr Pro Gly Pro Val Val His Gly Tyr Trp Phe Arg Glu Gly
35 40 45
Ala Asn Thr Asp Gln Asp Ala Pro Val Ala Thr Asn Asn Pro Ala Arg
50 55 60
Ala Val Trp Glu Glu Thr Arg Asp Arg Phe His Leu Leu Gly Asp Pro
65 70 75 80
His Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp Ala Arg Arg Ser Asp
85 90 95
Ala Gly Arg Tyr Phe Phe Arg Met Glu Lys Gly Ser Ile Lys Trp Asn
100 105 110
Tyr Lys His His Arg Leu Ser Val Asn Val Thr Ala Leu Thr His Arg
115 120 125
Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys Pro Gln Asn
130 135 140
Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr Pro Pro Met
145 150 155 160
Ile Ser Trp Ile Gly Thr Ser Val Ser Pro Leu Asp Pro Ser Thr Thr
165 170 175
Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro Gln Asp His Gly Thr
180 185 190
Ser Leu Thr Cys Gln Val Thr Phe Pro Gly Ala Ser Val Thr Thr Asn
195 200 205
Lys Thr Val His Leu Asn Val Ser Tyr Pro Pro Gln Asn Leu Thr Met
210 215 220
Thr Val Phe Gln Gly Asp Gly Thr Val Ser Thr Val Leu Gly Asn Gly
225 230 235 240
Ser Ser Leu Ser Leu Pro Glu Gly Gln Ser Leu Arg Leu Val Cys Ala
245 250 255
Val Asp Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Leu Ser Trp
260 265 270
Arg Gly Leu Thr Leu Cys Pro Ser Gln Pro Ser Asn Pro Gly Val Leu
275 280 285
Glu Leu Pro Trp Val His Leu Arg Asp Ala Ala Glu Phe Thr Cys Arg
290 295 300
Ala Gln Asn Pro Leu Gly Ser Gln Gln Val Tyr Leu Asn Val Ser Leu
305 310 315 320
Gln Ser Lys Ala Thr Ser Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp
325 330 335
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
340 345 350
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
355 360 365
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
370 375 380
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
385 390 395 400
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
405 410 415
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
420 425 430
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
435 440 445
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
450 455 460
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
465 470 475 480
Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
485 490 495
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
500 505 510
Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp
515 520 525
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
530 535 540
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
545 550 555 560
Gly Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
565 570
<210> 21
<211> 326
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 21
Gln Thr Ser Lys Leu Leu Thr Met Gln Ser Ser Val Thr Val Gln Glu
1 5 10 15
Gly Leu Cys Val His Val Pro Cys Ser Phe Ser Tyr Pro Ser His Gly
20 25 30
Trp Ile Tyr Pro Gly Pro Val Val His Gly Tyr Trp Phe Arg Glu Gly
35 40 45
Ala Asn Thr Asp Gln Asp Ala Pro Val Ala Thr Asn Asn Pro Ala Arg
50 55 60
Ala Val Trp Glu Glu Thr Arg Asp Arg Phe His Leu Leu Gly Asp Pro
65 70 75 80
His Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp Ala Arg Arg Ser Asp
85 90 95
Ala Gly Arg Tyr Phe Phe Arg Met Glu Lys Gly Ser Ile Lys Trp Asn
100 105 110
Tyr Lys His His Arg Leu Ser Val Asn Val Thr Ala Leu Thr His Arg
115 120 125
Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys Pro Gln Asn
130 135 140
Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr Pro Pro Met
145 150 155 160
Ile Ser Trp Ile Gly Thr Ser Val Ser Pro Leu Asp Pro Ser Thr Thr
165 170 175
Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro Gln Asp His Gly Thr
180 185 190
Ser Leu Thr Cys Gln Val Thr Phe Pro Gly Ala Ser Val Thr Thr Asn
195 200 205
Lys Thr Val His Leu Asn Val Ser Tyr Pro Pro Gln Asn Leu Thr Met
210 215 220
Thr Val Phe Gln Gly Asp Gly Thr Val Ser Thr Val Leu Gly Asn Gly
225 230 235 240
Ser Ser Leu Ser Leu Pro Glu Gly Gln Ser Leu Arg Leu Val Cys Ala
245 250 255
Val Asp Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Leu Ser Trp
260 265 270
Arg Gly Leu Thr Leu Cys Pro Ser Gln Pro Ser Asn Pro Gly Val Leu
275 280 285
Glu Leu Pro Trp Val His Leu Arg Asp Ala Ala Glu Phe Thr Cys Arg
290 295 300
Ala Gln Asn Pro Leu Gly Ser Gln Gln Val Tyr Leu Asn Val Ser Leu
305 310 315 320
Gln Ser Lys Ala Thr Ser
325
<210> 22
<211> 588
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 22
Met Leu Leu Leu Leu Leu Pro Leu Leu Trp Gly Arg Glu Arg Ala Glu
1 5 10 15
Gly Gln Thr Ser Lys Leu Leu Thr Met Gln Ser Ser Val Thr Val Gln
20 25 30
Glu Gly Leu Cys Val His Val Pro Cys Ser Phe Ser Tyr Pro Ser His
35 40 45
Gly Trp Ile Tyr Pro Gly Pro Val Val His Gly Tyr Trp Phe Arg Glu
50 55 60
Gly Ala Asn Thr Asp Gln Asp Ala Pro Val Ala Thr Asn Asn Pro Ala
65 70 75 80
Arg Ala Val Trp Glu Glu Thr Arg Asp Arg Phe His Leu Leu Gly Asp
85 90 95
Pro His Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp Ala Arg Arg Ser
100 105 110
Asp Ala Gly Arg Tyr Phe Phe Ala Met Glu Lys Gly Ser Ile Lys Trp
115 120 125
Asn Tyr Lys His His Arg Leu Ser Val Asn Val Thr Ala Leu Thr His
130 135 140
Arg Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys Pro Gln
145 150 155 160
Asn Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr Pro Pro
165 170 175
Met Ile Ser Trp Ile Gly Thr Ser Val Ser Pro Leu Asp Pro Ser Thr
180 185 190
Thr Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro Gln Asp His Gly
195 200 205
Thr Ser Leu Thr Cys Gln Val Thr Phe Pro Gly Ala Ser Val Thr Thr
210 215 220
Asn Lys Thr Val His Leu Asn Val Ser Tyr Pro Pro Gln Asn Leu Thr
225 230 235 240
Met Thr Val Phe Gln Gly Asp Gly Thr Val Ser Thr Val Leu Gly Asn
245 250 255
Gly Ser Ser Leu Ser Leu Pro Glu Gly Gln Ser Leu Arg Leu Val Cys
260 265 270
Ala Val Asp Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Leu Ser
275 280 285
Trp Arg Gly Leu Thr Leu Cys Pro Ser Gln Pro Ser Asn Pro Gly Val
290 295 300
Leu Glu Leu Pro Trp Val His Leu Arg Asp Ala Ala Glu Phe Thr Cys
305 310 315 320
Arg Ala Gln Asn Pro Leu Gly Ser Gln Gln Val Tyr Leu Asn Val Ser
325 330 335
Leu Gln Ser Lys Ala Thr Ser Gly Gly Gly Gly Gly Pro Lys Ser Cys
340 345 350
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
355 360 365
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
370 375 380
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
385 390 395 400
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
405 410 415
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
420 425 430
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
435 440 445
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
450 455 460
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
465 470 475 480
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
485 490 495
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
500 505 510
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
515 520 525
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
530 535 540
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
545 550 555 560
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
565 570 575
Pro Gly Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
580 585
<210> 23
<211> 562
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 23
Gln Thr Ser Lys Leu Leu Thr Met Gln Ser Ser Val Thr Val Gln Glu
1 5 10 15
Gly Leu Cys Val His Val Pro Cys Ser Phe Ser Tyr Pro Ser His Gly
20 25 30
Trp Ile Tyr Pro Gly Pro Val Val His Gly Tyr Trp Phe Arg Glu Gly
35 40 45
Ala Asn Thr Asp Gln Asp Ala Pro Val Ala Thr Asn Asn Pro Ala Arg
50 55 60
Ala Val Trp Glu Glu Thr Arg Asp Arg Phe His Leu Leu Gly Asp Pro
65 70 75 80
His Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp Ala Arg Arg Ser Asp
85 90 95
Ala Gly Arg Tyr Phe Phe Ala Met Glu Lys Gly Ser Ile Lys Trp Asn
100 105 110
Tyr Lys His His Arg Leu Ser Val Asn Val Thr Ala Leu Thr His Arg
115 120 125
Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys Pro Gln Asn
130 135 140
Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr Pro Pro Met
145 150 155 160
Ile Ser Trp Ile Gly Thr Ser Val Ser Pro Leu Asp Pro Ser Thr Thr
165 170 175
Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro Gln Asp His Gly Thr
180 185 190
Ser Leu Thr Cys Gln Val Thr Phe Pro Gly Ala Ser Val Thr Thr Asn
195 200 205
Lys Thr Val His Leu Asn Val Ser Tyr Pro Pro Gln Asn Leu Thr Met
210 215 220
Thr Val Phe Gln Gly Asp Gly Thr Val Ser Thr Val Leu Gly Asn Gly
225 230 235 240
Ser Ser Leu Ser Leu Pro Glu Gly Gln Ser Leu Arg Leu Val Cys Ala
245 250 255
Val Asp Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Leu Ser Trp
260 265 270
Arg Gly Leu Thr Leu Cys Pro Ser Gln Pro Ser Asn Pro Gly Val Leu
275 280 285
Glu Leu Pro Trp Val His Leu Arg Asp Ala Ala Glu Phe Thr Cys Arg
290 295 300
Ala Gln Asn Pro Leu Gly Ser Gln Gln Val Tyr Leu Asn Val Ser Leu
305 310 315 320
Gln Ser Lys Ala Thr Ser Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp
325 330 335
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
340 345 350
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
355 360 365
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
370 375 380
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
385 390 395 400
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
405 410 415
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
420 425 430
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
435 440 445
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
450 455 460
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
465 470 475 480
Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
485 490 495
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
500 505 510
Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp
515 520 525
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
530 535 540
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
545 550 555 560
Gly Gly
<210> 24
<211> 326
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 24
Gln Thr Ser Lys Leu Leu Thr Met Gln Ser Ser Val Thr Val Gln Glu
1 5 10 15
Gly Leu Cys Val His Val Pro Cys Ser Phe Ser Tyr Pro Ser His Gly
20 25 30
Trp Ile Tyr Pro Gly Pro Val Val His Gly Tyr Trp Phe Arg Glu Gly
35 40 45
Ala Asn Thr Asp Gln Asp Ala Pro Val Ala Thr Asn Asn Pro Ala Arg
50 55 60
Ala Val Trp Glu Glu Thr Arg Asp Arg Phe His Leu Leu Gly Asp Pro
65 70 75 80
His Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp Ala Arg Arg Ser Asp
85 90 95
Ala Gly Arg Tyr Phe Phe Ala Met Glu Lys Gly Ser Ile Lys Trp Asn
100 105 110
Tyr Lys His His Arg Leu Ser Val Asn Val Thr Ala Leu Thr His Arg
115 120 125
Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys Pro Gln Asn
130 135 140
Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr Pro Pro Met
145 150 155 160
Ile Ser Trp Ile Gly Thr Ser Val Ser Pro Leu Asp Pro Ser Thr Thr
165 170 175
Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro Gln Asp His Gly Thr
180 185 190
Ser Leu Thr Cys Gln Val Thr Phe Pro Gly Ala Ser Val Thr Thr Asn
195 200 205
Lys Thr Val His Leu Asn Val Ser Tyr Pro Pro Gln Asn Leu Thr Met
210 215 220
Thr Val Phe Gln Gly Asp Gly Thr Val Ser Thr Val Leu Gly Asn Gly
225 230 235 240
Ser Ser Leu Ser Leu Pro Glu Gly Gln Ser Leu Arg Leu Val Cys Ala
245 250 255
Val Asp Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Leu Ser Trp
260 265 270
Arg Gly Leu Thr Leu Cys Pro Ser Gln Pro Ser Asn Pro Gly Val Leu
275 280 285
Glu Leu Pro Trp Val His Leu Arg Asp Ala Ala Glu Phe Thr Cys Arg
290 295 300
Ala Gln Asn Pro Leu Gly Ser Gln Gln Val Tyr Leu Asn Val Ser Leu
305 310 315 320
Gln Ser Lys Ala Thr Ser
325
<210> 25
<211> 595
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 25
Met Leu Leu Leu Leu Leu Leu Pro Leu Leu Trp Gly Arg Glu Arg Val
1 5 10 15
Glu Gly Gln Lys Ser Asn Arg Lys Asp Tyr Ser Leu Thr Met Gln Ser
20 25 30
Ser Val Thr Val Gln Glu Gly Met Cys Val His Val Arg Cys Ser Phe
35 40 45
Ser Tyr Pro Val Asp Ser Gln Thr Asp Ser Asp Pro Val His Gly Tyr
50 55 60
Trp Phe Arg Ala Gly Asn Asp Ile Ser Trp Lys Ala Pro Val Ala Thr
65 70 75 80
Asn Asn Pro Ala Trp Ala Val Gln Glu Glu Thr Arg Asp Arg Phe His
85 90 95
Leu Leu Gly Asp Pro Gln Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp
100 105 110
Ala Arg Met Ser Asp Ala Gly Arg Tyr Phe Phe Ala Met Glu Lys Gly
115 120 125
Asn Ile Lys Trp Asn Tyr Lys Tyr Asp Gln Leu Ser Val Asn Val Thr
130 135 140
Ala Leu Thr His Arg Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser
145 150 155 160
Gly Cys Phe Gln Asn Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln
165 170 175
Gly Thr Pro Pro Met Ile Ser Trp Met Gly Thr Ser Val Ser Pro Leu
180 185 190
His Pro Ser Thr Thr Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro
195 200 205
Gln His His Gly Thr Ser Leu Thr Cys Gln Val Thr Leu Pro Gly Ala
210 215 220
Gly Val Thr Thr Asn Arg Thr Ile Gln Leu Asn Val Ser Tyr Pro Pro
225 230 235 240
Gln Asn Leu Thr Val Thr Val Phe Gln Gly Glu Gly Thr Ala Ser Thr
245 250 255
Ala Leu Gly Asn Ser Ser Ser Leu Ser Val Leu Glu Gly Gln Ser Leu
260 265 270
Arg Leu Val Cys Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Trp
275 280 285
Thr Trp Arg Ser Leu Thr Leu Tyr Pro Ser Gln Pro Ser Asn Pro Leu
290 295 300
Val Leu Glu Leu Gln Val His Leu Gly Asp Glu Gly Glu Phe Thr Cys
305 310 315 320
Arg Ala Gln Asn Ser Leu Gly Ser Gln His Val Ser Leu Asn Leu Ser
325 330 335
Leu Gln Gln Glu Tyr Thr Gly Lys Met Arg Pro Val Ser Gly Gly Gly
340 345 350
Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
355 360 365
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
370 375 380
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
385 390 395 400
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
405 410 415
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
420 425 430
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
435 440 445
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
450 455 460
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
465 470 475 480
Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu
485 490 495
Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr
500 505 510
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
515 520 525
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
530 535 540
Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
545 550 555 560
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
565 570 575
Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Tyr Pro Tyr Asp Val Pro
580 585 590
Asp Tyr Ala
595
<210> 26
<211> 791
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 26
Met Leu Leu Pro Leu Leu Leu Ser Ser Leu Leu Gly Gly Ser Gln Ala
1 5 10 15
Met Asp Gly Arg Phe Trp Ile Arg Val Gln Glu Ser Val Met Val Pro
20 25 30
Glu Gly Leu Cys Ile Ser Val Pro Cys Ser Phe Ser Tyr Pro Arg Gln
35 40 45
Asp Trp Thr Gly Ser Thr Pro Ala Tyr Gly Tyr Trp Phe Lys Ala Val
50 55 60
Thr Glu Thr Thr Lys Gly Ala Pro Val Ala Thr Asn His Gln Ser Arg
65 70 75 80
Glu Val Glu Met Ser Thr Arg Gly Arg Phe Gln Leu Thr Gly Asp Pro
85 90 95
Ala Lys Gly Asn Cys Ser Leu Val Ile Arg Asp Ala Gln Met Gln Asp
100 105 110
Glu Ser Gln Tyr Phe Phe Arg Val Glu Arg Gly Ser Tyr Val Arg Tyr
115 120 125
Asn Phe Met Asn Asp Gly Phe Phe Leu Lys Val Thr Ala Leu Thr Gln
130 135 140
Lys Pro Asp Val Tyr Ile Pro Glu Thr Leu Glu Pro Gly Gln Pro Val
145 150 155 160
Thr Val Ile Cys Val Phe Asn Trp Ala Phe Glu Glu Cys Pro Pro Pro
165 170 175
Ser Phe Ser Trp Thr Gly Ala Ala Leu Ser Ser Gln Gly Thr Lys Pro
180 185 190
Thr Thr Ser His Phe Ser Val Leu Ser Phe Thr Pro Arg Pro Gln Asp
195 200 205
His Asn Thr Asp Leu Thr Cys His Val Asp Phe Ser Arg Lys Gly Val
210 215 220
Ser Ala Gln Arg Thr Val Arg Leu Arg Val Ala Tyr Ala Pro Arg Asp
225 230 235 240
Leu Val Ile Ser Ile Ser Arg Asp Asn Thr Pro Ala Leu Glu Pro Gln
245 250 255
Pro Gln Gly Asn Val Pro Tyr Leu Glu Ala Gln Lys Gly Gln Phe Leu
260 265 270
Arg Leu Leu Cys Ala Ala Asp Ser Gln Pro Pro Ala Thr Leu Ser Trp
275 280 285
Val Leu Gln Asn Arg Val Leu Ser Ser Ser His Pro Trp Gly Pro Arg
290 295 300
Pro Leu Gly Leu Glu Leu Pro Gly Val Lys Ala Gly Asp Ser Gly Arg
305 310 315 320
Tyr Thr Cys Arg Ala Glu Asn Arg Leu Gly Ser Gln Gln Arg Ala Leu
325 330 335
Asp Leu Ser Val Gln Tyr Pro Pro Glu Asn Leu Arg Val Met Val Ser
340 345 350
Gln Ala Asn Arg Thr Val Leu Glu Asn Leu Gly Asn Gly Thr Ser Leu
355 360 365
Pro Val Leu Glu Gly Gln Ser Leu Cys Leu Val Cys Val Thr His Ser
370 375 380
Ser Pro Pro Ala Arg Leu Ser Trp Thr Gln Arg Gly Gln Val Leu Ser
385 390 395 400
Pro Ser Gln Pro Ser Asp Pro Gly Val Leu Glu Leu Pro Arg Val Gln
405 410 415
Val Glu His Glu Gly Glu Phe Thr Cys His Ala Arg His Pro Leu Gly
420 425 430
Ser Gln His Val Ser Leu Ser Leu Ser Val His Tyr Ser Pro Lys Leu
435 440 445
Leu Gly Pro Ser Cys Ser Trp Glu Ala Glu Gly Leu His Cys Ser Cys
450 455 460
Ser Ser Gln Ala Ser Pro Ala Pro Ser Leu Arg Trp Trp Leu Gly Glu
465 470 475 480
Glu Leu Leu Glu Gly Asn Ser Ser Gln Asp Ser Phe Glu Val Thr Pro
485 490 495
Ser Ser Ala Gly Pro Trp Ala Asn Ser Ser Leu Ser Leu His Gly Gly
500 505 510
Leu Ser Ser Gly Leu Arg Leu Arg Cys Glu Ala Trp Asn Val His Gly
515 520 525
Ala Gln Ser Gly Ser Ile Leu Gln Leu Pro Asp Lys Lys Gly Leu Ile
530 535 540
Ser Thr Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr His Thr
545 550 555 560
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
565 570 575
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
580 585 590
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
595 600 605
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
610 615 620
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
625 630 635 640
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
645 650 655
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
660 665 670
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro
675 680 685
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val
690 695 700
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
705 710 715 720
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
725 730 735
Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
740 745 750
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
755 760 765
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Tyr Pro
770 775 780
Tyr Asp Val Pro Asp Tyr Ala
785 790
<210> 27
<211> 766
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 27
Met Asp Gly Arg Phe Trp Ile Arg Val Gln Glu Ser Val Met Val Pro
1 5 10 15
Glu Gly Leu Cys Ile Ser Val Pro Cys Ser Phe Ser Tyr Pro Arg Gln
20 25 30
Asp Trp Thr Gly Ser Thr Pro Ala Tyr Gly Tyr Trp Phe Lys Ala Val
35 40 45
Thr Glu Thr Thr Lys Gly Ala Pro Val Ala Thr Asn His Gln Ser Arg
50 55 60
Glu Val Glu Met Ser Thr Arg Gly Arg Phe Gln Leu Thr Gly Asp Pro
65 70 75 80
Ala Lys Gly Asn Cys Ser Leu Val Ile Arg Asp Ala Gln Met Gln Asp
85 90 95
Glu Ser Gln Tyr Phe Phe Arg Val Glu Arg Gly Ser Tyr Val Arg Tyr
100 105 110
Asn Phe Met Asn Asp Gly Phe Phe Leu Lys Val Thr Ala Leu Thr Gln
115 120 125
Lys Pro Asp Val Tyr Ile Pro Glu Thr Leu Glu Pro Gly Gln Pro Val
130 135 140
Thr Val Ile Cys Val Phe Asn Trp Ala Phe Glu Glu Cys Pro Pro Pro
145 150 155 160
Ser Phe Ser Trp Thr Gly Ala Ala Leu Ser Ser Gln Gly Thr Lys Pro
165 170 175
Thr Thr Ser His Phe Ser Val Leu Ser Phe Thr Pro Arg Pro Gln Asp
180 185 190
His Asn Thr Asp Leu Thr Cys His Val Asp Phe Ser Arg Lys Gly Val
195 200 205
Ser Ala Gln Arg Thr Val Arg Leu Arg Val Ala Tyr Ala Pro Arg Asp
210 215 220
Leu Val Ile Ser Ile Ser Arg Asp Asn Thr Pro Ala Leu Glu Pro Gln
225 230 235 240
Pro Gln Gly Asn Val Pro Tyr Leu Glu Ala Gln Lys Gly Gln Phe Leu
245 250 255
Arg Leu Leu Cys Ala Ala Asp Ser Gln Pro Pro Ala Thr Leu Ser Trp
260 265 270
Val Leu Gln Asn Arg Val Leu Ser Ser Ser His Pro Trp Gly Pro Arg
275 280 285
Pro Leu Gly Leu Glu Leu Pro Gly Val Lys Ala Gly Asp Ser Gly Arg
290 295 300
Tyr Thr Cys Arg Ala Glu Asn Arg Leu Gly Ser Gln Gln Arg Ala Leu
305 310 315 320
Asp Leu Ser Val Gln Tyr Pro Pro Glu Asn Leu Arg Val Met Val Ser
325 330 335
Gln Ala Asn Arg Thr Val Leu Glu Asn Leu Gly Asn Gly Thr Ser Leu
340 345 350
Pro Val Leu Glu Gly Gln Ser Leu Cys Leu Val Cys Val Thr His Ser
355 360 365
Ser Pro Pro Ala Arg Leu Ser Trp Thr Gln Arg Gly Gln Val Leu Ser
370 375 380
Pro Ser Gln Pro Ser Asp Pro Gly Val Leu Glu Leu Pro Arg Val Gln
385 390 395 400
Val Glu His Glu Gly Glu Phe Thr Cys His Ala Arg His Pro Leu Gly
405 410 415
Ser Gln His Val Ser Leu Ser Leu Ser Val His Tyr Ser Pro Lys Leu
420 425 430
Leu Gly Pro Ser Cys Ser Trp Glu Ala Glu Gly Leu His Cys Ser Cys
435 440 445
Ser Ser Gln Ala Ser Pro Ala Pro Ser Leu Arg Trp Trp Leu Gly Glu
450 455 460
Glu Leu Leu Glu Gly Asn Ser Ser Gln Asp Ser Phe Glu Val Thr Pro
465 470 475 480
Ser Ser Ala Gly Pro Trp Ala Asn Ser Ser Leu Ser Leu His Gly Gly
485 490 495
Leu Ser Ser Gly Leu Arg Leu Arg Cys Glu Ala Trp Asn Val His Gly
500 505 510
Ala Gln Ser Gly Ser Ile Leu Gln Leu Pro Asp Lys Lys Gly Leu Ile
515 520 525
Ser Thr Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr His Thr
530 535 540
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
545 550 555 560
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
565 570 575
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
580 585 590
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
595 600 605
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
610 615 620
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
625 630 635 640
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
645 650 655
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro
660 665 670
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val
675 680 685
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
690 695 700
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
705 710 715 720
Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
725 730 735
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
740 745 750
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
755 760 765
<210> 28
<211> 530
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 28
Met Asp Gly Arg Phe Trp Ile Arg Val Gln Glu Ser Val Met Val Pro
1 5 10 15
Glu Gly Leu Cys Ile Ser Val Pro Cys Ser Phe Ser Tyr Pro Arg Gln
20 25 30
Asp Trp Thr Gly Ser Thr Pro Ala Tyr Gly Tyr Trp Phe Lys Ala Val
35 40 45
Thr Glu Thr Thr Lys Gly Ala Pro Val Ala Thr Asn His Gln Ser Arg
50 55 60
Glu Val Glu Met Ser Thr Arg Gly Arg Phe Gln Leu Thr Gly Asp Pro
65 70 75 80
Ala Lys Gly Asn Cys Ser Leu Val Ile Arg Asp Ala Gln Met Gln Asp
85 90 95
Glu Ser Gln Tyr Phe Phe Arg Val Glu Arg Gly Ser Tyr Val Arg Tyr
100 105 110
Asn Phe Met Asn Asp Gly Phe Phe Leu Lys Val Thr Ala Leu Thr Gln
115 120 125
Lys Pro Asp Val Tyr Ile Pro Glu Thr Leu Glu Pro Gly Gln Pro Val
130 135 140
Thr Val Ile Cys Val Phe Asn Trp Ala Phe Glu Glu Cys Pro Pro Pro
145 150 155 160
Ser Phe Ser Trp Thr Gly Ala Ala Leu Ser Ser Gln Gly Thr Lys Pro
165 170 175
Thr Thr Ser His Phe Ser Val Leu Ser Phe Thr Pro Arg Pro Gln Asp
180 185 190
His Asn Thr Asp Leu Thr Cys His Val Asp Phe Ser Arg Lys Gly Val
195 200 205
Ser Ala Gln Arg Thr Val Arg Leu Arg Val Ala Tyr Ala Pro Arg Asp
210 215 220
Leu Val Ile Ser Ile Ser Arg Asp Asn Thr Pro Ala Leu Glu Pro Gln
225 230 235 240
Pro Gln Gly Asn Val Pro Tyr Leu Glu Ala Gln Lys Gly Gln Phe Leu
245 250 255
Arg Leu Leu Cys Ala Ala Asp Ser Gln Pro Pro Ala Thr Leu Ser Trp
260 265 270
Val Leu Gln Asn Arg Val Leu Ser Ser Ser His Pro Trp Gly Pro Arg
275 280 285
Pro Leu Gly Leu Glu Leu Pro Gly Val Lys Ala Gly Asp Ser Gly Arg
290 295 300
Tyr Thr Cys Arg Ala Glu Asn Arg Leu Gly Ser Gln Gln Arg Ala Leu
305 310 315 320
Asp Leu Ser Val Gln Tyr Pro Pro Glu Asn Leu Arg Val Met Val Ser
325 330 335
Gln Ala Asn Arg Thr Val Leu Glu Asn Leu Gly Asn Gly Thr Ser Leu
340 345 350
Pro Val Leu Glu Gly Gln Ser Leu Cys Leu Val Cys Val Thr His Ser
355 360 365
Ser Pro Pro Ala Arg Leu Ser Trp Thr Gln Arg Gly Gln Val Leu Ser
370 375 380
Pro Ser Gln Pro Ser Asp Pro Gly Val Leu Glu Leu Pro Arg Val Gln
385 390 395 400
Val Glu His Glu Gly Glu Phe Thr Cys His Ala Arg His Pro Leu Gly
405 410 415
Ser Gln His Val Ser Leu Ser Leu Ser Val His Tyr Ser Pro Lys Leu
420 425 430
Leu Gly Pro Ser Cys Ser Trp Glu Ala Glu Gly Leu His Cys Ser Cys
435 440 445
Ser Ser Gln Ala Ser Pro Ala Pro Ser Leu Arg Trp Trp Leu Gly Glu
450 455 460
Glu Leu Leu Glu Gly Asn Ser Ser Gln Asp Ser Phe Glu Val Thr Pro
465 470 475 480
Ser Ser Ala Gly Pro Trp Ala Asn Ser Ser Leu Ser Leu His Gly Gly
485 490 495
Leu Ser Ser Gly Leu Arg Leu Arg Cys Glu Ala Trp Asn Val His Gly
500 505 510
Ala Gln Ser Gly Ser Ile Leu Gln Leu Pro Asp Lys Lys Gly Leu Ile
515 520 525
Ser Thr
530
<210> 29
<211> 475
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 29
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asn Tyr Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn
65 70 75 80
Glu Lys Phe Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr
85 90 95
Thr Ala Tyr Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
225 230 235 240
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
245 250 255
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
260 265 270
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
275 280 285
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
290 295 300
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
305 310 315 320
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
325 330 335
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala
340 345 350
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
355 360 365
Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln
370 375 380
Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly Gly His His His His His His
465 470 475
<210> 30
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 30
Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Gly
450
<210> 31
<211> 237
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 31
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu
20 25 30
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val
35 40 45
Ser Thr Ser Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly
50 55 60
Gln Ala Pro Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly
65 70 75 80
Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
85 90 95
Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln
100 105 110
His Ser Arg Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu
115 120 125
Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser
130 135 140
Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
145 150 155 160
Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala
165 170 175
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
180 185 190
Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
195 200 205
Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu
210 215 220
Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 32
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 32
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg
85 90 95
Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 33
<211> 468
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 33
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe
35 40 45
Ser Asn Ser Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val
115 120 125
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
130 135 140
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
145 150 155 160
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
165 170 175
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
180 185 190
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
195 200 205
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
210 215 220
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
225 230 235 240
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe
245 250 255
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
260 265 270
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
275 280 285
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
290 295 300
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
305 310 315 320
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
325 330 335
Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser
340 345 350
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
355 360 365
Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val
370 375 380
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
385 390 395 400
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
405 410 415
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
420 425 430
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
435 440 445
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly His His
450 455 460
His His His His
465
<210> 34
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 34
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
115 120 125
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
180 185 190
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp
340 345 350
Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
435 440
<210> 35
<211> 233
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 35
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu
20 25 30
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val
35 40 45
Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn
100 105 110
Trp Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr
115 120 125
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
130 135 140
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
145 150 155 160
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
165 170 175
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
180 185 190
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
195 200 205
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
210 215 220
Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 36
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 36
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 37
<211> 595
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 37
Met Leu Leu Leu Leu Leu Leu Pro Leu Leu Trp Gly Arg Glu Arg Val
1 5 10 15
Glu Gly Gln Lys Ser Asn Arg Lys Asp Tyr Ser Leu Thr Met Gln Ser
20 25 30
Ser Val Thr Val Gln Glu Gly Met Cys Val His Val Arg Cys Ser Phe
35 40 45
Ser Tyr Pro Val Asp Ser Gln Thr Asp Ser Asp Pro Val His Gly Tyr
50 55 60
Trp Phe Arg Ala Gly Asn Asp Ile Ser Trp Lys Ala Pro Val Ala Thr
65 70 75 80
Asn Asn Pro Ala Trp Ala Val Gln Glu Glu Thr Arg Asp Arg Phe His
85 90 95
Leu Leu Gly Asp Pro Gln Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp
100 105 110
Ala Arg Met Ser Asp Ala Gly Arg Tyr Phe Phe Arg Met Glu Lys Gly
115 120 125
Asn Ile Lys Trp Asn Tyr Lys Tyr Asp Gln Leu Ser Val Asn Val Thr
130 135 140
Ala Leu Thr His Arg Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser
145 150 155 160
Gly Cys Phe Gln Asn Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln
165 170 175
Gly Thr Pro Pro Met Ile Ser Trp Met Gly Thr Ser Val Ser Pro Leu
180 185 190
His Pro Ser Thr Thr Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro
195 200 205
Gln His His Gly Thr Ser Leu Thr Cys Gln Val Thr Leu Pro Gly Ala
210 215 220
Gly Val Thr Thr Asn Arg Thr Ile Gln Leu Asn Val Ser Tyr Pro Pro
225 230 235 240
Gln Asn Leu Thr Val Thr Val Phe Gln Gly Glu Gly Thr Ala Ser Thr
245 250 255
Ala Leu Gly Asn Ser Ser Ser Leu Ser Val Leu Glu Gly Gln Ser Leu
260 265 270
Arg Leu Val Cys Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Trp
275 280 285
Thr Trp Arg Ser Leu Thr Leu Tyr Pro Ser Gln Pro Ser Asn Pro Leu
290 295 300
Val Leu Glu Leu Gln Val His Leu Gly Asp Glu Gly Glu Phe Thr Cys
305 310 315 320
Arg Ala Gln Asn Ser Leu Gly Ser Gln His Val Ser Leu Asn Leu Ser
325 330 335
Leu Gln Gln Glu Tyr Thr Gly Lys Met Arg Pro Val Ser Gly Gly Gly
340 345 350
Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
355 360 365
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
370 375 380
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
385 390 395 400
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
405 410 415
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
420 425 430
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
435 440 445
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
450 455 460
Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
465 470 475 480
Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu
485 490 495
Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr
500 505 510
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
515 520 525
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
530 535 540
Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
545 550 555 560
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
565 570 575
Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Tyr Pro Tyr Asp Val Pro
580 585 590
Asp Tyr Ala
595
<210> 38
<211> 568
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 38
Gln Lys Ser Asn Arg Lys Asp Tyr Ser Leu Thr Met Gln Ser Ser Val
1 5 10 15
Thr Val Gln Glu Gly Met Cys Val His Val Arg Cys Ser Phe Ser Tyr
20 25 30
Pro Val Asp Ser Gln Thr Asp Ser Asp Pro Val His Gly Tyr Trp Phe
35 40 45
Arg Ala Gly Asn Asp Ile Ser Trp Lys Ala Pro Val Ala Thr Asn Asn
50 55 60
Pro Ala Trp Ala Val Gln Glu Glu Thr Arg Asp Arg Phe His Leu Leu
65 70 75 80
Gly Asp Pro Gln Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp Ala Arg
85 90 95
Met Ser Asp Ala Gly Arg Tyr Phe Phe Arg Met Glu Lys Gly Asn Ile
100 105 110
Lys Trp Asn Tyr Lys Tyr Asp Gln Leu Ser Val Asn Val Thr Ala Leu
115 120 125
Thr His Arg Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys
130 135 140
Phe Gln Asn Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr
145 150 155 160
Pro Pro Met Ile Ser Trp Met Gly Thr Ser Val Ser Pro Leu His Pro
165 170 175
Ser Thr Thr Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro Gln His
180 185 190
His Gly Thr Ser Leu Thr Cys Gln Val Thr Leu Pro Gly Ala Gly Val
195 200 205
Thr Thr Asn Arg Thr Ile Gln Leu Asn Val Ser Tyr Pro Pro Gln Asn
210 215 220
Leu Thr Val Thr Val Phe Gln Gly Glu Gly Thr Ala Ser Thr Ala Leu
225 230 235 240
Gly Asn Ser Ser Ser Leu Ser Val Leu Glu Gly Gln Ser Leu Arg Leu
245 250 255
Val Cys Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Trp Thr Trp
260 265 270
Arg Ser Leu Thr Leu Tyr Pro Ser Gln Pro Ser Asn Pro Leu Val Leu
275 280 285
Glu Leu Gln Val His Leu Gly Asp Glu Gly Glu Phe Thr Cys Arg Ala
290 295 300
Gln Asn Ser Leu Gly Ser Gln His Val Ser Leu Asn Leu Ser Leu Gln
305 310 315 320
Gln Glu Tyr Thr Gly Lys Met Arg Pro Val Ser Gly Gly Gly Gly Gly
325 330 335
Gly Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
340 345 350
Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
355 360 365
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
370 375 380
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
385 390 395 400
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
405 410 415
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
420 425 430
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
435 440 445
Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
450 455 460
Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
465 470 475 480
Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser
485 490 495
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
500 505 510
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val
515 520 525
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
530 535 540
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
545 550 555 560
Ser Leu Ser Leu Ser Pro Gly Gly
565
<210> 39
<211> 588
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 39
Met Leu Leu Leu Leu Leu Pro Leu Leu Trp Gly Arg Glu Arg Ala Glu
1 5 10 15
Gly Gln Thr Ser Lys Leu Leu Thr Met Gln Ser Ser Val Thr Val Gln
20 25 30
Glu Gly Leu Cys Val His Val Pro Cys Ser Phe Ser Tyr Pro Ser His
35 40 45
Gly Trp Ile Tyr Pro Gly Pro Val Val His Gly Tyr Trp Phe Arg Glu
50 55 60
Gly Ala Asn Thr Asp Gln Asp Ala Pro Val Ala Thr Asn Asn Pro Ala
65 70 75 80
Arg Ala Val Trp Glu Glu Thr Arg Asp Arg Phe His Leu Leu Gly Asp
85 90 95
Pro His Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp Ala Arg Arg Ser
100 105 110
Asp Ala Gly Arg Tyr Phe Phe Arg Met Glu Lys Gly Ser Ile Lys Trp
115 120 125
Asn Tyr Lys His His Arg Leu Ser Val Asn Val Thr Ala Leu Thr His
130 135 140
Arg Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys Pro Gln
145 150 155 160
Asn Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr Pro Pro
165 170 175
Met Ile Ser Trp Ile Gly Thr Ser Val Ser Pro Leu Asp Pro Ser Thr
180 185 190
Thr Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro Gln Asp His Gly
195 200 205
Thr Ser Leu Thr Cys Gln Val Thr Phe Pro Gly Ala Ser Val Thr Thr
210 215 220
Asn Lys Thr Val His Leu Asn Val Ser Tyr Pro Pro Gln Asn Leu Thr
225 230 235 240
Met Thr Val Phe Gln Gly Asp Gly Thr Val Ser Thr Val Leu Gly Asn
245 250 255
Gly Ser Ser Leu Ser Leu Pro Glu Gly Gln Ser Leu Arg Leu Val Cys
260 265 270
Ala Val Asp Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Leu Ser
275 280 285
Trp Arg Gly Leu Thr Leu Cys Pro Ser Gln Pro Ser Asn Pro Gly Val
290 295 300
Leu Glu Leu Pro Trp Val His Leu Arg Asp Ala Ala Glu Phe Thr Cys
305 310 315 320
Arg Ala Gln Asn Pro Leu Gly Ser Gln Gln Val Tyr Leu Asn Val Ser
325 330 335
Leu Gln Ser Lys Ala Thr Ser Gly Gly Gly Gly Gly Pro Lys Ser Cys
340 345 350
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
355 360 365
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
370 375 380
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
385 390 395 400
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
405 410 415
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
420 425 430
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
435 440 445
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
450 455 460
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
465 470 475 480
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
485 490 495
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
500 505 510
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
515 520 525
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
530 535 540
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
545 550 555 560
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
565 570 575
Pro Gly Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
580 585
<210> 40
<211> 562
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 40
Gln Thr Ser Lys Leu Leu Thr Met Gln Ser Ser Val Thr Val Gln Glu
1 5 10 15
Gly Leu Cys Val His Val Pro Cys Ser Phe Ser Tyr Pro Ser His Gly
20 25 30
Trp Ile Tyr Pro Gly Pro Val Val His Gly Tyr Trp Phe Arg Glu Gly
35 40 45
Ala Asn Thr Asp Gln Asp Ala Pro Val Ala Thr Asn Asn Pro Ala Arg
50 55 60
Ala Val Trp Glu Glu Thr Arg Asp Arg Phe His Leu Leu Gly Asp Pro
65 70 75 80
His Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp Ala Arg Arg Ser Asp
85 90 95
Ala Gly Arg Tyr Phe Phe Arg Met Glu Lys Gly Ser Ile Lys Trp Asn
100 105 110
Tyr Lys His His Arg Leu Ser Val Asn Val Thr Ala Leu Thr His Arg
115 120 125
Pro Asn Ile Leu Ile Pro Gly Thr Leu Glu Ser Gly Cys Pro Gln Asn
130 135 140
Leu Thr Cys Ser Val Pro Trp Ala Cys Glu Gln Gly Thr Pro Pro Met
145 150 155 160
Ile Ser Trp Ile Gly Thr Ser Val Ser Pro Leu Asp Pro Ser Thr Thr
165 170 175
Arg Ser Ser Val Leu Thr Leu Ile Pro Gln Pro Gln Asp His Gly Thr
180 185 190
Ser Leu Thr Cys Gln Val Thr Phe Pro Gly Ala Ser Val Thr Thr Asn
195 200 205
Lys Thr Val His Leu Asn Val Ser Tyr Pro Pro Gln Asn Leu Thr Met
210 215 220
Thr Val Phe Gln Gly Asp Gly Thr Val Ser Thr Val Leu Gly Asn Gly
225 230 235 240
Ser Ser Leu Ser Leu Pro Glu Gly Gln Ser Leu Arg Leu Val Cys Ala
245 250 255
Val Asp Ala Val Asp Ser Asn Pro Pro Ala Arg Leu Ser Leu Ser Trp
260 265 270
Arg Gly Leu Thr Leu Cys Pro Ser Gln Pro Ser Asn Pro Gly Val Leu
275 280 285
Glu Leu Pro Trp Val His Leu Arg Asp Ala Ala Glu Phe Thr Cys Arg
290 295 300
Ala Gln Asn Pro Leu Gly Ser Gln Gln Val Tyr Leu Asn Val Ser Leu
305 310 315 320
Gln Ser Lys Ala Thr Ser Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp
325 330 335
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly
340 345 350
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
355 360 365
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
370 375 380
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
385 390 395 400
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
405 410 415
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
420 425 430
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu
435 440 445
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
450 455 460
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
465 470 475 480
Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
485 490 495
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
500 505 510
Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp
515 520 525
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
530 535 540
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
545 550 555 560
Gly Gly
<210> 41
<211> 584
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 41
Met Leu Leu Pro Leu Leu Leu Ser Ser Leu Leu Gly Gly Ser Gln Ala
1 5 10 15
Met Asp Gly Arg Phe Trp Ile Arg Val Gln Glu Ser Val Met Val Pro
20 25 30
Glu Gly Leu Cys Ile Ser Val Pro Cys Ser Phe Ser Tyr Pro Arg Gln
35 40 45
Asp Trp Thr Gly Ser Thr Pro Ala Tyr Gly Tyr Trp Phe Lys Ala Val
50 55 60
Thr Glu Thr Thr Lys Gly Ala Pro Val Ala Thr Asn His Gln Ser Arg
65 70 75 80
Glu Val Glu Met Ser Thr Arg Gly Arg Phe Gln Leu Thr Gly Asp Pro
85 90 95
Ala Lys Gly Asn Cys Ser Leu Val Ile Arg Asp Ala Gln Met Gln Asp
100 105 110
Glu Ser Gln Tyr Phe Phe Arg Val Glu Arg Gly Ser Tyr Val Arg Tyr
115 120 125
Asn Phe Met Asn Asp Gly Phe Phe Leu Lys Val Thr Ala Leu Thr Gln
130 135 140
Lys Pro Asp Val Tyr Ile Pro Glu Thr Leu Glu Pro Gly Gln Pro Val
145 150 155 160
Thr Val Ile Cys Val Phe Asn Trp Ala Phe Glu Glu Cys Pro Pro Pro
165 170 175
Ser Phe Ser Trp Thr Gly Ala Ala Leu Ser Ser Gln Gly Thr Lys Pro
180 185 190
Thr Thr Ser His Phe Ser Val Leu Ser Phe Thr Pro Arg Pro Gln Asp
195 200 205
His Asn Thr Asp Leu Thr Cys His Val Asp Phe Ser Arg Lys Gly Val
210 215 220
Ser Ala Gln Arg Thr Val Arg Leu Arg Val Ala Tyr Ala Pro Arg Asp
225 230 235 240
Leu Val Ile Ser Ile Ser Arg Asp Asn Thr Pro Ala Leu Glu Pro Gln
245 250 255
Pro Gln Gly Asn Val Pro Tyr Leu Glu Ala Gln Lys Gly Gln Phe Leu
260 265 270
Arg Leu Leu Cys Ala Ala Asp Ser Gln Pro Pro Ala Thr Leu Ser Trp
275 280 285
Val Leu Gln Asn Arg Val Leu Ser Ser Ser His Pro Trp Gly Pro Arg
290 295 300
Pro Leu Gly Leu Glu Leu Pro Gly Val Lys Ala Gly Asp Ser Gly Arg
305 310 315 320
Tyr Thr Cys Arg Ala Glu Asn Arg Leu Gly Ser Gln Gln Arg Ala Leu
325 330 335
Asp Leu Ser Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr His
340 345 350
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
355 360 365
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
370 375 380
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
385 390 395 400
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
405 410 415
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
420 425 430
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
435 440 445
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
450 455 460
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro
465 470 475 480
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala
485 490 495
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
500 505 510
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
515 520 525
Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg
530 535 540
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
545 550 555 560
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Tyr
565 570 575
Pro Tyr Asp Val Pro Asp Tyr Ala
580
<210> 42
<211> 559
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 42
Met Asp Gly Arg Phe Trp Ile Arg Val Gln Glu Ser Val Met Val Pro
1 5 10 15
Glu Gly Leu Cys Ile Ser Val Pro Cys Ser Phe Ser Tyr Pro Arg Gln
20 25 30
Asp Trp Thr Gly Ser Thr Pro Ala Tyr Gly Tyr Trp Phe Lys Ala Val
35 40 45
Thr Glu Thr Thr Lys Gly Ala Pro Val Ala Thr Asn His Gln Ser Arg
50 55 60
Glu Val Glu Met Ser Thr Arg Gly Arg Phe Gln Leu Thr Gly Asp Pro
65 70 75 80
Ala Lys Gly Asn Cys Ser Leu Val Ile Arg Asp Ala Gln Met Gln Asp
85 90 95
Glu Ser Gln Tyr Phe Phe Arg Val Glu Arg Gly Ser Tyr Val Arg Tyr
100 105 110
Asn Phe Met Asn Asp Gly Phe Phe Leu Lys Val Thr Ala Leu Thr Gln
115 120 125
Lys Pro Asp Val Tyr Ile Pro Glu Thr Leu Glu Pro Gly Gln Pro Val
130 135 140
Thr Val Ile Cys Val Phe Asn Trp Ala Phe Glu Glu Cys Pro Pro Pro
145 150 155 160
Ser Phe Ser Trp Thr Gly Ala Ala Leu Ser Ser Gln Gly Thr Lys Pro
165 170 175
Thr Thr Ser His Phe Ser Val Leu Ser Phe Thr Pro Arg Pro Gln Asp
180 185 190
His Asn Thr Asp Leu Thr Cys His Val Asp Phe Ser Arg Lys Gly Val
195 200 205
Ser Ala Gln Arg Thr Val Arg Leu Arg Val Ala Tyr Ala Pro Arg Asp
210 215 220
Leu Val Ile Ser Ile Ser Arg Asp Asn Thr Pro Ala Leu Glu Pro Gln
225 230 235 240
Pro Gln Gly Asn Val Pro Tyr Leu Glu Ala Gln Lys Gly Gln Phe Leu
245 250 255
Arg Leu Leu Cys Ala Ala Asp Ser Gln Pro Pro Ala Thr Leu Ser Trp
260 265 270
Val Leu Gln Asn Arg Val Leu Ser Ser Ser His Pro Trp Gly Pro Arg
275 280 285
Pro Leu Gly Leu Glu Leu Pro Gly Val Lys Ala Gly Asp Ser Gly Arg
290 295 300
Tyr Thr Cys Arg Ala Glu Asn Arg Leu Gly Ser Gln Gln Arg Ala Leu
305 310 315 320
Asp Leu Ser Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr His
325 330 335
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
340 345 350
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
355 360 365
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
370 375 380
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
385 390 395 400
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
405 410 415
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
420 425 430
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
435 440 445
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro
450 455 460
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala
465 470 475 480
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
485 490 495
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
500 505 510
Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg
515 520 525
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
530 535 540
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
545 550 555
<210> 43
<211> 323
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 43
Met Asp Gly Arg Phe Trp Ile Arg Val Gln Glu Ser Val Met Val Pro
1 5 10 15
Glu Gly Leu Cys Ile Ser Val Pro Cys Ser Phe Ser Tyr Pro Arg Gln
20 25 30
Asp Trp Thr Gly Ser Thr Pro Ala Tyr Gly Tyr Trp Phe Lys Ala Val
35 40 45
Thr Glu Thr Thr Lys Gly Ala Pro Val Ala Thr Asn His Gln Ser Arg
50 55 60
Glu Val Glu Met Ser Thr Arg Gly Arg Phe Gln Leu Thr Gly Asp Pro
65 70 75 80
Ala Lys Gly Asn Cys Ser Leu Val Ile Arg Asp Ala Gln Met Gln Asp
85 90 95
Glu Ser Gln Tyr Phe Phe Arg Val Glu Arg Gly Ser Tyr Val Arg Tyr
100 105 110
Asn Phe Met Asn Asp Gly Phe Phe Leu Lys Val Thr Ala Leu Thr Gln
115 120 125
Lys Pro Asp Val Tyr Ile Pro Glu Thr Leu Glu Pro Gly Gln Pro Val
130 135 140
Thr Val Ile Cys Val Phe Asn Trp Ala Phe Glu Glu Cys Pro Pro Pro
145 150 155 160
Ser Phe Ser Trp Thr Gly Ala Ala Leu Ser Ser Gln Gly Thr Lys Pro
165 170 175
Thr Thr Ser His Phe Ser Val Leu Ser Phe Thr Pro Arg Pro Gln Asp
180 185 190
His Asn Thr Asp Leu Thr Cys His Val Asp Phe Ser Arg Lys Gly Val
195 200 205
Ser Ala Gln Arg Thr Val Arg Leu Arg Val Ala Tyr Ala Pro Arg Asp
210 215 220
Leu Val Ile Ser Ile Ser Arg Asp Asn Thr Pro Ala Leu Glu Pro Gln
225 230 235 240
Pro Gln Gly Asn Val Pro Tyr Leu Glu Ala Gln Lys Gly Gln Phe Leu
245 250 255
Arg Leu Leu Cys Ala Ala Asp Ser Gln Pro Pro Ala Thr Leu Ser Trp
260 265 270
Val Leu Gln Asn Arg Val Leu Ser Ser Ser His Pro Trp Gly Pro Arg
275 280 285
Pro Leu Gly Leu Glu Leu Pro Gly Val Lys Ala Gly Asp Ser Gly Arg
290 295 300
Tyr Thr Cys Arg Ala Glu Asn Arg Leu Gly Ser Gln Gln Arg Ala Leu
305 310 315 320
Asp Leu Ser
<210> 44
<211> 393
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 44
Met Ala Phe Ser Gly Ser Gln Ala Pro Tyr Leu Ser Pro Ala Val Pro
1 5 10 15
Phe Ser Gly Thr Ile Gln Gly Gly Leu Gln Asp Gly Leu Gln Ile Thr
20 25 30
Val Asn Gly Thr Val Leu Ser Ser Ser Gly Thr Arg Phe Ala Val Asn
35 40 45
Phe Gln Thr Gly Phe Ser Gly Asn Asp Ile Ala Phe His Phe Asn Pro
50 55 60
Arg Phe Glu Asp Gly Gly Tyr Val Val Cys Asn Thr Arg Gln Asn Gly
65 70 75 80
Ser Trp Gly Pro Glu Glu Arg Lys Thr His Met Pro Phe Gln Lys Gly
85 90 95
Met Pro Phe Asp Leu Cys Phe Leu Val Gln Ser Ser Asp Phe Lys Val
100 105 110
Met Val Asn Gly Ile Leu Phe Val Gln Tyr Phe His Arg Val Pro Phe
115 120 125
His Arg Val Asp Thr Ile Ser Val Asn Gly Ser Val Gln Leu Ser Tyr
130 135 140
Ile Ser Phe Gln Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr
145 150 155 160
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
165 170 175
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
180 185 190
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
195 200 205
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
210 215 220
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
225 230 235 240
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
245 250 255
Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr
260 265 270
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu
275 280 285
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys
290 295 300
Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
305 310 315 320
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
325 330 335
Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser
340 345 350
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
355 360 365
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
370 375 380
Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
385 390
<210> 45
<211> 368
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 45
Phe Ser Gly Thr Ile Gln Gly Gly Leu Gln Asp Gly Leu Gln Ile Thr
1 5 10 15
Val Asn Gly Thr Val Leu Ser Ser Ser Gly Thr Arg Phe Ala Val Asn
20 25 30
Phe Gln Thr Gly Phe Ser Gly Asn Asp Ile Ala Phe His Phe Asn Pro
35 40 45
Arg Phe Glu Asp Gly Gly Tyr Val Val Cys Asn Thr Arg Gln Asn Gly
50 55 60
Ser Trp Gly Pro Glu Glu Arg Lys Thr His Met Pro Phe Gln Lys Gly
65 70 75 80
Met Pro Phe Asp Leu Cys Phe Leu Val Gln Ser Ser Asp Phe Lys Val
85 90 95
Met Val Asn Gly Ile Leu Phe Val Gln Tyr Phe His Arg Val Pro Phe
100 105 110
His Arg Val Asp Thr Ile Ser Val Asn Gly Ser Val Gln Leu Ser Tyr
115 120 125
Ile Ser Phe Gln Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr
130 135 140
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
145 150 155 160
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
165 170 175
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
180 185 190
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
195 200 205
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
210 215 220
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
225 230 235 240
Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr
245 250 255
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu
260 265 270
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys
275 280 285
Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
290 295 300
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
305 310 315 320
Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser
325 330 335
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
340 345 350
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
355 360 365
<210> 46
<211> 132
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 46
Phe Ser Gly Thr Ile Gln Gly Gly Leu Gln Asp Gly Leu Gln Ile Thr
1 5 10 15
Val Asn Gly Thr Val Leu Ser Ser Ser Gly Thr Arg Phe Ala Val Asn
20 25 30
Phe Gln Thr Gly Phe Ser Gly Asn Asp Ile Ala Phe His Phe Asn Pro
35 40 45
Arg Phe Glu Asp Gly Gly Tyr Val Val Cys Asn Thr Arg Gln Asn Gly
50 55 60
Ser Trp Gly Pro Glu Glu Arg Lys Thr His Met Pro Phe Gln Lys Gly
65 70 75 80
Met Pro Phe Asp Leu Cys Phe Leu Val Gln Ser Ser Asp Phe Lys Val
85 90 95
Met Val Asn Gly Ile Leu Phe Val Gln Tyr Phe His Arg Val Pro Phe
100 105 110
His Arg Val Asp Thr Ile Ser Val Asn Gly Ser Val Gln Leu Ser Tyr
115 120 125
Ile Ser Phe Gln
130
<210> 47
<211> 476
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 47
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu
50 55 60
Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn
115 120 125
Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
145 150 155 160
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
210 215 220
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro
225 230 235 240
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn
370 375 380
Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Gly His His His His His His
465 470 475
<210> 48
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 48
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Gly
450
<210> 49
<211> 476
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 49
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
20 25 30
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn
65 70 75 80
Glu Lys Phe Gln Gly Arg Val Thr Ile Ser Ser Asp Lys Ser Ile Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met
100 105 110
Tyr Tyr Cys Ala Arg Gly Thr Tyr Tyr Tyr Gly Thr Arg Val Phe Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
145 150 155 160
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
210 215 220
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
225 230 235 240
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn
370 375 380
Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Gly His His His His His His
465 470 475
<210> 50
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 50
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Ser Ser Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Tyr Tyr Tyr Gly Thr Arg Val Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Gly
450
<210> 51
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 51
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu
20 25 30
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Lys Ser Leu
35 40 45
Gln Asn Val Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Gln Gln Lys Pro
50 55 60
Gly Gln Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Asn Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
85 90 95
Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
100 105 110
Met Gln His Leu Glu Tyr Pro Ile Thr Phe Gly Ala Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
130 135 140
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
165 170 175
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
195 200 205
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
210 215 220
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 52
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 52
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Lys Ser Leu Gln Asn Val
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Asn Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Tyr Pro Ile Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 53
<211> 473
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 53
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His 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 Gly Tyr Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Thr Ile Thr Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro
65 70 75 80
Asp Ser 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 Ser Leu Ala Gly Asn Ala Met Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
370 375 380
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Gly His His His His His His
465 470
<210> 54
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 54
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Thr Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Ala Gly Asn Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
435 440 445
<210> 55
<211> 233
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 55
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu
20 25 30
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Ile
35 40 45
Ser Asp Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg
50 55 60
Leu Leu Ile Lys Phe Ala Ser Gln Ser Ile Ser Gly Ile Pro Ala Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Asn Gly His Gly
100 105 110
Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr
115 120 125
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
130 135 140
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
145 150 155 160
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
165 170 175
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
180 185 190
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
195 200 205
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
210 215 220
Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 56
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 56
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Ile Ser Asp Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Lys Phe Ala Ser Gln Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Asn Gly His Gly Phe Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 57
<211> 472
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 57
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Met Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asn Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser Tyr Asn
65 70 75 80
Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser
85 90 95
Ala Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gly Gly Tyr Arg Ala Met Asp Tyr Trp Gly Gln
115 120 125
Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
130 135 140
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
145 150 155 160
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
165 170 175
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
180 185 190
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
195 200 205
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
210 215 220
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
225 230 235 240
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
370 375 380
Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Gly His His His His His His
465 470
<210> 58
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 58
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Met Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Ala Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
435 440 445
<210> 59
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 59
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val
20 25 30
Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile
35 40 45
Val Tyr Ser Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Leu Gln Lys Pro
50 55 60
Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr His Cys
100 105 110
Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val
115 120 125
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
130 135 140
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
165 170 175
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
195 200 205
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
210 215 220
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 60
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 60
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val Tyr Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr His Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 61
<211> 475
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 61
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala
65 70 75 80
Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
225 230 235 240
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
245 250 255
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
260 265 270
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
275 280 285
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
290 295 300
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
305 310 315 320
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
325 330 335
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
340 345 350
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
355 360 365
Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln
370 375 380
Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly Gly His His His His His His
465 470 475
<210> 62
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 62
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Gly
450
<210> 63
<211> 234
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 63
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser
20 25 30
Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val
35 40 45
Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala
50 55 60
Pro Lys Leu Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser
65 70 75 80
Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile
85 90 95
Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr
100 105 110
Thr Ser Ser Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val
115 120 125
Leu Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser
130 135 140
Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser
145 150 155 160
Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser
165 170 175
Pro Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn
180 185 190
Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp
195 200 205
Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr
210 215 220
Val Glu Lys Thr Val Ala Pro Thr Glu Cys
225 230
<210> 64
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 64
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Thr Glu Cys
210 215
<210> 65
<211> 473
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 65
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His 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 Asp Ser Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
85 90 95
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
370 375 380
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Gly His His His His His His
465 470
<210> 66
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 66
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
435 440 445
<210> 67
<211> 233
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 67
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His 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 Val
35 40 45
Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
85 90 95
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr
100 105 110
His Pro Ala Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr
115 120 125
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
130 135 140
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
145 150 155 160
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
165 170 175
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
180 185 190
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
195 200 205
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
210 215 220
Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 68
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 68
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 69
<211> 932
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 69
Met His Leu Leu Gly Pro Trp Leu Leu Leu Leu Val Leu Glu Tyr Leu
1 5 10 15
Ala Phe Ser Asp Ser Ser Lys Trp Val Phe Glu His Pro Glu Thr Leu
20 25 30
Tyr Ala Trp Glu Gly Ala Cys Val Trp Ile Pro Cys Thr Tyr Arg Ala
35 40 45
Leu Asp Gly Asp Leu Glu Ser Phe Ile Leu Phe His Asn Pro Glu Tyr
50 55 60
Asn Lys Asn Thr Ser Lys Phe Asp Gly Thr Arg Leu Tyr Glu Ser Thr
65 70 75 80
Lys Asp Gly Lys Val Pro Ser Glu Gln Lys Arg Val Gln Phe Leu Gly
85 90 95
Asp Lys Asn Lys Asn Cys Thr Leu Ser Ile His Pro Val His Leu Asn
100 105 110
Asp Ser Gly Gln Leu Gly Leu Arg Met Glu Ser Lys Thr Glu Lys Trp
115 120 125
Met Glu Arg Ile His Leu Asn Val Ser Glu Arg Pro Phe Pro Pro His
130 135 140
Ile Gln Leu Pro Pro Glu Ile Gln Glu Ser Gln Glu Val Thr Leu Thr
145 150 155 160
Cys Leu Leu Asn Phe Ser Cys Tyr Gly Tyr Pro Ile Gln Leu Gln Trp
165 170 175
Leu Leu Glu Gly Val Pro Met Arg Gln Ala Ala Val Thr Ser Thr Ser
180 185 190
Leu Thr Ile Lys Ser Val Phe Thr Arg Ser Glu Leu Lys Phe Ser Pro
195 200 205
Gln Trp Ser His His Gly Lys Ile Val Thr Cys Gln Leu Gln Asp Ala
210 215 220
Asp Gly Lys Phe Leu Ser Asn Asp Thr Val Gln Leu Asn Val Lys His
225 230 235 240
Thr Pro Lys Leu Glu Ile Lys Val Thr Pro Ser Asp Ala Ile Val Arg
245 250 255
Glu Gly Asp Ser Val Thr Met Thr Cys Glu Val Ser Ser Ser Asn Pro
260 265 270
Glu Tyr Thr Thr Val Ser Trp Leu Lys Asp Gly Thr Ser Leu Lys Lys
275 280 285
Gln Asn Thr Phe Thr Leu Asn Leu Arg Glu Val Thr Lys Asp Gln Ser
290 295 300
Gly Lys Tyr Cys Cys Gln Val Ser Asn Asp Val Gly Pro Gly Arg Ser
305 310 315 320
Glu Glu Val Phe Leu Gln Val Gln Tyr Ala Pro Glu Pro Ser Thr Val
325 330 335
Gln Ile Leu His Ser Pro Ala Val Glu Gly Ser Gln Val Glu Phe Leu
340 345 350
Cys Met Ser Leu Ala Asn Pro Leu Pro Thr Asn Tyr Thr Trp Tyr His
355 360 365
Asn Gly Lys Glu Met Gln Gly Arg Thr Glu Glu Lys Val His Ile Pro
370 375 380
Lys Ile Leu Pro Trp His Ala Gly Thr Tyr Ser Cys Val Ala Glu Asn
385 390 395 400
Ile Leu Gly Thr Gly Gln Arg Gly Pro Gly Ala Glu Leu Asp Val Gln
405 410 415
Tyr Pro Pro Lys Lys Val Thr Thr Val Ile Gln Asn Pro Met Pro Ile
420 425 430
Arg Glu Gly Asp Thr Val Thr Leu Ser Cys Asn Tyr Asn Ser Ser Asn
435 440 445
Pro Ser Val Thr Arg Tyr Glu Trp Lys Pro His Gly Ala Trp Glu Glu
450 455 460
Pro Ser Leu Gly Val Leu Lys Ile Gln Asn Val Gly Trp Asp Asn Thr
465 470 475 480
Thr Ile Ala Cys Ala Arg Cys Asn Ser Trp Cys Ser Trp Ala Ser Pro
485 490 495
Val Ala Leu Asn Val Gln Tyr Ala Pro Arg Asp Val Arg Val Arg Lys
500 505 510
Ile Lys Pro Leu Ser Glu Ile His Ser Gly Asn Ser Val Ser Leu Gln
515 520 525
Cys Asp Phe Ser Ser Ser His Pro Lys Glu Val Gln Phe Phe Trp Glu
530 535 540
Lys Asn Gly Arg Leu Leu Gly Lys Glu Ser Gln Leu Asn Phe Asp Ser
545 550 555 560
Ile Ser Pro Glu Asp Ala Gly Ser Tyr Ser Cys Trp Val Asn Asn Ser
565 570 575
Ile Gly Gln Thr Ala Ser Lys Ala Trp Thr Leu Glu Val Leu Tyr Ala
580 585 590
Pro Arg Arg Leu Arg Val Ser Met Ser Pro Gly Asp Gln Val Met Glu
595 600 605
Gly Lys Ser Ala Thr Leu Thr Cys Glu Ser Asp Ala Asn Pro Pro Val
610 615 620
Ser His Tyr Thr Trp Phe Asp Trp Asn Asn Gln Ser Leu Pro Tyr His
625 630 635 640
Ser Gln Lys Leu Arg Leu Glu Pro Val Lys Val Gln His Ser Gly Ala
645 650 655
Tyr Trp Cys Gln Gly Thr Asn Ser Val Gly Lys Gly Arg Ser Pro Leu
660 665 670
Ser Thr Leu Thr Val Tyr Tyr Ser Pro Glu Thr Ile Gly Arg Arg Gly
675 680 685
Gly Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
690 695 700
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
705 710 715 720
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
725 730 735
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
740 745 750
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
755 760 765
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
770 775 780
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
785 790 795 800
Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
805 810 815
Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp
820 825 830
Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe
835 840 845
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
850 855 860
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
865 870 875 880
Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
885 890 895
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
900 905 910
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Tyr Pro Tyr Asp Val
915 920 925
Pro Asp Tyr Ala
930
<210> 70
<211> 904
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 70
Asp Ser Ser Lys Trp Val Phe Glu His Pro Glu Thr Leu Tyr Ala Trp
1 5 10 15
Glu Gly Ala Cys Val Trp Ile Pro Cys Thr Tyr Arg Ala Leu Asp Gly
20 25 30
Asp Leu Glu Ser Phe Ile Leu Phe His Asn Pro Glu Tyr Asn Lys Asn
35 40 45
Thr Ser Lys Phe Asp Gly Thr Arg Leu Tyr Glu Ser Thr Lys Asp Gly
50 55 60
Lys Val Pro Ser Glu Gln Lys Arg Val Gln Phe Leu Gly Asp Lys Asn
65 70 75 80
Lys Asn Cys Thr Leu Ser Ile His Pro Val His Leu Asn Asp Ser Gly
85 90 95
Gln Leu Gly Leu Arg Met Glu Ser Lys Thr Glu Lys Trp Met Glu Arg
100 105 110
Ile His Leu Asn Val Ser Glu Arg Pro Phe Pro Pro His Ile Gln Leu
115 120 125
Pro Pro Glu Ile Gln Glu Ser Gln Glu Val Thr Leu Thr Cys Leu Leu
130 135 140
Asn Phe Ser Cys Tyr Gly Tyr Pro Ile Gln Leu Gln Trp Leu Leu Glu
145 150 155 160
Gly Val Pro Met Arg Gln Ala Ala Val Thr Ser Thr Ser Leu Thr Ile
165 170 175
Lys Ser Val Phe Thr Arg Ser Glu Leu Lys Phe Ser Pro Gln Trp Ser
180 185 190
His His Gly Lys Ile Val Thr Cys Gln Leu Gln Asp Ala Asp Gly Lys
195 200 205
Phe Leu Ser Asn Asp Thr Val Gln Leu Asn Val Lys His Thr Pro Lys
210 215 220
Leu Glu Ile Lys Val Thr Pro Ser Asp Ala Ile Val Arg Glu Gly Asp
225 230 235 240
Ser Val Thr Met Thr Cys Glu Val Ser Ser Ser Asn Pro Glu Tyr Thr
245 250 255
Thr Val Ser Trp Leu Lys Asp Gly Thr Ser Leu Lys Lys Gln Asn Thr
260 265 270
Phe Thr Leu Asn Leu Arg Glu Val Thr Lys Asp Gln Ser Gly Lys Tyr
275 280 285
Cys Cys Gln Val Ser Asn Asp Val Gly Pro Gly Arg Ser Glu Glu Val
290 295 300
Phe Leu Gln Val Gln Tyr Ala Pro Glu Pro Ser Thr Val Gln Ile Leu
305 310 315 320
His Ser Pro Ala Val Glu Gly Ser Gln Val Glu Phe Leu Cys Met Ser
325 330 335
Leu Ala Asn Pro Leu Pro Thr Asn Tyr Thr Trp Tyr His Asn Gly Lys
340 345 350
Glu Met Gln Gly Arg Thr Glu Glu Lys Val His Ile Pro Lys Ile Leu
355 360 365
Pro Trp His Ala Gly Thr Tyr Ser Cys Val Ala Glu Asn Ile Leu Gly
370 375 380
Thr Gly Gln Arg Gly Pro Gly Ala Glu Leu Asp Val Gln Tyr Pro Pro
385 390 395 400
Lys Lys Val Thr Thr Val Ile Gln Asn Pro Met Pro Ile Arg Glu Gly
405 410 415
Asp Thr Val Thr Leu Ser Cys Asn Tyr Asn Ser Ser Asn Pro Ser Val
420 425 430
Thr Arg Tyr Glu Trp Lys Pro His Gly Ala Trp Glu Glu Pro Ser Leu
435 440 445
Gly Val Leu Lys Ile Gln Asn Val Gly Trp Asp Asn Thr Thr Ile Ala
450 455 460
Cys Ala Arg Cys Asn Ser Trp Cys Ser Trp Ala Ser Pro Val Ala Leu
465 470 475 480
Asn Val Gln Tyr Ala Pro Arg Asp Val Arg Val Arg Lys Ile Lys Pro
485 490 495
Leu Ser Glu Ile His Ser Gly Asn Ser Val Ser Leu Gln Cys Asp Phe
500 505 510
Ser Ser Ser His Pro Lys Glu Val Gln Phe Phe Trp Glu Lys Asn Gly
515 520 525
Arg Leu Leu Gly Lys Glu Ser Gln Leu Asn Phe Asp Ser Ile Ser Pro
530 535 540
Glu Asp Ala Gly Ser Tyr Ser Cys Trp Val Asn Asn Ser Ile Gly Gln
545 550 555 560
Thr Ala Ser Lys Ala Trp Thr Leu Glu Val Leu Tyr Ala Pro Arg Arg
565 570 575
Leu Arg Val Ser Met Ser Pro Gly Asp Gln Val Met Glu Gly Lys Ser
580 585 590
Ala Thr Leu Thr Cys Glu Ser Asp Ala Asn Pro Pro Val Ser His Tyr
595 600 605
Thr Trp Phe Asp Trp Asn Asn Gln Ser Leu Pro Tyr His Ser Gln Lys
610 615 620
Leu Arg Leu Glu Pro Val Lys Val Gln His Ser Gly Ala Tyr Trp Cys
625 630 635 640
Gln Gly Thr Asn Ser Val Gly Lys Gly Arg Ser Pro Leu Ser Thr Leu
645 650 655
Thr Val Tyr Tyr Ser Pro Glu Thr Ile Gly Arg Arg Gly Gly Gly Gly
660 665 670
Gly Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
675 680 685
Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
690 695 700
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
705 710 715 720
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
725 730 735
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
740 745 750
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
755 760 765
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
770 775 780
Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
785 790 795 800
Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
805 810 815
Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser
820 825 830
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
835 840 845
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val
850 855 860
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
865 870 875 880
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
885 890 895
Ser Leu Ser Leu Ser Pro Gly Gly
900
<210> 71
<211> 668
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 71
Asp Ser Ser Lys Trp Val Phe Glu His Pro Glu Thr Leu Tyr Ala Trp
1 5 10 15
Glu Gly Ala Cys Val Trp Ile Pro Cys Thr Tyr Arg Ala Leu Asp Gly
20 25 30
Asp Leu Glu Ser Phe Ile Leu Phe His Asn Pro Glu Tyr Asn Lys Asn
35 40 45
Thr Ser Lys Phe Asp Gly Thr Arg Leu Tyr Glu Ser Thr Lys Asp Gly
50 55 60
Lys Val Pro Ser Glu Gln Lys Arg Val Gln Phe Leu Gly Asp Lys Asn
65 70 75 80
Lys Asn Cys Thr Leu Ser Ile His Pro Val His Leu Asn Asp Ser Gly
85 90 95
Gln Leu Gly Leu Arg Met Glu Ser Lys Thr Glu Lys Trp Met Glu Arg
100 105 110
Ile His Leu Asn Val Ser Glu Arg Pro Phe Pro Pro His Ile Gln Leu
115 120 125
Pro Pro Glu Ile Gln Glu Ser Gln Glu Val Thr Leu Thr Cys Leu Leu
130 135 140
Asn Phe Ser Cys Tyr Gly Tyr Pro Ile Gln Leu Gln Trp Leu Leu Glu
145 150 155 160
Gly Val Pro Met Arg Gln Ala Ala Val Thr Ser Thr Ser Leu Thr Ile
165 170 175
Lys Ser Val Phe Thr Arg Ser Glu Leu Lys Phe Ser Pro Gln Trp Ser
180 185 190
His His Gly Lys Ile Val Thr Cys Gln Leu Gln Asp Ala Asp Gly Lys
195 200 205
Phe Leu Ser Asn Asp Thr Val Gln Leu Asn Val Lys His Thr Pro Lys
210 215 220
Leu Glu Ile Lys Val Thr Pro Ser Asp Ala Ile Val Arg Glu Gly Asp
225 230 235 240
Ser Val Thr Met Thr Cys Glu Val Ser Ser Ser Asn Pro Glu Tyr Thr
245 250 255
Thr Val Ser Trp Leu Lys Asp Gly Thr Ser Leu Lys Lys Gln Asn Thr
260 265 270
Phe Thr Leu Asn Leu Arg Glu Val Thr Lys Asp Gln Ser Gly Lys Tyr
275 280 285
Cys Cys Gln Val Ser Asn Asp Val Gly Pro Gly Arg Ser Glu Glu Val
290 295 300
Phe Leu Gln Val Gln Tyr Ala Pro Glu Pro Ser Thr Val Gln Ile Leu
305 310 315 320
His Ser Pro Ala Val Glu Gly Ser Gln Val Glu Phe Leu Cys Met Ser
325 330 335
Leu Ala Asn Pro Leu Pro Thr Asn Tyr Thr Trp Tyr His Asn Gly Lys
340 345 350
Glu Met Gln Gly Arg Thr Glu Glu Lys Val His Ile Pro Lys Ile Leu
355 360 365
Pro Trp His Ala Gly Thr Tyr Ser Cys Val Ala Glu Asn Ile Leu Gly
370 375 380
Thr Gly Gln Arg Gly Pro Gly Ala Glu Leu Asp Val Gln Tyr Pro Pro
385 390 395 400
Lys Lys Val Thr Thr Val Ile Gln Asn Pro Met Pro Ile Arg Glu Gly
405 410 415
Asp Thr Val Thr Leu Ser Cys Asn Tyr Asn Ser Ser Asn Pro Ser Val
420 425 430
Thr Arg Tyr Glu Trp Lys Pro His Gly Ala Trp Glu Glu Pro Ser Leu
435 440 445
Gly Val Leu Lys Ile Gln Asn Val Gly Trp Asp Asn Thr Thr Ile Ala
450 455 460
Cys Ala Arg Cys Asn Ser Trp Cys Ser Trp Ala Ser Pro Val Ala Leu
465 470 475 480
Asn Val Gln Tyr Ala Pro Arg Asp Val Arg Val Arg Lys Ile Lys Pro
485 490 495
Leu Ser Glu Ile His Ser Gly Asn Ser Val Ser Leu Gln Cys Asp Phe
500 505 510
Ser Ser Ser His Pro Lys Glu Val Gln Phe Phe Trp Glu Lys Asn Gly
515 520 525
Arg Leu Leu Gly Lys Glu Ser Gln Leu Asn Phe Asp Ser Ile Ser Pro
530 535 540
Glu Asp Ala Gly Ser Tyr Ser Cys Trp Val Asn Asn Ser Ile Gly Gln
545 550 555 560
Thr Ala Ser Lys Ala Trp Thr Leu Glu Val Leu Tyr Ala Pro Arg Arg
565 570 575
Leu Arg Val Ser Met Ser Pro Gly Asp Gln Val Met Glu Gly Lys Ser
580 585 590
Ala Thr Leu Thr Cys Glu Ser Asp Ala Asn Pro Pro Val Ser His Tyr
595 600 605
Thr Trp Phe Asp Trp Asn Asn Gln Ser Leu Pro Tyr His Ser Gln Lys
610 615 620
Leu Arg Leu Glu Pro Val Lys Val Gln His Ser Gly Ala Tyr Trp Cys
625 630 635 640
Gln Gly Thr Asn Ser Val Gly Lys Gly Arg Ser Pro Leu Ser Thr Leu
645 650 655
Thr Val Tyr Tyr Ser Pro Glu Thr Ile Gly Arg Arg
660 665
<210> 72
<211> 571
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 72
Met His Leu Leu Gly Pro Trp Leu Leu Leu Leu Val Leu Glu Tyr Leu
1 5 10 15
Ala Phe Ser Asp Ser Ser Lys Trp Val Phe Glu His Pro Glu Thr Leu
20 25 30
Tyr Ala Trp Glu Gly Ala Cys Val Trp Ile Pro Cys Thr Tyr Arg Ala
35 40 45
Leu Asp Gly Asp Leu Glu Ser Phe Ile Leu Phe His Asn Pro Glu Tyr
50 55 60
Asn Lys Asn Thr Ser Lys Phe Asp Gly Thr Arg Leu Tyr Glu Ser Thr
65 70 75 80
Lys Asp Gly Lys Val Pro Ser Glu Gln Lys Arg Val Gln Phe Leu Gly
85 90 95
Asp Lys Asn Lys Asn Cys Thr Leu Ser Ile His Pro Val His Leu Asn
100 105 110
Asp Ser Gly Gln Leu Gly Leu Arg Met Glu Ser Lys Thr Glu Lys Trp
115 120 125
Met Glu Arg Ile His Leu Asn Val Ser Glu Arg Pro Phe Pro Pro His
130 135 140
Ile Gln Leu Pro Pro Glu Ile Gln Glu Ser Gln Glu Val Thr Leu Thr
145 150 155 160
Cys Leu Leu Asn Phe Ser Cys Tyr Gly Tyr Pro Ile Gln Leu Gln Trp
165 170 175
Leu Leu Glu Gly Val Pro Met Arg Gln Ala Ala Val Thr Ser Thr Ser
180 185 190
Leu Thr Ile Lys Ser Val Phe Thr Arg Ser Glu Leu Lys Phe Ser Pro
195 200 205
Gln Trp Ser His His Gly Lys Ile Val Thr Cys Gln Leu Gln Asp Ala
210 215 220
Asp Gly Lys Phe Leu Ser Asn Asp Thr Val Gln Leu Asn Val Lys His
225 230 235 240
Thr Pro Lys Leu Glu Ile Lys Val Thr Pro Ser Asp Ala Ile Val Arg
245 250 255
Glu Gly Asp Ser Val Thr Met Thr Cys Glu Val Ser Ser Ser Asn Pro
260 265 270
Glu Tyr Thr Thr Val Ser Trp Leu Lys Asp Gly Thr Ser Leu Lys Lys
275 280 285
Gln Asn Thr Phe Thr Leu Asn Leu Arg Glu Val Thr Lys Asp Gln Ser
290 295 300
Gly Lys Tyr Cys Cys Gln Val Ser Asn Asp Val Gly Pro Gly Arg Ser
305 310 315 320
Glu Glu Val Phe Leu Gln Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp
325 330 335
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly
340 345 350
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
355 360 365
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
370 375 380
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
385 390 395 400
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
405 410 415
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
420 425 430
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu
435 440 445
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
450 455 460
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
465 470 475 480
Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
485 490 495
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
500 505 510
Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp
515 520 525
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
530 535 540
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
545 550 555 560
Gly Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
565 570
<210> 73
<211> 543
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 73
Asp Ser Ser Lys Trp Val Phe Glu His Pro Glu Thr Leu Tyr Ala Trp
1 5 10 15
Glu Gly Ala Cys Val Trp Ile Pro Cys Thr Tyr Arg Ala Leu Asp Gly
20 25 30
Asp Leu Glu Ser Phe Ile Leu Phe His Asn Pro Glu Tyr Asn Lys Asn
35 40 45
Thr Ser Lys Phe Asp Gly Thr Arg Leu Tyr Glu Ser Thr Lys Asp Gly
50 55 60
Lys Val Pro Ser Glu Gln Lys Arg Val Gln Phe Leu Gly Asp Lys Asn
65 70 75 80
Lys Asn Cys Thr Leu Ser Ile His Pro Val His Leu Asn Asp Ser Gly
85 90 95
Gln Leu Gly Leu Arg Met Glu Ser Lys Thr Glu Lys Trp Met Glu Arg
100 105 110
Ile His Leu Asn Val Ser Glu Arg Pro Phe Pro Pro His Ile Gln Leu
115 120 125
Pro Pro Glu Ile Gln Glu Ser Gln Glu Val Thr Leu Thr Cys Leu Leu
130 135 140
Asn Phe Ser Cys Tyr Gly Tyr Pro Ile Gln Leu Gln Trp Leu Leu Glu
145 150 155 160
Gly Val Pro Met Arg Gln Ala Ala Val Thr Ser Thr Ser Leu Thr Ile
165 170 175
Lys Ser Val Phe Thr Arg Ser Glu Leu Lys Phe Ser Pro Gln Trp Ser
180 185 190
His His Gly Lys Ile Val Thr Cys Gln Leu Gln Asp Ala Asp Gly Lys
195 200 205
Phe Leu Ser Asn Asp Thr Val Gln Leu Asn Val Lys His Thr Pro Lys
210 215 220
Leu Glu Ile Lys Val Thr Pro Ser Asp Ala Ile Val Arg Glu Gly Asp
225 230 235 240
Ser Val Thr Met Thr Cys Glu Val Ser Ser Ser Asn Pro Glu Tyr Thr
245 250 255
Thr Val Ser Trp Leu Lys Asp Gly Thr Ser Leu Lys Lys Gln Asn Thr
260 265 270
Phe Thr Leu Asn Leu Arg Glu Val Thr Lys Asp Gln Ser Gly Lys Tyr
275 280 285
Cys Cys Gln Val Ser Asn Asp Val Gly Pro Gly Arg Ser Glu Glu Val
290 295 300
Phe Leu Gln Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr His
305 310 315 320
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
325 330 335
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
340 345 350
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
355 360 365
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
370 375 380
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
385 390 395 400
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
405 410 415
Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile
420 425 430
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro
435 440 445
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala
450 455 460
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
465 470 475 480
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
485 490 495
Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg
500 505 510
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
515 520 525
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
530 535 540
<210> 74
<211> 307
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 74
Asp Ser Ser Lys Trp Val Phe Glu His Pro Glu Thr Leu Tyr Ala Trp
1 5 10 15
Glu Gly Ala Cys Val Trp Ile Pro Cys Thr Tyr Arg Ala Leu Asp Gly
20 25 30
Asp Leu Glu Ser Phe Ile Leu Phe His Asn Pro Glu Tyr Asn Lys Asn
35 40 45
Thr Ser Lys Phe Asp Gly Thr Arg Leu Tyr Glu Ser Thr Lys Asp Gly
50 55 60
Lys Val Pro Ser Glu Gln Lys Arg Val Gln Phe Leu Gly Asp Lys Asn
65 70 75 80
Lys Asn Cys Thr Leu Ser Ile His Pro Val His Leu Asn Asp Ser Gly
85 90 95
Gln Leu Gly Leu Arg Met Glu Ser Lys Thr Glu Lys Trp Met Glu Arg
100 105 110
Ile His Leu Asn Val Ser Glu Arg Pro Phe Pro Pro His Ile Gln Leu
115 120 125
Pro Pro Glu Ile Gln Glu Ser Gln Glu Val Thr Leu Thr Cys Leu Leu
130 135 140
Asn Phe Ser Cys Tyr Gly Tyr Pro Ile Gln Leu Gln Trp Leu Leu Glu
145 150 155 160
Gly Val Pro Met Arg Gln Ala Ala Val Thr Ser Thr Ser Leu Thr Ile
165 170 175
Lys Ser Val Phe Thr Arg Ser Glu Leu Lys Phe Ser Pro Gln Trp Ser
180 185 190
His His Gly Lys Ile Val Thr Cys Gln Leu Gln Asp Ala Asp Gly Lys
195 200 205
Phe Leu Ser Asn Asp Thr Val Gln Leu Asn Val Lys His Thr Pro Lys
210 215 220
Leu Glu Ile Lys Val Thr Pro Ser Asp Ala Ile Val Arg Glu Gly Asp
225 230 235 240
Ser Val Thr Met Thr Cys Glu Val Ser Ser Ser Asn Pro Glu Tyr Thr
245 250 255
Thr Val Ser Trp Leu Lys Asp Gly Thr Ser Leu Lys Lys Gln Asn Thr
260 265 270
Phe Thr Leu Asn Leu Arg Glu Val Thr Lys Asp Gln Ser Gly Lys Tyr
275 280 285
Cys Cys Gln Val Ser Asn Asp Val Gly Pro Gly Arg Ser Glu Glu Val
290 295 300
Phe Leu Gln
305
<210> 75
<211> 584
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 75
Met Leu Leu Pro Leu Leu Leu Ser Ser Leu Leu Gly Gly Ser Gln Ala
1 5 10 15
Met Asp Gly Arg Phe Trp Ile Arg Val Gln Glu Ser Val Met Val Pro
20 25 30
Glu Gly Leu Cys Ile Ser Val Pro Cys Ser Phe Ser Tyr Pro Arg Gln
35 40 45
Asp Trp Thr Gly Ser Thr Pro Ala Tyr Gly Tyr Trp Phe Lys Ala Val
50 55 60
Thr Glu Thr Thr Lys Gly Ala Pro Val Ala Thr Asn His Gln Ser Arg
65 70 75 80
Glu Val Glu Met Ser Thr Arg Gly Arg Phe Gln Leu Thr Gly Asp Pro
85 90 95
Ala Lys Gly Asn Cys Ser Leu Val Ile Arg Asp Ala Gln Met Gln Asp
100 105 110
Glu Ser Gln Tyr Phe Phe Arg Val Glu Arg Gly Ser Tyr Val Arg Tyr
115 120 125
Asn Phe Met Asn Asp Gly Phe Phe Leu Lys Val Thr Ala Leu Thr Gln
130 135 140
Lys Pro Asp Val Tyr Ile Pro Glu Thr Leu Glu Pro Gly Gln Pro Val
145 150 155 160
Thr Val Ile Cys Val Phe Asn Trp Ala Phe Glu Glu Cys Pro Pro Pro
165 170 175
Ser Phe Ser Trp Thr Gly Ala Ala Leu Ser Ser Gln Gly Thr Lys Pro
180 185 190
Thr Thr Ser His Phe Ser Val Leu Ser Phe Thr Pro Arg Pro Gln Asp
195 200 205
His Asn Thr Asp Leu Thr Cys His Val Asp Phe Ser Arg Lys Gly Val
210 215 220
Ser Ala Gln Arg Thr Val Arg Leu Arg Val Ala Tyr Ala Pro Arg Asp
225 230 235 240
Leu Val Ile Ser Ile Ser Arg Asp Asn Thr Pro Ala Leu Glu Pro Gln
245 250 255
Pro Gln Gly Asn Val Pro Tyr Leu Glu Ala Gln Lys Gly Gln Phe Leu
260 265 270
Arg Leu Leu Cys Ala Ala Asp Ser Gln Pro Pro Ala Thr Leu Ser Trp
275 280 285
Val Leu Gln Asn Arg Val Leu Ser Ser Ser His Pro Trp Gly Pro Arg
290 295 300
Pro Leu Gly Leu Glu Leu Pro Gly Val Lys Ala Gly Asp Ser Gly Arg
305 310 315 320
Tyr Thr Cys Arg Ala Glu Asn Arg Leu Gly Ser Gln Gln Arg Ala Leu
325 330 335
Asp Leu Ser Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr His
340 345 350
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
355 360 365
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
370 375 380
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
385 390 395 400
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
405 410 415
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
420 425 430
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
435 440 445
Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile
450 455 460
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro
465 470 475 480
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala
485 490 495
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
500 505 510
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
515 520 525
Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg
530 535 540
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
545 550 555 560
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Tyr
565 570 575
Pro Tyr Asp Val Pro Asp Tyr Ala
580
<210> 76
<211> 559
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 76
Met Asp Gly Arg Phe Trp Ile Arg Val Gln Glu Ser Val Met Val Pro
1 5 10 15
Glu Gly Leu Cys Ile Ser Val Pro Cys Ser Phe Ser Tyr Pro Arg Gln
20 25 30
Asp Trp Thr Gly Ser Thr Pro Ala Tyr Gly Tyr Trp Phe Lys Ala Val
35 40 45
Thr Glu Thr Thr Lys Gly Ala Pro Val Ala Thr Asn His Gln Ser Arg
50 55 60
Glu Val Glu Met Ser Thr Arg Gly Arg Phe Gln Leu Thr Gly Asp Pro
65 70 75 80
Ala Lys Gly Asn Cys Ser Leu Val Ile Arg Asp Ala Gln Met Gln Asp
85 90 95
Glu Ser Gln Tyr Phe Phe Arg Val Glu Arg Gly Ser Tyr Val Arg Tyr
100 105 110
Asn Phe Met Asn Asp Gly Phe Phe Leu Lys Val Thr Ala Leu Thr Gln
115 120 125
Lys Pro Asp Val Tyr Ile Pro Glu Thr Leu Glu Pro Gly Gln Pro Val
130 135 140
Thr Val Ile Cys Val Phe Asn Trp Ala Phe Glu Glu Cys Pro Pro Pro
145 150 155 160
Ser Phe Ser Trp Thr Gly Ala Ala Leu Ser Ser Gln Gly Thr Lys Pro
165 170 175
Thr Thr Ser His Phe Ser Val Leu Ser Phe Thr Pro Arg Pro Gln Asp
180 185 190
His Asn Thr Asp Leu Thr Cys His Val Asp Phe Ser Arg Lys Gly Val
195 200 205
Ser Ala Gln Arg Thr Val Arg Leu Arg Val Ala Tyr Ala Pro Arg Asp
210 215 220
Leu Val Ile Ser Ile Ser Arg Asp Asn Thr Pro Ala Leu Glu Pro Gln
225 230 235 240
Pro Gln Gly Asn Val Pro Tyr Leu Glu Ala Gln Lys Gly Gln Phe Leu
245 250 255
Arg Leu Leu Cys Ala Ala Asp Ser Gln Pro Pro Ala Thr Leu Ser Trp
260 265 270
Val Leu Gln Asn Arg Val Leu Ser Ser Ser His Pro Trp Gly Pro Arg
275 280 285
Pro Leu Gly Leu Glu Leu Pro Gly Val Lys Ala Gly Asp Ser Gly Arg
290 295 300
Tyr Thr Cys Arg Ala Glu Asn Arg Leu Gly Ser Gln Gln Arg Ala Leu
305 310 315 320
Asp Leu Ser Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr His
325 330 335
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
340 345 350
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
355 360 365
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
370 375 380
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
385 390 395 400
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
405 410 415
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
420 425 430
Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile
435 440 445
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro
450 455 460
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala
465 470 475 480
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
485 490 495
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
500 505 510
Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg
515 520 525
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
530 535 540
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
545 550 555
<210> 77
<211> 546
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 77
Met Ile Ala Ser Gln Phe Leu Ser Ala Leu Thr Leu Val Leu Leu Ile
1 5 10 15
Lys Glu Ser Gly Ala Trp Ser Tyr Asn Thr Ser Thr Glu Ala Met Thr
20 25 30
Tyr Asp Glu Ala Ser Ala Tyr Cys Gln Gln Arg Tyr Thr His Leu Val
35 40 45
Ala Ile Gln Asn Lys Glu Glu Ile Glu Tyr Leu Asn Ser Ile Leu Ser
50 55 60
Tyr Ser Pro Ser Tyr Tyr Trp Ile Gly Ile Arg Lys Val Asn Asn Val
65 70 75 80
Trp Val Trp Val Gly Thr Gln Lys Pro Leu Thr Glu Glu Ala Lys Asn
85 90 95
Trp Ala Pro Gly Glu Pro Asn Asn Arg Gln Lys Asp Glu Asp Cys Val
100 105 110
Glu Ile Tyr Ile Lys Arg Glu Lys Asp Val Gly Met Trp Asn Asp Glu
115 120 125
Arg Cys Ser Lys Lys Lys Leu Ala Leu Cys Tyr Thr Ala Ala Cys Thr
130 135 140
Asn Thr Ser Cys Ser Gly His Gly Glu Cys Val Glu Thr Ile Asn Asn
145 150 155 160
Tyr Thr Cys Lys Cys Asp Pro Gly Phe Ser Gly Leu Lys Cys Glu Gln
165 170 175
Ile Val Asn Cys Thr Ala Leu Glu Ser Pro Glu His Gly Ser Leu Val
180 185 190
Cys Ser His Pro Leu Gly Asn Phe Ser Tyr Asn Ser Ser Cys Ser Ile
195 200 205
Ser Cys Asp Arg Gly Tyr Leu Pro Ser Ser Met Glu Thr Met Gln Cys
210 215 220
Met Ser Ser Gly Glu Trp Ser Ala Pro Ile Pro Ala Cys Asn Val Val
225 230 235 240
Glu Cys Asp Ala Val Thr Asn Pro Ala Asn Gly Phe Val Glu Cys Phe
245 250 255
Gln Asn Pro Gly Ser Phe Pro Trp Asn Thr Thr Cys Thr Phe Asp Cys
260 265 270
Glu Glu Gly Phe Glu Leu Met Gly Ala Gln Ser Leu Gln Cys Thr Ser
275 280 285
Ser Gly Asn Trp Asp Asn Glu Lys Pro Thr Cys Lys Ala Gly Gly Gly
290 295 300
Gly Gly Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
305 310 315 320
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
325 330 335
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
340 345 350
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
355 360 365
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
370 375 380
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
385 390 395 400
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
405 410 415
Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
420 425 430
Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu
435 440 445
Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro
450 455 460
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
465 470 475 480
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
485 490 495
Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
500 505 510
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
515 520 525
Lys Ser Leu Ser Leu Ser Pro Gly Gly Tyr Pro Tyr Asp Val Pro Asp
530 535 540
Tyr Ala
545
<210> 78
<211> 516
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 78
Trp Ser Tyr Asn Thr Ser Thr Glu Ala Met Thr Tyr Asp Glu Ala Ser
1 5 10 15
Ala Tyr Cys Gln Gln Arg Tyr Thr His Leu Val Ala Ile Gln Asn Lys
20 25 30
Glu Glu Ile Glu Tyr Leu Asn Ser Ile Leu Ser Tyr Ser Pro Ser Tyr
35 40 45
Tyr Trp Ile Gly Ile Arg Lys Val Asn Asn Val Trp Val Trp Val Gly
50 55 60
Thr Gln Lys Pro Leu Thr Glu Glu Ala Lys Asn Trp Ala Pro Gly Glu
65 70 75 80
Pro Asn Asn Arg Gln Lys Asp Glu Asp Cys Val Glu Ile Tyr Ile Lys
85 90 95
Arg Glu Lys Asp Val Gly Met Trp Asn Asp Glu Arg Cys Ser Lys Lys
100 105 110
Lys Leu Ala Leu Cys Tyr Thr Ala Ala Cys Thr Asn Thr Ser Cys Ser
115 120 125
Gly His Gly Glu Cys Val Glu Thr Ile Asn Asn Tyr Thr Cys Lys Cys
130 135 140
Asp Pro Gly Phe Ser Gly Leu Lys Cys Glu Gln Ile Val Asn Cys Thr
145 150 155 160
Ala Leu Glu Ser Pro Glu His Gly Ser Leu Val Cys Ser His Pro Leu
165 170 175
Gly Asn Phe Ser Tyr Asn Ser Ser Cys Ser Ile Ser Cys Asp Arg Gly
180 185 190
Tyr Leu Pro Ser Ser Met Glu Thr Met Gln Cys Met Ser Ser Gly Glu
195 200 205
Trp Ser Ala Pro Ile Pro Ala Cys Asn Val Val Glu Cys Asp Ala Val
210 215 220
Thr Asn Pro Ala Asn Gly Phe Val Glu Cys Phe Gln Asn Pro Gly Ser
225 230 235 240
Phe Pro Trp Asn Thr Thr Cys Thr Phe Asp Cys Glu Glu Gly Phe Glu
245 250 255
Leu Met Gly Ala Gln Ser Leu Gln Cys Thr Ser Ser Gly Asn Trp Asp
260 265 270
Asn Glu Lys Pro Thr Cys Lys Ala Gly Gly Gly Gly Gly Pro Lys Ser
275 280 285
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
290 295 300
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
305 310 315 320
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
325 330 335
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
340 345 350
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
355 360 365
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
370 375 380
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro
385 390 395 400
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
405 410 415
Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
420 425 430
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
435 440 445
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
450 455 460
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
465 470 475 480
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
485 490 495
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
500 505 510
Ser Pro Gly Gly
515
<210> 79
<211> 280
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 79
Trp Ser Tyr Asn Thr Ser Thr Glu Ala Met Thr Tyr Asp Glu Ala Ser
1 5 10 15
Ala Tyr Cys Gln Gln Arg Tyr Thr His Leu Val Ala Ile Gln Asn Lys
20 25 30
Glu Glu Ile Glu Tyr Leu Asn Ser Ile Leu Ser Tyr Ser Pro Ser Tyr
35 40 45
Tyr Trp Ile Gly Ile Arg Lys Val Asn Asn Val Trp Val Trp Val Gly
50 55 60
Thr Gln Lys Pro Leu Thr Glu Glu Ala Lys Asn Trp Ala Pro Gly Glu
65 70 75 80
Pro Asn Asn Arg Gln Lys Asp Glu Asp Cys Val Glu Ile Tyr Ile Lys
85 90 95
Arg Glu Lys Asp Val Gly Met Trp Asn Asp Glu Arg Cys Ser Lys Lys
100 105 110
Lys Leu Ala Leu Cys Tyr Thr Ala Ala Cys Thr Asn Thr Ser Cys Ser
115 120 125
Gly His Gly Glu Cys Val Glu Thr Ile Asn Asn Tyr Thr Cys Lys Cys
130 135 140
Asp Pro Gly Phe Ser Gly Leu Lys Cys Glu Gln Ile Val Asn Cys Thr
145 150 155 160
Ala Leu Glu Ser Pro Glu His Gly Ser Leu Val Cys Ser His Pro Leu
165 170 175
Gly Asn Phe Ser Tyr Asn Ser Ser Cys Ser Ile Ser Cys Asp Arg Gly
180 185 190
Tyr Leu Pro Ser Ser Met Glu Thr Met Gln Cys Met Ser Ser Gly Glu
195 200 205
Trp Ser Ala Pro Ile Pro Ala Cys Asn Val Val Glu Cys Asp Ala Val
210 215 220
Thr Asn Pro Ala Asn Gly Phe Val Glu Cys Phe Gln Asn Pro Gly Ser
225 230 235 240
Phe Pro Trp Asn Thr Thr Cys Thr Phe Asp Cys Glu Glu Gly Phe Glu
245 250 255
Leu Met Gly Ala Gln Ser Leu Gln Cys Thr Ser Ser Gly Asn Trp Asp
260 265 270
Asn Glu Lys Pro Thr Cys Lys Ala
275 280
<210> 80
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 80
Met Ala Asn Cys Gln Ile Ala Ile Leu Tyr Gln Arg Phe Gln Arg Val
1 5 10 15
Val Phe Gly Ile Ser Gln Leu Leu Cys Phe Ser Ala Leu Ile Ser Glu
20 25 30
Leu Thr Asn Gln Lys Glu Val Ala Ala Trp Thr Tyr His Tyr Ser Thr
35 40 45
Lys Ala Tyr Ser Trp Asn Ile Ser Arg Lys Tyr Cys Gln Asn Arg Tyr
50 55 60
Thr Asp Leu Val Ala Ile Gln Asn Lys Asn Glu Ile Asp Tyr Leu Asn
65 70 75 80
Lys Val Leu Pro Tyr Tyr Ser Ser Tyr Tyr Trp Ile Gly Ile Arg Lys
85 90 95
Asn Asn Lys Thr Trp Thr Trp Val Gly Thr Lys Lys Ala Leu Thr Asn
100 105 110
Glu Ala Glu Asn Trp Ala Asp Asn Glu Pro Asn Asn Lys Arg Asn Asn
115 120 125
Glu Asp Cys Val Glu Ile Tyr Ile Lys Ser Pro Ser Ala Pro Gly Lys
130 135 140
Trp Asn Asp Glu His Cys Leu Lys Lys Lys His Ala Leu Cys Tyr Thr
145 150 155 160
Ala Ser Cys Gln Asp Met Ser Cys Ser Lys Gln Gly Glu Cys Leu Glu
165 170 175
Thr Ile Gly Asn Tyr Thr Cys Ser Cys Tyr Pro Gly Phe Tyr Gly Pro
180 185 190
Glu Cys Glu Tyr Val Arg Glu Cys Gly Glu Leu Glu Leu Pro Gln His
195 200 205
Val Leu Met Asn Cys Ser His Pro Leu Gly Asn Phe Ser Phe Asn Ser
210 215 220
Gln Cys Ser Phe His Cys Thr Asp Gly Tyr Gln Val Asn Gly Pro Ser
225 230 235 240
Lys Leu Glu Cys Leu Ala Ser Gly Ile Trp Thr Asn Lys Pro Pro Gln
245 250 255
Cys Leu Ala Ala Gln Cys Pro Pro Leu Lys Ile Pro Glu Arg Gly Asn
260 265 270
Met Thr Cys Leu His Ser Ala Lys Ala Phe Gln His Gln Ser Ser Cys
275 280 285
Ser Phe Ser Cys Glu Glu Gly Phe Ala Leu Val Gly Pro Glu Val Val
290 295 300
Gln Cys Thr Ala Ser Gly Val Trp Thr Ala Pro Ala Pro Val Cys Lys
305 310 315 320
Ala Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp Lys Thr His Thr Cys
325 330 335
Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu
340 345 350
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
355 360 365
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
370 375 380
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
385 390 395 400
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
405 410 415
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
420 425 430
Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys
435 440 445
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser
450 455 460
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys
465 470 475 480
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
485 490 495
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
500 505 510
Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
515 520 525
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
530 535 540
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Tyr Pro Tyr
545 550 555 560
Asp Val Pro Asp Tyr Ala
565
<210> 81
<211> 516
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 81
Trp Thr Tyr His Tyr Ser Thr Lys Ala Tyr Ser Trp Asn Ile Ser Arg
1 5 10 15
Lys Tyr Cys Gln Asn Arg Tyr Thr Asp Leu Val Ala Ile Gln Asn Lys
20 25 30
Asn Glu Ile Asp Tyr Leu Asn Lys Val Leu Pro Tyr Tyr Ser Ser Tyr
35 40 45
Tyr Trp Ile Gly Ile Arg Lys Asn Asn Lys Thr Trp Thr Trp Val Gly
50 55 60
Thr Lys Lys Ala Leu Thr Asn Glu Ala Glu Asn Trp Ala Asp Asn Glu
65 70 75 80
Pro Asn Asn Lys Arg Asn Asn Glu Asp Cys Val Glu Ile Tyr Ile Lys
85 90 95
Ser Pro Ser Ala Pro Gly Lys Trp Asn Asp Glu His Cys Leu Lys Lys
100 105 110
Lys His Ala Leu Cys Tyr Thr Ala Ser Cys Gln Asp Met Ser Cys Ser
115 120 125
Lys Gln Gly Glu Cys Leu Glu Thr Ile Gly Asn Tyr Thr Cys Ser Cys
130 135 140
Tyr Pro Gly Phe Tyr Gly Pro Glu Cys Glu Tyr Val Arg Glu Cys Gly
145 150 155 160
Glu Leu Glu Leu Pro Gln His Val Leu Met Asn Cys Ser His Pro Leu
165 170 175
Gly Asn Phe Ser Phe Asn Ser Gln Cys Ser Phe His Cys Thr Asp Gly
180 185 190
Tyr Gln Val Asn Gly Pro Ser Lys Leu Glu Cys Leu Ala Ser Gly Ile
195 200 205
Trp Thr Asn Lys Pro Pro Gln Cys Leu Ala Ala Gln Cys Pro Pro Leu
210 215 220
Lys Ile Pro Glu Arg Gly Asn Met Thr Cys Leu His Ser Ala Lys Ala
225 230 235 240
Phe Gln His Gln Ser Ser Cys Ser Phe Ser Cys Glu Glu Gly Phe Ala
245 250 255
Leu Val Gly Pro Glu Val Val Gln Cys Thr Ala Ser Gly Val Trp Thr
260 265 270
Ala Pro Ala Pro Val Cys Lys Ala Gly Gly Gly Gly Gly Pro Lys Ser
275 280 285
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
290 295 300
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
305 310 315 320
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
325 330 335
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
340 345 350
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
355 360 365
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
370 375 380
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro
385 390 395 400
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
405 410 415
Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
420 425 430
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
435 440 445
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
450 455 460
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
465 470 475 480
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
485 490 495
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
500 505 510
Ser Pro Gly Gly
515
<210> 82
<211> 280
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 82
Trp Thr Tyr His Tyr Ser Thr Lys Ala Tyr Ser Trp Asn Ile Ser Arg
1 5 10 15
Lys Tyr Cys Gln Asn Arg Tyr Thr Asp Leu Val Ala Ile Gln Asn Lys
20 25 30
Asn Glu Ile Asp Tyr Leu Asn Lys Val Leu Pro Tyr Tyr Ser Ser Tyr
35 40 45
Tyr Trp Ile Gly Ile Arg Lys Asn Asn Lys Thr Trp Thr Trp Val Gly
50 55 60
Thr Lys Lys Ala Leu Thr Asn Glu Ala Glu Asn Trp Ala Asp Asn Glu
65 70 75 80
Pro Asn Asn Lys Arg Asn Asn Glu Asp Cys Val Glu Ile Tyr Ile Lys
85 90 95
Ser Pro Ser Ala Pro Gly Lys Trp Asn Asp Glu His Cys Leu Lys Lys
100 105 110
Lys His Ala Leu Cys Tyr Thr Ala Ser Cys Gln Asp Met Ser Cys Ser
115 120 125
Lys Gln Gly Glu Cys Leu Glu Thr Ile Gly Asn Tyr Thr Cys Ser Cys
130 135 140
Tyr Pro Gly Phe Tyr Gly Pro Glu Cys Glu Tyr Val Arg Glu Cys Gly
145 150 155 160
Glu Leu Glu Leu Pro Gln His Val Leu Met Asn Cys Ser His Pro Leu
165 170 175
Gly Asn Phe Ser Phe Asn Ser Gln Cys Ser Phe His Cys Thr Asp Gly
180 185 190
Tyr Gln Val Asn Gly Pro Ser Lys Leu Glu Cys Leu Ala Ser Gly Ile
195 200 205
Trp Thr Asn Lys Pro Pro Gln Cys Leu Ala Ala Gln Cys Pro Pro Leu
210 215 220
Lys Ile Pro Glu Arg Gly Asn Met Thr Cys Leu His Ser Ala Lys Ala
225 230 235 240
Phe Gln His Gln Ser Ser Cys Ser Phe Ser Cys Glu Glu Gly Phe Ala
245 250 255
Leu Val Gly Pro Glu Val Val Gln Cys Thr Ala Ser Gly Val Trp Thr
260 265 270
Ala Pro Ala Pro Val Cys Lys Ala
275 280
<210> 83
<211> 474
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 83
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Arg Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn
65 70 75 80
Gln Lys Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val
100 105 110
Tyr Phe Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Pro Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
130 135 140
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
145 150 155 160
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
165 170 175
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
180 185 190
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
195 200 205
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
210 215 220
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
225 230 235 240
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
245 250 255
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
260 265 270
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
275 280 285
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
290 295 300
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
305 310 315 320
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro
340 345 350
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
355 360 365
Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val
370 375 380
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
385 390 395 400
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
405 410 415
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
420 425 430
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
435 440 445
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
450 455 460
Ser Pro Gly Gly His His His His His His
465 470
<210> 84
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 84
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Pro Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Gly
<210> 85
<211> 232
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 85
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His 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 Ser Ala Ser Ser Ser Val
35 40 45
Ser Tyr Met Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg
50 55 60
Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe
65 70 75 80
Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu
85 90 95
Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn
100 105 110
Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg Thr Val
115 120 125
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
130 135 140
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
145 150 155 160
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
165 170 175
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
180 185 190
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
195 200 205
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
210 215 220
Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 86
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 86
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr
85 90 95
Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 87
<211> 476
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 87
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His 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 Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val
65 70 75 80
Asp Ser 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 Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
145 150 155 160
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
210 215 220
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro
225 230 235 240
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Gly His His His His His His
465 470 475
<210> 88
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 88
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Gly
450
<210> 89
<211> 234
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 89
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
20 25 30
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val
35 40 45
Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
50 55 60
Arg Leu Leu Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly
100 105 110
Ser Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 90
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 90
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 91
<211> 396
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 91
Met Leu Leu Leu Leu Leu Pro Leu Leu Trp Gly Arg Glu Arg Ala Glu
1 5 10 15
Gly Gln Ala Cys Gly Leu Val Ala Ser Asn Leu Asn Leu Lys Pro Gly
20 25 30
Glu Cys Leu Arg Val Arg Gly Glu Val Ala Pro Asp Ala Lys Ser Phe
35 40 45
Val Leu Asn Leu Gly Lys Asp Ser Asn Asn Leu Cys Leu His Phe Asn
50 55 60
Pro Arg Phe Asn Ala His Gly Asp Ala Asn Thr Ile Val Cys Asn Ser
65 70 75 80
Lys Asp Gly Gly Ala Trp Gly Thr Glu Gln Arg Glu Ala Val Phe Pro
85 90 95
Phe Gln Pro Gly Ser Val Ala Glu Val Cys Ile Thr Phe Asp Gln Ala
100 105 110
Asn Leu Thr Lys Leu Pro Asp Gly Tyr Glu Phe Lys Phe Pro Asn Arg
115 120 125
Leu Asn Leu Glu Ala Ile Asn Tyr Met Ala Ala Asp Gly Asp Phe Lys
130 135 140
Ile Lys Cys Val Ala Phe Asp Gly Gly Gly Gly Gly Pro Lys Ser Cys
145 150 155 160
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
165 170 175
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
180 185 190
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
195 200 205
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
210 215 220
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
225 230 235 240
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
245 250 255
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
260 265 270
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
275 280 285
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
290 295 300
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
305 310 315 320
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
325 330 335
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
340 345 350
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
355 360 365
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
370 375 380
Pro Gly Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
385 390 395
<210> 92
<211> 370
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 92
Gln Ala Cys Gly Leu Val Ala Ser Asn Leu Asn Leu Lys Pro Gly Glu
1 5 10 15
Cys Leu Arg Val Arg Gly Glu Val Ala Pro Asp Ala Lys Ser Phe Val
20 25 30
Leu Asn Leu Gly Lys Asp Ser Asn Asn Leu Cys Leu His Phe Asn Pro
35 40 45
Arg Phe Asn Ala His Gly Asp Ala Asn Thr Ile Val Cys Asn Ser Lys
50 55 60
Asp Gly Gly Ala Trp Gly Thr Glu Gln Arg Glu Ala Val Phe Pro Phe
65 70 75 80
Gln Pro Gly Ser Val Ala Glu Val Cys Ile Thr Phe Asp Gln Ala Asn
85 90 95
Leu Thr Lys Leu Pro Asp Gly Tyr Glu Phe Lys Phe Pro Asn Arg Leu
100 105 110
Asn Leu Glu Ala Ile Asn Tyr Met Ala Ala Asp Gly Asp Phe Lys Ile
115 120 125
Lys Cys Val Ala Phe Asp Gly Gly Gly Gly Gly Pro Lys Ser Cys Asp
130 135 140
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly
145 150 155 160
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
165 170 175
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
180 185 190
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
195 200 205
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
210 215 220
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
225 230 235 240
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu
245 250 255
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
260 265 270
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
275 280 285
Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
290 295 300
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
305 310 315 320
Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp
325 330 335
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
340 345 350
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
355 360 365
Gly Gly
370
<210> 93
<211> 134
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 93
Gln Ala Cys Gly Leu Val Ala Ser Asn Leu Asn Leu Lys Pro Gly Glu
1 5 10 15
Cys Leu Arg Val Arg Gly Glu Val Ala Pro Asp Ala Lys Ser Phe Val
20 25 30
Leu Asn Leu Gly Lys Asp Ser Asn Asn Leu Cys Leu His Phe Asn Pro
35 40 45
Arg Phe Asn Ala His Gly Asp Ala Asn Thr Ile Val Cys Asn Ser Lys
50 55 60
Asp Gly Gly Ala Trp Gly Thr Glu Gln Arg Glu Ala Val Phe Pro Phe
65 70 75 80
Gln Pro Gly Ser Val Ala Glu Val Cys Ile Thr Phe Asp Gln Ala Asn
85 90 95
Leu Thr Lys Leu Pro Asp Gly Tyr Glu Phe Lys Phe Pro Asn Arg Leu
100 105 110
Asn Leu Glu Ala Ile Asn Tyr Met Ala Ala Asp Gly Asp Phe Lys Ile
115 120 125
Lys Cys Val Ala Phe Asp
130
<210> 94
<211> 512
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 94
Met Leu Leu Leu Leu Leu Pro Leu Leu Trp Gly Arg Glu Arg Ala Glu
1 5 10 15
Gly Gln Ala Asp Asn Phe Ser Leu His Asp Ala Leu Ser Gly Ser Gly
20 25 30
Asn Pro Asn Pro Gln Gly Trp Pro Gly Ala Trp Gly Asn Gln Pro Ala
35 40 45
Gly Ala Gly Gly Tyr Pro Gly Ala Ser Tyr Pro Gly Ala Tyr Pro Gly
50 55 60
Gln Ala Pro Pro Gly Ala Tyr Pro Gly Gln Ala Pro Pro Gly Ala Tyr
65 70 75 80
His Gly Ala Pro Gly Ala Tyr Pro Gly Ala Pro Ala Pro Gly Val Tyr
85 90 95
Pro Gly Pro Pro Ser Gly Pro Gly Ala Tyr Pro Ser Ser Gly Gln Pro
100 105 110
Ser Ala Pro Gly Ala Tyr Pro Ala Thr Gly Pro Tyr Gly Ala Pro Ala
115 120 125
Gly Pro Leu Ile Val Pro Tyr Asn Leu Pro Leu Pro Gly Gly Val Val
130 135 140
Pro Arg Met Leu Ile Thr Ile Leu Gly Thr Val Lys Pro Asn Ala Asn
145 150 155 160
Arg Ile Ala Leu Asp Phe Gln Arg Gly Asn Asp Val Ala Phe His Phe
165 170 175
Asn Pro Arg Phe Asn Glu Asn Asn Arg Arg Val Ile Val Cys Asn Thr
180 185 190
Lys Leu Asp Asn Asn Trp Gly Arg Glu Glu Arg Gln Ser Val Phe Pro
195 200 205
Phe Glu Ser Gly Lys Pro Phe Lys Ile His Val Leu Val Glu Pro Asp
210 215 220
His Phe Lys Val Ala Val Asn Asp Ala His Leu Leu Gln Tyr Asn His
225 230 235 240
Arg Val Lys Lys Leu Asn Glu Ile Ser Lys Leu Gly Ile Ser Gly Asp
245 250 255
Ile Asp Leu Thr Ser Ala Ser Tyr Thr Met Ile Gly Gly Gly Gly Gly
260 265 270
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
275 280 285
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
290 295 300
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
305 310 315 320
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
325 330 335
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
340 345 350
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
355 360 365
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
370 375 380
Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
385 390 395 400
Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
405 410 415
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
420 425 430
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
435 440 445
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
450 455 460
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
465 470 475 480
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
485 490 495
Leu Ser Leu Ser Pro Gly Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
500 505 510
<210> 95
<211> 486
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 95
Gln Ala Asp Asn Phe Ser Leu His Asp Ala Leu Ser Gly Ser Gly Asn
1 5 10 15
Pro Asn Pro Gln Gly Trp Pro Gly Ala Trp Gly Asn Gln Pro Ala Gly
20 25 30
Ala Gly Gly Tyr Pro Gly Ala Ser Tyr Pro Gly Ala Tyr Pro Gly Gln
35 40 45
Ala Pro Pro Gly Ala Tyr Pro Gly Gln Ala Pro Pro Gly Ala Tyr His
50 55 60
Gly Ala Pro Gly Ala Tyr Pro Gly Ala Pro Ala Pro Gly Val Tyr Pro
65 70 75 80
Gly Pro Pro Ser Gly Pro Gly Ala Tyr Pro Ser Ser Gly Gln Pro Ser
85 90 95
Ala Pro Gly Ala Tyr Pro Ala Thr Gly Pro Tyr Gly Ala Pro Ala Gly
100 105 110
Pro Leu Ile Val Pro Tyr Asn Leu Pro Leu Pro Gly Gly Val Val Pro
115 120 125
Arg Met Leu Ile Thr Ile Leu Gly Thr Val Lys Pro Asn Ala Asn Arg
130 135 140
Ile Ala Leu Asp Phe Gln Arg Gly Asn Asp Val Ala Phe His Phe Asn
145 150 155 160
Pro Arg Phe Asn Glu Asn Asn Arg Arg Val Ile Val Cys Asn Thr Lys
165 170 175
Leu Asp Asn Asn Trp Gly Arg Glu Glu Arg Gln Ser Val Phe Pro Phe
180 185 190
Glu Ser Gly Lys Pro Phe Lys Ile His Val Leu Val Glu Pro Asp His
195 200 205
Phe Lys Val Ala Val Asn Asp Ala His Leu Leu Gln Tyr Asn His Arg
210 215 220
Val Lys Lys Leu Asn Glu Ile Ser Lys Leu Gly Ile Ser Gly Asp Ile
225 230 235 240
Asp Leu Thr Ser Ala Ser Tyr Thr Met Ile Gly Gly Gly Gly Gly Pro
245 250 255
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
260 265 270
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
275 280 285
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
290 295 300
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
305 310 315 320
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
325 330 335
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
340 345 350
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly
355 360 365
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
370 375 380
Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
385 390 395 400
Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile
405 410 415
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
420 425 430
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys
435 440 445
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
450 455 460
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
465 470 475 480
Ser Leu Ser Pro Gly Gly
485
<210> 96
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 96
Gln Ala Asp Asn Phe Ser Leu His Asp Ala Leu Ser Gly Ser Gly Asn
1 5 10 15
Pro Asn Pro Gln Gly Trp Pro Gly Ala Trp Gly Asn Gln Pro Ala Gly
20 25 30
Ala Gly Gly Tyr Pro Gly Ala Ser Tyr Pro Gly Ala Tyr Pro Gly Gln
35 40 45
Ala Pro Pro Gly Ala Tyr Pro Gly Gln Ala Pro Pro Gly Ala Tyr His
50 55 60
Gly Ala Pro Gly Ala Tyr Pro Gly Ala Pro Ala Pro Gly Val Tyr Pro
65 70 75 80
Gly Pro Pro Ser Gly Pro Gly Ala Tyr Pro Ser Ser Gly Gln Pro Ser
85 90 95
Ala Pro Gly Ala Tyr Pro Ala Thr Gly Pro Tyr Gly Ala Pro Ala Gly
100 105 110
Pro Leu Ile Val Pro Tyr Asn Leu Pro Leu Pro Gly Gly Val Val Pro
115 120 125
Arg Met Leu Ile Thr Ile Leu Gly Thr Val Lys Pro Asn Ala Asn Arg
130 135 140
Ile Ala Leu Asp Phe Gln Arg Gly Asn Asp Val Ala Phe His Phe Asn
145 150 155 160
Pro Arg Phe Asn Glu Asn Asn Arg Arg Val Ile Val Cys Asn Thr Lys
165 170 175
Leu Asp Asn Asn Trp Gly Arg Glu Glu Arg Gln Ser Val Phe Pro Phe
180 185 190
Glu Ser Gly Lys Pro Phe Lys Ile His Val Leu Val Glu Pro Asp His
195 200 205
Phe Lys Val Ala Val Asn Asp Ala His Leu Leu Gln Tyr Asn His Arg
210 215 220
Val Lys Lys Leu Asn Glu Ile Ser Lys Leu Gly Ile Ser Gly Asp Ile
225 230 235 240
Asp Leu Thr Ser Ala Ser Tyr Thr Met Ile
245 250
<210> 97
<211> 1428
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 97
atgggttgga gcctcatctt gctcttcctt gtcgctgttg ctacgcgtgt ccactccgaa 60
gtgcagctgg tggagtctgg cggaggactg gtgcagccag ggggcagcct gagactgtct 120
tgcgccgcct ccggcttcaa catcaaggac acctacatcc actgggtccg ccaggcacca 180
ggcaagggac tggaatgggt ggcccggatc taccctacca acggctacac cagatacgcc 240
gactccgtga agggccggtt caccatctcc gccgacacct ccaagaacac cgcctacctg 300
cagatgaatt ccctgagggc cgaggacacc gccgtgtact actgctccag atggggaggc 360
gacggcttct acgccatgga ctactggggc cagggcaccc tggtcacagt gtcctctgct 420
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 480
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 600
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 660
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 720
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 780
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 840
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 900
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 960
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 1020
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1080
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatgccg ggatgagctg 1140
accaagaacc aggtcagcct gtggtgcctg gtcaaaggct tctatcccag cgacatcgcc 1200
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1260
gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1320
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1380
aagagcctct ccctgtctcc gggtgggcat caccaccatc accattga 1428
<210> 98
<211> 705
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 98
atgagggtcc ccgctcagct cctggggctc ctgctgctct ggctcccagg tgcacgatgt 60
gacatccaga tgacccagtc cccctcctcc ctgtctgcct ccgtgggcga cagagtgacc 120
atcacctgtc gggcctccca ggatgtgaac accgccgtgg cctggtatca gcagaagcct 180
ggcaaggccc ctaagctgct gatctactcc gcctccttcc tgtactccgg cgtgccctcc 240
cggttctccg gctccagatc cggcaccgac ttcaccctga ccatctccag cctgcagcct 300
gaggacttcg ccacctacta ctgccagcag cactacacca cccctccaac cttcggccag 360
ggcaccaagg tggagatcaa gcgtacggtg gctgcaccat ctgtcttcat cttcccgcca 420
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 480
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 540
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 600
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 660
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttga 705
<210> 99
<211> 1431
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 99
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattcccag 60
gtacaactgc agcagcctgg ggctgagctg gtgaagcctg gggcctcagt gaagatgtcc 120
tgcaaggctt ctggctacac atttaccagt tacaatatgc actgggtaaa acagacacct 180
ggtcggggcc tggaatggat tggagctatt tatcccggaa atggtgatac ttcctacaat 240
cagaagttca aaggcaaggc cacattgact gcagacaaat cctccagcac agcctacatg 300
cagctcagca gcctgacatc tgaggactct gcggtctatt actgtgcaag atcgacttac 360
tacggcggtg actggtactt caatgtctgg ggcgcaggga ccacggtcac cgtctctgca 420
gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 480
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 600
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 660
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agcagagccc 720
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 780
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 840
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 900
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 960
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 1020
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1080
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatg ccgggatgag 1140
ctgaccaaga accaggtcag cctgtggtgc ctggtcaaag gcttctatcc cagcgacatc 1200
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1260
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1320
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1380
cagaagagcc tctccctgtc tccgggtggg catcaccacc atcaccattg a 1431
<210> 100
<211> 699
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 100
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattcacaa 60
attgttctct cccagtctcc agcaatcctg tctgcatctc caggggagaa ggtcacaatg 120
acttgcaggg ccagctcaag tgtaagttac atccactggt tccagcagaa gccaggatcc 180
tcccccaaac cctggattta tgccacatcc aacctggctt ctggagtccc tgttcgcttc 240
agtggcagtg ggtctgggac ttcttactct ctcacaatca gcagagtgga ggctgaagat 300
gctgccactt attactgcca gcagtggact agtaacccac ccacgttcgg aggggggacc 360
aagctggaaa tcaaacgtac ggtggctgca ccatctgtct tcatcttccc gccatctgat 420
gagcagttga aatctggaac tgcctctgtt gtgtgcctgc tgaataactt ctaccccaga 480
gaagccaaag tgcagtggaa ggtggacaac gccctgcaga gcggaaacag ccaggaaagc 540
gtgacagagc aggattccaa ggattccaca tacagcctga gcagcacact gacactgtcc 600
aaggccgact acgagaagca caaggtgtac gcctgcgaag tgacacacca gggactgtcc 660
tcccctgtga caaagagctt caacagagga gaatgctga 699
<210> 101
<211> 1425
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 101
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattcccag 60
gtgcagctga aacagagcgg cccgggcctg gtgcagccga gccagagcct gagcattacc 120
tgcaccgtga gcggctttag cctgaccaac tatggcgtgc attgggtgcg ccagagcccg 180
ggcaaaggcc tggaatggct gggcgtgatt tggagcggcg gcaacaccga ttataacacc 240
ccgtttacca gccgcctgag cattaacaaa gataacagca aaagccaggt gttttttaaa 300
atgaacagcc tgcagagcaa cgataccgcg atttattatt gcgcgcgcgc gctgacctat 360
tatgattatg aatttgcgta ttggggccag ggcaccctgg tgaccgtgag cgcggctagc 420
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 480
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 540
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 600
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 660
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agaaagttga gcccaaatct 720
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 780
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 840
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 900
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 960
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 1020
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1080
aaagggcagc cccgagaacc acaggtgtac accctgcccc catgccggga tgagctgacc 1140
aagaaccagg tcagcctgtg gtgcctggtc aaaggcttct atcccagcga catcgccgtg 1200
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1260
tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1320
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1380
agcctctccc tgtctccggg tgggcatcac caccatcacc attga 1425
<210> 102
<211> 702
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 102
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgac 60
atcctgctca cccagagccc ggtgatcctg tcggtcagcc ccggcgagcg ggtgagcttc 120
agctgccgcg ccagccagtc gatcgggacg aacatccact ggtaccagca gcggaccaac 180
ggcagccccc gcctgctcat caagtacgcg agcgagagca tcagcgggat cccctcgcgg 240
ttcagcggca gcgggagcgg caccgacttc accctgagca tcaacagcgt ggagtcggag 300
gacatcgccg actactactg ccagcagaac aacaactggc cgacgacctt cggcgccggg 360
accaagctgg agctcaagcg caccgtcgcc gcgcccagcg tgttcatctt cccgcccagc 420
gacgagcagc tgaagagcgg cacggccagc gtggtctgcc tgctcaacaa cttctacccc 480
cgggaggcca aggtgcagtg gaaggtggac aacgccctgc agtcggggaa cagccaggag 540
agcgtcaccg agcaggacag caaggacagc acctacagcc tgtcgagcac cctcacgctg 600
agcaaggccg actacgagaa gcacaaggtg tacgcgtgcg aggtgaccca ccagggcctg 660
agcagccccg tcaccaagtc gttcaaccgc ggagaatgct ga 702
<210> 103
<211> 1788
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 103
atgctgctgc tgctgctgct gcccctgctc tgggggaggg agagggtgga aggacagaag 60
agtaaccgga aggattactc gctgacgatg cagagttccg tgaccgtgca agagggcatg 120
tgtgtccatg tgcgctgctc cttctcctac ccagtggaca gccagactga ctctgaccca 180
gttcatggct actggttccg ggcagggaat gatataagct ggaaggctcc agtggccaca 240
aacaacccag cttgggcagt gcaggaggaa actcgggacc gattccacct ccttggggac 300
ccacagacca aaaattgcac cctgagcatc agagatgcca gaatgagtga tgcggggaga 360
tacttctttc gtatggagaa aggaaatata aaatggaatt ataaatatga ccagctctct 420
gtgaacgtga cagccttgac ccacaggccc aacatcctta tccccggtac cctggagtct 480
ggctgcttcc agaatctgac ctgctctgtg ccctgggcct gtgagcaggg gacgccccct 540
atgatctcct ggatggggac ctctgtgtcc cccctgcacc cctccaccac ccgctcctca 600
gtgctcaccc tcatcccaca gccccagcac cacggcacca gcctcacctg tcaggtgacc 660
ttgcctgggg ccggcgtgac cacgaacagg accatccaac tcaatgtgtc ctaccctcct 720
cagaacttga ctgtgactgt cttccaagga gaaggcacag catccacagc tctggggaac 780
agctcatctc tttcagtcct agagggccag tctctgcgct tggtctgtgc tgttgacagc 840
aatccccctg ccaggctgag ctggacctgg aggagtctga ccctgtaccc ctcacagccc 900
tcaaaccctc tggtactgga gctgcaagtg cacctggggg atgaagggga attcacctgt 960
cgagctcaga actctctggg ttcccagcac gtttccctga acctctccct gcaacaggag 1020
tacacaggca aaatgaggcc tgtatcagga ggcggaggtg gaggccccaa atcttgtgac 1080
aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 1140
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 1200
gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 1260
gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 1320
gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 1380
aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1440
cagccccgag aaccacaggt gtgcaccctg cccccatccc gggatgagct gaccaagaac 1500
caggtcagcc tgagctgcgc ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1560
gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1620
ggctccttct tcctcgtgag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1680
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1740
tccctgtctc cgggtgggta cccatacgat gttccagatt acgcttga 1788
<210> 104
<211> 1788
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 104
atgctgctgc tgctgctgct gcccctgctc tgggggaggg agagggtgga aggacagaag 60
agtaaccgga aggattactc gctgacgatg cagagttccg tgaccgtgca agagggcatg 120
tgtgtccatg tgcgctgctc cttctcctac ccagtggaca gccagactga ctctgaccca 180
gttcatggct actggttccg ggcagggaat gatataagct ggaaggctcc agtggccaca 240
aacaacccag cttgggcagt gcaggaggaa actcgggacc gattccacct ccttggggac 300
ccacagacca aaaattgcac cctgagcatc agagatgcca gaatgagtga tgcggggaga 360
tacttctttg ccatggagaa aggaaatata aaatggaatt ataaatatga ccagctctct 420
gtgaacgtga cagccttgac ccacaggccc aacatcctta tccccggtac cctggagtct 480
ggctgcttcc agaatctgac ctgctctgtg ccctgggcct gtgagcaggg gacgccccct 540
atgatctcct ggatggggac ctctgtgtcc cccctgcacc cctccaccac ccgctcctca 600
gtgctcaccc tcatcccaca gccccagcac cacggcacca gcctcacctg tcaggtgacc 660
ttgcctgggg ccggcgtgac cacgaacagg accatccaac tcaatgtgtc ctaccctcct 720
cagaacttga ctgtgactgt cttccaagga gaaggcacag catccacagc tctggggaac 780
agctcatctc tttcagtcct agagggccag tctctgcgct tggtctgtgc tgttgacagc 840
aatccccctg ccaggctgag ctggacctgg aggagtctga ccctgtaccc ctcacagccc 900
tcaaaccctc tggtactgga gctgcaagtg cacctggggg atgaagggga attcacctgt 960
cgagctcaga actctctggg ttcccagcac gtttccctga acctctccct gcaacaggag 1020
tacacaggca aaatgaggcc tgtatcagga ggcggaggtg gaggccccaa atcttgtgac 1080
aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 1140
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 1200
gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 1260
gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 1320
gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 1380
aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1440
cagccccgag aaccacaggt gtgcaccctg cccccatccc gggatgagct gaccaagaac 1500
caggtcagcc tgagctgcgc ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1560
gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1620
ggctccttct tcctcgtgag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1680
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1740
tccctgtctc cgggtgggta cccatacgat gttccagatt acgcttga 1788
<210> 105
<211> 1767
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 105
atgctgctgc tgctgctgcc cctgctctgg gggagggaga gggcggaagg acagacaagt 60
aaactgctga cgatgcagag ttccgtgacg gtgcaggaag gcctgtgtgt ccatgtgccc 120
tgctccttct cctacccctc gcatggctgg atttaccctg gcccagtagt tcatggctac 180
tggttccggg aaggggccaa tacagaccag gatgctccag tggccacaaa caacccagct 240
cgggcagtgt gggaggagac tcgggaccga ttccacctcc ttggggaccc acataccaag 300
aattgcaccc tgagcatcag agatgccaga agaagtgatg cggggagata cttctttcgt 360
atggagaaag gaagtataaa atggaattat aaacatcacc ggctctctgt gaatgtgaca 420
gccttgaccc acaggcccaa catcctcatc ccaggcaccc tggagtccgg ctgcccccag 480
aatctgacct gctctgtgcc ctgggcctgt gagcagggga caccccctat gatctcctgg 540
atagggacct ccgtgtcccc cctggacccc tccaccaccc gctcctcggt gctcaccctc 600
atcccacagc cccaggacca tggcaccagc ctcacctgtc aggtgacctt ccctggggcc 660
agcgtgacca cgaacaagac cgtccatctc aacgtgtcct acccgcctca gaacttgacc 720
atgactgtct tccaaggaga cggcacagta tccacagtct tgggaaatgg ctcatctctg 780
tcactcccag agggccagtc tctgcgcctg gtctgtgcag ttgatgcagt tgacagcaat 840
ccccctgcca ggctgagcct gagctggaga ggcctgaccc tgtgcccctc acagccctca 900
aacccggggg tgctggagct gccttgggtg cacctgaggg atgcagctga attcacctgc 960
agagctcaga accctctcgg ctctcagcag gtctacctga acgtctccct gcagagcaaa 1020
gccacatcag gcggaggtgg aggccccaaa tcttgtgaca aaactcacac atgcccaccg 1080
tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 1140
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1200
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1260
acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1320
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1380
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1440
tgcaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gagctgcgcg 1500
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1560
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctcgtgagc 1620
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1680
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtgggtac 1740
ccatacgatg ttccagatta cgcttga 1767
<210> 106
<211> 1767
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 106
atgctgctgc tgctgctgcc cctgctctgg gggagggaga gggcggaagg acagacaagt 60
aaactgctga cgatgcagag ttccgtgacg gtgcaggaag gcctgtgtgt ccatgtgccc 120
tgctccttct cctacccctc gcatggctgg atttaccctg gcccagtagt tcatggctac 180
tggttccggg aaggggccaa tacagaccag gatgctccag tggccacaaa caacccagct 240
cgggcagtgt gggaggagac tcgggaccga ttccacctcc ttggggaccc acataccaag 300
aattgcaccc tgagcatcag agatgccaga agaagtgatg cggggagata cttctttgcc 360
atggagaaag gaagtataaa atggaattat aaacatcacc ggctctctgt gaatgtgaca 420
gccttgaccc acaggcccaa catcctcatc ccaggcaccc tggagtccgg ctgcccccag 480
aatctgacct gctctgtgcc ctgggcctgt gagcagggga caccccctat gatctcctgg 540
atagggacct ccgtgtcccc cctggacccc tccaccaccc gctcctcggt gctcaccctc 600
atcccacagc cccaggacca tggcaccagc ctcacctgtc aggtgacctt ccctggggcc 660
agcgtgacca cgaacaagac cgtccatctc aacgtgtcct acccgcctca gaacttgacc 720
atgactgtct tccaaggaga cggcacagta tccacagtct tgggaaatgg ctcatctctg 780
tcactcccag agggccagtc tctgcgcctg gtctgtgcag ttgatgcagt tgacagcaat 840
ccccctgcca ggctgagcct gagctggaga ggcctgaccc tgtgcccctc acagccctca 900
aacccggggg tgctggagct gccttgggtg cacctgaggg atgcagctga attcacctgc 960
agagctcaga accctctcgg ctctcagcag gtctacctga acgtctccct gcagagcaaa 1020
gccacatcag gcggaggtgg aggccccaaa tcttgtgaca aaactcacac atgcccaccg 1080
tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 1140
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1200
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1260
acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1320
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1380
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1440
tgcaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gagctgcgcg 1500
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1560
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctcgtgagc 1620
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1680
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtgggtac 1740
ccatacgatg ttccagatta cgcttga 1767
<210> 107
<211> 2376
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 107
atgctactgc cactgctgct gtcctcgctg ctgggcgggt cccaggctat ggatgggaga 60
ttctggatac gagtgcagga gtcagtgatg gtgccggagg gcctgtgcat ctctgtgccc 120
tgctctttct cctacccccg acaggactgg acagggtcta ccccagctta tggctactgg 180
ttcaaagcag tgactgagac aaccaagggt gctcctgtgg ccacaaacca ccagagtcga 240
gaggtggaaa tgagcacccg gggccgattc cagctcactg gggatcccgc caaggggaac 300
tgctccttgg tgatcagaga cgcgcagatg caggatgagt cacagtactt ctttcgggtg 360
gagagaggaa gctatgtgag atataatttc atgaacgatg ggttctttct aaaagtaaca 420
gccctgactc agaagcctga tgtctacatc cccgagaccc tggagcccgg gcagccggtg 480
acggtcatct gtgtgtttaa ctgggccttt gaggaatgtc cacccccttc tttctcctgg 540
acgggggctg ccctctcctc ccaaggaacc aaaccaacga cctcccactt ctcagtgctc 600
agcttcacgc ccagacccca ggaccacaac accgacctca cctgccatgt ggacttctcc 660
agaaagggtg tgagcgcaca gaggaccgtc cgactccgtg tggcctatgc ccccagagac 720
cttgttatca gcatttcacg tgacaacacg ccagccctgg agccccagcc ccagggaaat 780
gtcccatacc tggaagccca aaaaggccag ttcctgcggc tcctctgtgc tgctgacagc 840
cagccccctg ccacactgag ctgggtcctg cagaacagag tcctctcctc gtcccatccc 900
tggggcccta gacccctggg gctggagctg cccggggtga aggctgggga ttcagggcgc 960
tacacctgcc gagcggagaa caggcttggc tcccagcagc gagccctgga cctctctgtg 1020
cagtatcctc cagagaacct gagagtgatg gtttcccaag caaacaggac agtcctggaa 1080
aaccttggga acggcacgtc tctcccagta ctggagggcc aaagcctgtg cctggtctgt 1140
gtcacacaca gcagcccccc agccaggctg agctggaccc agaggggaca ggttctgagc 1200
ccctcccagc cctcagaccc cggggtcctg gagctgcctc gggttcaagt ggagcacgaa 1260
ggagagttca cctgccacgc tcggcaccca ctgggctccc agcacgtctc tctcagcctc 1320
tccgtgcact actccccgaa gctgctgggc ccctcctgct cctgggaggc tgagggtctg 1380
cactgcagct gctcctccca ggccagcccg gccccctctc tgcgctggtg gcttggggag 1440
gagctgctgg aggggaacag cagccaggac tccttcgagg tcacccccag ctcagccggg 1500
ccctgggcca acagctccct gagcctccat ggagggctca gctccggcct caggctccgc 1560
tgtgaggcct ggaacgtcca tggggcccag agtggatcca tcctgcagct gccagataag 1620
aagggactca tctcaacggg cggaggtgga ggccccaaat cttgtgacaa aactcacaca 1680
tgcccaccgt gcccagcacc tgaactcctg gggggaccgt cagtcttcct cttcccccca 1740
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 1800
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1860
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1920
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 1980
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 2040
ccacaggtgt gcaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 2100
agctgcgcgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 2160
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2220
ctcgtgagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 2280
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 2340
ggtgggtacc catacgatgt tccagattac gcttga 2376
<210> 108
<211> 1428
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 108
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattcccaa 60
gtgcaattgg tgcagtccgg cgttgaagtt aaaaagcccg gtgcgtccgt gaaggtttcc 120
tgtaaggcga gtggatacac cttcacaaac tattatatgt attgggtcag gcaagctccg 180
ggacagggtt tggaatggat gggaggtatc aatccatcca atggtggtac gaattttaat 240
gagaagttca aaaatagagt gactctgact accgacagtt ctacgactac agcctacatg 300
gaattgaagt ccctgcaatt cgacgatacg gcagtttatt attgtgctag gagggattat 360
agattcgaca tgggttttga ttattggggc caagggacta ctgtaacagt atcatccgct 420
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 480
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 600
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 660
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 720
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaagcagc cgggggaccg 780
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 840
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 900
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 960
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 1020
tacaagtgca aggtctccaa caaagccctc ggagccccca tcgagaaaac catctccaaa 1080
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatgccg ggatgagctg 1140
accaagaacc aggtcagcct gtggtgcctg gtcaaaggct tctatcccag cgacatcgcc 1200
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1260
gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1320
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1380
aagagcctct ccctgtctcc gggtgggcat caccaccatc accattga 1428
<210> 109
<211> 714
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 109
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgaa 60
attgttctca ctcagtctcc ggcaacgttg tcactcagtc ctggtgagag agctacgttg 120
tcctgccggg ctagcaaggg agtttcaaca tcaggatatt cctacctcca ctggtaccaa 180
cagaaaccgg gtcaggctcc gcgcctcctc atttacctcg catcctacct ggaatctggg 240
gtgcccgcgc ggttttctgg gtctggctct gggactgatt tcactctcac tatttcctca 300
ttggaacccg aggattttgc ggtgtactat tgccagcact cacgggatct gcctcttact 360
tttggaggag gtactaaagt ggaaataaaa cgcaccgtcg ccgcgcccag cgtgttcatc 420
ttcccgccca gcgacgagca gctgaagagc ggcacggcca gcgtggtctg cctgctcaac 480
aacttctacc cccgggaggc caaggtgcag tggaaggtgg acaacgccct gcagtcgggg 540
aacagccagg agagcgtcac cgagcaggac agcaaggaca gcacctacag cctgtcgagc 600
accctcacgc tgagcaaggc cgactacgag aagcacaagg tgtacgcgtg cgaggtgacc 660
caccagggcc tgagcagccc cgtcaccaag tcgttcaacc gcggagaatg ctga 714
<210> 110
<211> 1407
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 110
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattcccaa 60
gtgcagctcg ttgaatcagg tgggggtgtg gtacaacctg ggagatcact gcgactggat 120
tgcaaggctt ccggtatcac gttttcaaac tcaggtatgc attgggtccg acaggcacca 180
ggaaaaggac tcgagtgggt agccgtaatc tggtatgacg gctcaaaacg ctactatgcg 240
gatagtgtaa aaggaaggtt cacgatctca cgcgataact ctaagaacac cctgttcctt 300
cagatgaact ccctgcgagc agaagatacg gcagtttatt attgtgcaac caacgatgat 360
tattggggcc agggaacctt ggttaccgtc tcatcagcta gcaccaaggg cccatcggtc 420
ttccccctgg caccctcctc caagagcacc tctgggggca cagcggccct gggctgcctg 480
gtcaaggact acttccccga accggtgacg gtgtcgtgga actcaggcgc cctgaccagc 540
ggcgtgcaca ccttcccggc tgtcctacag tcctcaggac tctactccct cagcagcgtg 600
gtgaccgtgc cctccagcag cttgggcacc cagacctaca tctgcaacgt gaatcacaag 660
cccagcaaca ccaaggtgga caagaaagtt gagcccaaat cttgtgacaa aactcacaca 720
tgcccaccgt gcccagcacc tgaagcagcc gggggaccgt cagtcttcct cttcccccca 780
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 840
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 900
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 960
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 1020
aaagccctcg gagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1080
ccacaggtgt acaccctgcc cccatgccgg gatgagctga ccaagaacca ggtcagcctg 1140
tggtgcctgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 1200
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1260
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1320
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1380
ggtgggcatc accaccatca ccattga 1407
<210> 111
<211> 702
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 111
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgag 60
atcgttctta ctcaatctcc tgcaacgctt tccctcagtc caggagaacg cgcgaccctt 120
tcatgcagag cctctcagag tgtttcctca tatctcgcct ggtatcagca aaaaccaggg 180
caagcacccc gcttgttgat ttacgacgcg agcaatcggg ccacaggcat tccagccagg 240
ttttcaggaa gcggatcagg caccgatttc acgctgacca ttagctccct tgagccagaa 300
gatttcgcag tctactattg tcagcaatca tcaaactggc ctcgaacctt cggccagggt 360
acaaaagttg aaataaagcg caccgtcgcc gcgcccagcg tgttcatctt cccgcccagc 420
gacgagcagc tgaagagcgg cacggccagc gtggtctgcc tgctcaacaa cttctacccc 480
cgggaggcca aggtgcagtg gaaggtggac aacgccctgc agtcggggaa cagccaggag 540
agcgtcaccg agcaggacag caaggacagc acctacagcc tgtcgagcac cctcacgctg 600
agcaaggccg actacgagaa gcacaaggtg tacgcgtgcg aggtgaccca ccagggcctg 660
agcagccccg tcaccaagtc gttcaaccgc ggagaatgct ga 702
<210> 112
<211> 1788
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 112
atgctgctgc tgctgctgct gcccctgctc tgggggaggg agagggtgga aggacagaag 60
agtaaccgga aggattactc gctgacgatg cagagttccg tgaccgtgca agagggcatg 120
tgtgtccatg tgcgctgctc cttctcctac ccagtggaca gccagactga ctctgaccca 180
gttcatggct actggttccg ggcagggaat gatataagct ggaaggctcc agtggccaca 240
aacaacccag cttgggcagt gcaggaggaa actcgggacc gattccacct ccttggggac 300
ccacagacca aaaattgcac cctgagcatc agagatgcca gaatgagtga tgcggggaga 360
tacttctttc gtatggagaa aggaaatata aaatggaatt ataaatatga ccagctctct 420
gtgaacgtga cagccttgac ccacaggccc aacatcctta tccccggtac cctggagtct 480
ggctgcttcc agaatctgac ctgctctgtg ccctgggcct gtgagcaggg gacgccccct 540
atgatctcct ggatggggac ctctgtgtcc cccctgcacc cctccaccac ccgctcctca 600
gtgctcaccc tcatcccaca gccccagcac cacggcacca gcctcacctg tcaggtgacc 660
ttgcctgggg ccggcgtgac cacgaacagg accatccaac tcaatgtgtc ctaccctcct 720
cagaacttga ctgtgactgt cttccaagga gaaggcacag catccacagc tctggggaac 780
agctcatctc tttcagtcct agagggccag tctctgcgct tggtctgtgc tgttgacagc 840
aatccccctg ccaggctgag ctggacctgg aggagtctga ccctgtaccc ctcacagccc 900
tcaaaccctc tggtactgga gctgcaagtg cacctggggg atgaagggga attcacctgt 960
cgagctcaga actctctggg ttcccagcac gtttccctga acctctccct gcaacaggag 1020
tacacaggca aaatgaggcc tgtatcagga ggcggaggtg gaggccccaa atcttgtgac 1080
aaaactcaca catgcccacc gtgcccagca cctgaagcag ccgggggacc gtcagtcttc 1140
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 1200
gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 1260
gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 1320
gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 1380
aaggtctcca acaaagccct cggagccccc atcgagaaaa ccatctccaa agccaaaggg 1440
cagccccgag aaccacaggt gtgcaccctg cccccatccc gggatgagct gaccaagaac 1500
caggtcagcc tgagctgcgc ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1560
gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1620
ggctccttct tcctcgtgag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1680
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1740
tccctgtctc cgggtgggta cccatacgat gttccagatt acgcttga 1788
<210> 113
<211> 1767
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 113
atgctgctgc tgctgctgcc cctgctctgg gggagggaga gggcggaagg acagacaagt 60
aaactgctga cgatgcagag ttccgtgacg gtgcaggaag gcctgtgtgt ccatgtgccc 120
tgctccttct cctacccctc gcatggctgg atttaccctg gcccagtagt tcatggctac 180
tggttccggg aaggggccaa tacagaccag gatgctccag tggccacaaa caacccagct 240
cgggcagtgt gggaggagac tcgggaccga ttccacctcc ttggggaccc acataccaag 300
aattgcaccc tgagcatcag agatgccaga agaagtgatg cggggagata cttctttcgt 360
atggagaaag gaagtataaa atggaattat aaacatcacc ggctctctgt gaatgtgaca 420
gccttgaccc acaggcccaa catcctcatc ccaggcaccc tggagtccgg ctgcccccag 480
aatctgacct gctctgtgcc ctgggcctgt gagcagggga caccccctat gatctcctgg 540
atagggacct ccgtgtcccc cctggacccc tccaccaccc gctcctcggt gctcaccctc 600
atcccacagc cccaggacca tggcaccagc ctcacctgtc aggtgacctt ccctggggcc 660
agcgtgacca cgaacaagac cgtccatctc aacgtgtcct acccgcctca gaacttgacc 720
atgactgtct tccaaggaga cggcacagta tccacagtct tgggaaatgg ctcatctctg 780
tcactcccag agggccagtc tctgcgcctg gtctgtgcag ttgatgcagt tgacagcaat 840
ccccctgcca ggctgagcct gagctggaga ggcctgaccc tgtgcccctc acagccctca 900
aacccggggg tgctggagct gccttgggtg cacctgaggg atgcagctga attcacctgc 960
agagctcaga accctctcgg ctctcagcag gtctacctga acgtctccct gcagagcaaa 1020
gccacatcag gcggaggtgg aggccccaaa tcttgtgaca aaactcacac atgcccaccg 1080
tgcccagcac ctgaagcagc cgggggaccg tcagtcttcc tcttcccccc aaaacccaag 1140
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1200
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1260
acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1320
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1380
ggagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1440
tgcaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gagctgcgcg 1500
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1560
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctcgtgagc 1620
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1680
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtgggtac 1740
ccatacgatg ttccagatta cgcttga 1767
<210> 114
<211> 1755
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 114
atgctactgc cactgctgct gtcctcgctg ctgggcgggt cccaggctat ggatgggaga 60
ttctggatac gagtgcagga gtcagtgatg gtgccggagg gcctgtgcat ctctgtgccc 120
tgctctttct cctacccccg acaggactgg acagggtcta ccccagctta tggctactgg 180
ttcaaagcag tgactgagac aaccaagggt gctcctgtgg ccacaaacca ccagagtcga 240
gaggtggaaa tgagcacccg gggccgattc cagctcactg gggatcccgc caaggggaac 300
tgctccttgg tgatcagaga cgcgcagatg caggatgagt cacagtactt ctttcgggtg 360
gagagaggaa gctatgtgag atataatttc atgaacgatg ggttctttct aaaagtaaca 420
gccctgactc agaagcctga tgtctacatc cccgagaccc tggagcccgg gcagccggtg 480
acggtcatct gtgtgtttaa ctgggccttt gaggaatgtc cacccccttc tttctcctgg 540
acgggggctg ccctctcctc ccaaggaacc aaaccaacga cctcccactt ctcagtgctc 600
agcttcacgc ccagacccca ggaccacaac accgacctca cctgccatgt ggacttctcc 660
agaaagggtg tgagcgcaca gaggaccgtc cgactccgtg tggcctatgc ccccagagac 720
cttgttatca gcatttcacg tgacaacacg ccagccctgg agccccagcc ccagggaaat 780
gtcccatacc tggaagccca aaaaggccag ttcctgcggc tcctctgtgc tgctgacagc 840
cagccccctg ccacactgag ctgggtcctg cagaacagag tcctctcctc gtcccatccc 900
tggggcccta gacccctggg gctggagctg cccggggtga aggctgggga ttcagggcgc 960
tacacctgcc gagcggagaa caggcttggc tcccagcagc gagccctgga cctctctggc 1020
ggaggtggag gccccaaatc ttgtgacaaa actcacacat gcccaccgtg cccagcacct 1080
gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 1140
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 1200
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1260
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1320
tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1380
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgtg caccctgccc 1440
ccatcccggg atgagctgac caagaaccag gtcagcctga gctgcgcggt caaaggcttc 1500
tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1560
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tcgtgagcaa gctcaccgtg 1620
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1680
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtgggtaccc atacgatgtt 1740
ccagattacg cttga 1755
<210> 115
<211> 1182
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 115
atggccttca gcggttccca ggctccctac ctgagtccag ctgtcccctt ttctgggact 60
attcaaggag gtctccagga cggacttcag atcactgtca atgggaccgt tctcagctcc 120
agtggaacca ggtttgctgt gaactttcag actggcttca gtggaaatga cattgccttc 180
cacttcaacc ctcggtttga agatggaggg tacgtggtgt gcaacacgag gcagaacgga 240
agctgggggc ccgaggagag gaagacacac atgcctttcc agaaggggat gccctttgac 300
ctctgcttcc tggtgcagag ctcagatttc aaggtgatgg tgaacgggat cctcttcgtg 360
cagtacttcc accgcgtgcc cttccaccgt gtggacacca tctccgtcaa tggctctgtg 420
cagctgtcct acatcagctt ccagggcgga ggtggaggcc ccaaatcttg tgacaaaact 480
cacacatgcc caccgtgccc agcacctgaa gcagccgggg gaccgtcagt cttcctcttc 540
cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg 600
gtggacgtga gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag 660
gtgcataatg ccaagacaaa gccgcgggag gagcagtaca acagcacgta ccgtgtggtc 720
agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc 780
tccaacaaag ccctcggagc ccccatcgag aaaaccatct ccaaagccaa agggcagccc 840
cgagaaccac aggtgtgcac cctgccccca tcccgggatg agctgaccaa gaaccaggtc 900
agcctgagct gcgcggtcaa aggcttctat cccagcgaca tcgccgtgga gtgggagagc 960
aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 1020
ttcttcctcg tgagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1080
tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 1140
tctccgggtg ggtacccata cgatgttcca gattacgctt ga 1182
<210> 116
<211> 1431
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 116
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattcccag 60
gtacaactgc agcagcctgg ggctgagctg gtgaagcctg gggcctcagt gaagatgtcc 120
tgcaaggctt ctggctacac atttaccagt tacaatatgc actgggtaaa acagacacct 180
ggtcggggcc tggaatggat tggagctatt tatcccggaa atggtgatac ttcctacaat 240
cagaagttca aaggcaaggc cacattgact gcagacaaat cctccagcac agcctacatg 300
cagctcagca gcctgacatc tgaggactct gcggtctatt actgtgcaag atcgacttac 360
tacggcggtg actggtactt caatgtctgg ggcgcaggga ccacggtcac cgtctctgca 420
gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 480
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 600
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 660
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agcagagccc 720
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaagc agccggggga 780
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 840
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 900
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 960
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 1020
gagtacaagt gcaaggtctc caacaaagcc ctcggagccc ccatcgagaa aaccatctcc 1080
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatg ccgggatgag 1140
ctgaccaaga accaggtcag cctgtggtgc ctggtcaaag gcttctatcc cagcgacatc 1200
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1260
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1320
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1380
cagaagagcc tctccctgtc tccgggtggg catcaccacc atcaccattg a 1431
<210> 117
<211> 1431
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 117
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgaa 60
gttcaactgg tggagagcgg cggggggctt gtgaaaccag gcgggtccct gaaactgagc 120
tgtgctgcga gcggctacac cttcacaagc tacgttatgc attgggtgag gcaggcacct 180
ggtaagggtc ttgagtggat cggctatata aatccctaca atgatggcac gaagtacaac 240
gagaaattcc aagggcgcgt gactatttct agcgataagt caatctctac tgcctatatg 300
gaactttctt ctttgagaag cgaagacaca gctatgtact actgcgcccg aggcacctac 360
tactatggaa cccgcgtatt tgattattgg gggcaaggca ccttggtgac agtaagctca 420
gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 480
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 600
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 660
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 720
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaagc agccggggga 780
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 840
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 900
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 960
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 1020
gagtacaagt gcaaggtctc caacaaagcc ctcggagccc ccatcgagaa aaccatctcc 1080
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatg ccgggatgag 1140
ctgaccaaga accaggtcag cctgtggtgc ctggtcaaag gcttctatcc cagcgacatc 1200
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1260
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1320
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1380
cagaagagcc tctccctgtc tccgggtggg catcaccacc atcaccattg a 1431
<210> 118
<211> 717
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 118
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgat 60
atcgtaatga cgcaatcccc agcgacgctc agtctcagcc ccggcgaacg ggcgactctt 120
tcatgtagga gctccaaaag cctccagaat gtcaacggta atacgtacct ttactggttt 180
caacagaagc ctggtcagag tccacaactt ctgatatacc gcatgtctaa tctgaatagt 240
ggcgtcccgg acagattttc tggaagcggc agcggaaccg aatttactct cacgatcagt 300
tcactcgaac ctgaggactt cgccgtttac tactgtatgc aacatctcga gtatcctatc 360
acgtttggag ctgggacgaa attggaaatc aagcgcaccg tcgccgcgcc cagcgtgttc 420
atcttcccgc ccagcgacga gcagctgaag agcggcacgg ccagcgtggt ctgcctgctc 480
aacaacttct acccccggga ggccaaggtg cagtggaagg tggacaacgc cctgcagtcg 540
gggaacagcc aggagagcgt caccgagcag gacagcaagg acagcaccta cagcctgtcg 600
agcaccctca cgctgagcaa ggccgactac gagaagcaca aggtgtacgc gtgcgaggtg 660
acccaccagg gcctgagcag ccccgtcacc aagtcgttca accgcggaga atgctga 717
<210> 119
<211> 1422
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 119
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgag 60
gtgcagctgg tggagtctgg gggaggcttg gtccagcctg gggggtccct gagactctcc 120
tgtgcagcct ctggattcac ctttagtggc tatggcatga gctgggtccg ccaggctcca 180
gggaaggggc tggagtgggt ggccaccata actagtggtg gaacttacac ctactatcca 240
gactctgtga agggccgatt caccatctcc agagacaacg ccaagaactc actgtatctg 300
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag atccctcgcg 360
ggaaatgcta tggactactg gggccaagga accctggtca ccgtctcctc agctagcacc 420
aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 480
gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540
ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 600
tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 660
aacgtgaatc acaagcccag caacaccaag gtggacaaga aagttgagcc caaatcttgt 720
gacaaaactc acacatgccc accgtgccca gcacctgaag cagccggggg accgtcagtc 780
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 840
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 900
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 960
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1020
tgcaaggtct ccaacaaagc cctcggagcc cccatcgaga aaaccatctc caaagccaaa 1080
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat gccgggatga gctgaccaag 1140
aaccaggtca gcctgtggtg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1200
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1260
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1320
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1380
ctctccctgt ctccgggtgg gcatcaccac catcaccatt ga 1422
<210> 120
<211> 702
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 120
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgaa 60
attgtgttga cacagtctcc agccaccctg tctttgtctc caggggaaag agccaccctc 120
tcctgcaggg ccagtcagac tattagcgac tacttacact ggtaccaaca gaaacctggc 180
caggctccca ggctcctcat caaatttgca tcccaatcca tttctggcat cccagccagg 240
ttcagtggca gtgggtctgg gacagacttc actctcacca tcagcagcct agagcctgaa 300
gattttgcag tttattactg tcagaatggt cacggctttc ctcggacgtt cggccaaggg 360
accaaggtgg aaatcaaacg caccgtcgcc gcgcccagcg tgttcatctt cccgcccagc 420
gacgagcagc tgaagagcgg cacggccagc gtggtctgcc tgctcaacaa cttctacccc 480
cgggaggcca aggtgcagtg gaaggtggac aacgccctgc agtcggggaa cagccaggag 540
agcgtcaccg agcaggacag caaggacagc acctacagcc tgtcgagcac cctcacgctg 600
agcaaggccg actacgagaa gcacaaggtg tacgcgtgcg aggtgaccca ccagggcctg 660
agcagccccg tcaccaagtc gttcaaccgc ggagaatgct ga 702
<210> 121
<211> 1419
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 121
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattcccaa 60
gttcaacttc aacaacccgg cgcagagctg gttaagcctg gggcgagtgt aatgatgagt 120
tgcaaagcaa gcggatacac gtttaccaac tacaatatgc attgggtaaa acagacgcct 180
gggcaaggtc ttgaatggat cggcaccatc taccctggca acgatgatac gtcatacaac 240
cagaagttta aggataaggc cacgctgacc gccgataaat cctcctctgc agcgtacatg 300
cagttgtcta gtcttacgtc tgaggactct gcggtgtact attgcgccag ggggggttat 360
agagctatgg actactgggg gcaagggacc tccgtgaccg tatcctcagc tagcaccaag 420
ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 480
ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 540
gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 600
ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 660
gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 720
aaaactcaca catgcccacc gtgcccagca cctgaagcag ccgggggacc gtcagtcttc 780
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 840
gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 900
gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 960
gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 1020
aaggtctcca acaaagccct cggagccccc atcgagaaaa ccatctccaa agccaaaggg 1080
cagccccgag aaccacaggt gtacaccctg cccccatgcc gggatgagct gaccaagaac 1140
caggtcagcc tgtggtgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1200
gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1260
ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1320
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1380
tccctgtctc cgggtgggca tcaccaccat caccattga 1419
<210> 122
<211> 717
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 122
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgat 60
gtgttgatga cgcaaacccc attgtctctc ccagtaagcc tgggcgacca agcgagtatc 120
tcttgccgct catcccaatc aatcgtttat tccaatggca acacatatct gggatggtac 180
ctccaaaaac cagggcaaag cccaaagctg cttatatata aagtgtcaaa tcgatttagc 240
ggagtcccgg acagattttc agggtcaggg tccggaacag attttacgtt gaaaatctct 300
cgcgtagaag cagaggacct gggggtctat cattgctttc agggtagtca tgtcccatat 360
acctttggcg gtggtacaaa ggtagaaatc aagcgcaccg tcgccgcgcc cagcgtgttc 420
atcttcccgc ccagcgacga gcagctgaag agcggcacgg ccagcgtggt ctgcctgctc 480
aacaacttct acccccggga ggccaaggtg cagtggaagg tggacaacgc cctgcagtcg 540
gggaacagcc aggagagcgt caccgagcag gacagcaagg acagcaccta cagcctgtcg 600
agcaccctca cgctgagcaa ggccgactac gagaagcaca aggtgtacgc gtgcgaggtg 660
acccaccagg gcctgagcag ccccgtcacc aagtcgttca accgcggaga atgctga 717
<210> 123
<211> 1428
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 123
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgaa 60
gttcaattgc tggagagcgg cggaggtttg gtccagcccg gcggttcttt gcgactgtcc 120
tgcgcagcct ctggtttcac attttcttcc tacattatga tgtgggtgcg ccaggctcct 180
ggaaagggac ttgaatgggt aagcagcatt tatccctctg gtgggatcac tttctacgcc 240
gataccgtga aggggagatt cactatatca cgagacaact caaagaatac cctctatctt 300
cagatgaata gtttgcgagc cgaggatacg gctgtctact actgtgccag gatcaagttg 360
ggtaccgtga caactgttga ttattggggt caaggaactc tcgtaaccgt cagcagtgct 420
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 480
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 600
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 660
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 720
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 780
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 840
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 900
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 960
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 1020
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1080
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatgccg ggatgagctg 1140
accaagaacc aggtcagcct gtggtgcctg gtcaaaggct tctatcccag cgacatcgcc 1200
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1260
gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1320
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1380
aagagcctct ccctgtctcc gggtgggcat caccaccatc accattga 1428
<210> 124
<211> 705
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 124
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattcccag 60
agtgccctga cgcagcctgc ttctgtctct gggagtccag ggcagtccat taccattagt 120
tgtactggta catcctctga cgtgggtggg tataactatg ttagttggta tcaacagcat 180
cccggtaaag ctcccaaact gatgatctac gacgtgagta ataggcccag cggtgttagt 240
aacaggtttt caggatctaa gagtggtaac acagcgtcat tgactataag tgggctgcaa 300
gctgaggatg aagctgatta ctactgctca tcatatacgt catcaagtac aagagtattt 360
gggaccggta cgaaagtcac agtccttgga cagccaaaag ccaatccgac agtaactttg 420
ttcccgccaa gctcagagga gctgcaagcg aataaagcaa ctcttgtgtg tctgataagt 480
gatttttacc cgggagcggt cactgtggcg tggaaggcag acgggtcacc agttaaggct 540
ggagtggaga ccacgaaacc gagcaagcaa agcaacaaca aatatgccgc atcatcatat 600
ctgtctctga cccccgagca gtggaagtcc catcgaagtt actcttgcca ggtcacccat 660
gagggctcta ctgttgagaa gacggtcgct cccacggagt gttaa 705
<210> 125
<211> 1422
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 125
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgaa 60
gtgcaactgg tcgagtcagg gggcgggctt gttcagccgg ggggtagctt gcgactgtcc 120
tgtgccgctt caggattcac attcagcgat tcctggattc attgggtccg gcaagcccca 180
gggaagggac tcgaatgggt ggcatggatt tctccttatg gcggtagcac ctactatgcg 240
gactcagtga aaggacgctt tacgatatca gcagatactt caaaaaatac ggcgtatctt 300
caaatgaatt cactccgagc tgaggatact gccgtgtatt actgcgcgag acggcattgg 360
ccgggaggtt ttgattattg gggtcaggga accctcgtta ccgtgtcatc agctagcacc 420
aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 480
gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540
ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 600
tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 660
aacgtgaatc acaagcccag caacaccaag gtggacaaga aagttgagcc caaatcttgt 720
gacaaaactc acacatgccc accgtgccca gcacctgaag cagccggggg accgtcagtc 780
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 840
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 900
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 960
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1020
tgcaaggtct ccaacaaagc cctcggagcc cccatcgaga aaaccatctc caaagccaaa 1080
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat gccgggatga gctgaccaag 1140
aaccaggtca gcctgtggtg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1200
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1260
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1320
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1380
ctctccctgt ctccgggtgg gcatcaccac catcaccatt ga 1422
<210> 126
<211> 702
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 126
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgac 60
atacaaatga cccaaagtcc aagctctctt tcagcatcag ttggagatcg cgttactatc 120
acctgccgcg cgagtcaaga cgtaagcact gctgtagcat ggtatcaaca gaagccaggg 180
aaggccccaa agctcctgat atacagcgcc agtttcctgt atagtggtgt acccagccga 240
ttttctggca gtggaagtgg cacggacttt acactcacca tcagtagctt gcagccagaa 300
gattttgcga cgtattactg tcaacaatat ttgtaccacc cagcgacttt tgggcaggga 360
accaaggtcg agataaagcg caccgtcgcc gcgcccagcg tgttcatctt cccgcccagc 420
gacgagcagc tgaagagcgg cacggccagc gtggtctgcc tgctcaacaa cttctacccc 480
cgggaggcca aggtgcagtg gaaggtggac aacgccctgc agtcggggaa cagccaggag 540
agcgtcaccg agcaggacag caaggacagc acctacagcc tgtcgagcac cctcacgctg 600
agcaaggccg actacgagaa gcacaaggtg tacgcgtgcg aggtgaccca ccagggcctg 660
agcagccccg tcaccaagtc gttcaaccgc ggagaatgct ga 702
<210> 127
<211> 2799
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 127
atgcatctgc tggggccctg gctgctgctg ctggtgctgg agtacttggc tttctctgac 60
tcaagtaaat gggtttttga gcaccctgaa accctctacg cctgggaggg ggcctgcgtc 120
tggatcccct gcacctacag agccctagat ggtgacctgg aaagcttcat cctgttccac 180
aatcctgagt ataacaagaa cacctcgaag tttgatggga caagactcta tgaaagcaca 240
aaggatggga aggttccttc tgagcagaaa agggtgcaat tcctgggaga caagaataag 300
aactgcacac tgagtatcca cccggtgcac ctcaatgaca gtggtcagct ggggctgagg 360
atggagtcca agactgagaa atggatggaa cgaatacacc tcaatgtctc tgaaaggcct 420
tttccacctc atatccagct ccctccagaa attcaagagt cccaggaagt cactctgacc 480
tgcttgctga atttctcctg ctatgggtat ccgatccaat tgcagtggct cctagagggg 540
gttccaatga ggcaggctgc tgtcacctcg acctccttga ccatcaagtc tgtcttcacc 600
cggagcgagc tcaagttctc cccacagtgg agtcaccatg ggaagattgt gacctgccag 660
cttcaggatg cagatgggaa gttcctctcc aatgacacgg tgcagctgaa cgtgaagcac 720
accccgaagt tggagatcaa ggtcactccc agtgatgcca tagtgaggga gggggactct 780
gtgaccatga cctgcgaggt cagcagcagc aacccggagt acacgacggt atcctggctc 840
aaggatggga cctcgctgaa gaagcagaat acattcacgc taaacctgcg cgaagtgacc 900
aaggaccaga gtgggaagta ctgctgtcag gtctccaatg acgtgggccc gggaaggtcg 960
gaagaagtgt tcctgcaagt gcagtatgcc ccggaacctt ccacggttca gatcctccac 1020
tcaccggctg tggagggaag tcaagtcgag tttctttgca tgtcactggc caatcctctt 1080
ccaacaaatt acacgtggta ccacaatggg aaagaaatgc agggaaggac agaggagaaa 1140
gtccacatcc caaagatcct cccctggcac gctgggactt attcctgtgt ggcagaaaac 1200
attcttggta ctggacagag gggcccggga gctgagctgg atgtccagta tcctcccaag 1260
aaggtgacca cagtgattca aaaccccatg ccgattcgag aaggagacac agtgaccctt 1320
tcctgtaact acaattccag taaccccagt gttacccggt atgaatggaa accccatggc 1380
gcctgggagg agccatcgct tggggtgctg aagatccaaa acgttggctg ggacaacaca 1440
accatcgcct gcgcaaggtg taatagttgg tgctcgtggg cctcccctgt cgccctgaat 1500
gtccagtatg ccccccgaga cgtgagggtc cggaaaatca agcccctttc cgagattcac 1560
tctggaaact cggtcagcct ccaatgtgac ttctcaagca gccaccccaa agaagtccag 1620
ttcttctggg agaaaaatgg caggcttctg gggaaagaaa gccagctgaa ttttgactcc 1680
atctccccag aagatgctgg gagttacagc tgctgggtga acaactccat aggacagaca 1740
gcgtccaagg cctggacact tgaagtgctg tatgcaccca ggaggctgcg tgtgtccatg 1800
agcccggggg accaagtgat ggaggggaag agtgcaaccc tgacctgtga gagcgacgcc 1860
aaccctcccg tctcccacta cacctggttt gactggaata accaaagcct cccctaccac 1920
agccagaagc tgagattgga gccggtgaag gtccagcact cgggtgccta ctggtgccag 1980
gggaccaaca gtgtgggcaa gggccgttcg cctctcagca ccctcaccgt ctactatagc 2040
ccggagacca tcggcaggcg aggcggaggt ggaggcccca aatcttgtga caaaactcac 2100
acatgcccac cgtgcccagc acctgaagca gccgggggac cgtcagtctt cctcttcccc 2160
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 2220
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 2280
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 2340
gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 2400
aacaaagccc tcggagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 2460
gaaccacagg tgtgcaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 2520
ctgagctgcg cggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 2580
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 2640
ttcctcgtga gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 2700
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 2760
ccgggtgggt acccatacga tgttccagat tacgcttga 2799
<210> 128
<211> 1716
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 128
atgcatctgc tggggccctg gctgctgctg ctggtgctgg agtacttggc tttctctgac 60
tcaagtaaat gggtttttga gcaccctgaa accctctacg cctgggaggg ggcctgcgtc 120
tggatcccct gcacctacag agccctagat ggtgacctgg aaagcttcat cctgttccac 180
aatcctgagt ataacaagaa cacctcgaag tttgatggga caagactcta tgaaagcaca 240
aaggatggga aggttccttc tgagcagaaa agggtgcaat tcctgggaga caagaataag 300
aactgcacac tgagtatcca cccggtgcac ctcaatgaca gtggtcagct ggggctgagg 360
atggagtcca agactgagaa atggatggaa cgaatacacc tcaatgtctc tgaaaggcct 420
tttccacctc atatccagct ccctccagaa attcaagagt cccaggaagt cactctgacc 480
tgcttgctga atttctcctg ctatgggtat ccgatccaat tgcagtggct cctagagggg 540
gttccaatga ggcaggctgc tgtcacctcg acctccttga ccatcaagtc tgtcttcacc 600
cggagcgagc tcaagttctc cccacagtgg agtcaccatg ggaagattgt gacctgccag 660
cttcaggatg cagatgggaa gttcctctcc aatgacacgg tgcagctgaa cgtgaagcac 720
accccgaagt tggagatcaa ggtcactccc agtgatgcca tagtgaggga gggggactct 780
gtgaccatga cctgcgaggt cagcagcagc aacccggagt acacgacggt atcctggctc 840
aaggatggga cctcgctgaa gaagcagaat acattcacgc taaacctgcg cgaagtgacc 900
aaggaccaga gtgggaagta ctgctgtcag gtctccaatg acgtgggccc gggaaggtcg 960
gaagaagtgt tcctgcaagg cggaggtgga ggccccaaat cttgtgacaa aactcacaca 1020
tgcccaccgt gcccagcacc tgaagcagcc gggggaccgt cagtcttcct cttcccccca 1080
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 1140
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1200
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1260
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 1320
aaagccctcg gagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1380
ccacaggtgt gcaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1440
agctgcgcgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 1500
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1560
ctcgtgagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1620
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1680
ggtgggtacc catacgatgt tccagattac gcttga 1716
<210> 129
<211> 1755
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 129
atgctactgc cactgctgct gtcctcgctg ctgggcgggt cccaggctat ggatgggaga 60
ttctggatac gagtgcagga gtcagtgatg gtgccggagg gcctgtgcat ctctgtgccc 120
tgctctttct cctacccccg acaggactgg acagggtcta ccccagctta tggctactgg 180
ttcaaagcag tgactgagac aaccaagggt gctcctgtgg ccacaaacca ccagagtcga 240
gaggtggaaa tgagcacccg gggccgattc cagctcactg gggatcccgc caaggggaac 300
tgctccttgg tgatcagaga cgcgcagatg caggatgagt cacagtactt ctttcgggtg 360
gagagaggaa gctatgtgag atataatttc atgaacgatg ggttctttct aaaagtaaca 420
gccctgactc agaagcctga tgtctacatc cccgagaccc tggagcccgg gcagccggtg 480
acggtcatct gtgtgtttaa ctgggccttt gaggaatgtc cacccccttc tttctcctgg 540
acgggggctg ccctctcctc ccaaggaacc aaaccaacga cctcccactt ctcagtgctc 600
agcttcacgc ccagacccca ggaccacaac accgacctca cctgccatgt ggacttctcc 660
agaaagggtg tgagcgcaca gaggaccgtc cgactccgtg tggcctatgc ccccagagac 720
cttgttatca gcatttcacg tgacaacacg ccagccctgg agccccagcc ccagggaaat 780
gtcccatacc tggaagccca aaaaggccag ttcctgcggc tcctctgtgc tgctgacagc 840
cagccccctg ccacactgag ctgggtcctg cagaacagag tcctctcctc gtcccatccc 900
tggggcccta gacccctggg gctggagctg cccggggtga aggctgggga ttcagggcgc 960
tacacctgcc gagcggagaa caggcttggc tcccagcagc gagccctgga cctctctggc 1020
ggaggtggag gccccaaatc ttgtgacaaa actcacacat gcccaccgtg cccagcacct 1080
gaagcagccg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 1140
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 1200
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1260
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1320
tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctcgg agcccccatc 1380
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgtg caccctgccc 1440
ccatcccggg atgagctgac caagaaccag gtcagcctga gctgcgcggt caaaggcttc 1500
tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1560
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tcgtgagcaa gctcaccgtg 1620
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1680
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtgggtaccc atacgatgtt 1740
ccagattacg cttga 1755
<210> 130
<211> 1641
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 130
atgattgctt cacagtttct ctcagctctc actttggtgc ttctcattaa agagagtgga 60
gcctggtctt acaacacctc cacggaagct atgacttatg atgaggccag tgcttattgt 120
cagcaaaggt acacacacct ggttgcaatt caaaacaaag aagagattga gtacctaaac 180
tccatattga gctattcacc aagttattac tggattggaa tcagaaaagt caacaatgtg 240
tgggtctggg taggaaccca gaaacctctg acagaagaag ccaagaactg ggctccaggt 300
gaacccaaca ataggcaaaa agatgaggac tgcgtggaga tctacatcaa gagagaaaaa 360
gatgtgggca tgtggaatga tgagaggtgc agcaagaaga agcttgccct atgctacaca 420
gctgcctgta ccaatacatc ctgcagtggc cacggtgaat gtgtagagac catcaataat 480
tacacttgca agtgtgaccc tggcttcagt ggactcaagt gtgagcaaat tgtgaactgt 540
acagccctgg aatcccctga gcatggaagc ctggtttgca gtcacccact gggaaacttc 600
agctacaatt cttcctgctc tatcagctgt gataggggtt acctgccaag cagcatggag 660
accatgcagt gtatgtcctc tggagaatgg agtgctccta ttccagcctg caatgtggtt 720
gagtgtgatg ctgtgacaaa tccagccaat gggttcgtgg aatgtttcca aaaccctgga 780
agcttcccat ggaacacaac ctgtacattt gactgtgaag aaggatttga actaatggga 840
gcccagagcc ttcagtgtac ctcatctggg aattgggaca acgagaagcc aacgtgtaaa 900
gctggcggag gtggaggccc caaatcttgt gacaaaactc acacatgccc accgtgccca 960
gcacctgaag cagccggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 1020
ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 1080
cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 1140
ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1200
caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcggagcc 1260
cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 1320
ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgagctg cgcggtcaaa 1380
ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1440
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcgt gagcaagctc 1500
accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 1560
gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg gtacccatac 1620
gatgttccag attacgcttg a 1641
<210> 131
<211> 1701
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 131
atggccaact gccaaatagc catcttgtac cagagattcc agagagtggt ctttggaatt 60
tcccaactcc tttgcttcag tgccctgatc tctgaactaa caaaccagaa agaagtggca 120
gcatggactt atcattacag cacaaaagca tactcatgga atatttcccg taaatactgc 180
cagaatcgct acacagactt agtggccatc cagaataaaa atgaaattga ttacctcaat 240
aaggtcctac cctactacag ctcctactac tggattggga tccgaaagaa caataagaca 300
tggacatggg tgggaaccaa aaaggctctc accaacgagg ctgagaactg ggctgataat 360
gaacctaaca acaaaaggaa caacgaggac tgcgtggaga tatacatcaa gagtccgtca 420
gcccctggca agtggaatga tgagcactgc ttgaagaaaa agcacgcatt gtgttacaca 480
gcctcctgcc aggacatgtc ctgcagcaaa caaggagagt gcctcgagac catcgggaac 540
tacacctgct cctgttaccc tggattctat gggccagaat gtgaatacgt gagagagtgt 600
ggagaacttg agctccctca acacgtgctc atgaactgca gccaccctct gggaaacttc 660
tcttttaact cgcagtgcag cttccactgc actgacgggt accaagtaaa tgggcccagc 720
aagctggaat gcttggcttc tggaatctgg acaaataagc ctccacagtg tttagctgcc 780
cagtgcccac ccctgaagat tcctgaacga ggaaacatga cctgccttca ttctgcaaaa 840
gcattccagc atcagtctag ctgcagcttc agttgtgaag agggatttgc attagttgga 900
ccggaagtgg tgcaatgcac agcctcgggg gtatggacag ccccagcccc agtgtgtaaa 960
gctggcggag gtggaggccc caaatcttgt gacaaaactc acacatgccc accgtgccca 1020
gcacctgaag cagccggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 1080
ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 1140
cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 1200
ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1260
caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcggagcc 1320
cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 1380
ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgagctg cgcggtcaaa 1440
ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1500
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcgt gagcaagctc 1560
accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 1620
gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg gtacccatac 1680
gatgttccag attacgcttg a 1701
<210> 132
<211> 1425
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 132
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattcccaa 60
gttcaactgg tccagagtgg aggcggagta gtgcaacccg gtaggtcact ccggctgagt 120
tgtaaggctt cagggtatac tttcacgcgc tacacgatgc actgggtacg acaagccccc 180
ggaaaagggc tggaatggat aggctacatc aatccgagta gaggctacac aaactataat 240
cagaaggtca aagataggtt tactatttcc cgcgataaca gcaaaaatac ggcttttctc 300
caaatggact ctttgaggcc cgaagacact ggggtttatt tttgtgccag gtattacgat 360
gaccactatt gtttggacta ctggggacag ggcaccccag tcacggttag cagtgctagc 420
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 480
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 540
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 600
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 660
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agaaagttga gcccaaatct 720
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aagcagccgg gggaccgtca 780
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 840
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 900
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 960
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 1020
aagtgcaagg tctccaacaa agccctcgga gcccccatcg agaaaaccat ctccaaagcc 1080
aaagggcagc cccgagaacc acaggtgtac accctgcccc catgccggga tgagctgacc 1140
aagaaccagg tcagcctgtg gtgcctggtc aaaggcttct atcccagcga catcgccgtg 1200
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1260
tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1320
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1380
agcctctccc tgtctccggg tgggcatcac caccatcacc attga 1425
<210> 133
<211> 699
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 133
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgat 60
atacaaatga cccaatcacc atctagcctc tctgcctcag taggtgaccg ggttacgata 120
acctgttctg cctcctctag cgtctcctat atgaattggt atcaacaaac accaggcaaa 180
gcgcccaaac gatggatcta cgacacgtcc aagttggcat ctggagtgcc ctcacgcttc 240
tcaggaagcg gatcagggac ggattacacc tttaccatta gcagcctgca accagaggac 300
attgcaactt attattgcca gcaatggtca tcaaatccat tcaccttcgg tcaaggcact 360
aagctccaga taactcgcac cgtcgccgcg cccagcgtgt tcatcttccc gcccagcgac 420
gagcagctga agagcggcac ggccagcgtg gtctgcctgc tcaacaactt ctacccccgg 480
gaggccaagg tgcagtggaa ggtggacaac gccctgcagt cggggaacag ccaggagagc 540
gtcaccgagc aggacagcaa ggacagcacc tacagcctgt cgagcaccct cacgctgagc 600
aaggccgact acgagaagca caaggtgtac gcgtgcgagg tgacccacca gggcctgagc 660
agccccgtca ccaagtcgtt caaccgcgga gaatgctga 699
<210> 134
<211> 1425
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 134
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattcccaa 60
gttcaactgg tccagagtgg aggcggagta gtgcaacccg gtaggtcact ccggctgagt 120
tgtaaggctt cagggtatac tttcacgcgc tacacgatgc actgggtacg acaagccccc 180
ggaaaagggc tggaatggat aggctacatc aatccgagta gaggctacac aaactataat 240
cagaaggtca aagataggtt tactatttcc cgcgataaca gcaaaaatac ggcttttctc 300
caaatggact ctttgaggcc cgaagacact ggggtttatt tttgtgccag gtattacgat 360
gaccactatt gtttggacta ctggggacag ggcaccccag tcacggttag cagtgctagc 420
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 480
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 540
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 600
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 660
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agaaagttga gcccaaatct 720
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aagcagccgg gggaccgtca 780
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 840
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 900
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 960
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 1020
aagtgcaagg tctccaacaa agccctcgga gcccccatcg agaaaaccat ctccaaagcc 1080
aaagggcagc cccgagaacc acaggtgtac accctgcccc catgccggga tgagctgacc 1140
aagaaccagg tcagcctgtg gtgcctggtc aaaggcttct atcccagcga catcgccgtg 1200
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1260
tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1320
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1380
agcctctccc tgtctccggg tgggcatcac caccatcacc attga 1425
<210> 135
<211> 699
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 135
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattccgat 60
atacaaatga cccaatcacc atctagcctc tctgcctcag taggtgaccg ggttacgata 120
acctgttctg cctcctctag cgtctcctat atgaattggt atcaacaaac accaggcaaa 180
gcgcccaaac gatggatcta cgacacgtcc aagttggcat ctggagtgcc ctcacgcttc 240
tcaggaagcg gatcagggac ggattacacc tttaccatta gcagcctgca accagaggac 300
attgcaactt attattgcca gcaatggtca tcaaatccat tcaccttcgg tcaaggcact 360
aagctccaga taactcgcac cgtcgccgcg cccagcgtgt tcatcttccc gcccagcgac 420
gagcagctga agagcggcac ggccagcgtg gtctgcctgc tcaacaactt ctacccccgg 480
gaggccaagg tgcagtggaa ggtggacaac gccctgcagt cggggaacag ccaggagagc 540
gtcaccgagc aggacagcaa ggacagcacc tacagcctgt cgagcaccct cacgctgagc 600
aaggccgact acgagaagca caaggtgtac gcgtgcgagg tgacccacca gggcctgagc 660
agccccgtca ccaagtcgtt caaccgcgga gaatgctga 699
<210> 136
<211> 1194
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 136
atgctgctgc tgctgctgcc cctgctctgg gggagggaga gggcggaagg acaggcttgt 60
ggtctggtcg ccagcaacct gaatctcaaa cctggagagt gccttcgagt gcgaggcgag 120
gtggctcctg acgctaagag cttcgtgctg aacctgggca aagacagcaa caacctgtgc 180
ctgcacttca accctcgctt caacgcccac ggcgacgcca acaccatcgt gtgcaacagc 240
aaggacggcg gggcctgggg gaccgagcag cgggaggctg tctttccctt ccagcctgga 300
agtgttgcag aggtgtgcat caccttcgac caggccaacc tgaccgtcaa gctgccagat 360
ggatacgaat tcaagttccc caaccgcctc aacctggagg ccatcaacta catggcagct 420
gacggtgact tcaagatcaa atgtgtggcc tttgacggcg gaggtggagg ccccaaatct 480
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aagcagccgg gggaccgtca 540
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 600
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 660
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 720
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 780
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 840
aaagggcagc cccgagaacc acaggtgtgc accctgcccc catcccggga tgagctgacc 900
aagaaccagg tcagcctgag ctgcgcggtc aaaggcttct atcccagcga catcgccgtg 960
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1020
tccgacggct ccttcttcct cgtgagcaag ctcaccgtgg acaagagcag gtggcagcag 1080
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1140
agcctctccc tgtctccggg tgggtaccca tacgatgttc cagattacgc ttga 1194
<210> 137
<211> 1539
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 137
atgctgctgc tgctgctgcc cctgctctgg gggagggaga gggcggaagg acaggcagac 60
aatttttcgc tccatgatgc gttatctggg tctggaaacc caaaccctca aggatggcct 120
ggcgcatggg ggaaccagcc tgctggggca gggggctacc caggggcttc ctatcctggg 180
gcctaccccg ggcaggcacc cccaggggct tatcctggac aggcacctcc aggcgcctac 240
catggagcac ctggagctta tcccggagca cctgcacctg gagtctaccc agggccaccc 300
agcggccctg gggcctaccc atcttctgga cagccaagtg cccccggagc ctaccctgcc 360
actggcccct atggcgcccc tgctgggcca ctgattgtgc cttataacct gcctttgcct 420
gggggagtgg tgcctcgcat gctgataaca attctgggca cggtgaagcc caatgcaaac 480
agaattgctt tagatttcca aagagggaat gatgttgcct tccactttaa cccacgcttc 540
aatgagaaca acaggagagt cattgtttgc aatacaaagc tggataataa ctggggaagg 600
gaagaaagac agtcggtttt cccatttgaa agtgggaaac cattcaaaat acatgtactg 660
gttgaacctg accacttcaa ggttgcagtg aatgatgctc acttgttgca gtacaatcat 720
cgggttaaaa aactcaatga aatcagcaaa ctgggaattt ctggtgacat agacctcacc 780
agtgcttcat ataccatgat aggcggaggt ggaggcccca aatcttgtga caaaactcac 840
acatgcccac cgtgcccagc acctgaagca gccgggggac cgtcagtctt cctcttcccc 900
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 960
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1020
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1080
gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 1140
aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1200
gaaccacagg tgtgcaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1260
ctgagctgcg cggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1320
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1380
ttcctcgtga gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1440
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1500
ccgggtgggt acccatacga tgttccagat tacgcttga 1539

Claims (53)

1.一种双特异性分子，所述双特异性分子包含：
细胞靶向部分；以及
聚糖结合部分。
2.根据权利要求1所述的双特异性分子，其中所述细胞靶向部分是癌细胞靶向部分。
3.根据权利要求2所述的双特异性分子，其中所述癌细胞靶向部分与选自由以下组成的组的癌细胞表面分子结合：5T4、AXL受体酪氨酸激酶(AXL)、B细胞成熟抗原(BCMA)、c-MET、C4.4a、碳酸酐酶6(CA6)、碳酸酐酶9(CA9)、钙粘蛋白6、CD19、CD20、CD22、CD25、CD27L、CD30、CD33、CD37、CD44、CD44v6、CD56、CD70、CD74、CD79b、CD123、CD138、癌胚抗原(CEA)、cKit、Cripto蛋白、CS1、δ样规范Notch配体3(DLL3)、内皮素受体B型(EDNRB)、肝配蛋白A4(EFNA4)、表皮生长因子受体(EGFR)、EGFRvIII、外切核苷酸焦磷酸酶/磷酸二酯酶3(ENPP3)、EPH受体A2(EPHA2)、成纤维细胞生长因子受体2(FGFR2)、成纤维细胞生长因子受体3(FGFR3)、FMS样酪氨酸激酶3(FLT3)、叶酸受体1(FOLR1)、GD2神经节苷脂、非转移性糖蛋白B(GPNMB)、鸟苷酸环化酶2C(GUCY2C)、人表皮生长因子受体2(HER2)、人表皮生长因子受体3(HER3)、整联蛋白α、溶酶体相关膜蛋白1(LAMP-1)、Lewis Y、LIV-1、富含亮氨酸重复蛋白15(LRRC15)、间皮素(MSLN)、粘蛋白1(MUC1)、粘蛋白16(MUC16)、钠依赖性磷酸盐转运蛋白2B(NaPi2b)、连接素4、NMB、NOTCH3、p-钙粘蛋白(p-CAD)、程序性细胞死亡受体配体1(PD-L1)、程序性细胞死亡受体配体2(PD-L2)、前列腺特异性膜抗原(PSMA)、蛋白质酪氨酸激酶7(PTK7)、溶质载体家族44成员4(SLC44A4)、SLIT样家族成员6(SLITRK6)、STEAP家族成员1(STEAP1)、组织因子(TF)、T细胞免疫球蛋白和粘蛋白蛋白1(TIM-1)、Tn抗原、滋养层细胞表面抗原(TROP-2)和Wilms肿瘤1(WT1)。
4.根据权利要求1所述的双特异性分子，其中所述细胞靶向部分是免疫细胞靶向部分。
5.根据权利要求4所述的双特异性分子，其中所述免疫细胞靶向部分与选自由以下组成的组的免疫细胞表面分子结合：PD-1、PD-L1、PD-L2、CLTA-4、VISTA、LAG-3、TIM-3、CD24、CD47、SIRPα、CD3、CD8、CD4、CD28、CD80、CD86、CD19、ICOS、OX40、OX40L、GD3神经节苷脂、TIGIT、Siglec-2、Siglec-3、Siglec-7、Siglec-8、Siglec-9、Siglec-10、Siglec-15、半乳凝素-9、B7-H3、B7-H4、CD40、CD40L、B7RP1、CD70、CD27、BTLA、HVEM、KIR、4-1BB、4-1BBL、CD226、CD155、CD112、GITR、GITRL、A2aR、CD137、CD137L、CD45、CD206、CD163、TRAIL、NKG2D、CD16和TGF-β。
6.根据权利要求1至5中任一项所述的双特异性分子，其中所述聚糖结合部分包括唾液酸聚糖结合部分。
7.根据权利要求6所述的双特异性分子，其中所述唾液酸聚糖结合部分包含凝集素的唾液酸聚糖结合结构域。
8.根据权利要求7所述的双特异性分子，其中所述凝集素是唾液酸结合免疫球蛋白样凝集素(Siglec)。
9.根据权利要求8所述的双特异性分子，其中所述Siglec是CD33相关Siglec。
10.根据权利要求9所述的双特异性分子，其中所述CD33相关Siglec选自由以下组成的组：Siglec-7、Siglec-9和Siglec-10。
11.根据权利要求10所述的双特异性分子，其中所述CD33相关Siglec是Siglec-7。
12.根据权利要求10所述的双特异性分子，其中所述CD33相关Siglec是Siglec-9。
13.根据权利要求8所述的双特异性分子，其中所述Siglec是Siglec-15。
14.根据权利要求6所述的双特异性分子，其中所述唾液酸聚糖结合部分包含Siglec样粘附素的唾液酸聚糖结合结构域。
15.根据权利要求1至5中任一项所述的双特异性分子，其中所述聚糖结合部分包含C型凝集素的聚糖结合结构域。
16.根据权利要求15所述的双特异性分子，其中所述C型凝集素是DECTIN-1、凝集素样氧化低密度脂蛋白受体-1(LOX-1)、C型凝集素样受体-1(CLEC-1)、C型凝集素样受体2(CLEC-2)、髓样抑制性C型凝集素样受体(MICL)、CLEC9A、DC免疫受体(DCIR)、DECTIN-2、血液DC抗原-2(BDCA-2)、巨噬细胞诱导型C型凝集素(MINCLE)、巨噬细胞半乳糖凝集素(MGL)或无唾液酸糖蛋白受体(ASGPR)。
17.根据权利要求1至5中任一项所述的双特异性分子，其中所述聚糖结合部分包含半乳凝素的聚糖结合结构域。
18.根据权利要求17所述的双特异性分子，其中所述半乳凝素是Gal-1、Gal-2、Gal-3、Gal-4、Gal-5、Gal-6、Gal-7、Gal-8、Gal-9、Gal-10、Gal-11、Gal-12、Gal-13、Gal-14或Gal-15。
19.根据权利要求17所述的双特异性分子，其中所述半乳凝素是Gal-1。
20.根据权利要求17所述的双特异性分子，其中所述半乳凝素是Gal-3。
21.根据权利要求1至5中任一项所述的双特异性分子，其中所述聚糖结合部分包含选择素的聚糖结合结构域。
22.根据权利要求21所述的双特异性分子，其中所述选择素是P-选择素(CD62P)、E-选择素(CD62E)或L-选择素(CD62L)。
23.根据权利要求1至22中任一项所述的双特异性分子，其中所述细胞靶向部分包含靶细胞表面上受体的配体，或与靶细胞上的细胞表面分子结合的小分子。
24.根据权利要求1至22中任一项所述的双特异性分子，其中所述细胞靶向部分包含抗体的抗原结合结构域。
25.根据权利要求1至22中任一项所述的双特异性分子，其中所述细胞靶向部分包含抗体重链和抗体轻链，所述抗体重链包含可变重链(VH)区，所述抗体轻链包含可变轻链(VL)区。
26.根据权利要求25所述的双特异性分子，其中所述抗体重链包含CH1结构域、铰链区、CH2结构域、CH3结构域或它们的任何组合。
27.根据权利要求25或权利要求26所述的双特异性分子，其中所述抗体重链包含CH2结构域、CH3结构域或两者。
28.根据权利要求25至27中任一项所述的双特异性分子，其中所述抗体重链包含片段可结晶(Fc)区。
29.根据权利要求1至28中任一项所述的双特异性分子，其中所述聚糖结合部分包含抗体重链结构域。
30.根据权利要求29所述的双特异性分子，其中所述聚糖结合部分的所述抗体重链结构域包含CH1结构域、铰链区、CH2结构域、CH3结构域或它们的任何组合。
31.根据权利要求29或权利要求30所述的双特异性分子，其中所述聚糖结合部分的所述抗体重链结构域包含CH2结构域、CH3结构域或两者。
32.根据权利要求29至31中任一项所述的双特异性分子，其中所述聚糖结合部分的所述抗体重链结构域包含片段可结晶(Fc)区。
33.根据权利要求31或权利要求32所述的双特异性分子，其中所述细胞靶向部分包含含有CH3结构域的抗体重链，并且其中所述双特异性分子是包含杵臼结构修饰的CH3结构域的异二聚体。
34.根据权利要求1至32中任一项所述的双特异性分子，其中所述双特异性分子是包含所述细胞靶向部分与所述聚糖结合部分融合的融合蛋白。
35.根据权利要求34所述的双特异性分子，其中所述细胞靶向部分直接与所述聚糖结合部分融合。
36.根据权利要求34所述的双特异性分子，其中所述细胞靶向部分经由接头间接地与所述聚糖结合部分融合。
37.根据权利要求1至32中任一项所述的双特异性分子，其中所述双特异性分子是包含所述细胞靶向部分与所述聚糖结合部分缀合的缀合物。
38.一种核酸，所述核酸编码：
根据权利要求1至36中任一项所述的双特异性分子的细胞靶向部分；
根据权利要求1至36中任一项所述的双特异性分子的聚糖结合部分；或
两者。
39.一种表达载体，所述表达载体包含根据权利要求38所述的核酸。
40.一种药物组合物，所述药物组合物包含：
根据权利要求1至37中任一项所述的双特异性分子；以及
药学上可接受的载剂。
41.根据权利要求40所述的药物组合物，其中所述细胞靶向部分是癌细胞靶向部分。
42.根据权利要求40所述的药物组合物，其中所述细胞靶向部分是免疫细胞靶向部分。
43.一种试剂盒，所述试剂盒包含：
一个或多个单位剂量的根据权利要求40至42中任一项所述的药物组合物；以及
用于向有需要的个体施用所述一个或多个单位剂量的所述药物组合物的说明书。
44.根据权利要求43所述的试剂盒，所述试剂盒包含两个或更多个单位剂量的所述药物组合物。
45.根据权利要求43或权利要求44所述的试剂盒，其中所述细胞靶向部分是癌细胞靶向部分，并且其中所述说明书包括将所述一个或多个单位剂量的所述药物组合物施用于需要增强抗肿瘤免疫的个体的说明书。
46.根据权利要求43或权利要求44所述的试剂盒，其中所述细胞靶向部分是免疫细胞靶向部分，并且其中所述说明书包括将所述一个或多个单位剂量的所述药物组合物施用于需要增强或阻遏免疫应答的个体的说明书。
47.一种增强有需要的个体的抗肿瘤免疫的方法，所述方法包括：
向所述个体施用有效量的根据权利要求41所述的药物组合物。
48.一种增强或阻遏有需要的个体的免疫应答的方法，所述方法包括：
向所述个体施用有效量的根据权利要求42所述的药物组合物。
49.根据权利要求47或权利要求48所述的方法，其中所述施用是通过肠胃外施用进行。
50.一种双特异性分子，所述双特异性分子包含：
与Fc区融合的细胞靶向部分；以及
与Fc区融合的包含受体的配体结合结构域的部分，
其中所述细胞靶向部分和包含受体的配体结合结构域的所述部分经由Fc区异二聚化。
51.根据权利要求50所述的双特异性分子，其中所述细胞靶向部分如权利要求2至5中任一项限定。
52.根据权利要求50或权利要求51所述的双特异性分子，其中包含受体的配体结合结构域的所述部分包含与细胞表面配体结合的受体的配体结合结构域。
53.根据权利要求50至52中任一项所述的双特异性分子，其中所述双特异性分子是包含杵臼结构修饰的CH3结构域的异二聚体。
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