CN111566127B - 制导和导航控制蛋白及其制备和使用方法 - Google Patents

制导和导航控制蛋白及其制备和使用方法 Download PDF

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CN111566127B
CN111566127B CN201980006846.7A CN201980006846A CN111566127B CN 111566127 B CN111566127 B CN 111566127B CN 201980006846 A CN201980006846 A CN 201980006846A CN 111566127 B CN111566127 B CN 111566127B
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CN111566127A (zh
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朱义
欧勒·奥尔森
夏冬
大卫·耶利曼
卡特里娜·贝科娃
安妮玛丽·卢梭
比尔·布雷迪
布莱尔·伦肖
布莱恩·科瓦切维奇
梁玉
卡米拉·王
高泽人
黄辉
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Chengdu Bailidote Biological Pharmaceutical Co ltd
Seattle Immunization Co
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Chengdu Bailidote Biological Pharmaceutical Co ltd
Seattle Immunization Co
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Abstract

本申请提供了制导和导航控制(GNC)蛋白。在一个实施方案中，制导和导航控制(GNC)蛋白包括T细胞活化受体的结合结构域、肿瘤相关抗原的结合结构域、免疫检查点受体的结合结构域和T细胞共刺激受体的结合结构域。肿瘤相关抗原的结合结构域不与T细胞共刺激受体的结合结构域相邻。在一个实施方案中，T细胞活化受体的结合结构域与肿瘤相关抗原(TAA)的结合结构域相邻。

Description

制导和导航控制蛋白及其制备和使用方法
相关申请的交叉引用
本申请要求2018年3月27日提交的美国临时专利申请第62/648880号和2018年3月27日提交的美国临时专利申请第62/648888号的权益，其全部公开内容明确地以引用方式并入本文。
技术领域
本申请总体涉及具有针对免疫细胞和肿瘤细胞两者上的表面分子的多特异性结合活性的制导和导航控制(Guidance and Navigation Contral，GNC)蛋白的技术领域，并且更具体地涉及制备和使用GNC蛋白。
背景技术
癌细胞发展各种策略以逃避免疫系统。免疫逃逸的基础机制之一是免疫系统对癌细胞的识别降低。癌症特异性抗原呈递缺陷或缺乏会导致免疫耐受和癌症进展。在存在有效的免疫识别的情况下，肿瘤使用其他机制来避免被免疫系统消除。免疫活性肿瘤产生抑制微环境以下调免疫应答。多个参与者参与成形抑制性肿瘤微环境，包括肿瘤细胞、调节性T细胞、髓系衍生的抑制性细胞、基质细胞和其它细胞类型。免疫应答的抑制可以通过免疫抑制细胞因子的分泌或从局部环境中消除必需的存活因子以细胞接触非依赖性方式进行。细胞接触依赖性抑制依赖于在细胞表面上表达的分子，例如程序性死亡配体1(PD-L1)，T淋巴细胞相关蛋白4(CTLA-4)等[Dunn等人，2004，《免疫》(Immunity)，21(2)：137-48；Adachi&Tamada，2015，《癌症科学》(Cancer Sci.)，106(8):945-50]。
随着人们继续更好地了解肿瘤逃避免疫系统识别的机制，最近出现了针对这些机制的新的治疗模式。2011年3月25日，美国食品和药物管理局(FDA)批准用于治疗不可切除的或转移性黑色素瘤的易普利姆玛注射剂(伊匹单抗(Yervoy)，Bristol-myerssquibb)。伊匹单抗与活化的T细胞上表达的细胞毒性T淋巴细胞相关蛋白4(CTLA-4)结合并阻断CTLA-4与抗原呈递细胞上的CD80/86的相互作用，从而阻断通过CTLA-4递送到T细胞中的阴性或抑制性信号，导致抗原特异性T细胞的再活化，从而在许多患者中根除肿瘤。在2014年的几年后，FDA批准可瑞达(Keytruda)(Pembrolizumab，默沙东)和Opdivo(Nivolumab，Bristol-myerssquibb)用于治疗晚期黑色素瘤。这些单克隆抗体与在活化和/或耗尽的T细胞上表达的PD-1结合并阻断PD-1与在肿瘤上表达的PD-L1的相互作用，从而消除通过PD-1进入T细胞的抑制信号，导致抗原特异性T细胞的再活化，在许多患者中再次导致肿瘤的根除。此后，已经进行了另外的临床试验，将单一单克隆抗体Yervoy与单克隆抗体Yevroy和Opdivo的组合在晚期黑色素瘤的治疗中进行比较，其表明，联合使用抗体可以改善患者的总体生存期和无进展生存期。(Hodi等人，2016，《柳叶刀·肿瘤》(Lancet Oncol.)17(11):1558-1568，Hellman等人，2018，《癌细胞》(Cancer Cell)33(5)：853-861)。然而，由于许多临床试验已经显示使用对一种或多种免疫检查点分子特异的单克隆抗体治疗癌症患者有很大好处，数据显示，只有那些产生抗原特异性T细胞识别的新T细胞表位的高突变负荷的患者才会显示出临床反应(Snyder等人，2014，NEJM 371:2189-2199)。具有低肿瘤突变负荷的那些患者通常不显示客观的临床反应(Snyder等人，2014，NEJM 371：2189-2199，Hellman等人，2018，《癌细胞》(Cancer Cell)33(5):853-861)。
近年来，其他研究小组已经开发了不需要抗原呈递细胞存在新表位呈递来激活T细胞的替代方法。一个实例是双特异性抗体的开发，其中对肿瘤相关抗原特异的抗体的结合结构域，例如CD19，与T细胞上对CD3特异的抗体结合结构域连接，从而产生双特异性T细胞接合器或咬合(BiTe)分子。2014年，FDA批准了一种称为Blinatumumab的双特异性抗体，用于治疗前体B细胞急性成淋巴细胞性白血病(Precursor B-Cell Acute LymphoblasticLeukemia)。Blinatumumab将在白血病细胞上表达的对CD19特异的scFv与在T细胞上表达的对CD3特异性的scFv连接(Bejnjamin和Stein 2016，Ther Adv Hematol 7(3):142-146)。然而，尽管在患有复发性或难治性ALL的患者中初始应答率>50％，但许多患者对Blinatumumab治疗有抗性或用Blinatumumab成功治疗后复发。有证据表明对Blinatumumab耐药或Blinatumumab治疗后复发可归因于在肿瘤细胞上表达的免疫检查点抑制分子的表达，例如通过在活化的T细胞上表达的PD-1驱动抑制信号的PD-L1(Feucht等人，2016，Oncoarget 7(47):76902-76919)。在一例对Blinatumab治疗耐药的患者中，进行了第二轮Blinatumab治疗，但添加了一种单克隆抗体pembrolizumab(Keytruda，Merck)，其特异性地与PD-1结合，并阻断了T细胞表达的PD-1与肿瘤细胞表达的PD-L1的相互作用，导致该患者骨髓中的肿瘤细胞显著应答和降低，从45％减少到不到5％(Feucht等人，2016，Oncoarget7(47):76902-76919)。这些结果表明将双特异性咬合(BiTe)分子与一种或多种单克隆抗体组合与任一单独药剂相比可以显著增加临床活性。尽管结果很有希望，但由于多项临床试验和招募有代表性的人群的困难，导致联合治疗的成本肯定很高。
采用嵌合抗原受体T细胞(CAR-T)的过继细胞治疗是另一种有前景的用于治疗癌症的免疫疗法。CAR-T疗法的临床成功已经显示CD19阳性治疗难治性B细胞恶性肿瘤患者的持久完全缓解和生存期延长(Gill&June 2015，Immunol Rev，263：68-89)。然而，与制造个性化和基因修饰的CAR-T免疫治疗相关的成本和复杂性已经将它们的生产和使用限制到用于治疗相对少量患者的专门中心。细胞因子释放综合征(CRS)，也称为细胞因子风暴是工程改造的CAR-T细胞输注后最显著的副作用(Bonifant等人，201，Mol Ther Oncolytics.，3：16011)。在许多情况下，CRS的发作和严重程度似乎是特定个人事件。目前减轻CRS的选择主要集中在快速响应和管理护理上，因为在T细胞输注之前控制CRS的选择是有限的。
虽然目前已确定了针对CD19阳性B细胞恶性肿瘤的CAR-T疗法的功效，但迄今尚未明确证实针对实体瘤的CAR-T疗法的功效。目前，许多临床试验正在进行中，以探索用于CAR-T疗法的多种实体瘤相关抗原(TAA)。目前认为实体瘤CAR-T疗法的主要障碍是T细胞向肿瘤内转运效率低、肿瘤微环境免疫抑制、抗原识别特异性不佳以及治疗相关不良事件缺乏控制(Li等人，2018，J Hematol Oncol.，11(1):22-40)。控制治疗效果以及CAR-T细胞输注之前和之后的任何副作用的选择是有限的。
发明内容
本申请提供了对T细胞和肿瘤细胞表面分子具有多特异性抗原结合活性的制导和导航控制(GNC)蛋白。在一个实施方案中，制导和导航控制(GNC)蛋白包括T细胞活化受体的结合结构域、肿瘤相关抗原的结合结构域、免疫检查点受体的结合结构域和T细胞共刺激受体的结合结构域。
在一个实施方案中，肿瘤相关抗原的结合结构域不与T细胞共刺激受体的结合结构域相邻。在一个实施方案中，T细胞活化受体的结合结构域与肿瘤相关抗原(TAA)的结合结构域相邻。T细胞活化受体可包括但不限于CD3。T细胞共刺激受体可包括但不限于4-1BB、CD28、OX40、GITR、CD40L、ICOS,Light,CD27,CD30或其组合。免疫检查点受体可以包括但不限于PD-L1、PD-1、TIGIT、TIM-3、LAG-3、CTLA4、BTLA、VISTA、PDL2、CD160、LOX-1、siglec-15、CD47或其组合。
肿瘤相关抗原(TAA)可包括但不限于ROR1、CD19、EGFRVIII、BCMA、CD20、CD33、CD123、CD22、CD30、CEA、HER2、EGFR、LMP1、LMP2A、间皮素(Mesothelin)、PSMA、EpCAM、glypican-3、gpA33、GD2、TROP2或其组合。在一个实施方案中，肿瘤相关抗原可以是ROR1。在一个实施方案中，肿瘤相关抗原可以是CD19。在一个实施方案中，肿瘤相关抗原可以是EGFRVIII。
在实施方案中，肿瘤相关抗原可以是肺癌细胞、肝癌细胞、乳腺癌细胞、结直肠癌细胞、肛门癌细胞、胰腺癌细胞、胆囊癌细胞、胆管癌细胞、头颈部癌细胞、鼻咽癌细胞、皮肤癌细胞、黑色素瘤细胞、卵巢癌细胞、前列腺癌细胞、尿道癌细胞、肺癌细胞、非小细胞肺癌细胞、小细胞肺癌细胞、脑瘤细胞、胶质瘤细胞、神经母细胞瘤细胞、食管癌细胞、胃癌细胞、肝癌细胞、肾癌细胞、膀胱癌细胞、宫颈癌细胞、子宫内膜癌细胞、甲状腺癌细胞、眼癌细胞、肉瘤细胞、骨癌细胞、白血病细胞、骨髓瘤细胞、淋巴瘤细胞或其组合上的受体。在一个实施方案中，肿瘤相关抗原可以是B细胞上的受体。
在一个实施方案中，制导和导航控制(GNC)蛋白可以是抗体或抗体单体或其片段。在一个实施方案中，GNC蛋白可以是三特异性抗体。在一个实施方案中，GNC蛋白可以是四特异性抗体。在一个实施方案中，GNC蛋白包括Fc结构域或其片段。可以使用来自抗体的任何Fc结构域。示例性Fc结构域可包括来自IgG、IgA、IgD、IgM、IgE或其片段或组合的Fc结构域。Fc结构域可以是天然的或工程化的。在一个实施方案中，Fc结构域可以含有抗原结合位点。
在一个实施方案中，制导和导航控制(GNC)蛋白是抗体。在一个实施方案中，肿瘤相关抗原包括ROR1、CD19或EGRFVIII。在一个实施方案中，T细胞活化受体包括CD3，并且CD3的结合结构域可以通过接头与肿瘤相关(TAA)抗原的结合结构域连接以形成CD3-TAA对。在一个实施方案中，IgG Fc结构域可以介于CD3-TAA对和免疫检查点受体的结合结构域之间。在一个实施方案中，免疫检查点受体可以是PD-L1。
在一个实施方案中，接头可以是共价键。在一个实施方案中，接头可以是肽接头。在一个实施方案中，肽接头具有不超过100个氨基酸的长度。在一个实施方案中，肽接头具有不超过2、5、10、20、30、40、50、60、70,80,90或100个氨基酸的长度。在一个实施方案中，肽接头具有不超过10个氨基酸的长度。在一个实施方案中，肽接头具有约2个氨基酸至约10个氨基酸的长度。在一个实施方案中，肽接头包括2、5或10个氨基酸。
在一个实施方案中，制导和导航控制(GNC)蛋白具有N端和C端，从N端到C端依次包括CD3结合结构域、EGFRVIII结合结构域、IgG Fc结构域、PD-L1结合结构域和4-1BB结合结构域。在一个实施方案中，GNC蛋白可以包括与SEQ ID NO.80和82具有百分比同源性的氨基酸序列。百分比同源性不低于70％、80％、90％、95％、98％或99％。在一个实施方案中，GNC蛋白是四特异性抗体。
在一个实施方案中，制导和导航控制(GNC)蛋白具有N端和C端，从N端到C端依次包括4-1BB结合结构域、PD-L1结合结构域、IgG Fc结构域、ROR1结合结构域和CD3结合结构域。在一个实施方案中，GNC蛋白包括与SEQ ID NO.88和90具有百分比同源性的氨基酸序列。百分比同源性不低于70％、80％、90％、95％、98％或99％。在一个实施方案中，GNC蛋白是四特异性抗体。
制导和导航控制(GNC)蛋白具有N端和C端，从N端到C端依次包括CD3结合结构域、CD19结合结构域、IgG Fc结构域、PD-L1结合结构域和4-1BB结合结构域。在一个实施方案中，GNC蛋白包括与SEQ ID NO.104和106具有百分比同源性的氨基酸序列。百分比同源性不低于70％、80％、90％、95％、98％或99％。在一个实施方案中，GNC蛋白是四特异性抗体。
在一个实施方案中，GNC蛋白包括与SEQ ID NO.50、52、80、82、84、86、88、90、92、94、96、98、100、102、104、106、108和110具有百分比同源性的氨基酸，且百分比同源性不低于70％、80％、90％、95％、98％或99％。
另一方面，本申请提供了编码所述GNC蛋白或其公开的片段的核酸序列。在一个实施方案中，所述核酸具有与SEQ ID NO.49、51、79、81、83、85、87、89、91、93、95、97、99、101、103、105、107和109具有百分比同源性的氨基酸，且百分比同源性不低于70％、80％、90％、95％、98％或99％。
在一个实施方案中，所述制导和导航控制(GNC)蛋白包括细胞毒性细胞结合部分和癌症靶向部分。任何细胞毒性细胞可以是所公开的GNC蛋白的潜在结合靶标。细胞毒性细胞的实例包括但不限于T细胞、NK细胞、巨噬细胞和树突细胞。
在一个实施方案中，GNC蛋白包括T细胞结合部分。T细胞结合部分对T细胞受体具有结合特异性。T细胞受体的实例包括但不限于CD3、CD28、PDL1、PD1、OX40、4-1BB、GITR、TIGIT、TIM-3、LAG-3、CTLA4、CD40L、VISTA、ICOS、BTLA、Light、CD30、NKp30、CD28H、CD27、CD226、CD96、CD112R、A2AR、CD160、CD244、CECAM1、CD200R、TNFRSF25(DR3)或其组合。
在一个实施方案中，GNC蛋白包括NK细胞结合部分。NK细胞结合部分对NK细胞受体具有结合特异性。NK细胞受体的实例包括但不限于活化NK细胞的受体，例如CD16、NKG2D、KIR2DS1、KIR2DS2、KIR2DS4、KIR3DS1、NKG2C、NKG2E、NKG2H；激动剂受体，例如NKp30a、NKp30b、NKp46、NKp80、DNAM-1、CD96、CD160、4-1BB、GITR、CD27、OX-40、CRTAM；和拮抗剂受体，例如KIR2DL1、KIR2DL2、KIR2DL3、KIR3DL1、KIR3DL2、KIR3DL3、NKG2A、NKp30c、TIGIT、SIGLEC7、SIGLEC9、LILR、LAIR-1、KLRG1、PD-1、CTLA-4、CD161。
在一个实施方案中，GNC蛋白包括巨噬细胞结合部分。巨噬细胞结合部分对巨噬细胞受体具有结合特异性。巨噬细胞受体的实例包括但不限于巨噬细胞上的激动剂受体，例如TLR2、TLR4、CD16、CD64、CD40、CD80、CD86、TREM-1、TREM-2、ILT-1、ILT-6a、ILT-7、ILT-8、EMR2、Dectin-1、CD69；拮抗剂受体，例如CD32b、SIRPα、LAIR-1、VISTA、TIM-3、CD200R、CD300a、CD300f、SIGLEC1、SIGLEC3、SIGLEC5,SIGLEC7、SIGLEC9、ILT-2、ILT-3、ILT-4、ILT-5、LILRB3、LILRB4、DCIR；和其它表面受体如CSF-1R、LOX-1、CCR2、FRβ、CD163、CR3、DC-SIGN、CD206、SR-A、CD36、MARCO。
在一个实施方案中，GNC蛋白包括树突细胞结合部分。树突细胞结合部分对树突细胞受体具有结合特异性。树突细胞受体的实例包括但不限于树突细胞上的激动剂受体，例如TLR、CD16、CD64、CD40、CD80、CD86、HVEM,CD70；拮抗剂受体，例如VISTA、TIM-3、LAG-3、BTLA；和其它表面受体，例如CSF-1R、LOX-1、CCR7、DC-SIGN、GM-CSF-R、IL-4R、IL-10R、CD36、CD206、DCIR、RIG-1、CLEC9A、CXCR4。
癌症靶向部分对癌细胞受体具有结合特异性。示例性癌细胞受体包括但不限于BCMA、CD19、CD20、CD33、CD123、CD22、CD30、ROR1、CEA、HER2、EGFR、EGFRvIII、LMP1、LMP2A、间皮素(Mesothelin)、PSMA、EpCAM、glypican-3、gpA33、GD2、TROP2或其组合。
在一个实施方案中，GNC蛋白包括至少一个T细胞结合部分和至少一个癌细胞结合部分，其中T细胞结合部分对T细胞受体具有结合特异性，所述T细胞受体包括CD3、CD28、PDL1、PD1、OX40、4-1BB、GITR、TIGIT、TIM-3、LAG-3、CTLA4、CD40、VISTA、ICOS、BTLA、Light、CD30、CD27或其组合，并且其中癌细胞结合部分对癌细胞受体具有结合特异性。
在一个实施方案中，GNC蛋白能够通过将T细胞结合部分结合至T细胞上的T细胞受体来活化T细胞。在一个实施方案中，GNC蛋白包括双特异性抗体或抗体单体、三特异性抗体或抗体单体、四特异性抗体或抗体单体、其抗原结合片段或其组合。
在一个实施方案中，GNC蛋白可具有第一部分和第二部分。在一个实施方案中，第一部分可以包括T细胞结合部分、NK细胞结合部分、巨噬细胞结合部分或树突细胞结合部分。所述第二部分包括癌症靶向部分。
本申请还提供了纳入本文公开的GNC蛋白的细胞毒性细胞。在一个实施方案中，细胞毒性剂包括GNC蛋白和细胞毒性细胞。细胞毒性细胞可以是T细胞、NK细胞、巨噬细胞、树突细胞或其组合。在一个实施方案中，T细胞可以是自体T细胞、同种T细胞或通用供体T细胞。在一个实施方案中，细胞毒性细胞包括具有T细胞活化受体和T细胞共刺激受体的T细胞，以及通过与T细胞活化受体、T细胞共刺激受体或其组合相互作用而结合至T细胞的GNC蛋白。
本申请还提供了纳入本文公开的GNC蛋白的癌细胞。在一个实施方案中，癌细胞包括具有肿瘤相关抗原的癌细胞，并且权利要求1的GNC蛋白通过与肿瘤相关抗原的相互作用结合至癌细胞。
本申请还提供了纳入本文公开的GNC蛋白的生物复合体。在一个实施方案中，生物复合体包括具有T细胞活化受体和T细胞共刺激受体的T细胞，具有肿瘤相关抗原的癌细胞和如权利要求1所述的GNC蛋白，其中所述GNC蛋白是通过与T细胞活化受体、T细胞共刺激受体或其组合的相互作用结合至T细胞，并且其中GNC蛋白通过与肿瘤相关抗原的相互作用结合至癌细胞。
在另一方面，本申请提供用于治疗癌症病症的药物组合物。在一个实施方案中，药物组合物包括本文公开的GNC蛋白或细胞毒性细胞和药学上可接受的载体。
在另一方面，本申请提供了用于制备和使用所公开的GNC蛋白的方法。
在另一方面，本申请提供用于治疗患有癌症的受试者的方法。在一个实施方案中，该方法包括为受试者施用有效量的本文公开的药物组合物的步骤。
通过以下结合附图对优选实施例的详细描述，本申请的目的和优点将变得显而易见。
附图说明
结合附图，通过下面的描述和所附权利要求，本公开的前述和其它特征将变得更加清楚。应当理解，这些附图仅描述了根据本公开安排的若干实施例，因此不应被认为是对其范围的限制，将通过使用附图以附加的特性和细节来描述本公开，其中：
图1显示了以由多个抗原结合结构域(AgBd)和接头组成为特征的GNC蛋白的一般方案；
图2显示作为本文公开的GNC蛋白的实施方案的GNC抗体的实例：2A，具有EGFRvIIIAgBD(SI-39E18)的四特异性GNC抗体；2B，具有ROR1 AgBD(SI-35E20)的四特异性GNC抗体；2C，具有CD19 AgBD(SI-38E17)的四特异性GNC抗体；
图3示出了四特异性GNC抗体如何通过多个AgBD结合T细胞和肿瘤细胞两者；
图4显示与人ROR1转染的CHO细胞结合的四特异性GNC抗体的实例；
图5显示与人4-1BB转染的CHO细胞结合的四特异性GNC抗体的实例；
图6显示与人PD-L1转染的CHO细胞结合的四特异性GNC抗体的实例；
图7显示具有结合结构域323H7的示例性四特异性GNC抗体，其对以PBMC作为效应子的B-ALL细胞系Kasumi2的经ROR1介导的RTCC的Ig结构域是特异性的；
图8显示具有结合结构域323H7的示例性四特异性GNC抗体，其对以CD8+、CD45RO+记忆T细胞作为效应子的B-ALL细胞系Kasumi2的经ROR1介导的RTCC的Ig结构域是特异性的；
图9显示具有结合结构域323H7的示例性四特异性GNC抗体，其对以CD8+、CD45RA+初始T细胞作为效应子的B-ALL细胞系Kasumi2的经ROR1介导的RTCC的Ig结构域是特异性的；
图10显示具有结合结构域338H4的示例性四特异性GNC抗体，其对以PBMC作为效应子的B-ALL细胞系Kasumi2的经ROR1介导的RTCC的卷曲结构域(Frizzled domain)是特异性的；
图11显示具有结合结构域338H4的示例性四特异性GNC抗体，其对以CD8+、CD45RO+记忆T细胞作为效应子的B-ALL细胞系Kasumi2的经ROR1介导的RTCC的卷曲结构域是特异性的；
图12显示具有结合结构域338H4的示例性四特异性GNC抗体，其对以CD8+、CD45RA+初始T细胞作为效应子的B-ALL细胞系Kasumi2的经ROR1介导的RTCC的卷曲结构域是特异性的；
图13显示了响应于使用四特异性GNC抗体的EGFRvIII处理的重定向的panT细胞对膀胱癌细胞系UM-UC-3-EGFRvIII的活性；
图14显示了测量响应于使用靶向EGFRvIII的四特异性GNC抗体处理的CD8 T细胞增殖的结果；
图15显示跟踪响应于使用靶向EGFRvIII的四特异性GNC抗体处理的IFNγ分泌的结果；
图16显示了证明针对膀胱癌细胞系UM-UC-3-EGFRvIII的重定向的初始T细胞的细胞毒性的结果；
图17显示了测定PBMC对使用靶向EGFRvIII的四特异性GNC抗体处理，CD8 T细胞的增殖的响应的结果；
图18显示响应于使用靶向EGFRvIII的四特异性GNC抗体处理，在单核细胞存在下针对膀胱癌细胞系UM-UC-3-EGFRvIII的重定向的panT细胞活性的结果；
图19显示了PD-L1和4-1BB结构域对四特异性GNC抗体的活性和重定向的PBMC针对膀胱癌细胞系UM-UC-3-EGFRvIII的细胞毒性的功能影响；
图20显示响应于使用靶向ROR1的四特异性GNC抗体处理的针对Kasumi-2靶细胞系的重定向的panT细胞活性的结果；
图21显示了响应于使用靶向CD19的四特异性GNC抗体处理的针对Kasimu-2肿瘤细胞系的重定向的PBMC活性的结果；
图22显示了响应于使用靶向CD19的四特异性GNC抗体处理的CD8 T细胞增殖；和
图23显示了PBMC响应于靶向CD19的四特异性GNC抗体处理产生IFNγ。
具体实施方式
在下面的详细描述中，参考了形成说明书一部分的附图。在附图中，类似的符号通常标识类似的组分，除非上下文另外指示。在详细描述、附图和权利要求中描述的说明性实施例并不意味着是限制性的。可以利用其他实施例，并且可以进行其他改变，而不偏离本文呈现的主题的精神或范围。将容易理解的是，如本文一般描述的以及在附图中示出的本公开的这些方面可以被排列、替代、组合、分离以及设计成多种不同的构型，本文明确地考虑了所有这些构型。
本申请涉及制备和使用GNC蛋白的方法。在一个实施方案中，制导和导航控制(GNC)蛋白可以包括多个抗原特异性结合结构域(AgBD)并且可以具有通过T细胞和肿瘤细胞上的多个表面分子的结合将T细胞(或其他效应细胞)引导至癌细胞(或其他靶细胞)的能力(图1)。在一个实施方案中，GNC蛋白可以由用于结合T细胞上的至少一种表面分子的部分1和用于结合癌细胞上的至少一种表面抗原的部分2组成(表1A)。
在T细胞疗法中，细胞毒性T细胞通过T细胞增殖信号传导以及经由其表面上的激动剂受体或拮抗剂受体的共刺激信号传导来调节。为了调节这些信号传导以及T细胞和癌症之间的相互作用，对于部分1和部分2可以分别且独立地包括多个AgBD。GNC蛋白可具有至少一个连接部分1和部分2的接头。接头可以在长度上变化。在一个实施方案中，接头可以是共价键。在一个实施方案中，接头可以是具有约1至约100个氨基酸残基的肽。
在一些实施方案中，通过使用DNA/RNA或蛋白-蛋白相互作用的互补接头，任何接头分子可用于在体外或体内将两个或更多个AgBD连接在一起，所述互补接头包括但不限于生物素-亲和素、亮氨酸拉链和任何双杂交阳性蛋白的接头。
在一些实施方案中，接头可以是抗体主链结构或抗体片段，使得GNC蛋白和GNC抗体可以具有相同的含义，如图2中所示的示例四特异性GNC抗体结构。在一个实施方案中，GNC蛋白可以是双特异性、三特异性、四特异性、五特异性、六特异性、七特异性或八特异性蛋白。在一个实施方案中，GNC蛋白可以是单克隆抗体。在一个实施方案中，GNC蛋白可以是双特异性、三特异性、四特异性、五特异性、六特异性、七特异性或八特异性抗体单体。在一个实施方案中，GNC蛋白可以是双特异性、三特异性、四特异性、五特异性、六特异性、七特异性或八特异性抗体。
GNC蛋白或抗体能够在体内或离体指导T细胞与癌细胞的结合，由多个AgBD介导(图3)。T细胞可以来自相同患者或不同个体，并且癌细胞可以在体内、体外或离体存在。本申请提供的实例使得GNC蛋白能够作为T细胞疗法中的主要制剂，即GNC-T疗法，用于在过继转移之前离体激活和控制细胞毒性T细胞。
除T细胞外，其它细胞毒性细胞可被GNC蛋白用于癌症杀伤或预防目的。表1B显示了具有NK细胞结合结构域的GNC蛋白中的功能部分(部分1和部分2)和抗原结合结构域的示例性组成。表1C显示了具有巨噬细胞结合结构域的GNC蛋白中的功能部分(部分1和部分2)和抗原结合结构域的示例性组成。表1D显示了具有树突细胞结合结构域的GNC蛋白中的功能部分(部分1和部分2)和抗原结合结构域的示例性组成。
多个AgBD可分为部分1和部分2，因为其分别与细胞毒性细胞如T细胞和癌细胞的相互作用。(表1A)。然而，多个AgBD的重排可以是随机的和数量不等的(表2)。具有两个AgBD的GNC蛋白可同时结合表面分子(例如T细胞上的CD3)和肿瘤抗原(例如肿瘤细胞上的ROR1)，以将T细胞重定向或引导至肿瘤细胞。因为4-1BB是共刺激因子并且该结合刺激其对活化的T细胞的激动剂活性，所以添加例如特异性结合4-1BB的第三AgBD可以帮助增强抗CD3诱导的T细胞活化。将第四AgBD添加至GNC蛋白，例如特异性结合肿瘤细胞上的PD-L1，可以阻断肿瘤细胞上的PD-L1的抑制通路，其通过其与T细胞上的PD-1的结合而介导。利用这些基本原理，可以设计和构建GNC蛋白以获得特异性地结合不等数量的T细胞拮抗剂和激动剂的多个AgBD，不仅将活化的T细胞重定向至肿瘤细胞，而且控制它们在体内的活性(表2)。因此，GNC蛋白的设计可以是任何多特异性蛋白。表3提供了具有抗体结合结构域特异性的一些示例性GNC蛋白和抗体。
在一个实施方案中，GNC蛋白可以包括由两个官能团表征的多特异性抗原结合部分：部分1包括多个抗原结合结构域(AgBD)，其特异性涉及T细胞活化、激动剂共刺激和/或抑制性拮抗剂活性，并且部分2包括至少一种癌细胞结合特异性。GNC蛋白可同时结合表面分子(例如T细胞的CD3)和肿瘤抗原(例如肿瘤细胞的ROR1)，从而将T细胞重定向或引导至肿瘤细胞。添加GNC蛋白中第三个结合结构域可通过其直接结合4-1BB(其为发挥激动剂活性的共刺激因子)来帮助增强CD3诱导的T细胞活化。此外，添加GNC蛋白中的第四结合结构域可以结合肿瘤细胞上的PD-L1以阻断通过其与T细胞上的PD-1的结合介导的肿瘤细胞上的PD-L1的抑制通路。在一些实施方案中，GNC蛋白获得将活化的T细胞重新定向至肿瘤细胞的多种结合能力，并且多种结合可通过调节激动剂或拮抗剂活性或两者来帮助调节T细胞活化。一些结合能力可能类似于CAR-T细胞上的嵌合抗原受体或双特异性抗体(例如咬合抗体)的结合能力。不希望受理论束缚，通过各种结构域与细胞毒性细胞受体和肿瘤相关抗原的相互作用，GNC蛋白作为治疗剂可以提供比传统的基于细胞的疗法(例如CAR-T和抗体疗法)显著的优势，包括但不限于改善结合效力、优化细胞信号传导和细胞毒性，以及降低副作用例如降低细胞因子风暴综合征的严重性。
在一个实施方案中，本申请提供了具有4个不同结合结构域的示例性GNC蛋白。GNC蛋白可以是具有其接头和主链包括抗体片段的“四特异性抗体”。在4个不同的抗原结合结构域中，一个特异性结合T细胞上的CD3，第二个结合结构域特异性针对肿瘤相关抗原，包括但不限于其他肿瘤抗原，例如ROR1、CEA、HER2、EGFR、EGFRvIII、LMP1、LMP2A、间皮素、PSMA、EpCAM、磷脂酰肌醇蛋白聚糖3(glypican-3)、gpA33、GD2、TROP2、BCMA、CD19、CD20、CD33、CD123、CD22、CD30，以及第三和第四结合结构域特异性针对两种不同的免疫检查点调节剂，即PD-L1、PD-1、OX40、4-1BB、GITR、TIGIT、TIM-3、LAG-3、CTLA4、CD40、VISTA、ICOS、BTLA、Light、HVEM、CD73、CD39等。由于在功能和组成上的定义不同，GNC蛋白被归为一类新的治疗癌症的免疫调节剂。表4显示了示例性四特异性GNC抗体的列表。
在一个实施方案中，GNC介导的免疫治疗可以包括抗体疗法和细胞疗法的类型。在本文中，优点可包括但不限于包括IgG Fc结构域可赋予与双特异性咬合分子相比更长的血清半衰期的特性；第二，包括对免疫检查点调节剂特异性的两个结合结构域可以抑制这些抑制通路并且同时接合这些共刺激通路；第三，T细胞上的CD3与肿瘤相关抗原的交联将T细胞的重定向并引导T细胞杀死肿瘤细胞，而不需要从患者中除去T细胞并在将其重新引入患者之前对其进行基因修饰使其对肿瘤细胞具有特异性，这也称为嵌合抗原受体T细胞(CAR-T)疗法；第四，GNC蛋白介导的抗体疗法或T细胞疗法不涉及T细胞的基因修饰，后者可能带来将修饰的T细胞转化为克隆扩充的风险，即T细胞白血病。
通过增加结合能力的一个或多个，GNC蛋白介导的免疫治疗相对于常规免疫治疗的优势包括但不限于，第一，包括IgG Fc结构域可赋予与双特异性咬合分子相比更长的血清半衰期的特性；第二，包括对免疫检查点调节剂特异性的两个结合结构域可以抑制这些抑制通路并且同时接合这些共刺激通路；第三，T细胞上的CD3与肿瘤相关抗原的交联将T细胞的重定向并引导T细胞杀死肿瘤细胞，而不需要从患者中除去T细胞并在将其重新引入患者之前对其进行基因修饰使其对肿瘤细胞具有特异性，这也称为嵌合抗原受体T细胞(CAR-T)疗法；第四，GNC蛋白介导的抗体疗法或T细胞疗法不涉及T细胞的基因修饰，后者可能带来将修饰的T细胞转化为克隆扩充的风险，即T细胞白血病。
通过参考以下对本文包括的具体实施方案和实施例的详细描述，可以更容易地理解本公开。尽管已参考本发明的某些实施方案的特定细节描述了本公开，但并不希望此些细节应被视为对本发明的范围的限制。
实施例
尽管以下实施例仅以说明而非限制的方式提供。本领域技术人员将容易地认识到可以改变或修改各种非关键参数以产生基本上相同或相似的结果。
实施例1：四特异性GNC抗体与人ROR1转染的CHO细胞的结合的FACS分析
测试表3和4中所列的四特异性GNC抗体与稳定表达全长人ROR1的中国仓鼠卵巢细胞(CHO)的结合。以2倍终浓度制备抗体，并在50μl PBS/2％FBS中在96孔板的3个孔中以1:5滴定，然后加入在50μl PBS/2％FBS中的5,000ROR1-CHO细胞。将该混合物在冰上孵育30分钟，用200μl的PBS/2％FBS洗涤一次，然后加入储备液的1:1000稀释的第二抗体PE山羊抗-人IgG Fc，并将该混合物在冰上孵育30分钟。将细胞用2×200μl的PBS/2％FBS洗涤，重悬浮于50μl的PBS/2％FBS中，并在BD LSRFORTESSA上分析，结合谱显示于图4中。具有对ROR1的Ig结构域特异性的323H7结合结构域的四特异性抗体SI-35E18、19和20显示出比具有对ROR1的卷曲结构域特异性的338H4结合结构域的四特异性GNC抗体SI-3521、22和23更高的结合，与具有对ROR1的kringle结构域特异的330F11结合结构域的四特异性GNC抗体SI-3524、25和26不结合。
实施例2：四特异性GNC抗体与人4-1BB转染的CHO细胞的结合的FACS分析
测试表3和4中所列的四特异性GNC抗体与稳定表达全长人ROR1的中国仓鼠卵巢细胞(CHO)的结合。以2倍终浓度制备抗体，并在50μl PBS/2％FBS中在96孔板的3个孔中以1:5滴定，然后加入在50μl PBS/2％FBS中的5,000ROR1-CHO细胞。将该混合物在冰上孵育30分钟，用200μl的PBS/2％FBS洗涤一次，然后加入储备液的1:1000稀释的第二抗体PE山羊抗-人IgG Fc，并将该混合物在冰上孵育30分钟。将细胞用2×200μl的PBS/2％FBS洗涤，重悬浮于50μl的PBS/2％FBS中，并在BD LSRFORTESSA上分析，结合谱显示于图5中。除了对照SI-27E12之外，所有四特异性GNC抗体均含有4-1BB结合结构域，460C3、420H5或466F6，并且以不同强度与表达4-1BB的CHO细胞结合。
实施例3：四特异性GNC抗体与人PDL1转染的CHO细胞的结合的FACS分析
测试表3和4中所列的四特异性GNC抗体与稳定表达全长人ROR1的中国仓鼠卵巢细胞(CHO)的结合。以2倍终浓度制备抗体，并在50μl PBS/2％FBS中在96孔板的3个孔中以1:5滴定，然后加入在50μl PBS/2％FBS中的5,000ROR1-CHO细胞。将该混合物在冰上孵育30分钟，用200μl的PBS/2％FBS洗涤一次，然后加入储备液的1:1000稀释的第二抗体PE山羊抗-人IgG Fc，并将该混合物在冰上孵育30分钟。将细胞用2×200μl的PBS/2％FBS洗涤，重悬浮于50μl的PBS/2％FBS中，并在BD LSRFORTESSA上分析，结合谱显示于图6中。除了对照SI-27E15之外，所有四特异性GNC抗体都含有相同的PDL1结合结构域，PL230C6，并且显示出与表达PDL1的CHO细胞非常相似的结合强度。
实施例4：以外周血单核细胞为效应子，以B-急性成淋巴细胞性白血病(B-ALL)细 胞系Kasumi-2为靶标的重定向T细胞毒性(RTCC)测定
使用人外周血单核细胞(PBMC)作为效应子，测试表3和4中所列的四特异性GNC抗体针对B-ALL细胞系Kasumi 2的RTCC活性。将Kasumi 2靶细胞5×106用CFSE(Invitrogen，#C 34554)以0.5μM在10ml培养基中在37℃标记20分钟。将细胞用50ml培养基洗涤3次，然后重悬浮于10ml培养基中，然后再次计数。以2倍终浓度制备抗体，在200μl的RPMI+10％FBS中，在96孔板的10孔中以1:3滴定。通过标准ficoll密度梯度从“leukopak”纯化人PBMC，所述“leukopak”是从正常人外周血收集的富集的白细胞分离术产物。在最终目的96孔板中，通过向测定的各孔中加入100μl的靶细胞(5,000)，50μl的PBMC(25,000)和100μl的各抗体稀释液来组合靶细胞、PBMC和连续滴定的抗体。将测定板在37℃孵育约72小时，然后收获每个测定孔的内容物并分析剩余的CFSE-标记的靶细胞的数目。如图7所示，四特异性GNC抗体均含有相同的PDL1结合结构域PL230C6、相同的ROR1结合结构域323H7和相同的CD3结合结构域284A10，但具有4-1BB结合结构域460C3、420H5和466F6中的一个，并且除了不具有4-1BB结合结构域但似乎对四特异性GNC抗体SI-35E18、19和20具有类似效力的对照SI-27E12之外，与对照相比，显示出更高的RTCC活性。
实施例5：以CD8+、CD45RO+记忆T细胞为效应子，以B-急性成淋巴细胞性白血病(B- ALL)细胞系Kasumi-2为靶标的重定向T细胞毒性(RTCC)测定
使用人CD8+、CD45RO+记忆T细胞作为效应子，测试表3和4中所列的四特异性GNC抗体针对B-ALL细胞系Kasumi 2的RTCC活性。将Kasumi 2靶细胞5×106用CFSE(Invitrogen，#C 34554)以0.5μM在10ml培养基中在37℃标记20分钟。将细胞用50ml培养基洗涤3次，然后重悬浮于10ml培养基中，然后再次计数。以2倍终浓度制备抗体，在200μl的RPMI+10％FBS中，在96孔板的10孔中以1:3滴定。根据制造商的方案，使用EasySepTM人记忆CD8+T细胞富集试剂盒(干细胞技术，#19159)，从来自正常供体的PBMC中富集人CD8+、CD45RO+记忆T细胞。通过FACS分析确定最终细胞群为98％CD8+、CD45RO+T细胞。在最终目的96孔板中，通过向测定的各孔中加入100μl的靶细胞(5,000)，50μl的CD8+、CD45RO+记忆T细胞(25,000)和100μl的各抗体稀释液来组合靶细胞、T细胞和连续滴定的抗体。将测定板在37℃孵育约72小时，然后收获每个测定孔的内容物并分析剩余的CFSE-标记的靶细胞的数目。如图8所示，四特异性抗体均含有相同的PDL1结合结构域PL230C6、相同的ROR1结合结构域323H7和相同的CD3结合结构域284A10，但具有4-1BB结合结构域460C3、420H5和466F6中的一个，并且与不包含4-1BB、PDL1、ROR1或CD3结合结构域之一的对照相比，显示出更高的RTCC活性。
实施例6：以CD8+、CD45RA+初始T细胞为效应子，以B-急性成淋巴细胞性白血病(B- ALL)细胞系Kasumi-2为靶标的重定向T细胞毒性(RTCC)测定
使用人CD8+、CD45RA+记忆T细胞作为效应子，测试表3和4中所列的四特异性GNC抗体针对B-ALL细胞系Kasumi 2的RTCC活性。将Kasumi 2靶细胞5×10e6用CFSE(Invitrogen，#C 34554)以0.5μM在10ml培养基中在37℃标记20分钟。将细胞用50ml培养基洗涤3次，然后重悬浮于10ml培养基中，然后再次计数。以2倍终浓度制备抗体，在200μl的RPMI+10％FBS中，在96孔板的10孔中以1:3滴定。根据制造商的方案，使用EasySepTM人初始CD8+T细胞分离试剂盒(干细胞技术，#19258)，从来自正常供体的外周血单核细胞中富集人CD8+、CD45RA+记忆T细胞。通过FACS分析确定最终细胞群为98％CD8+、CD45RA+T细胞(数据未显示)。在最终目的96孔板中，通过向测定的各孔中加入100μl的靶细胞(5,000)，50μl的CD8+、CD45RO+T细胞(25,000)和100μl的各抗体稀释液来组合靶细胞、T细胞和连续滴定的抗体。将测定板在37℃孵育约72小时，然后收获每个测定孔的内容物并分析剩余的CFSE-标记的靶细胞的数目。如图9所示，所有四特异性GNC抗体含有相同的PDL1结合结构域PL230C6、相同的ROR1结合结构域323H7和相同的CD3结合结构域284A10，但具有4-1BB结合结构域460C3、420H5和466F6中的一个，并且与不包含4-1BB、PDL1、ROR1或CD3结合结构域之一的对照相比，显示出更高的RTCC活性。
实施例7：以外周血单核细胞为效应子，以B-急性成淋巴细胞性白血病(B-ALL)细 胞系Kasumi-2为靶标的重定向T细胞毒性(RTCC)测定
使用人外周血单核细胞(PBMC)作为效应子，测试表3和4中所列的四特异性GNC抗体针对B-ALL细胞系Kasumi 2的RTCC活性。将Kasumi 2靶细胞5×106用CFSE(Invitrogen，#C 34554)以0.5μM在10ml培养基中在37℃标记20分钟。将细胞用50ml培养基洗涤3次，然后重悬浮于10ml培养基中，然后再次计数。以2倍终浓度制备抗体，在200μl的RPMI+10％FBS中，在96孔板的10孔中以1:3滴定。通过标准ficoll密度梯度从“leukopak”纯化人PBMC，所述“leukopak”是从正常人外周血收集的富集的白细胞分离术产物。在最终目的96孔板中，通过向测定的各孔中加入100μl的靶细胞(5,000)，50μl的PBMC(25,000)和100μl的各抗体稀释液来组合靶细胞、PBMC和连续滴定的抗体。将测定板在37℃孵育约72小时，然后收获每个测定孔的内容物并分析剩余的CFSE-标记的靶细胞的数目。如图10所示，四特异性GNC抗体均含有相同的PDL1结合结构域PL230C6、相同的ROR1结合结构域338H4和相同的CD3结合结构域284A10，但具有4-1BB结合结构域460C3、420H5和466F6中的一个，并且除了不具有4-1BB结合结构域但似乎对四特异性GNC抗体SI-35E18、19和20具有类似效力的对照SI-27E12之外，与对照相比，显示出更高的RTCC活性。
实施例8：以CD8+、CD45RO+记忆T细胞为效应子，以B-急性成淋巴细胞性白血病(B- ALL)细胞系Kasumi-2为靶标的重定向T细胞毒性(RTCC)测定
使用人CD8+、CD45RO+记忆T细胞作为效应子，测试表3和4中所列的四特异性GNC抗体针对B-ALL细胞系Kasumi 2的RTCC活性。将Kasumi 2靶细胞5×106用CFSE(Invitrogen，#C 34554)以0.5μM在10ml培养基中在37℃标记20分钟。将细胞用50ml培养基洗涤3次，然后重悬浮于10ml培养基中，然后再次计数。以2倍终浓度制备抗体，在200μl的RPMI+10％FBS中，在96孔板的10孔中以1:3滴定。根据制造商的方案，使用EasySepTM人记忆CD8+T细胞富集试剂盒(干细胞技术，#19159)，从来自正常供体的PBMC中富集人CD8+、CD45RO+记忆T细胞。通过FACS分析确定最终细胞群为98％CD8+、CD45RO+T细胞(数据未显示)。在最终目的96孔板中，通过向测定的各孔中加入100μl的靶细胞(5,000)，50μl的CD8+、CD45RO+记忆T细胞(25,000)和100μl的各抗体稀释液来组合靶细胞、T细胞和连续滴定的抗体。将测定板在37℃孵育约72小时，然后收获每个测定孔的内容物并分析剩余的CFSE-标记的靶细胞的数目。如图11所示，四特异性抗体均含有相同的PD-L1结合结构域PL230C6、相同的ROR1结合结构域338H4和相同的CD3结合结构域284A10，但具有4-1BB结合结构域460C3、420H5和466F6中的一个，并且与不包含4-1BB、PDL1、ROR1或CD3结合结构域之一的对照相比，显示出更高的RTCC活性。
实施例9：以CD8+、CD45RA+初始T细胞为效应子，以B-急性成淋巴细胞性白血病(B- ALL)细胞系Kasumi-2为靶标的重定向T细胞毒性(RTCC)测定
使用人CD8+、CD45RA+记忆T细胞作为效应子，测试表3和4中所列的四特异性GNC抗体针对B-ALL细胞系Kasumi 2的RTCC活性。将Kasumi 2靶细胞5×106用CFSE(Invitrogen，#C 34554)以0.5μM在10ml培养基中在37℃标记20分钟。将细胞用50ml培养基洗涤3次，然后重悬浮于10ml培养基中，然后再次计数。以2倍终浓度制备抗体，在200μl的RPMI+10％FBS中，在96孔板的10孔中以1:3滴定。根据制造商的方案，使用EasySepTM人初始CD8+T细胞分离试剂盒(干细胞技术，#19258)，从来自正常供体的PBMC中富集人CD8+、CD45RA+记忆T细胞。通过FACS分析确定最终细胞群为98％CD8+、CD45RA+T细胞。在最终目的96孔板中，通过向测定的各孔中加入100μl的靶细胞(5,000)，50μl的CD8+、CD45RO+T细胞(25,000)和100μl的各抗体稀释液来组合靶细胞、T细胞和连续滴定的抗体。将测定板在37℃孵育约72小时，然后收获每个测定孔的内容物并分析剩余的CFSE-标记的靶细胞的数目。如图12所示，四特异性抗GNC体均含有相同的PD-L1结合结构域PL230C6、相同的ROR1结合结构域338H4和相同的CD3结合结构域284A10，但具有4-1BB结合结构域460C3、420H5和466F6中的一个，但是与不包含41-BB、PD-L1、ROR1或CD3结合结构域之一的对照相比，未显示出更高的RTCC活性。这与实施例6中描述的和图6所示的四特异性GNC抗体形成对比，这些抗体确实显示了与CD8+、CD45RA+初始T细胞的RTCC活性。
实施例10：针对膀胱癌细胞系UM-UC-3-EGFRvIII的重定向的panT细胞的细胞毒 性。
评价在表5中列出的一组四特异性GNC抗体裂解靶细胞UM-UC-3-EGFRvIII的能力。用EasySepTM人panT细胞分离试剂盒(Stemcell Technologies)分离panT细胞。UM-UC-3-EGFRvIII细胞系稳定表达通过慢病毒转导(Sartorius)递送的核定位红色荧光蛋白(RFP)。将UM-UC-3-EGFRvIII-RFP肿瘤细胞与panT细胞共培养。通过计数在与panT细胞共培养96小时后留在培养物中的活靶标的数目，用流式细胞术(BD LSRFortessa)评估靶细胞裂解。这两种四特异性抗体SI-39E18和SI-39E29在靶肿瘤细胞裂解中是最有效的(图13)。这两个分子也由CD3和肿瘤抗原的相邻结合结构域组成(表5)。
实施例11：响应于使用靶向EGFRvIII的四特异性抗体处理的CD8 T细胞增殖。
在靶细胞UM-UC-3-EGFRvIII存在下，评价表5中列出的一组四特异性GNC抗体刺激CD8 T细胞增殖的能力。用CellTrace Violet染料(赛默飞世尔科技(Thermo FisherScientific))标记PanT细胞。将UM-UC-3-EGFRvIII-RFP肿瘤细胞与panT细胞共培养。在共培养96小时后，用流式细胞仪(BD LSRFortessa)通过稀释CellTrace Violet染料评估CD8T细胞增殖。在靶细胞存在下，两种四特异性GNC抗体SI-39E18和SI-39E29在刺激CD8 T细胞增殖方面最有效(图14)。这两个分子由CD3和肿瘤抗原的相邻结合结构域组成(表5)。具有强T细胞刺激活性的其它分子包括含有相邻CD3和PD-L1结构域的结构(表5)。
实施例12：响应于使用靶向EGFRvIII的四特异性抗体处理的IFNγ分泌。
评价表5中列出的一组四特异性GNC抗体诱导PBMC分泌IFNγ的能力。通过Ficoll梯度分离PBMC。将PBMC与测试分子孵育96h。收集上清液并使用ELISA(R&D系统)分析IFNγ的存在(图15)。在该研究中具有最强活性的四特异性GNC抗体均含有邻近的CD3和PD-L1结构域(表5)。最不活泼的基团具有邻近CD3和肿瘤抗原或4-1BB结构域的分子。这组四特异性GNC抗体的唯一例外是SI-39E18，其包括相邻的CD3和肿瘤抗原结构域。该分子刺激IFNγ适度产生，IFNγ低于与CD3和PD-L1结构域相邻的分子中最活跃的基团，但高于其他结构排列相似的分子。适度产生IFNγ可能有益于该药剂的抗肿瘤活性。
实施例13：重定向的初始T细胞针对膀胱癌细胞系UM-UC-3-EGFRvIII的细胞毒性。
测试了四特异性GNC抗体SI-39E18的重定向天然T细胞裂解靶细胞UM-UC-3-EGFRvIII的能力。用EasySepTM人初始panT细胞分离试剂盒(Stemcell Technologies)分离初始T细胞。将UM-UC-3-EGFRvIII-RFP肿瘤细胞与初始或panT细胞共培养。通过计数RFP标记的肿瘤细胞核评价肿瘤细胞的裂解。在活细胞成像仪IncuCyte(Sartorius)上获得图像。孵育120小时后评价抗体的活性。在较低效应子与靶标比率为2.5比1下测试处理。SI-39E18在重定向初始T细胞方面是有效的。初始T细胞的EC50为22.08pM，panT细胞的EC50为0.07pM(图16)。
实施例14：PBMC对使用靶向EGFRvIII的四特异性GNC抗体处理，CD8 T细胞的增殖 的响应。
评价表1中列出的一组四特异性GNC抗体在不存在靶细胞的情况下诱导CD8 T细胞增殖的能力。用CellTrace Violet染料(赛默飞世尔科技)标记PBMC并与测试分子一起培养96h。用流式细胞仪(BD LSRFortessa)通过稀释CellTrace Violet染料评估CD8 T细胞增殖。本研究中最有效的分子具有结构相似性(图17)。所有这些分子含有相邻的CD3和PD-L1结构域(表5)。
实施例15.在单核细胞存在下针对膀胱癌细胞系UM-UC-3-EGFRvIII重定向的panT 细胞活性。
评价表5中列出的一组四特异性GNC抗体在单核细胞存在下裂解靶细胞UM-UC-3-EGFRvIII的能力。用EasySepTM人单核细胞分离试剂盒(Stemcell Technologies)从PBMC中分离单核细胞。将UM-UC-3-EGFRvIII-RFP肿瘤细胞与panT细胞和单核细胞共培养。通过计数RFP标记的肿瘤细胞核评价靶细胞裂解。在活细胞成像仪IncuCyte(Sartorius)上获得图像。孵育96小时后评价抗体的活性。这两种四特异性GNC抗体，SI-39E18和SI-39E29，与含有邻近的CD3和PD-L1结合结构域的分子一起，对靶肿瘤细胞裂解(图18)最有效(表5)。
实施例16.针对膀胱癌细胞系UM-UC-3-EGFRvIII的重定向PBMC细胞毒性、不同4- 1BB结构域的功能活性以及PD-L1和4-1BB结构域的功能影响。
评估表5中所列的四特异性GNC抗体重定向PBMC癌细胞系UM-UC-3-EGFRvIII(UM-UC-3-EGFRvIII)的能力。将UM-UC-3-EGFRvIII-RFP肿瘤细胞与PBMC共培养。通过计数RFP标记的肿瘤细胞核评价肿瘤细胞的裂解。在活细胞成像仪IncuCyte(Sartorius)上获得图像。孵育96小时后评价抗体的活性。具有不同4-1BB结构域的四特异性GNC抗体，SI-39E4、SI-39E2和SI-39E3，显示相似的活性(图19)。PD-L1和4-1BB结构域被沉默(非功能性)FITC结构域SI-39E1和SI-39E5替代的四特异性GNC抗体显示裂解活性降低。该观察证实了4-1BB和PD-L1结构域的功能贡献。
实施例17.PBMC响应于使用靶向EGFRvIII的四特异性GNC抗体处理产生颗粒酶B， AgBD位置对EC50值的影响。
评价表5中列出的一组四特异性和靶向EGFRvIII的GNC抗体诱导PBMC分泌粒酶B的能力。将PBMC与测试分子孵育96h。收集上清液并使用ELISA(R&D Systems)分析粒酶B的存在，绘制粒酶B的水平以测定每种四特异性GNC抗体的EC50。表6列出了各四特异性GNC抗体中AgBD的结构位置。如表6所示，在本研究中最具活性的分子均含有邻近的CD3和PD-L1结构域以及4-1BB×TAA(EGFRvIII)。这种高水平的粒酶B分泌可能不是细胞毒性所需的，因为体内细胞毒性可能变得太高。在本文中，显示出中度但至少低20倍的活性的下一组分子SI-39E29和SI-39E18包含邻近的CD3和TAA(在本研究中的EGFRvIII)。
实施例18.响应于使用靶向ROR1的四特异性GNC抗体处理的针对Kasumi-2靶细胞系的重定向的panT细胞活性。
评价表7中列出的一组四特异性GNC抗体和表4中的SI-35E20裂解靶细胞Kasumi-2的能力。Kasumi-2细胞系稳定地表达通过慢病毒转导(Clontech)递送的绿色荧光蛋白(GFP)。将Kasumi-2肿瘤细胞与panT细胞共培养。通过计数在与panT细胞共培养96小时后留在培养物中的活靶标的数目，用流式细胞术(BD LSRFortessa)评估靶细胞裂解(图20)。SI-35E20表征如图4-9所示。该结果表明SI-35E20介导的重定向的panT细胞活性针对Kasumi-2靶细胞系的效力是相当的。
实施例19.响应于使用靶向CD19的四特异性GNC抗体处理的针对Kasumi-2靶细胞 系的重定向的PBMC T细胞活性。
评价在表8中列出的一组四特异性GNC抗体裂解靶细胞Kasumi-2的能力。将Kasumi-2-GFP肿瘤细胞与PBMC共培养。通过计数在与PBMC共培养8小时后留在培养物中的活靶标的数目，用流式细胞术(BD LSRFortessa)评估靶细胞裂解(图21)。SI-38E17是本研究中更有效力的分子。
实施例20.响应于使用靶向CD19的四特异性GNC抗体处理的CD8 T细胞增殖。
在靶细胞Kasumi-2存在下，评价表8中列出的一组四特异性GNC抗体刺激CD8 T细胞增殖的能力。用CellTrace Violet染料(赛默飞世尔科技(Thermo Fisher Scientific))标记PBMC。将Kasumi-2-GFP肿瘤细胞与PBMC共培养。在共培养8天后，用流式细胞仪(BDLSRFortessa)通过稀释CellTrace Violet染料评估CD8 T细胞增殖。在靶细胞存在下，两种四特异性GNC抗体SI-38E17和SI-38E41在刺激CD8 T细胞增殖方面最有效(图22)。这两个分子由CD3和肿瘤抗原的相邻结合结构域构成。
实施例21.PBMC响应于靶向CD19的四特异性抗体的处理产生IFNγ。
在靶细胞Kasumi-2的存在下，评价在表8中列出的一组四特异性GNC抗体诱导PBMC分泌IFNγ的能力。靶细胞和PBMC与测试分子孵育8天。收集上清液并使用ELISA(R&DSystems)分析IFNγ的存在。含有邻近的CD3和PD-L1结构域的分子在诱导PBMC产生IFNγ以及随后的抗体SI-38E5方面是最有效的。SI-38E17在本研究中显示中度活性(图23)。
术语“抗体”以最广泛的含义使用，并且具体涵盖单一单克隆抗体(包括激动剂抗体和拮抗剂抗体)，具有多表位特异性的抗体组合物，以及抗体片段(例如，Fab、F(ab′)2和Fv)，只要它们表现出所需的生物学活性即可。在一些实施方案中，抗体可以是单克隆抗体、多克隆抗体、嵌合抗体、单链抗体、双特异性抗体或双效抗体、模拟抗体、人抗体和人源化抗体及其活性片段。与已知抗原结合的分子的活性片段的实例包括Fab、F(ab′)2、scFv和Fv片段，包括Fab免疫球蛋白表达文库的产物和任何上述抗体和片段的表位结合片段。在一些实施方案中，抗体可包括免疫球蛋白分子和免疫球蛋白分子的免疫活性部分，即含有免疫特异性结合抗原的结合位点的分子。免疫球蛋白可以是任何类型(IgG、IgM、IgD、IgE、IgA和IgY)或免疫球蛋白分子的类(IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类。在一个实施方案中，抗体可以是全抗体和衍生自全抗体的任何抗原结合片段。典型的抗体是指通常包括两条重(H)链和两条轻(L)链的异源四聚体蛋白。每条重链由重链可变结构域(缩写为VH)和重链恒定结构域组成。每条轻链由轻链可变结构域(缩写为VL)和轻链恒定结构域组成。VH和VL区可进一步细分为高变互补决定区(CDR)和称为框架区(FR)的更保守区的结构域。每个可变结构域(VH或VL)通常由三个CDR和四个FR组成，按以下顺序排列：从氨基末端到羧基末端的FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。在轻链和重链的可变区内有与抗原相互作用的结合区。
如本文所用，术语“单克隆抗体”是指从基本上均质的抗体群获得的抗体，即包括该群体的各抗体是相同的，除了可能以少量存在的天然存在的突变。单克隆抗体是高度特异性的，针对单一抗原位点。此外，与通常包括针对不同决定簇(表位)的不同抗体的常规(多克隆)抗体制剂相反，每种单克隆抗体针对抗原上的单一决定簇。除了它们的特异性，单克隆抗体是有利的，因为它们是通过杂交瘤培养物合成的，没有被其它免疫球蛋白污染。修饰语“单克隆”表示抗体的特性是从基本上均质的抗体群获得的，并且不应被解释为需要通过任何特定方法产生抗体。例如，根据本公开使用的单克隆抗体可以通过Kohler&Milstein,《自然》(Nature),256:495(1975)首次描述的杂交瘤方法制备，或者可以通过重组DNA方法制备(参见，例如，美国专利第4,816,567号)。
单克隆抗体可以包括“嵌合”抗体(免疫球蛋白)，其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类或亚类的抗体中的相应序列相同或同源，而其余的链与衍生自特定物种或属于特定抗体类或亚类的抗体中的相应序列相同或同源，以及此类抗体的片段，只要它们表现出所需的生物学活性(美国专利第4,816,567号；和Morrison等人，《美国科学院院报》(Proc.Natl.Acad.Sci.USA)，81：6851-6855[1984])。
单克隆抗体可以使用各种方法产生，包括小鼠杂交瘤或噬菌体展示(Siegel，Transfus.Clin.Biol.，9：15-22(2002)for a review)或直接从原代B细胞的抗体的分子克隆(参见Tiller，New Biotechnol.，28：453-7(2011))。在本公开内容中，通过用人PD-L1蛋白和在细胞表面瞬时表达人PD-L1的细胞来免疫兔子产生抗体。已知兔子产生高亲和力、多样性和特异性的抗体(Weber等人，Exp.Mol.Med.，49：e305)。将来自免疫动物的B细胞体外培养并筛选抗-PD-L1抗体的产生。使用重组DNA技术分离抗体可变基因，重组表达所得抗体并进一步筛选期望的特征，例如抑制PD-L1与PD-1结合的能力、结合非人灵长类动物PD-L1的能力和增强人T细胞活化的能力。这种抗体发现的一般方法类似于Seeber等人在《公共科学图书馆·综合》(PLOS One)9:e86184(2014)中描述的方法。
术语“抗原或表位结合部分或片段”是指能够结合抗原(在这种情况下是PD-L1)的抗体的片段。这些片段可以具有完整抗体的抗原结合功能和其它功能。结合片段的实例包括但不限于由通过合成接头连接在单一多肽链中的抗体的单臂的VL和VH结构域组成的单链Fv片段(scFv)或为由VL、恒定轻链(CL)、VH和恒定重链1(CH1)结构域组成的单价片段的Fab片段。抗体片段可以是甚至更小的亚片段并且可以由与单个CDR结构域一样小的结构域，特别是来自VL和/或VH结构域的CDR3区组成(例如参见Beiboer等人，J.Mol.Biol.,296：833-49(2000))。使用本领域技术人员已知的常规方法产生抗体片段。可以使用与完整抗体使用的相同技术筛选抗体片段的效用。
“抗原或表位结合片段”可以通过许多本领域已知的技术衍生自本公开的抗体。例如，纯化的单克隆抗体可以用酶例如胃蛋白酶切割，并进行HPLC凝胶过滤。然后通过膜过滤等收集并浓缩含有Fab片段的合适级分。关于分离抗体的活性片段的一般技术的进一步描述，参见例如Khaw,B.A.等人，《核医学杂志》(J.Nucl.Med.)，23：1011-1019(1982)；Rousseaux等人，Methods Enzymology，121：663-69,学术出版社(Academic Press),1986。
抗体的木瓜蛋白酶消化产生两个相同的抗原结合片段，称为“Fab”片段，每个片段具有单个抗原结合位点，和残余的“Fc”片段，其名称反映了其容易结晶的能力。胃蛋白酶处理产生具有两个抗原结合位点且仍能交联抗原的F(ab′)2片段。
Fab片段可以含有轻链的恒定结构域和重链的第一恒定结构域(CH1)。Fab′片段与Fab片段的不同在于在重链CH1结构域的羧基端添加了几个残基，包括来自抗体铰链区的一个或多个半胱氨酸。Fab′-SH是本文对Fab′的命名，其中恒定结构域的半胱氨酸残基带有游离硫醇基。F(ab′)2抗体片段最初作为Fab′片段对产生，Fab′片段之间具有铰链半胱氨酸。其它抗体片段的化学偶联也是已知的。
“Fv”是含有完整抗原识别和结合位点的最小抗体片段。该区域由一个重链和一个轻链可变结构域紧密非共价缔合的二聚体组成。在这种构型中，每个可变结构域的三个CDR相互作用以限定VH-VL二聚体表面上的抗原结合位点。6个CDR共同赋予抗体抗原结合特异性。然而，即使是单个可变结构域(或者仅包括三个对抗原特异的CDR的Fv的一半)也具有识别和结合抗原的能力，尽管亲和力低于整个结合位点。
来自任何脊椎动物物种的抗体(免疫球蛋白)的“轻链”可以基于它们的恒定结构域的氨基酸序列被指定为两种明显不同的类型中的一种，称为κ和λ。
根据重链恒定结构域的氨基酸序列，免疫球蛋白可分为不同的类别。有五种主要类别的免疫球蛋白：IgA、IgD、IgE、IgG和IgM，并且这些中的几种可以进一步分为亚类(同种型)，例如，IgG-1、IgG-2、IgG-3和IgG-4；IgA-1和IgA-2。对应于不同免疫球蛋白类别的重链恒定结构域分别称为α、δ、ε、γ和μ。不同类别免疫球蛋白的亚单位结构和三维构型是熟知的。
“人源化抗体”是指一类工程抗体，其CDR衍生自非人供体免疫球蛋白，分子的其余免疫球蛋白衍生部分衍生自一种(或多种)人免疫球蛋白。此外，可改变构架支持残基以保持结合亲和力。获得“人源化抗体”的方法是本领域技术人员熟知的。(参见，例如，Queen等人,《美国科学院院报》(Proc.Natl Acad Sci USA),86：10029-10032(1989),Hodgson等人,Bio/Technology,9：421(1991))。在一个实施方案中，“人源化抗体”可以通过基因工程方法获得，该方法能够在大型动物如兔中产生亲和力成熟的人样多克隆抗体(参见，例如美国专利第7,129,084号)。
如本文所用，术语“多肽”、“肽”和“蛋白”可互换并且定义为意指由通过肽键连接的氨基酸组成的生物分子。
如本文所用的术语“一(a)”、“一(an)”和“所述(the)”被定义为意指“一个或多个”并且包括复数，除非上下文不适当。
“分离的”是指不含其天然存在的至少一些组分的生物分子。当用于描述本文公开的各种多肽时，“分离的”是指已经从其表达的细胞或细胞培养物中鉴定和分离和/或回收的多肽。通常，分离的多肽将通过至少一个纯化步骤制备。“分离的抗体”是指基本上不含具有不同抗原特异性的其它抗体的抗体。
“重组”意指使用重组核酸技术在外源宿主细胞中产生抗体。
术语“抗原”是指可以在生物体，特别是动物，更特别是哺乳动物(包括人)中诱导免疫应答的实体或其片段。该术语包括免疫原及其负责抗原性或抗原决定簇的区域。
还如本文所用，术语“免疫原性”是指引起或增强针对免疫原性剂的抗体、T细胞或其它反应性免疫细胞的产生并且有助于人或动物中的免疫应答的物质。当个体针对所施用的本公开的免疫原性组合物产生足够的抗体、T细胞和其它反应性免疫细胞以减轻或缓解待治疗的病症时，发生免疫应答。
“特异性结合(specific binding)”或“特异性结合(specific binds)”或“特异于”特定抗原或表位是指可测量地不同于非特异性相互作用的结合。例如，可以通过与对照分子的结合相比确定分子的结合来测量特定结合，对照分子通常是结构相似的没有结合活性的分子。例如，特异性结合可以通过与类似于靶标的对照分子竞争来测定。
对特定抗原或表位的特异性结合例如可以通过对抗原或表位具有至少约10-4M、至少约10-5M、至少约10-6M、至少约10-7M、至少约10-8M、至少约10-9、或者至少约10-10M、至少约10-11M、至少约10-12M或更大的KD的抗体来表现，其中KD指的是特定抗体-抗原相互作用的离解速率。在一些实施例中，特定结合抗原的抗体将具有相对于抗原或表位的对照分子的20、50、100、500、1000、5,000、10,000或更多倍的KD。
此外，特定抗原或表位的特异性结合可由对抗原或表位具有至少是相对于对照的表位的20、50、100、500、1000、5,000、10,000或更多倍KA或Ka的抗体表现，其中KA或Ka指的是特定抗体-抗原相互作用的缔合率。
通过序列同一性确定两个序列之间的“同源性”。如果待比较的两个序列长度不同，则序列同一性优选涉及与较长序列的核苷酸残基相同的较短序列的核苷酸残基的百分比。可以使用计算机程序常规地确定序列同一性。在给定序列与本公开的上述序列之间的比较中出现的偏差可以由例如添加、缺失、取代、插入或重组引起。
虽然已参考特定实施例或实例描述了本发明，但应了解，所述实施例是说明性的且本发明的范围不限于此。本公开的替代实施例对于本公开所属领域的普通技术人员来说是显而易见的。这些替代实施例被认为包括在本公开的范围内。因此，本发明的范围由所附权利要求书限定且由上文描述支持。本公开中引用或提及的所有参考文献在此全文引入作为参考。
表
表1A.具有T细胞结合结构域的GNC蛋白中的功能部分(部分1和部分2)和抗原结合结构域的组成。
表1B.具有NK细胞结合结构域的GNC蛋白中的功能部分(部分1和部分2)和抗原结合结构域的组成。
表1C.具有巨噬细胞结合结构域的GNC蛋白中的功能部分(部分1和部分2)和抗原结合结构域的组成。
表1D.具有DC细胞结合结构域的GNC蛋白中的功能部分(部分1和部分2)和抗原结合结构域的组成。
表2.T细胞活化、T细胞激动剂、T细胞拮抗剂和肿瘤抗原结合结构域在单一GNC蛋白中的可能组合的实例。
表3.GNC蛋白中使用的抗体结合结构域的特异性。
表4.四特异性GNC蛋白的列表。
表5.具有EGFRvIII肿瘤抗原结合结构域的四特异性GNC抗体。
表6.PBMC响应于使用靶向EGFRvIII的四特异性GNC抗体处理产生颗粒酶B，AgBD对EC50的影响。
表7.具有ROR1肿瘤抗原结合结构域的四特异性GNC抗体。
表8.具有CD19肿瘤抗原结合结构域的四特异性GNC抗体
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制导和导航控制蛋白及其制备和使用方法
序列表
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四特异性GNC抗体的序列表
氨基酸序列中的CDR加下划线
>SEQ ID 01抗CD3 284A10 VHv1 nt
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCA
>SEQ ID 02抗CD3 284A10 VHv1 aa
EVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSS
>SEQ ID 03抗CD3 284A10 VLv1 nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 04抗CD3 284A10 VLv1 aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIK
>SEQ ID 05抗CD3 480C8 VHv1 nt
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCGACCTCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTAATAGTAAGAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCA
>SEQ ID 06抗CD3 480C8 VHv1 aa
EVQLVESGGGLVQPGGSLRLSCAASGIDLSSNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAINSKNIWGQGTLVTVSS
>SEQ ID 07抗CD3 480C8 VLv1 nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 08抗CD3 480C8 VLv1 aa
DIQMTQSPSTLSASVGDRVTITCQASESISSWLAWYQQKPGKAPKLLIYEASKLAS GVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNAFGGGTKVEIK
>SEQ ID 09抗PD-L1 PL230C6 VHv3 nt
CAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCCAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTAGT
>SEQ ID 10抗PD-L1 PL230C6 VHv3 aa
QSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSS
>SEQ ID 11抗PD-L1 PL230C6 VLv2 nt
GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 12抗PD-L1 PL230C6 VLv2 aa
AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIK
>SEQ ID 13抗4-1BB 420H5 VHv3 nt
CAGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCAACTACTGGATATGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATGTTGGTAGTAGTGGTGACACTTACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGATAGTAGTAGTTATTATATGTTTAACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
>SEQ ID 14抗4-1BB 420H5 VHv3 aa
QSLVESGGGLVQPGGSLRLSCAASGFSFSSNYWICWVRQAPGKGLEWIACIYVGSSGDTYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSSSYYMFNLWGQGTLVTVSS
>SEQ ID 15抗4-1BB 420H5 VLv3 nt
GCCCTTGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATACCTATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTTATGCATCCGATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCGGTTACTATACTAGTAGTGCTGATACGAGGGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 16抗4-1BB 420H5 VLv3 aa
ALVMTQSPSTLSASVGDRVTINCQASEDIDTYLAWYQQKPGKAPKLLIFYASDLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGGYYTSSADTRGAFGGGTKVEIK
>SEQ ID 17抗4-1BB 466F6 VHv2 nt
CGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCGAGCTCCGCGAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
>SEQ ID 18抗4-1BB 466F6 VHv2 aa
RSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSS
>SEQ ID 19抗4-1BB 466F6 VLv5 nt
GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 20抗4-1BB 466F6 VLv5 aa
DVVMTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK
>SEQ ID 21抗4-1BB 460C3 VHv1 nt
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCGACTTCAGTAGGAGATACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATATATACTGGTAGCCGCGATACTCCTCACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGAAGGTAGCCTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
>SEQ ID 22抗4-1BB 460C3 VHv1 aa
EVQLLESGGGLVQPGGSLRLSCAASGIDFSRRYYMCWVRQAPGKGLEWIACIYTGSRDTPHYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGSLWGQGTLVTVSS
>SEQ ID 23抗4-1BB 460C3 VLv1 nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTACAATACTGTTATTGATACTTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 24抗4-1BB 460C3 VLv1 aa
DIQMTQSPSTLSASVGDRVTITCQSSQSVYSNWFSWYQQKPGKAPKLLIYSASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGYNTVIDTFAFGGGTKVEIK
>SEQ ID 25抗ROR1 324C6 VHv2 nt
CAGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCTCCCTCAGTAGGTACTACATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAACCATTTATACTAGTGGTAGTACATGGTACGCGAGCTGGACAAAAGGCAGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGATCCTATTATGGCGGTGATAAGACTGGTTTAGGCATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA
>SEQ ID 26抗ROR1 324C6 VHv2 nt
QSLVESGGGLVQPGGSLRLSCTASGFSLSRYYMTWVRQAPGKGLEWIGTIYTSGSTWYASWTKGRFTISKDNTKNTVDLQMNSLRAEDTAVYYCARSYYGGDKTGLGIWGQGTLVTVSS
>SEQ ID 27抗ROR1 324C6 VLv1 nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTGATAGTTGGTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATCAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAATCTGCTTATGGTGTTAGTGGTACTAGTAGTTATTTATATACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 28抗ROR1 324C6 VLv1 aa
DIQMTQSPSTLSASVGDRVTITCQASQSIDSWLSWYQQKPGKAPKLLIYQASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQSAYGVSGTSSYLYTFGGGTKVEIK
>SEQ ID 29抗ROR1 323H7 VHv4 nt
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA
>SEQ ID 30抗ROR1 323H7 VHv4 aa
EVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSS
>SEQ ID 31抗ROR1 323H7 VLv1 nt
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 32抗ROR1 323H7 VLv1 aa
DIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIK
>SEQ ID 33抗ROR1 338H4 VHv3 nt
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCTCCCTCAGTAGCTATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAGGGGGCTGGAGTGGATCGGAATCATTTATGCTAGTGGTAGCACATACTACGCGAGCTCGGCGAAAGGCAGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAATTTATGACGGCATGGACCTCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA
>SEQ ID 34抗ROR1 338H4 VHv3 aa
EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMSWVRQAPGRGLEWIGIIYASGSTYYASSAKGRFTISKDNTKNTVDLQMNSLRAEDTAVYYCARIYDGMDLWGQGTLVTVSS
>SEQ ID 35抗ROR1 338H4 VLv4 nt
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTCAGAACATTTACAGCTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCGCCTGATCTATCTGGCATCTACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTACACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAAAGCAATTATAACGGTAATTATGGTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 36抗ROR1 338H4 VLv4 aa
DIQMTQSPSSLSASVGDRVTINCQASQNIYSYLSWYQQKPGKVPKRLIYLASTLASGVPSRFSGSGSGTDYTLTISSLQPEDVATYYCQSNYNGNYGFGGGTKVEIK
>SEQ ID 37抗ROR1 330F11 VHv1 nt
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAATAACTACTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAACCATTAGTAGTGGTGCGTATACATGGTTCGCCACCTGGGCGACAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGATATTCTTCTACTACTGATTGGACCTACTTTAACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA
>SEQ ID 38抗ROR1 330F11 VHv1 aa
EVQLVESGGGLVQPGGSLRLSCAASGFSLNNYWMSWVRQAPGKGLEWIGTISSGAYTWFATWATGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYSSTTDWTYFNIWGQGTLVTVSS
>SEQ ID 39抗ROR1 330F11 VLv1 nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAATAACTACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAGGGCATCCACTCTGGAATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAAGCTATAATGGTGTTGGTAGGACTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 40抗ROR1 330F11 VLv1 aa
DIQMTQSPSTLSASVGDRVTITCQASQSINNYLAWYQQKPGKAPKLLIYRASTLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQSYNGVGRTAFGGGTKVEIK
>SEQ ID 41抗FITC 4-4-20VH nt
GAGGTGAAGCTGGATGAGACTGGAGGAGGCTTGGTGCAACCTGGGAGGCCCATGAAACTCTCCTGTGTTGCCTCTGGATTCACTTTTAGTGACTACTGGATGAACTGGGTCCGCCAGTCTCCAGAGAAAGGACTGGAGTGGGTAGCACAAATTAGAAACAAACCTTATAATTATGAAACATATTATTCAGATTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGTAGTGTCTACCTGCAAATGAACAACTTAAGAGTTGAAGACATGGGTATCTATTACTGTACGGGTTCTTACTATGGTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA
>SEQ ID 42抗FITC 4-4-20VH aa
EVKLDETGGGLVQPGRPMKLSCVASGFTFSDYWMNWVRQSPEKGLEWVAQIRNKPYNYETYYSDSVKGRFTISRDDSKSSVYLQMNNLRVEDMGIYYCTGSYYGMDYWGQGTSVTVSS
>SEQ ID 43抗FITC 4-4-20VL nt
GATGTCGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTGTACACAGTAATGGAAACACCTATTTACGTTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGGTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA
>SEQ ID 44抗FITC 4-4-20VL aa
DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLRWYLQKPGQSPKVLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIK
>SEQ ID 45人IgG1无效(有ADCC/CDC无效突变的G1m-fa)nt
GCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT
>SEQ ID 46人IgG1无效(有ADCC/CDC无效突变的G1m-fa)aa
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
>SEQ ID 47人Ig Kappa nt
CGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 48人Ig Kappa aa
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 49SI-35E18(460C3-L1H1-scFv x PL230C6-Fab x 323H7-H4L1-scFvx284A10-H1L1-scFv)重链nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTACAATACTGTTATTGATACTTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCGACTTCAGTAGGAGATACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATATATACTGGTAGCCGCGATACTCCTCACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGAAGGTAGCCTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCCAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTAGTGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 50SI-35E18(460C3-L1H1-scFv x PL230C6-Fab x 323H7-H4L1-scFvx284A10-H1L1-scFv)重链aa
DIQMTQSPSTLSASVGDRVTITCQSSQSVYSNWFSWYQQKPGKAPKLLIYSASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGYNTVIDTFAFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGIDFSRRYYMCWVRQAPGKGLEWIACIYTGSRDTPHYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGSLWGQGTLVTVSSGGGGSGGGGSQSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIKGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIK
>SEQ ID 51SI-35E18(460C3-L1H1-scFv x PL230C6-Fab x 323H7-H4L1-scFvx284A10-H1L1-scFv)轻链nt
GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 52SI-35E18(460C3-L1H1-scFv x PL230C6-Fab x 323H7-H4L1-scFvx284A10-H1L1-scFv)轻链aa
AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 53抗CD3 284A10 VHv1b nt
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACA
>SEQ ID 54抗CD3 284A10 VHv1b aaEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVST
>SEQ ID 55抗4-1BB 466F6b VHv2 nt
CGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTGTCGACA
>SEQ ID 56抗4-1BB 466F6b VHv2 aa
RSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVST
>SEQ ID 57抗PD-L1 PL230C6 VHv3b nt
CAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACCGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTGTCGACA
>SEQ ID 58抗PD-L1 PL230C6 VHv3b aa
QSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVST
>SEQ ID 59抗huPD-L1 PL221G5 VHv1 nt
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
>SEQ ID 60抗huPD-L1 PL221G5 VHv1 aa
EVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSS
>SEQ ID 61抗huPD-L1 PL221G5 VLv1 nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 62抗huPD-L1 PL221G5 VLv1 aa
DIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIK
>SEQ ID 63抗huCD19 21D4 VH nt
GAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAGAAACCAGGAGAGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGTTCATGGATCGGCTGGGTGCGCCAGGCACCTGGGAAAGGCCTGGAATGGATGGGGATCATCTATCCTGATGACTCTGATACCAGATACAGTCCATCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGGACTGCCTACCTGCAGTGGAGTAGCCTGAAGGCCTCGGACACCGCTATGTATTACTGTGCGAGACATGTTACTATGATTTGGGGAGTTATTATTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
>SEQ ID 64抗huCD19 21D4 VH aa
EVQLVQSGAEVKKPGESLKISCKGSGYSFSSSWIGWVRQAPGKGLEWMGIIYPDDSDTRYSPSFQGQVTISADKSIRTAYLQWSSLKASDTAMYYCARHVTMIWGVIIDFWGQGTLVTVSS
>SEQ ID 65抗huCD19 21D4 VL nt
GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAATAGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA
>SEQ ID 66抗huCD19 21D4 VL aa
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIK
>SEQ ID 67抗huEGFRvIII 806VH nt
GATGTGCAGCTTCAGGAGTCGGGACCTAGCCTGGTGAAACCTTCTCAGTCTCTGTCCCTCACCTGCACTGTCACTGGCTACTCAATCACCAGTGATTTTGCCTGGAACTGGATTCGGCAGTTTCCAGGAAACAAGCTGGAGTGGATGGGCTACATAAGTTATAGTGGTAACACTAGGTACAACCCATCTCTCAAAAGTCGAATCTCTATCACTCGCGACACATCCAAGAACCAATTCTTCCTGCAGTTGAACTCTGTGACTATTGAGGACACAGCCACATATTACTGTGTAACGGCGGGACGCGGGTTTCCTTATTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA
>SEQ ID 68抗huEGFRvIII 806VH aa
DVQLQESGPSLVKPSQSLSLTCTVTGYSITSDFAWNWIRQFPGNKLEWMGYISYSGNTRYNPSLKSRISITRDTSKNQFFLQLNSVTIEDTATYYCVTAGRGFPYWGQGTLVTVSA
>SEQ ID 69抗huEGFRvIII 806VL nt
GACATCCTGATGACCCAATCTCCATCCTCCATGTCTGTATCTCTGGGAGACACAGTCAGCATCACTTGCCATTCAAGTCAGGACATTAACAGTAATATAGGGTGGTTGCAGCAGAGACCAGGGAAATCATTTAAGGGCCTGATCTATCATGGAACCAACTTGGACGATGAAGTTCCATCAAGGTTCAGTGGCAGTGGATCTGGAGCCGATTATTCTCTCACCATCAGCAGCCTGGAATCTGAAGATTTTGCAGACTATTACTGTGTACAGTATGCTCAGTTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA
>SEQ ID 70抗huEGFRvIII 806VL aa
DILMTQSPSSMSVSLGDTVSITCHSSQDINSNIGWLQQRPGKSFKGLIYHGTNLDDEVPSRFSGSGSGADYSLTISSLESEDFADYYCVQYAQFPWTFGGGTKLEIK
>SEQ ID 71GGGGSGGGGSG linker nt
GGCGGTGGAGGGTCCGGCGGTGGTGGCTCCGGA
>SEQ ID 72GGGGSGGGGSG linker aa
GGGGSGGGGSG
>SEQ ID 73GGGGSGGGGS linker 01nt
GGCGGTGGAGGGTCCGGCGGTGGTGGATCA
>SEQ ID 74GGGGSGGGGS linker 01aa
GGGGSGGGGS
>SEQ ID 75GGGGSGGGGS linker 02nt
GGCGGTGGAGGGTCCGGCGGTGGTGGATCC
>SEQ ID 76GGGGSGGGGS linker 02aa
GGGGSGGGGS
>SEQ ID 77GGGGSGGGGSGGGGSGGGGS linker nt
GGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCA
>SEQ ID 78GGGGSGGGGSGGGGSGGGGS linker aa
GGGGSGGGGSGGGGSGGGGS
>SEQ ID 79SI-39E18(284A10-L1H1-scFv x 806-Fab x PL221G5-H1L1-scFv x420H5-H3L3-scFv)重链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGATGTGCAGCTTCAGGAGTCGGGACCTAGCCTGGTGAAACCTTCTCAGTCTCTGTCCCTCACCTGCACTGTCACTGGCTACTCAATCACCAGTGATTTTGCCTGGAACTGGATTCGGCAGTTTCCAGGAAACAAGCTGGAGTGGATGGGCTACATAAGTTATAGTGGTAACACTAGGTACAACCCATCTCTCAAAAGTCGAATCTCTATCACTCGCGACACATCCAAGAACCAATTCTTCCTGCAGTTGAACTCTGTGACTATTGAGGACACAGCCACATATTACTGTGTAACGGCGGGACGCGGGTTTCCTTATTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCAACTACTGGATATGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGTATTTATGTTGGTAGTAGTGGTGACACTTACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGATAGTAGTAGTTATTATATGTTTAACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGCCCTTGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATACCTATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTTACGCATCCGATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCGGTTACTATACTAGTAGTGCTGATACGAGGGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 80SI-39E18(284A10-L1H1-scFv x 806-Fab x PL221G5-H1L1-scFv x420H5-H3L3-scFv)重链aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSGGGGSGGGGSDVQLQESGPSLVKPSQSLSLTCTVTGYSITSDFAWNWIRQFPGNKLEWMGYISYSGNTRYNPSLKSRISITRDTSKNQFFLQLNSVTIEDTATYYCVTAGRGFPYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIKGGGGSGGGGSQSLVESGGGLVQPGGSLRLSCAASGFSFSSNYWICWVRQAPGKGLEWIACIYVGSSGDTYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSSSYYMFNLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSALVMTQSPSTLSASVGDRVTINCQASED IDTYLAWYQQKPGKAPKLLIFYASDLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGGYYTSSADTRGAFGGGTKVEIK
>SEQ ID 81SI-39E18(284A10-L1H1-scFv x 806-Fab x PL221G5-H1L1-scFv x420H5-H3L3-scFv)轻链nt
GACATCCTGATGACCCAATCTCCATCCTCCATGTCTGTATCTCTGGGAGACACAGTCAGCATCACTTGCCATTCAAGTCAGGACATTAACAGTAATATAGGGTGGTTGCAGCAGAGACCAGGGAAATCATTTAAGGGCCTGATCTATCATGGAACCAACTTGGACGATGAAGTTCCATCAAGGTTCAGTGGCAGTGGATCTGGAGCCGATTATTCTCTCACCATCAGCAGCCTGGAATCTGAAGATTTTGCAGACTATTACTGTGTACAGTATGCTCAGTTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 82SI-39E18(284A10-L1H1-scFv x 806-Fab x PL221G5-H1L1-scFv x420H5-H3L3-scFv)轻链aa
DILMTQSPSSMSVSLGDTVSITCHSSQDINSNIGWLQQRPGKSFKGLIYHGTNLDDEVPSRFSGSGSGADYSLTISSLESEDFADYYCVQYAQFPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 83SI-39E29(806-LH-scFv x 284A10-Fab x PL221G5-H1L1-scFvx420H5-H3L3-scFv)重链nt
GACATCCTGATGACCCAATCTCCATCCTCCATGTCTGTATCTCTGGGAGACACAGTCAGCATCACTTGCCATTCAAGTCAGGACATTAACAGTAATATAGGGTGGTTGCAGCAGAGACCAGGGAAATCATTTAAGGGCCTGATCTATCATGGAACCAACTTGGACGATGAAGTTCCATCAAGGTTCAGTGGCAGTGGATCTGGAGCCGATTATTCTCTCACCATCAGCAGCCTGGAATCTGAAGATTTTGCAGACTATTACTGTGTACAGTATGCTCAGTTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGATGTGCAGCTTCAGGAGTCGGGACCTAGCCTGGTGAAACCTTCTCAGTCTCTGTCCCTCACCTGCACTGTCACTGGCTACTCAATCACCAGTGATTTTGCCTGGAACTGGATTCGGCAGTTTCCAGGAAACAAGCTGGAGTGGATGGGCTACATAAGTTATAGTGGTAACACTAGGTACAACCCATCTCTCAAAAGTCGAATCTCTATCACTCGCGACACATCCAAGAACCAATTCTTCCTGCAGTTGAACTCTGTGACTATTGAGGACACAGCCACATATTACTGTGTAACGGCGGGACGCGGGTTTCCTTATTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCAACTACTGGATATGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGTATTTATGTTGGTAGTAGTGGTGACACTTACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGATAGTAGTAGTTATTATATGTTTAACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGCCCTTGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATACCTATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTTACGCATCCGATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCGGTTACTATACTAGTAGTGCTGATACGAGGGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 84SI-39E29(806-LH-scFv x 284A10-Fab x PL221G5-H1L1-scFv x420H5-H3L3-scFv)重链aa
DILMTQSPSSMSVSLGDTVSITCHSSQDINSNIGWLQQRPGKSFKGLIYHGTNLDDEVPSRFSGSGSGADYSLTISSLESEDFADYYCVQYAQFPWTFGGGTKLEIKGGGGSGGGGSGGGGSGGGGSDVQLQESGPSLVKPSQSLSLTCTVTGYSITSDFAWNWIRQFPGNKLEWMGYISYSGNTRYNPSLKSRISITRDTSKNQFFLQLNSVTIEDTATYYCVTAGRGFPYWGQGTLVTVSAGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIKGGGGSGGGGSQSLVESGGGLVQPGGSLRLSCAASGFSFSSNYWICWVRQAPGKGLEWIACIYVGSSGDTYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSSSYYMFNLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSALVMTQSPSTLSASVGDRVTINCQASEDIDTYL AWYQQKPGKAPKLLIFYASDLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGGYYTSSADTRGAFGGGTKVEIK
>SEQ ID 85SI-39E29(806-LH-scFv x 284A10-Fab x PL221G5-H1L1-scFv x420H5-H3L3-scFv)轻链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 86SI-39E29(806-LH-scFv x 284A10-Fab x PL221G5-H1L1-scFv x420H5-H3L3-scFv)轻链aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 87SI-35E20(466F6-L5H2-scFv x PL230C6-Fab x 323H7-H4L1-scFv x284A10-H1L1-scFv)重链nt
GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCGAGCTCCGCGAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCCAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTAGTGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 88SI-35E20(466F6-L5H2-scFv x PL230C6-Fab x 323H7-H4L1-scFv x284A10-H1L1-scFv)重链aa
DVVMTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSQSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIY VNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIKGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINCQASESISSW LAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIK
>SEQ ID 89SI-35E20(466F6-L5H2-scFv x PL230C6-Fab x 323H7-H4L1-scFv x284A10-H1L1-scFv)轻链nt
GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 90SI-35E20(466F6-L5H2-scFv x PL230C6-Fab x 323H7-H4L1-scFv x284A10-H1L1-scFv)轻链aa
AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 91SI-35E58(284A10-L1H1-scFv x PL230C6-Fab x 323H7-H4L1-scFv x466F6-H2L5-scFv)重链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACCGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGGTCCGGAGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGGTCCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 92SI-35E58(284A10-L1H1-scFv x PL230C6-Fab x 323H7-H4L1-scFv x466F6-H2L5-scFv)重链aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGGSGGGGSQSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLA SGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQASQNI RTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK
>SEQ ID 93SI-35E58(284A10-L1H1-scFv x PL230C6-Fab x 323H7-H4L1-scFv x466F6-H2L5-scFv)轻链nt
GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 94SI-35E58(284A10-L1H1-scFv x PL230C6-Fab x 323H7-H4L1-scFvx466F6-H2L5-scFv)轻链aa
AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 95SI-35E88(284A10-L1H1-scFv x 323H7-Fab x PL230C6-H3L2-scFv x466F6-H2L5-scFv)重链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACCGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCCGGTGGAGGCGGTTCAGGCGGAGGTGGAAGTGGTGGTGGCGGCTCTGGAGGCGGCGGATCTGCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGGTCCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 96SI-35E88(284A10-L1H1-scFv x 323H7-Fab x PL230C6-H3L2-scFv x466F6-H2L5-scFv)重链aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSAYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQASQNIRTYL SWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK
>SEQ ID 97SI-35E88(284A10-L1H1-scFv x 323H7-Fab x PL230C6-H3L2-scFv x466F6-H2L5-scFv)轻链nt
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCATCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 98SI-35E88(284A10-L1H1-scFv x 323H7-Fab x PL230C6-H3L2-scFv x466F6-H2L5-scFv)轻链aa
DIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 99SI-35E99(284A10-L1H1-scFv x 323H7-Fab x PL221G5-H1L1-scFv x466F6-H2L5-scFv)重链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACAGGCGGTGGAGGGTCCGGCGGTGGTGGATCAGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGCTCCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 100 SI-35E99(284A10-L1H1-scFv x 323H7-Fab x PL221G5-H1L1-scFvx 466F6-H2L5-scFv)重链aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKA STLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQAS QNIRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK
>SEQ ID 101SI-35E99(284A10-L1H1-scFv x 323H7-Fab x PL221G5-H1L1-scFvx 466F6-H2L5-scFv)轻链nt
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCATCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 102SI-35E99(284A10-L1H1-scFv x 323H7-Fab x PL221G5-H1L1-scFvx 466F6-H2L5-scFv)轻链aa
DIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 103SI-38E17(284A10-L1H1-scFv x 21D4-Fab x PL221G5-H1L1-scFv x466F6-H2L5-scFv)重链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAGAAACCAGGAGAGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGTTCATGGATCGGCTGGGTGCGCCAGGCACCTGGGAAAGGCCTGGAATGGATGGGGATCATCTATCCTGATGACTCTGATACCAGATACAGTCCATCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGGACTGCCTACCTGCAGTGGAGTAGCCTGAAGGCCTCGGACACCGCTATGTATTACTGTGCGAGACATGTTACTATGATTTGGGGAGTTATTATTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCGAGCTCCGCGAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 104SI-38E17(284A10-L1H1-scFv x 21D4-Fab x PL221G5-H1L1-scFv x466F6-H2L5-scFv)重链aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGESLKISCKGSGYSFSSSWIGWVRQAPGKGLEWMGIIYPDDSDTRYSPSFQGQVTISADKSIRTAYLQWSSLKASDTAMYYCARHVTMIWGVIIDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKAS TLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIKGGGGSGGGGSRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQASQN IRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK
>SEQ ID 105SI-38E17(284A10-L1H1-scFv x 21D4-Fab x PL221G5-H1L1-scFv x466F6-H2L5-scFv)轻链nt
GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAATAGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 106SI-38E17(284A10-L1H1-scFv x 21D4-Fab x PL221G5-H1L1-scFv x466F6-H2L5-scFv)轻链aa
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 107SI-38E33(21D4-LH-scFv x 284A10-Fab x PL221G5-H1L1-scFv x466F6-H2L5-scFv)重链nt
GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAATAGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAGAAACCAGGAGAGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGTTCATGGATCGGCTGGGTGCGCCAGGCACCTGGGAAAGGCCTGGAATGGATGGGGATCATCTATCCTGATGACTCTGATACCAGATACAGTCCATCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGGACTGCCTACCTGCAGTGGAGTAGCCTGAAGGCCTCGGACACCGCTATGTATTACTGTGCGAGACATGTTACTATGATTTGGGGAGTTATTATTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCGAGCTCCGCGAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 108SI-38E33(21D4-LH-scFv x 284A10-Fab x PL221G5-H1L1-scFv x466F6-H2L5-scFv)重链aa
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIKGGGGSGGGGSGGGGSGGGGSEVQLVQSGAEVKKPGESLKISCKGSGYSFSSSWIGWVRQAPGKGLEWMGIIYPDDSDTRYSPSFQGQVTISADKSIRTAYLQWSSLKASDTAMYYCARHVTMIWGVIIDFWGQGTLVTVSSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIKGGGGSGGGGSRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQASQNIRTYL SWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK
SEQ ID 109SI-38E33(21D4-LH-scFv x 284A10-Fab x PL221G5-H1L1-scFv x466F6-H2L5-scFv)轻链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
SEQ ID 110SI-38E33(21D4-LH-scFv x 284A10-Fab x PL221G5-H1L1-scFv x466F6-H2L5-scFv)轻链aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
序列表
<110> 西雅图免疫公司
四川百利药业有限责任公司
<120> 制导和导航控制蛋白及其制备和使用方法
<130> SIBA103PCT
<141> 2019-03-26
<150> US62648880
<151> 2018-03-27
<150> US62648888
<151> 2018-03-27
<160> 110
<170> SIPOSequenceListing 1.0
<210> 1
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 1
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccatcagt accaatgcaa tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg gatcggagtc attactggtc gtgatatcac atactacgcg 180
agctgggcga aaggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgcg cgacggtgga 300
tcatctgcta ttactagtaa caacatttgg ggccaaggaa ctctggtcac cgtttcttca 360
<210> 2
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<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 Thr Ile Ser Thr Asn
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 3
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 3
gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300
aattctttcg gcggagggac caaggtggag atcaaa 336
<210> 4
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 4
Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 5
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 5
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggaat cgacctcagt agcaatgcaa tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg gatcggagtc attactggtc gtgatatcac atactacgcg 180
agctgggcga aaggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgcg cgacggtgga 300
tcatctgcta ttaatagtaa gaacatttgg ggccaaggaa ctctggtcac cgtttcttca 360
<210> 6
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 6
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 Ile Asp Leu Ser Ser Asn
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Gly Gly Ser Ser Ala Ile Asn Ser Lys Asn Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 7
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 7
gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300
aatgctttcg gcggagggac caaggtggag atcaaa 336
<210> 8
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 8
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Thr Tyr Val Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 9
<211> 345
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 9
cagtcggtgg aggagtctgg gggaggcttg gtccagcctg gggggtccct gagactctcc 60
tgtacagcct ctggaatcga ccttaatacc tacgacatga tctgggtccg ccaggctcca 120
ggcaaggggc tagagtgggt tggaatcatt acttatagtg gtagtagata ctacgcgaac 180
tgggcgaaag gccgattcac catctccaaa gacaatacca agaacacggt gtatctgcaa 240
atgaacagcc tgagagctga ggacacggct gtgtattact gtgccagaga ttatatgagt 300
ggttcccact tgtggggcca gggaaccctg gtcaccgtct ctagt 345
<210> 10
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 10
Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Thr Ala Ser Gly Ile Asp Leu Asn Thr Tyr Asp
20 25 30
Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly
35 40 45
Ile Ile Thr Tyr Ser Gly Ser Arg Tyr Tyr Ala Asn Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Val Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
Asp Tyr Met Ser Gly Ser His Leu Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 11
<211> 330
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 11
gcctatgata tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
atcaagtgtc aggccagtga ggacatttat agcttcttgg cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatccattct gcatcctctc tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttacta ttgtcaacag ggttatggta aaaataatgt tgataatgct 300
ttcggcggag ggaccaaggt ggagatcaaa 330
<210> 12
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 12
Ala Tyr Asp Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Lys Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
His Ser Ala Ser Ser Leu Ala 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 Gly Tyr Gly Lys Asn Asn
85 90 95
Val Asp Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 13
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 13
cagtcgctgg tggagtctgg gggaggcttg gtacagcctg gggggtccct gagactctcc 60
tgtgcagcct ctggattctc cttcagtagc aactactgga tatgctgggt ccgccaggct 120
ccagggaagg ggctggagtg gatcgcatgc atttatgttg gtagtagtgg tgacacttac 180
tacgcgagct ccgcgaaagg ccggttcacc atctccagag acaattccaa gaacacgctg 240
tatctgcaaa tgaacagcct gagagccgag gacacggccg tatattactg tgcgagagat 300
agtagtagtt attatatgtt taacttgtgg ggccagggaa ccctggtcac cgtctcgagc 360
<210> 14
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 14
Gln Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Asn Tyr
20 25 30
Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Ala Cys Ile Tyr Val Gly Ser Ser Gly Asp Thr Tyr Tyr Ala Ser Ser
50 55 60
Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Asp Ser Ser Ser Tyr Tyr Met Phe Asn Leu Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 15
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 15
gcccttgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcaattgcc aggccagtga ggacattgat acctatttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatcttttat gcatccgatc tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaaggc ggttactata ctagtagtgc tgatacgagg 300
ggtgctttcg gcggagggac caaggtggag atcaaa 336
<210> 16
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 16
Ala Leu Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Asp Ile Asp Thr Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Phe Tyr Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Gly Tyr Tyr Thr Ser Ser
85 90 95
Ala Asp Thr Arg Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 17
<211> 345
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 17
cggtcgctgg tggagtctgg gggaggcttg gtccagcctg gggggtccct gagactctcc 60
tgtacagcct ctggattcac catcagtagc taccacatgc agtgggtccg ccaggctcca 120
gggaaggggc tggagtacat cggaaccatt agtagtggtg gtaatgtata ctacgcgagc 180
tccgcgagag gcagattcac catctccaga ccctcgtcca agaacacggt ggatcttcaa 240
atgaacagcc tgagagccga ggacacggct gtgtattact gtgcgagaga ctctggttat 300
agtgatccta tgtggggcca gggaaccctg gtcaccgtct cgagc 345
<210> 18
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 18
Arg Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Ile Ser Ser Tyr His
20 25 30
Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly
35 40 45
Thr Ile Ser Ser Gly Gly Asn Val Tyr Tyr Ala Ser Ser Ala Arg Gly
50 55 60
Arg Phe Thr Ile Ser Arg Pro Ser Ser Lys Asn Thr Val Asp Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
Asp Ser Gly Tyr Ser Asp Pro Met Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 19
<211> 333
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 19
gacgttgtga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
atcacctgtc aggccagtca gaacattagg acttacttat cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcagccaatc tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcga cctggagcct 240
ggcgatgctg caacttacta ttgtcagtct acctatcttg gtactgatta tgttggcggt 300
gctttcggcg gagggaccaa ggtggagatc aaa 333
<210> 20
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 20
Asp Val Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Arg Thr Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ala Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asp Leu Glu Pro
65 70 75 80
Gly Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Leu Gly Thr Asp
85 90 95
Tyr Val Gly Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 21
<211> 345
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 21
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggaat cgacttcagt aggagatact acatgtgctg ggtccgccag 120
gctccaggga aggggctgga gtggatcgca tgcatatata ctggtagccg cgatactcct 180
cactacgcga gctccgcgaa aggccggttc accatctcca gagacaattc caagaacacg 240
ctgtatctgc aaatgaacag cctgagagcc gaggacacgg ccgtatatta ctgtgcgaga 300
gaaggtagcc tgtggggcca gggaaccctg gtcaccgtct cgagc 345
<210> 22
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 22
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 Ile Asp Phe Ser Arg Arg
20 25 30
Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Ala Cys Ile Tyr Thr Gly Ser Arg Asp Thr Pro His Tyr Ala Ser
50 55 60
Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Glu Gly Ser Leu Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 23
<211> 333
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 23
gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc agtccagtca gagtgtttat agtaactggt tctcctggta tcagcagaaa 120
ccagggaaag cccctaagct cctgatctat tctgcatcca ctctggcatc tggggtccca 180
tcaaggttca gcggcagtgg atctgggaca gaattcactc tcaccatcag cagcctgcag 240
cctgatgatt ttgcaactta ttactgcgca ggcggttaca atactgttat tgatactttt 300
gctttcggcg gagggaccaa ggtggagatc aaa 333
<210> 24
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 24
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ser Ser Gln Ser Val Tyr Ser Asn
20 25 30
Trp Phe Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Asn Thr Val
85 90 95
Ile Asp Thr Phe Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 25
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 25
cagtcgctgg tggagtctgg gggaggcttg gtccagcctg gggggtccct gagactctcc 60
tgtactgcct ctggattctc cctcagtagg tactacatga cctgggtccg ccaggctcca 120
gggaaggggc tggagtggat cggaaccatt tatactagtg gtagtacatg gtacgcgagc 180
tggacaaaag gcagattcac catctccaaa gacaatacca agaacacggt ggatcttcaa 240
atgaacagcc tgagagccga ggacacggct gtgtattact gtgcgagatc ctattatggc 300
ggtgataaga ctggtttagg catctggggc cagggaactc tggttaccgt ctcttca 357
<210> 26
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 26
Gln Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Ser Arg Tyr Tyr
20 25 30
Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Thr Ile Tyr Thr Ser Gly Ser Thr Trp Tyr Ala Ser Trp Thr Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Val Asp Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
Ser Tyr Tyr Gly Gly Asp Lys Thr Gly Leu Gly Ile Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 27
<211> 339
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 27
gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc aggccagtca gagcattgat agttggttat cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatcag gcatccactc tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaatct gcttatggtg ttagtggtac tagtagttat 300
ttatatactt tcggcggagg gaccaaggtg gagatcaaa 339
<210> 28
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 28
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Asp Ser Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gln Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Ala Tyr Gly Val Ser Gly
85 90 95
Thr Ser Ser Tyr Leu Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 29
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 29
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccatcagt cgctaccaca tgacttgggt ccgccaggct 120
ccagggaagg ggctggagtg gatcggacat atttatgtta ataatgatga cacagactac 180
gcgagctccg cgaaaggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccacct atttctgtgc gagattggat 300
gttggtggtg gtggtgctta tattggggac atctggggcc agggaactct ggttaccgtc 360
tcttca 366
<210> 30
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 30
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 Ile Ser Arg Tyr
20 25 30
His Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly His Ile Tyr Val Asn Asn Asp Asp Thr Asp Tyr Ala Ser Ser Ala
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 Thr Tyr Phe Cys
85 90 95
Ala Arg Leu Asp Val Gly Gly Gly Gly Ala Tyr Ile Gly Asp Ile Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 31
<211> 339
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 31
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc agtccagtca gagtgtttat aacaacaacg acttagcctg gtatcagcag 120
aaaccaggga aagttcctaa gctcctgatc tattatgctt ccactctggc atctggggtc 180
ccatctcggt tcagtggcag tggatctggg acagatttca ctctcaccat cagcagcctg 240
cagcctgaag atgttgcaac ttattactgt gcaggcggtt atgatacgga tggtcttgat 300
acgtttgctt tcggcggagg gaccaaggtg gagatcaaa 339
<210> 32
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 32
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 Gln Ser Ser Gln Ser Val Tyr Asn Asn
20 25 30
Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu
35 40 45
Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
65 70 75 80
Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Asp Thr
85 90 95
Asp Gly Leu Asp Thr Phe Ala Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 33
<211> 345
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 33
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtactg cctctggatt ctccctcagt agctatgcaa tgagctgggt ccgccaggct 120
ccagggaggg ggctggagtg gatcggaatc atttatgcta gtggtagcac atactacgcg 180
agctcggcga aaggcagatt caccatctcc aaagacaata ccaagaacac ggtggatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag aatttatgac 300
ggcatggacc tctggggcca gggaactctg gttaccgtct cttca 345
<210> 34
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 34
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 Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Tyr Ala Ser Gly Ser Thr Tyr Tyr Ala Ser Ser Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Val Asp Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ile Tyr Asp Gly Met Asp Leu Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 35
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 35
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcaattgcc aggccagtca gaacatttac agctacttat cctggtatca gcagaaacca 120
gggaaagttc ctaagcgcct gatctatctg gcatctactc tggcatctgg ggtcccatct 180
cggttcagtg gcagtggatc tgggacagat tacactctca ccatcagcag cctgcagcct 240
gaagatgttg caacttatta ctgtcaaagc aattataacg gtaattatgg tttcggcgga 300
gggaccaagg tggagatcaa a 321
<210> 36
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 36
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 Asn Cys Gln Ala Ser Gln Asn Ile Tyr Ser Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Arg Leu Ile
35 40 45
Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Ser Asn Tyr Asn Gly Asn Tyr
85 90 95
Gly Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 37
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 37
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt ctccctcaat aactactgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg gatcggaacc attagtagtg gtgcgtatac atggttcgcc 180
acctgggcga caggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag atattcttct 300
actactgatt ggacctactt taacatctgg ggccagggaa ctctggttac cgtctcttca 360
<210> 38
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 38
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 Ser Leu Asn Asn Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Thr Ile Ser Ser Gly Ala Tyr Thr Trp Phe Ala Thr Trp Ala Thr
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Tyr Ser Ser Thr Thr Asp Trp Thr Tyr Phe Asn Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 39
<211> 324
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 39
gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc aggccagtca gagcattaat aactacttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatagg gcatccactc tggaatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaaagc tataatggtg ttggtaggac tgctttcggc 300
ggagggacca aggtggagat caaa 324
<210> 40
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 40
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Asn Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Tyr Asn Gly Val Gly Arg
85 90 95
Thr Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 41
<211> 354
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 41
gaggtgaagc tggatgagac tggaggaggc ttggtgcaac ctgggaggcc catgaaactc 60
tcctgtgttg cctctggatt cacttttagt gactactgga tgaactgggt ccgccagtct 120
ccagagaaag gactggagtg ggtagcacaa attagaaaca aaccttataa ttatgaaaca 180
tattattcag attctgtgaa aggcagattc accatctcaa gagatgattc caaaagtagt 240
gtctacctgc aaatgaacaa cttaagagtt gaagacatgg gtatctatta ctgtacgggt 300
tcttactatg gtatggacta ctggggtcaa ggaacctcag tcaccgtctc ctca 354
<210> 42
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 42
Glu Val Lys Leu Asp Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Pro Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Asn Lys Pro Tyr Asn Tyr Glu Thr Tyr Tyr Ser Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser
65 70 75 80
Val Tyr Leu Gln Met Asn Asn Leu Arg Val Glu Asp Met Gly Ile Tyr
85 90 95
Tyr Cys Thr Gly Ser Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 43
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 43
gatgtcgtga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagccttgta cacagtaatg gaaacaccta tttacgttgg 120
tacctgcaga agccaggcca gtctccaaag gtcctgatct acaaagtttc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tatttctgct ctcaaagtac acatgttccg 300
tggacgttcg gtggaggcac caagctggaa atcaaa 336
<210> 44
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 44
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Arg Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Val 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 Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 45
<211> 987
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 45
gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaagc cgcgggggca 360
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600
gagtacaagt gcgcggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 720
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840
ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 900
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960
cagaagagcc tctccctgtc tccgggt 987
<210> 46
<211> 329
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 46
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 47
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 47
cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60
ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120
tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180
agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 240
aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 300
agcttcaaca ggggagagtg t 321
<210> 48
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 48
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 49
<211> 3681
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 49
gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc agtccagtca gagtgtttat agtaactggt tctcctggta tcagcagaaa 120
ccagggaaag cccctaagct cctgatctat tctgcatcca ctctggcatc tggggtccca 180
tcaaggttca gcggcagtgg atctgggaca gaattcactc tcaccatcag cagcctgcag 240
cctgatgatt ttgcaactta ttactgcgca ggcggttaca atactgttat tgatactttt 300
gctttcggcg gagggaccaa ggtggagatc aaaggcggtg gcggtagtgg gggaggcggt 360
tctggcggcg gagggtccgg cggtggagga tcagaggtgc agctgttgga gtctggggga 420
ggcttggtac agcctggggg gtccctgaga ctctcctgtg cagcctctgg aatcgacttc 480
agtaggagat actacatgtg ctgggtccgc caggctccag ggaaggggct ggagtggatc 540
gcatgcatat atactggtag ccgcgatact cctcactacg cgagctccgc gaaaggccgg 600
ttcaccatct ccagagacaa ttccaagaac acgctgtatc tgcaaatgaa cagcctgaga 660
gccgaggaca cggccgtata ttactgtgcg agagaaggta gcctgtgggg ccagggaacc 720
ctggtcaccg tctcgagcgg cggtggaggg tccggcggtg gtggatccca gtcggtggag 780
gagtctgggg gaggcttggt ccagcctggg gggtccctga gactctcctg tacagcctct 840
ggaatcgacc ttaataccta cgacatgatc tgggtccgcc aggctccagg caaggggcta 900
gagtgggttg gaatcattac ttatagtggt agtagatact acgcgaactg ggcgaaaggc 960
cgattcacca tctccaaaga caataccaag aacacggtgt atctgcaaat gaacagcctg 1020
agagctgagg acacggctgt gtattactgt gccagagatt atatgagtgg ttcccacttg 1080
tggggccagg gaaccctggt caccgtctct agtgctagca ccaagggccc atcggtcttc 1140
cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 1200
aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 1260
gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 1320
accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 1380
agcaacacca aggtggacaa gagagttgag cccaaatctt gtgacaaaac tcacacatgc 1440
ccaccgtgcc cagcacctga agccgcgggg gcaccgtcag tcttcctctt ccccccaaaa 1500
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 1560
agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 1620
gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 1680
accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcgcggt ctccaacaaa 1740
gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1800
caggtgtata ccctgccccc atcccgggat gagctgacca agaaccaggt cagcctgacc 1860
tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1920
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1980
tatagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 2040
gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 2100
ggcggtggag ggtccggcgg tggtggatcc gaggtgcagc tgttggagtc tgggggaggc 2160
ttggtacagc ctggggggtc cctgagactc tcctgtgcag cctctggatt caccatcagt 2220
cgctaccaca tgacttgggt ccgccaggct ccagggaagg ggctggagtg gatcggacat 2280
atttatgtta ataatgatga cacagactac gcgagctccg cgaaaggccg gttcaccatc 2340
tccagagaca attccaagaa cacgctgtat ctgcaaatga acagcctgag agccgaggac 2400
acggccacct atttctgtgc gagattggat gttggtggtg gtggtgctta tattggggac 2460
atctggggcc agggaactct ggttaccgtc tcttcaggcg gtggcggtag tgggggaggc 2520
ggttctggcg gcggagggtc cggcggtgga ggatcagaca tccagatgac ccagtctcca 2580
tcctccctgt ctgcatctgt aggagacaga gtcaccatca cttgccagtc cagtcagagt 2640
gtttataaca acaacgactt agcctggtat cagcagaaac cagggaaagt tcctaagctc 2700
ctgatctatt atgcttccac tctggcatct ggggtcccat ctcggttcag tggcagtgga 2760
tctgggacag atttcactct caccatcagc agcctgcagc ctgaagatgt tgcaacttat 2820
tactgtgcag gcggttatga tacggatggt cttgatacgt ttgctttcgg cggagggacc 2880
aaggtggaga tcaaaggcgg tggagggtcc ggcggtggtg gatccgaggt gcagctggtg 2940
gagtctgggg gaggcttggt ccagcctggg gggtccctga gactctcctg tgcagcctct 3000
ggattcacca tcagtaccaa tgcaatgagc tgggtccgcc aggctccagg gaaggggctg 3060
gagtggatcg gagtcattac tggtcgtgat atcacatact acgcgagctg ggcgaaaggc 3120
agattcacca tctccagaga caattccaag aacacgctgt atcttcaaat gaacagcctg 3180
agagccgagg acacggctgt gtattactgt gcgcgcgacg gtggatcatc tgctattact 3240
agtaacaaca tttggggcca aggaactctg gtcaccgttt cttcaggcgg tggcggtagt 3300
gggggaggcg gttctggcgg cggagggtcc ggcggtggag gatcagacgt cgtgatgacc 3360
cagtctcctt ccaccctgtc tgcatctgta ggagacagag tcaccatcaa ttgccaagcc 3420
agtgagagca ttagcagttg gttagcctgg tatcagcaga aaccagggaa agcccctaag 3480
ctcctgatct atgaagcatc caaactggca tctggggtcc catcaaggtt cagcggcagt 3540
ggatctggga cagagttcac tctcaccatc agcagcctgc agcctgatga ttttgcaact 3600
tattactgcc aaggctattt ttattttatt agtcgtactt atgtaaattc tttcggcgga 3660
gggaccaagg tggagatcaa a 3681
<210> 50
<211> 1227
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 50
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ser Ser Gln Ser Val Tyr Ser Asn
20 25 30
Trp Phe Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Asn Thr Val
85 90 95
Ile Asp Thr Phe Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Asp Phe
145 150 155 160
Ser Arg Arg Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly
165 170 175
Leu Glu Trp Ile Ala Cys Ile Tyr Thr Gly Ser Arg Asp Thr Pro His
180 185 190
Tyr Ala Ser Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
195 200 205
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
210 215 220
Ala Val Tyr Tyr Cys Ala Arg Glu Gly Ser Leu Trp Gly Gln Gly Thr
225 230 235 240
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
260 265 270
Leu Arg Leu Ser Cys Thr Ala Ser Gly Ile Asp Leu Asn Thr Tyr Asp
275 280 285
Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly
290 295 300
Ile Ile Thr Tyr Ser Gly Ser Arg Tyr Tyr Ala Asn Trp Ala Lys Gly
305 310 315 320
Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Val Tyr Leu Gln
325 330 335
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
340 345 350
Asp Tyr Met Ser Gly Ser His Leu Trp Gly Gln Gly Thr Leu Val Thr
355 360 365
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
370 375 380
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
385 390 395 400
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
405 410 415
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
420 425 430
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
435 440 445
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
450 455 460
Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
465 470 475 480
Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu
485 490 495
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
500 505 510
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
515 520 525
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
530 535 540
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
545 550 555 560
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala
565 570 575
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
580 585 590
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
595 600 605
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
610 615 620
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
625 630 635 640
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
645 650 655
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
660 665 670
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
675 680 685
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly
690 695 700
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
705 710 715 720
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
725 730 735
Phe Thr Ile Ser Arg Tyr His Met Thr Trp Val Arg Gln Ala Pro Gly
740 745 750
Lys Gly Leu Glu Trp Ile Gly His Ile Tyr Val Asn Asn Asp Asp Thr
755 760 765
Asp Tyr Ala Ser Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
770 775 780
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
785 790 795 800
Thr Ala Thr Tyr Phe Cys Ala Arg Leu Asp Val Gly Gly Gly Gly Ala
805 810 815
Tyr Ile Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
820 825 830
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
835 840 845
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
850 855 860
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ser Ser Gln Ser
865 870 875 880
Val Tyr Asn Asn Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
885 890 895
Val Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val
900 905 910
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
915 920 925
Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Ala Gly
930 935 940
Gly Tyr Asp Thr Asp Gly Leu Asp Thr Phe Ala Phe Gly Gly Gly Thr
945 950 955 960
Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
965 970 975
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
980 985 990
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Thr Asn Ala
995 1000 1005
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
1010 1015 1020
Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
1025 1030 1035 1040
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
1045 1050 1055
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
1060 1065 1070
Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp Gly Gln Gly
1075 1080 1085
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1090 1095 1100
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr
1105 1110 1115 1120
Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
1125 1130 1135
Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp Leu Ala Trp Tyr Gln
1140 1145 1150
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Glu Ala Ser Lys
1155 1160 1165
Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
1170 1175 1180
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr
1185 1190 1195 1200
Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser Arg Thr Tyr Val Asn
1205 1210 1215
Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1220 1225
<210> 51
<211> 651
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 51
gcctatgata tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
atcaagtgtc aggccagtga ggacatttat agcttcttgg cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatccattct gcatcctctc tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttacta ttgtcaacag ggttatggta aaaataatgt tgataatgct 300
ttcggcggag ggaccaaggt ggagatcaaa cgtacggtgg ctgcaccatc tgtcttcatc 360
ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420
aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480
aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540
accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600
catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 651
<210> 52
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 52
Ala Tyr Asp Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Lys Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
His Ser Ala Ser Ser Leu Ala 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 Gly Tyr Gly Lys Asn Asn
85 90 95
Val Asp Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 53
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Syntheized
<400> 53
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccatcagt accaatgcaa tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg gatcggagtc attactggtc gtgatatcac atactacgcg 180
agctgggcga aaggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agacggtggt 300
tcttctgcta ttactagtaa caacatttgg ggccagggaa ccctggtcac cgtgtcgaca 360
<210> 54
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Syntheized
<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 Ile Ser Thr Asn
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Thr
115 120
<210> 55
<211> 345
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 55
cggtcgctgg tggagtctgg gggaggcttg gtccagcctg gggggtccct gagactctcc 60
tgtacagcct ctggattcac catcagtagc taccacatgc agtgggtccg ccaggctcca 120
gggaaggggc tggagtacat cggaaccatt agtagtggtg gtaatgtata ctacgcaagc 180
tccgctagag gcagattcac catctccaga ccctcgtcca agaacacggt ggatcttcaa 240
atgaacagcc tgagagccga ggacacggct gtgtattact gtgcgagaga ctctggttat 300
agtgatccta tgtggggcca gggaaccctg gtcaccgtgt cgaca 345
<210> 56
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 56
Arg Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Ile Ser Ser Tyr His
20 25 30
Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly
35 40 45
Thr Ile Ser Ser Gly Gly Asn Val Tyr Tyr Ala Ser Ser Ala Arg Gly
50 55 60
Arg Phe Thr Ile Ser Arg Pro Ser Ser Lys Asn Thr Val Asp Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
Asp Ser Gly Tyr Ser Asp Pro Met Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Thr
115
<210> 57
<211> 345
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 57
cagtcggtgg aggagtctgg gggaggcttg gtccagcctg gggggtccct gagactctcc 60
tgtaccgcct ctggaatcga ccttaatacc tacgacatga tctgggtccg ccaggctcca 120
ggcaaggggc tagagtgggt tggaatcatt acttatagtg gtagtagata ctacgcgaac 180
tgggcgaaag gccgattcac catctccaaa gacaatacca agaacacggt gtatctgcaa 240
atgaacagcc tgagagctga ggacacggct gtgtattact gtgcgagaga ttatatgagt 300
ggttcccact tgtggggcca gggaaccctg gtcaccgtgt cgaca 345
<210> 58
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 58
Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Thr Ala Ser Gly Ile Asp Leu Asn Thr Tyr Asp
20 25 30
Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly
35 40 45
Ile Ile Thr Tyr Ser Gly Ser Arg Tyr Tyr Ala Asn Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Val Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
Asp Tyr Met Ser Gly Ser His Leu Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Thr
115
<210> 59
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 59
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt ctccttcagt agcgggtacg acatgtgctg ggtccgccag 120
gctccaggga aggggctgga gtggatcgca tgcattgctg ctggtagtgc tggtatcact 180
tacgacgcga actgggcgaa aggccggttc accatctcca gagacaattc caagaacacg 240
ctgtatctgc aaatgaacag cctgagagcc gaggacacgg ccgtatatta ctgtgcgaga 300
tcggcgtttt cgttcgacta cgccatggac ctctggggcc agggaaccct ggtcaccgtc 360
tcgagc 366
<210> 60
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 60
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 Ser Phe Ser Ser Gly
20 25 30
Tyr Asp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Ala Cys Ile Ala Ala Gly Ser Ala Gly Ile Thr Tyr Asp Ala Asn
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Ser Ala Phe Ser Phe Asp Tyr Ala Met Asp Leu Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 61
<211> 330
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 61
gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc aggccagtca gagcattagt tcccacttaa actggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctataag gcatccactc tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaacag ggttatagtt ggggtaatgt tgataatgtt 300
ttcggcggag ggaccaaggt ggagatcaaa 330
<210> 62
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 62
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser His
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Trp Gly Asn
85 90 95
Val Asp Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 63
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 63
gaggtgcagc tggtgcagtc tggagcagag gtgaagaaac caggagagtc tctgaagatc 60
tcctgtaagg gttctggata cagctttagc agttcatgga tcggctgggt gcgccaggca 120
cctgggaaag gcctggaatg gatggggatc atctatcctg atgactctga taccagatac 180
agtccatcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag gactgcctac 240
ctgcagtgga gtagcctgaa ggcctcggac accgctatgt attactgtgc gagacatgtt 300
actatgattt ggggagttat tattgacttc tggggccagg gaaccctggt caccgtctcc 360
tca 363
<210> 64
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 64
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Ser Ser
20 25 30
Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Arg Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg His Val Thr Met Ile Trp Gly Val Ile Ile Asp Phe Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 65
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 65
gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120
gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag tttaatagtt acccattcac tttcggccct 300
gggaccaaag tggatatcaa a 321
<210> 66
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 66
Ala Ile Gln Leu 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 Gly Ile Ser Ser Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu 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 Phe Asn Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 67
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 67
gatgtgcagc ttcaggagtc gggacctagc ctggtgaaac cttctcagtc tctgtccctc 60
acctgcactg tcactggcta ctcaatcacc agtgattttg cctggaactg gattcggcag 120
tttccaggaa acaagctgga gtggatgggc tacataagtt atagtggtaa cactaggtac 180
aacccatctc tcaaaagtcg aatctctatc actcgcgaca catccaagaa ccaattcttc 240
ctgcagttga actctgtgac tattgaggac acagccacat attactgtgt aacggcggga 300
cgcgggtttc cttattgggg ccaagggact ctggtcactg tctctgca 348
<210> 68
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 68
Asp Val Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Phe Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Arg Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Ile Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Val Thr Ala Gly Arg Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala
115
<210> 69
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 69
gacatcctga tgacccaatc tccatcctcc atgtctgtat ctctgggaga cacagtcagc 60
atcacttgcc attcaagtca ggacattaac agtaatatag ggtggttgca gcagagacca 120
gggaaatcat ttaagggcct gatctatcat ggaaccaact tggacgatga agttccatca 180
aggttcagtg gcagtggatc tggagccgat tattctctca ccatcagcag cctggaatct 240
gaagattttg cagactatta ctgtgtacag tatgctcagt ttccgtggac gttcggtgga 300
ggcaccaagc tggaaatcaa a 321
<210> 70
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 70
Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Met Ser Val Ser Leu Gly
1 5 10 15
Asp Thr Val Ser Ile Thr Cys His Ser Ser Gln Asp Ile Asn Ser Asn
20 25 30
Ile Gly Trp Leu Gln Gln Arg Pro Gly Lys Ser Phe Lys Gly Leu Ile
35 40 45
Tyr His Gly Thr Asn Leu Asp Asp Glu Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Ala Asp Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 71
<211> 33
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 71
ggcggtggag ggtccggcgg tggtggctcc gga 33
<210> 72
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 72
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10
<210> 73
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 73
ggcggtggag ggtccggcgg tggtggatca 30
<210> 74
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 74
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 75
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 75
ggcggtggag ggtccggcgg tggtggatcc 30
<210> 76
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 76
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 77
<211> 60
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 77
ggcggtggcg gtagtggggg aggcggttct ggcggcggag ggtccggcgg tggaggatca 60
<210> 78
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 78
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 79
<211> 3693
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 79
gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300
aattctttcg gcggagggac caaggtggag atcaaaggcg gtggcggtag tgggggaggc 360
ggttctggcg gcggagggtc cggcggtgga ggatcagagg tgcagctggt ggagtctggg 420
ggaggcttgg tccagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480
atcagtacca atgcaatgag ctgggtccgc caggctccag ggaaggggct ggagtggatc 540
ggagtcatta ctggtcgtga tatcacatac tacgcgagct gggcgaaagg cagattcacc 600
atctccagag acaattccaa gaacacgctg tatcttcaaa tgaacagcct gagagccgag 660
gacacggctg tgtattactg tgcgcgcgac ggtggatcat ctgctattac tagtaacaac 720
atttggggcc aaggaactct ggtcaccgtt tcttcaggcg gtggagggtc cggcggtggt 780
ggatccgatg tgcagcttca ggagtcggga cctagcctgg tgaaaccttc tcagtctctg 840
tccctcacct gcactgtcac tggctactca atcaccagtg attttgcctg gaactggatt 900
cggcagtttc caggaaacaa gctggagtgg atgggctaca taagttatag tggtaacact 960
aggtacaacc catctctcaa aagtcgaatc tctatcactc gcgacacatc caagaaccaa 1020
ttcttcctgc agttgaactc tgtgactatt gaggacacag ccacatatta ctgtgtaacg 1080
gcgggacgcg ggtttcctta ttggggccaa gggactctgg tcactgtctc tgcagctagc 1140
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 1200
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 1260
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 1320
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 1380
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 1440
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aagccgcggg ggcaccgtca 1500
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 1560
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 1620
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 1680
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 1740
aagtgcgcgg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1800
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 1860
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1920
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1980
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 2040
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 2100
agcctctccc tgtctccggg tggcggtgga gggtccggcg gtggtggatc cgaggtgcag 2160
ctgttggagt ctgggggagg cttggtacag cctggggggt ccctgagact ctcctgtgca 2220
gcctctggat tctccttcag tagcgggtac gacatgtgct gggtccgcca ggctccaggg 2280
aaggggctgg agtggatcgc atgcattgct gctggtagtg ctggtatcac ttacgacgcg 2340
aactgggcga aaggccggtt caccatctcc agagacaatt ccaagaacac gctgtatctg 2400
caaatgaaca gcctgagagc cgaggacacg gccgtatatt actgtgcgag atcggcgttt 2460
tcgttcgact acgccatgga cctctggggc cagggaaccc tggtcaccgt ctcgagcggc 2520
ggtggcggta gtgggggagg cggttctggc ggcggagggt ccggcggtgg aggatcagac 2580
atccagatga cccagtctcc ttccaccctg tctgcatctg taggagacag agtcaccatc 2640
acttgccagg ccagtcagag cattagttcc cacttaaact ggtatcagca gaaaccaggg 2700
aaagccccta agctcctgat ctataaggca tccactctgg catctggggt cccatcaagg 2760
ttcagcggca gtggatctgg gacagaattt actctcacca tcagcagcct gcagcctgat 2820
gattttgcaa cttattactg ccaacagggt tatagttggg gtaatgttga taatgttttc 2880
ggcggaggga ccaaggtgga gatcaaaggc ggtggagggt ccggcggtgg tggatcccag 2940
tcgctggtgg agtctggggg aggcttggta cagcctgggg ggtccctgag actctcctgt 3000
gcagcctctg gattctcctt cagtagcaac tactggatat gctgggtccg ccaggctcca 3060
gggaaggggc tggagtggat cgcatgtatt tatgttggta gtagtggtga cacttactac 3120
gcgagctccg cgaaaggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 3180
ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gagagatagt 3240
agtagttatt atatgtttaa cttgtggggc cagggaaccc tggtcaccgt ctcttcaggc 3300
ggtggcggta gtgggggagg cggttctggc ggcggagggt ccggcggtgg aggatcagcc 3360
cttgtgatga cccagtctcc ttccaccctg tctgcatctg taggagacag agtcaccatc 3420
aattgccagg ccagtgagga cattgatacc tatttagcct ggtatcagca gaaaccaggg 3480
aaagccccta agctcctgat cttttacgca tccgatctgg catctggggt cccatcaagg 3540
ttcagcggca gtggatctgg gacagaattt actctcacca tcagcagcct gcagcctgat 3600
gattttgcaa cttattactg ccaaggcggt tactatacta gtagtgctga tacgaggggt 3660
gctttcggcg gagggaccaa ggtggagatc aaa 3693
<210> 80
<211> 1231
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 80
Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
145 150 155 160
Ile Ser Thr Asn Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
165 170 175
Leu Glu Trp Ile Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala
180 185 190
Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn
225 230 235 240
Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Asp Val Gln Leu Gln Glu Ser Gly Pro Ser
260 265 270
Leu Val Lys Pro Ser Gln Ser Leu Ser Leu Thr Cys Thr Val Thr Gly
275 280 285
Tyr Ser Ile Thr Ser Asp Phe Ala Trp Asn Trp Ile Arg Gln Phe Pro
290 295 300
Gly Asn Lys Leu Glu Trp Met Gly Tyr Ile Ser Tyr Ser Gly Asn Thr
305 310 315 320
Arg Tyr Asn Pro Ser Leu Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr
325 330 335
Ser Lys Asn Gln Phe Phe Leu Gln Leu Asn Ser Val Thr Ile Glu Asp
340 345 350
Thr Ala Thr Tyr Tyr Cys Val Thr Ala Gly Arg Gly Phe Pro Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro
370 375 380
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
385 390 395 400
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
405 410 415
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
420 425 430
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
435 440 445
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
450 455 460
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
465 470 475 480
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
485 490 495
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
500 505 510
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
515 520 525
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
530 535 540
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
545 550 555 560
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
565 570 575
Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro
580 585 590
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
595 600 605
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
610 615 620
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
625 630 635 640
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
645 650 655
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
660 665 670
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
675 680 685
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
690 695 700
Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln
705 710 715 720
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
725 730 735
Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Gly Tyr Asp Met
740 745 750
Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala Cys
755 760 765
Ile Ala Ala Gly Ser Ala Gly Ile Thr Tyr Asp Ala Asn Trp Ala Lys
770 775 780
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
785 790 795 800
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
805 810 815
Arg Ser Ala Phe Ser Phe Asp Tyr Ala Met Asp Leu Trp Gly Gln Gly
820 825 830
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
835 840 845
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
850 855 860
Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
865 870 875 880
Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser His Leu Asn Trp Tyr Gln
885 890 895
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Thr
900 905 910
Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
915 920 925
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr
930 935 940
Tyr Tyr Cys Gln Gln Gly Tyr Ser Trp Gly Asn Val Asp Asn Val Phe
945 950 955 960
Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly
965 970 975
Gly Gly Ser Gln Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
980 985 990
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser
995 1000 1005
Ser Asn Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
1010 1015 1020
Glu Trp Ile Ala Cys Ile Tyr Val Gly Ser Ser Gly Asp Thr Tyr Tyr
1025 1030 1035 1040
Ala Ser Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
1045 1050 1055
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
1060 1065 1070
Val Tyr Tyr Cys Ala Arg Asp Ser Ser Ser Tyr Tyr Met Phe Asn Leu
1075 1080 1085
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
1090 1095 1100
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala
1105 1110 1115 1120
Leu Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp
1125 1130 1135
Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Asp Ile Asp Thr Tyr Leu
1140 1145 1150
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Phe
1155 1160 1165
Tyr Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
1170 1175 1180
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
1185 1190 1195 1200
Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Gly Tyr Tyr Thr Ser Ser Ala
1205 1210 1215
Asp Thr Arg Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1220 1225 1230
<210> 81
<211> 642
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 81
gacatcctga tgacccaatc tccatcctcc atgtctgtat ctctgggaga cacagtcagc 60
atcacttgcc attcaagtca ggacattaac agtaatatag ggtggttgca gcagagacca 120
gggaaatcat ttaagggcct gatctatcat ggaaccaact tggacgatga agttccatca 180
aggttcagtg gcagtggatc tggagccgat tattctctca ccatcagcag cctggaatct 240
gaagattttg cagactatta ctgtgtacag tatgctcagt ttccgtggac gttcggtgga 300
ggcaccaagc tggaaatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 82
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 82
Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Met Ser Val Ser Leu Gly
1 5 10 15
Asp Thr Val Ser Ile Thr Cys His Ser Ser Gln Asp Ile Asn Ser Asn
20 25 30
Ile Gly Trp Leu Gln Gln Arg Pro Gly Lys Ser Phe Lys Gly Leu Ile
35 40 45
Tyr His Gly Thr Asn Leu Asp Asp Glu Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Ala Asp Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 83
<211> 3678
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 83
gacatcctga tgacccaatc tccatcctcc atgtctgtat ctctgggaga cacagtcagc 60
atcacttgcc attcaagtca ggacattaac agtaatatag ggtggttgca gcagagacca 120
gggaaatcat ttaagggcct gatctatcat ggaaccaact tggacgatga agttccatca 180
aggttcagtg gcagtggatc tggagccgat tattctctca ccatcagcag cctggaatct 240
gaagattttg cagactatta ctgtgtacag tatgctcagt ttccgtggac gttcggtgga 300
ggcaccaagc tggaaatcaa aggcggtggc ggtagtgggg gaggcggttc tggcggcgga 360
gggtccggcg gtggaggatc agatgtgcag cttcaggagt cgggacctag cctggtgaaa 420
ccttctcagt ctctgtccct cacctgcact gtcactggct actcaatcac cagtgatttt 480
gcctggaact ggattcggca gtttccagga aacaagctgg agtggatggg ctacataagt 540
tatagtggta acactaggta caacccatct ctcaaaagtc gaatctctat cactcgcgac 600
acatccaaga accaattctt cctgcagttg aactctgtga ctattgagga cacagccaca 660
tattactgtg taacggcggg acgcgggttt ccttattggg gccaagggac tctggtcact 720
gtctctgcag gcggtggagg gtccggcggt ggtggatccg aggtgcagct ggtggagtct 780
gggggaggct tggtccagcc tggggggtcc ctgagactct cctgtgcagc ctctggattc 840
accatcagta ccaatgcaat gagctgggtc cgccaggctc cagggaaggg gctggagtgg 900
atcggagtca ttactggtcg tgatatcaca tactacgcga gctgggcgaa aggcagattc 960
accatctcca gagacaattc caagaacacg ctgtatcttc aaatgaacag cctgagagcc 1020
gaggacacgg ctgtgtatta ctgtgcgcgc gacggtggat catctgctat tactagtaac 1080
aacatttggg gccaaggaac tctggtcacc gtttcttcag ctagcaccaa gggcccatcg 1140
gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 1200
ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 1260
agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 1320
gtggtgaccg tgccctccag cagcttgggc acccagacct acatctgcaa cgtgaatcac 1380
aagcccagca acaccaaggt ggacaagaga gttgagccca aatcttgtga caaaactcac 1440
acatgcccac cgtgcccagc acctgaagcc gcgggggcac cgtcagtctt cctcttcccc 1500
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 1560
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1620
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1680
gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg cgcggtctcc 1740
aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1800
gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1860
ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1920
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1980
ttcctctata gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 2040
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 2100
ccgggtggcg gtggagggtc cggcggtggt ggatccgagg tgcagctgtt ggagtctggg 2160
ggaggcttgg tacagcctgg ggggtccctg agactctcct gtgcagcctc tggattctcc 2220
ttcagtagcg ggtacgacat gtgctgggtc cgccaggctc cagggaaggg gctggagtgg 2280
atcgcatgca ttgctgctgg tagtgctggt atcacttacg acgcgaactg ggcgaaaggc 2340
cggttcacca tctccagaga caattccaag aacacgctgt atctgcaaat gaacagcctg 2400
agagccgagg acacggccgt atattactgt gcgagatcgg cgttttcgtt cgactacgcc 2460
atggacctct ggggccaggg aaccctggtc accgtctcga gcggcggtgg cggtagtggg 2520
ggaggcggtt ctggcggcgg agggtccggc ggtggaggat cagacatcca gatgacccag 2580
tctccttcca ccctgtctgc atctgtagga gacagagtca ccatcacttg ccaggccagt 2640
cagagcatta gttcccactt aaactggtat cagcagaaac cagggaaagc ccctaagctc 2700
ctgatctata aggcatccac tctggcatct ggggtcccat caaggttcag cggcagtgga 2760
tctgggacag aatttactct caccatcagc agcctgcagc ctgatgattt tgcaacttat 2820
tactgccaac agggttatag ttggggtaat gttgataatg ttttcggcgg agggaccaag 2880
gtggagatca aaggcggtgg agggtccggc ggtggtggat cccagtcgct ggtggagtct 2940
gggggaggct tggtacagcc tggggggtcc ctgagactct cctgtgcagc ctctggattc 3000
tccttcagta gcaactactg gatatgctgg gtccgccagg ctccagggaa ggggctggag 3060
tggatcgcat gtatttatgt tggtagtagt ggtgacactt actacgcgag ctccgcgaaa 3120
ggccggttca ccatctccag agacaattcc aagaacacgc tgtatctgca aatgaacagc 3180
ctgagagccg aggacacggc cgtatattac tgtgcgagag atagtagtag ttattatatg 3240
tttaacttgt ggggccaggg aaccctggtc accgtctctt caggcggtgg cggtagtggg 3300
ggaggcggtt ctggcggcgg agggtccggc ggtggaggat cagcccttgt gatgacccag 3360
tctccttcca ccctgtctgc atctgtagga gacagagtca ccatcaattg ccaggccagt 3420
gaggacattg atacctattt agcctggtat cagcagaaac cagggaaagc ccctaagctc 3480
ctgatctttt acgcatccga tctggcatct ggggtcccat caaggttcag cggcagtgga 3540
tctgggacag aatttactct caccatcagc agcctgcagc ctgatgattt tgcaacttat 3600
tactgccaag gcggttacta tactagtagt gctgatacga ggggtgcttt cggcggaggg 3660
accaaggtgg agatcaaa 3678
<210> 84
<211> 1226
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 84
Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Met Ser Val Ser Leu Gly
1 5 10 15
Asp Thr Val Ser Ile Thr Cys His Ser Ser Gln Asp Ile Asn Ser Asn
20 25 30
Ile Gly Trp Leu Gln Gln Arg Pro Gly Lys Ser Phe Lys Gly Leu Ile
35 40 45
Tyr His Gly Thr Asn Leu Asp Asp Glu Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Ala Asp Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
115 120 125
Val Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln Ser
130 135 140
Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp Phe
145 150 155 160
Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met
165 170 175
Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Arg Tyr Asn Pro Ser Leu Lys
180 185 190
Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu
195 200 205
Gln Leu Asn Ser Val Thr Ile Glu Asp Thr Ala Thr Tyr Tyr Cys Val
210 215 220
Thr Ala Gly Arg Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr
225 230 235 240
Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Thr Asn Ala Met Ser
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Val Ile
290 295 300
Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly Arg Phe
305 310 315 320
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn
325 330 335
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gly
340 345 350
Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
370 375 380
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
385 390 395 400
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
405 410 415
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
420 425 430
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
435 440 445
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
450 455 460
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
465 470 475 480
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val
485 490 495
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
500 505 510
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
515 520 525
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
530 535 540
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
545 550 555 560
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
565 570 575
Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
580 585 590
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
595 600 605
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
610 615 620
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
625 630 635 640
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
645 650 655
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
660 665 670
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
675 680 685
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly
690 695 700
Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly
705 710 715 720
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
725 730 735
Ser Gly Phe Ser Phe Ser Ser Gly Tyr Asp Met Cys Trp Val Arg Gln
740 745 750
Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala Cys Ile Ala Ala Gly Ser
755 760 765
Ala Gly Ile Thr Tyr Asp Ala Asn Trp Ala Lys Gly Arg Phe Thr Ile
770 775 780
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
785 790 795 800
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Ala Phe Ser
805 810 815
Phe Asp Tyr Ala Met Asp Leu Trp Gly Gln Gly Thr Leu Val Thr Val
820 825 830
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
835 840 845
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr
850 855 860
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser
865 870 875 880
Gln Ser Ile Ser Ser His Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
885 890 895
Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val
900 905 910
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
915 920 925
Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
930 935 940
Gly Tyr Ser Trp Gly Asn Val Asp Asn Val Phe Gly Gly Gly Thr Lys
945 950 955 960
Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser
965 970 975
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
980 985 990
Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Asn Tyr Trp Ile
995 1000 1005
Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala Cys
1010 1015 1020
Ile Tyr Val Gly Ser Ser Gly Asp Thr Tyr Tyr Ala Ser Ser Ala Lys
1025 1030 1035 1040
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
1045 1050 1055
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
1060 1065 1070
Arg Asp Ser Ser Ser Tyr Tyr Met Phe Asn Leu Trp Gly Gln Gly Thr
1075 1080 1085
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1090 1095 1100
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Leu Val Met Thr Gln
1105 1110 1115 1120
Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Asn
1125 1130 1135
Cys Gln Ala Ser Glu Asp Ile Asp Thr Tyr Leu Ala Trp Tyr Gln Gln
1140 1145 1150
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Phe Tyr Ala Ser Asp Leu
1155 1160 1165
Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
1170 1175 1180
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr
1185 1190 1195 1200
Tyr Cys Gln Gly Gly Tyr Tyr Thr Ser Ser Ala Asp Thr Arg Gly Ala
1205 1210 1215
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1220 1225
<210> 85
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 85
gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300
aattctttcg gcggagggac caaggtggag atcaaacgta cggtggctgc accatctgtc 360
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657
<210> 86
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 86
Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Thr Tyr Val Asn Ser 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> 87
<211> 3681
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 87
gacgttgtga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
atcacctgtc aggccagtca gaacattagg acttacttat cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcagccaatc tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcga cctggagcct 240
ggcgatgctg caacttacta ttgtcagtct acctatcttg gtactgatta tgttggcggt 300
gctttcggcg gagggaccaa ggtggagatc aaaggcggtg gcggtagtgg gggaggcggt 360
tctggcggcg gagggtccgg cggtggagga tcacggtcgc tggtggagtc tgggggaggc 420
ttggtccagc ctggggggtc cctgagactc tcctgtacag cctctggatt caccatcagt 480
agctaccaca tgcagtgggt ccgccaggct ccagggaagg ggctggagta catcggaacc 540
attagtagtg gtggtaatgt atactacgcg agctccgcga gaggcagatt caccatctcc 600
agaccctcgt ccaagaacac ggtggatctt caaatgaaca gcctgagagc cgaggacacg 660
gctgtgtatt actgtgcgag agactctggt tatagtgatc ctatgtgggg ccagggaacc 720
ctggtcaccg tctcgagcgg cggtggaggg tccggcggtg gtggatccca gtcggtggag 780
gagtctgggg gaggcttggt ccagcctggg gggtccctga gactctcctg tacagcctct 840
ggaatcgacc ttaataccta cgacatgatc tgggtccgcc aggctccagg caaggggcta 900
gagtgggttg gaatcattac ttatagtggt agtagatact acgcgaactg ggcgaaaggc 960
cgattcacca tctccaaaga caataccaag aacacggtgt atctgcaaat gaacagcctg 1020
agagctgagg acacggctgt gtattactgt gccagagatt atatgagtgg ttcccacttg 1080
tggggccagg gaaccctggt caccgtctct agtgctagca ccaagggccc atcggtcttc 1140
cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 1200
aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 1260
gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 1320
accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 1380
agcaacacca aggtggacaa gagagttgag cccaaatctt gtgacaaaac tcacacatgc 1440
ccaccgtgcc cagcacctga agccgcgggg gcaccgtcag tcttcctctt ccccccaaaa 1500
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 1560
agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 1620
gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 1680
accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcgcggt ctccaacaaa 1740
gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1800
caggtgtata ccctgccccc atcccgggat gagctgacca agaaccaggt cagcctgacc 1860
tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1920
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1980
tatagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 2040
gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 2100
ggcggtggag ggtccggcgg tggtggatcc gaggtgcagc tgttggagtc tgggggaggc 2160
ttggtacagc ctggggggtc cctgagactc tcctgtgcag cctctggatt caccatcagt 2220
cgctaccaca tgacttgggt ccgccaggct ccagggaagg ggctggagtg gatcggacat 2280
atttatgtta ataatgatga cacagactac gcgagctccg cgaaaggccg gttcaccatc 2340
tccagagaca attccaagaa cacgctgtat ctgcaaatga acagcctgag agccgaggac 2400
acggccacct atttctgtgc gagattggat gttggtggtg gtggtgctta tattggggac 2460
atctggggcc agggaactct ggttaccgtc tcttcaggcg gtggcggtag tgggggaggc 2520
ggttctggcg gcggagggtc cggcggtgga ggatcagaca tccagatgac ccagtctcca 2580
tcctccctgt ctgcatctgt aggagacaga gtcaccatca cttgccagtc cagtcagagt 2640
gtttataaca acaacgactt agcctggtat cagcagaaac cagggaaagt tcctaagctc 2700
ctgatctatt atgcttccac tctggcatct ggggtcccat ctcggttcag tggcagtgga 2760
tctgggacag atttcactct caccatcagc agcctgcagc ctgaagatgt tgcaacttat 2820
tactgtgcag gcggttatga tacggatggt cttgatacgt ttgctttcgg cggagggacc 2880
aaggtggaga tcaaaggcgg tggagggtcc ggcggtggtg gatccgaggt gcagctggtg 2940
gagtctgggg gaggcttggt ccagcctggg gggtccctga gactctcctg tgcagcctct 3000
ggattcacca tcagtaccaa tgcaatgagc tgggtccgcc aggctccagg gaaggggctg 3060
gagtggatcg gagtcattac tggtcgtgat atcacatact acgcgagctg ggcgaaaggc 3120
agattcacca tctccagaga caattccaag aacacgctgt atcttcaaat gaacagcctg 3180
agagccgagg acacggctgt gtattactgt gcgcgcgacg gtggatcatc tgctattact 3240
agtaacaaca tttggggcca aggaactctg gtcaccgttt cttcaggcgg tggcggtagt 3300
gggggaggcg gttctggcgg cggagggtcc ggcggtggag gatcagacgt cgtgatgacc 3360
cagtctcctt ccaccctgtc tgcatctgta ggagacagag tcaccatcaa ttgccaagcc 3420
agtgagagca ttagcagttg gttagcctgg tatcagcaga aaccagggaa agcccctaag 3480
ctcctgatct atgaagcatc caaactggca tctggggtcc catcaaggtt cagcggcagt 3540
ggatctggga cagagttcac tctcaccatc agcagcctgc agcctgatga ttttgcaact 3600
tattactgcc aaggctattt ttattttatt agtcgtactt atgtaaattc tttcggcgga 3660
gggaccaagg tggagatcaa a 3681
<210> 88
<211> 1227
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 88
Asp Val Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Arg Thr Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ala Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asp Leu Glu Pro
65 70 75 80
Gly Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Leu Gly Thr Asp
85 90 95
Tyr Val Gly Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Arg Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Ile Ser
145 150 155 160
Ser Tyr His Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
165 170 175
Tyr Ile Gly Thr Ile Ser Ser Gly Gly Asn Val Tyr Tyr Ala Ser Ser
180 185 190
Ala Arg Gly Arg Phe Thr Ile Ser Arg Pro Ser Ser Lys Asn Thr Val
195 200 205
Asp Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Asp Ser Gly Tyr Ser Asp Pro Met Trp Gly Gln Gly Thr
225 230 235 240
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
260 265 270
Leu Arg Leu Ser Cys Thr Ala Ser Gly Ile Asp Leu Asn Thr Tyr Asp
275 280 285
Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly
290 295 300
Ile Ile Thr Tyr Ser Gly Ser Arg Tyr Tyr Ala Asn Trp Ala Lys Gly
305 310 315 320
Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Val Tyr Leu Gln
325 330 335
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
340 345 350
Asp Tyr Met Ser Gly Ser His Leu Trp Gly Gln Gly Thr Leu Val Thr
355 360 365
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
370 375 380
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
385 390 395 400
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
405 410 415
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
420 425 430
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
435 440 445
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
450 455 460
Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
465 470 475 480
Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu
485 490 495
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
500 505 510
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
515 520 525
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
530 535 540
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
545 550 555 560
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala
565 570 575
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
580 585 590
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
595 600 605
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
610 615 620
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
625 630 635 640
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
645 650 655
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
660 665 670
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
675 680 685
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly
690 695 700
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
705 710 715 720
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
725 730 735
Phe Thr Ile Ser Arg Tyr His Met Thr Trp Val Arg Gln Ala Pro Gly
740 745 750
Lys Gly Leu Glu Trp Ile Gly His Ile Tyr Val Asn Asn Asp Asp Thr
755 760 765
Asp Tyr Ala Ser Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
770 775 780
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
785 790 795 800
Thr Ala Thr Tyr Phe Cys Ala Arg Leu Asp Val Gly Gly Gly Gly Ala
805 810 815
Tyr Ile Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
820 825 830
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
835 840 845
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
850 855 860
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ser Ser Gln Ser
865 870 875 880
Val Tyr Asn Asn Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
885 890 895
Val Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val
900 905 910
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
915 920 925
Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Ala Gly
930 935 940
Gly Tyr Asp Thr Asp Gly Leu Asp Thr Phe Ala Phe Gly Gly Gly Thr
945 950 955 960
Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
965 970 975
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
980 985 990
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Thr Asn Ala
995 1000 1005
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
1010 1015 1020
Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
1025 1030 1035 1040
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
1045 1050 1055
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
1060 1065 1070
Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp Gly Gln Gly
1075 1080 1085
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1090 1095 1100
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr
1105 1110 1115 1120
Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
1125 1130 1135
Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp Leu Ala Trp Tyr Gln
1140 1145 1150
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Glu Ala Ser Lys
1155 1160 1165
Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
1170 1175 1180
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr
1185 1190 1195 1200
Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser Arg Thr Tyr Val Asn
1205 1210 1215
Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1220 1225
<210> 89
<211> 651
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 89
gcctatgata tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
atcaagtgtc aggccagtga ggacatttat agcttcttgg cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatccattct gcatcctctc tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttacta ttgtcaacag ggttatggta aaaataatgt tgataatgct 300
ttcggcggag ggaccaaggt ggagatcaaa cgtacggtgg ctgcaccatc tgtcttcatc 360
ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420
aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480
aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540
accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600
catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 651
<210> 90
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 90
Ala Tyr Asp Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Lys Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
His Ser Ala Ser Ser Leu Ala 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 Gly Tyr Gly Lys Asn Asn
85 90 95
Val Asp Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 91
<211> 3687
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 91
gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300
aattctttcg gcggagggac caaggtggag atcaaaggcg gtggcggtag tgggggaggc 360
ggttctggcg gcggagggtc cggcggtgga ggatcagagg tgcagctggt ggagtctggg 420
ggaggcttgg tccagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480
atcagtacca atgcaatgag ctgggtccgc caggctccag ggaaggggct ggagtggatc 540
ggagtcatta ctggtcgtga tatcacatac tacgcgagct gggcgaaagg cagattcacc 600
atctccagag acaattccaa gaacacgctg tatcttcaaa tgaacagcct gagagccgag 660
gacacggctg tgtattactg tgcgagagac ggtggttctt ctgctattac tagtaacaac 720
atttggggcc agggaaccct ggtcaccgtg tcgacaggcg gtggagggtc cggcggtggt 780
ggatcccagt cggtggagga gtctggggga ggcttggtcc agcctggggg gtccctgaga 840
ctctcctgta ccgcctctgg aatcgacctt aatacctacg acatgatctg ggtccgccag 900
gctccaggca aggggctaga gtgggttgga atcattactt atagtggtag tagatactac 960
gcgaactggg cgaaaggccg attcaccatc tccaaagaca ataccaagaa cacggtgtat 1020
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagattat 1080
atgagtggtt cccacttgtg gggccaggga accctggtca ccgtctcttc agctagcacc 1140
aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 1200
gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 1260
ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 1320
tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 1380
aacgtgaatc acaagcccag caacaccaag gtggacaaga gagttgagcc caaatcttgt 1440
gacaaaactc acacatgccc accgtgccca gcacctgaag ccgcgggggc accgtcagtc 1500
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 1560
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 1620
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 1680
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1740
tgcgcggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1800
gggcagcccc gagaaccaca ggtgtatacc ctgcccccat cccgggatga gctgaccaag 1860
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1920
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1980
gacggctcct tcttcctcta tagcaagctc accgtggaca agagcaggtg gcagcagggg 2040
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 2100
ctctccctgt ctccgggtgg cggtggaggg tccggcggtg gtgggtccgg agaggtgcag 2160
ctgttggagt ctgggggagg cttggtacag cctggggggt ccctgagact ctcctgtgca 2220
gcctctggat tcaccatcag tcgctaccac atgacttggg tccgccaggc tccagggaag 2280
gggctggagt ggatcggaca tatttatgtt aataatgatg acacagacta cgcgagctcc 2340
gcgaaaggcc ggttcaccat ctccagagac aattccaaga acacgctgta tctgcaaatg 2400
aacagcctga gagccgagga cacggccacc tatttctgtg cgagattgga tgttggtggt 2460
ggtggtgctt atattgggga catctggggc cagggaactc tggttaccgt ctcttcaggc 2520
ggtggcggta gtgggggagg cggttctggc ggcggagggt ccggcggtgg aggatcagac 2580
atccagatga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 2640
acttgccagt ccagtcagag tgtttataac aacaacgact tagcctggta tcagcagaaa 2700
ccagggaaag ttcctaagct cctgatctat tatgcttcca ctctggcatc tggggtccca 2760
tctcggttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 2820
cctgaagatg ttgcaactta ttactgtgca ggcggttatg atacggatgg tcttgatacg 2880
tttgctttcg gcggagggac caaggtggag atcaaaggcg gtggagggtc cggcggtggt 2940
gggtccggac ggtcgctggt ggagtctggg ggaggcttgg tccagcctgg ggggtccctg 3000
agactctcct gtactgcctc tggattcacc atcagtagct accacatgca gtgggtccgc 3060
caggctccag ggaaggggct ggagtacatc ggaaccatta gtagtggtgg taatgtatac 3120
tacgcaagct ccgctagagg cagattcacc atctccagac cctcgtccaa gaacacggtg 3180
gatcttcaaa tgaacagcct gagagccgag gacacggctg tgtattactg tgcgagagac 3240
tctggttata gtgatcctat gtggggccag ggaaccctgg tcaccgtctc ttcaggcggt 3300
ggcggtagtg ggggaggcgg ttctggcggc ggagggtccg gcggtggagg atcagacgtt 3360
gtgatgaccc agtctccatc ttccgtgtct gcatctgtag gagacagagt caccatcacc 3420
tgtcaggcca gtcagaacat taggacttac ttatcctggt atcagcagaa accagggaaa 3480
gcccctaagc tcctgatcta tgctgcagcc aatctggcat ctggggtccc atcaaggttc 3540
agcggcagtg gatctgggac agatttcact ctcaccatca gcgacctgga gcctggcgat 3600
gctgcaactt actattgtca gtctacctat cttggtactg attatgttgg cggtgctttc 3660
ggcggaggga ccaaggtgga gatcaaa 3687
<210> 92
<211> 1229
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 92
Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
145 150 155 160
Ile Ser Thr Asn Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
165 170 175
Leu Glu Trp Ile Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala
180 185 190
Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn
225 230 235 240
Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Thr Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Gln Ser Val Glu Glu Ser Gly Gly Gly Leu
260 265 270
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ile
275 280 285
Asp Leu Asn Thr Tyr Asp Met Ile Trp Val Arg Gln Ala Pro Gly Lys
290 295 300
Gly Leu Glu Trp Val Gly Ile Ile Thr Tyr Ser Gly Ser Arg Tyr Tyr
305 310 315 320
Ala Asn Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys
325 330 335
Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
340 345 350
Val Tyr Tyr Cys Ala Arg Asp Tyr Met Ser Gly Ser His Leu Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
370 375 380
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
385 390 395 400
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
405 410 415
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
420 425 430
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
435 440 445
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
450 455 460
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
465 470 475 480
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
485 490 495
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
500 505 510
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
515 520 525
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
530 535 540
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
545 550 555 560
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
565 570 575
Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
580 585 590
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
595 600 605
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
610 615 620
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
625 630 635 640
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
645 650 655
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
660 665 670
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
675 680 685
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
690 695 700
Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Glu Val Gln
705 710 715 720
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
725 730 735
Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Arg Tyr His Met Thr
740 745 750
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly His Ile
755 760 765
Tyr Val Asn Asn Asp Asp Thr Asp Tyr Ala Ser Ser Ala Lys Gly Arg
770 775 780
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
785 790 795 800
Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Leu
805 810 815
Asp Val Gly Gly Gly Gly Ala Tyr Ile Gly Asp Ile Trp Gly Gln Gly
820 825 830
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
835 840 845
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
850 855 860
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
865 870 875 880
Thr Cys Gln Ser Ser Gln Ser Val Tyr Asn Asn Asn Asp Leu Ala Trp
885 890 895
Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr Tyr Ala
900 905 910
Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
915 920 925
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val
930 935 940
Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Asp Thr Asp Gly Leu Asp Thr
945 950 955 960
Phe Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly
965 970 975
Ser Gly Gly Gly Gly Ser Gly Arg Ser Leu Val Glu Ser Gly Gly Gly
980 985 990
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly
995 1000 1005
Phe Thr Ile Ser Ser Tyr His Met Gln Trp Val Arg Gln Ala Pro Gly
1010 1015 1020
Lys Gly Leu Glu Tyr Ile Gly Thr Ile Ser Ser Gly Gly Asn Val Tyr
1025 1030 1035 1040
Tyr Ala Ser Ser Ala Arg Gly Arg Phe Thr Ile Ser Arg Pro Ser Ser
1045 1050 1055
Lys Asn Thr Val Asp Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
1060 1065 1070
Ala Val Tyr Tyr Cys Ala Arg Asp Ser Gly Tyr Ser Asp Pro Met Trp
1075 1080 1085
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
1090 1095 1100
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val
1105 1110 1115 1120
Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
1125 1130 1135
Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Arg Thr Tyr Leu Ser
1140 1145 1150
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala
1155 1160 1165
Ala Ala Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
1170 1175 1180
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asp Leu Glu Pro Gly Asp
1185 1190 1195 1200
Ala Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Leu Gly Thr Asp Tyr Val
1205 1210 1215
Gly Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1220 1225
<210> 93
<211> 651
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 93
gcctatgata tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
atcaagtgtc aggccagtga ggacatttat agcttcttgg cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatccattct gcatcctctc tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttacta ttgtcaacag ggttatggta aaaataatgt tgataatgct 300
ttcggcggag ggaccaaggt ggagatcaaa cgtacggtgg ctgcaccatc tgtcttcatc 360
ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420
aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480
aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540
accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600
catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 651
<210> 94
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 94
Ala Tyr Asp Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Lys Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
His Ser Ala Ser Ser Leu Ala 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 Gly Tyr Gly Lys Asn Asn
85 90 95
Val Asp Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 95
<211> 3675
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 95
gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300
aattctttcg gcggagggac caaggtggag atcaaaggcg gtggcggtag tgggggaggc 360
ggttctggcg gcggagggtc cggcggtgga ggatcagagg tgcagctggt ggagtctggg 420
ggaggcttgg tccagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480
atcagtacca atgcaatgag ctgggtccgc caggctccag ggaaggggct ggagtggatc 540
ggagtcatta ctggtcgtga tatcacatac tacgcgagct gggcgaaagg cagattcacc 600
atctccagag acaattccaa gaacacgctg tatcttcaaa tgaacagcct gagagccgag 660
gacacggctg tgtattactg tgcgagagac ggtggttctt ctgctattac tagtaacaac 720
atttggggcc agggaaccct ggtcaccgtg tcgacaggcg gtggagggtc cggcggtggt 780
ggatccgagg tgcagctgtt ggagtctggg ggaggcttgg tacagcctgg ggggtccctg 840
agactctcct gtgcagcctc tggattcacc atcagtcgct accacatgac ttgggtccgc 900
caggctccag ggaaggggct ggagtggatc ggacatattt atgttaataa tgatgacaca 960
gactacgcga gctccgcgaa aggccggttc accatctcca gagacaattc caagaacacg 1020
ctgtatctgc aaatgaacag cctgagagcc gaggacacgg ccacctattt ctgtgcgaga 1080
ttggatgttg gtggtggtgg tgcttatatt ggggacatct ggggccaggg aaccctggtc 1140
accgtctcga gcgctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 1200
agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 1260
gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 1320
ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 1380
ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 1440
agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 1500
gccgcggggg caccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 1560
tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 1620
aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 1680
gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 1740
ctgaatggca aggagtacaa gtgcgcggtc tccaacaaag ccctcccagc ccccatcgag 1800
aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtatac cctgccccca 1860
tcccgggatg agctgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 1920
cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1980
acgcctcccg tgctggactc cgacggctcc ttcttcctct atagcaagct caccgtggac 2040
aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 2100
aaccactaca cgcagaagag cctctccctg tctccgggtg gcggtggagg gtccggcggt 2160
ggtggatccc agtcggtgga ggagtctggg ggaggcttgg tccagcctgg ggggtccctg 2220
agactctcct gtaccgcctc tggaatcgac cttaatacct acgacatgat ctgggtccgc 2280
caggctccag gcaaggggct agagtgggtt ggaatcatta cttatagtgg tagtagatac 2340
tacgcgaact gggcgaaagg ccgattcacc atctccaaag acaataccaa gaacacggtg 2400
tatctgcaaa tgaacagcct gagagctgag gacacggctg tgtattactg tgcgagagat 2460
tatatgagtg gttcccactt gtggggccag ggaaccctgg tcaccgtctc ttccggtgga 2520
ggcggttcag gcggaggtgg aagtggtggt ggcggctctg gaggcggcgg atctgcctat 2580
gatatgaccc agtctccatc ttccgtgtct gcatctgtag gagacagagt caccatcaag 2640
tgtcaggcca gtgaggacat ttatagcttc ttggcctggt atcagcagaa accagggaaa 2700
gcccctaagc tcctgatcca ttctgcatcc tctctggcat ctggggtccc atcaaggttc 2760
agcggcagtg gatctgggac agatttcact ctcaccatca gcagcctgca gcctgaagat 2820
tttgcaactt actattgtca acagggttat ggtaaaaata atgttgataa tgctttcggc 2880
ggagggacca aggtggagat caaaggcggt ggagggtccg gcggtggtgg gtccggacgg 2940
tcgctggtgg agtctggggg aggcttggtc cagcctgggg ggtccctgag actctcctgt 3000
actgcctctg gattcaccat cagtagctac cacatgcagt gggtccgcca ggctccaggg 3060
aaggggctgg agtacatcgg aaccattagt agtggtggta atgtatacta cgcaagctcc 3120
gctagaggca gattcaccat ctccagaccc tcgtccaaga acacggtgga tcttcaaatg 3180
aacagcctga gagccgagga cacggctgtg tattactgtg cgagagactc tggttatagt 3240
gatcctatgt ggggccaggg aaccctggtc accgtctctt caggcggtgg cggtagtggg 3300
ggaggcggtt ctggcggcgg agggtccggc ggtggaggat cagacgttgt gatgacccag 3360
tctccatctt ccgtgtctgc atctgtagga gacagagtca ccatcacctg tcaggccagt 3420
cagaacatta ggacttactt atcctggtat cagcagaaac cagggaaagc ccctaagctc 3480
ctgatctatg ctgcagccaa tctggcatct ggggtcccat caaggttcag cggcagtgga 3540
tctgggacag atttcactct caccatcagc gacctggagc ctggcgatgc tgcaacttac 3600
tattgtcagt ctacctatct tggtactgat tatgttggcg gtgctttcgg cggagggacc 3660
aaggtggaga tcaaa 3675
<210> 96
<211> 1225
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 96
Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
145 150 155 160
Ile Ser Thr Asn Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
165 170 175
Leu Glu Trp Ile Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala
180 185 190
Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn
225 230 235 240
Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Thr Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
260 265 270
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
275 280 285
Phe Thr Ile Ser Arg Tyr His Met Thr Trp Val Arg Gln Ala Pro Gly
290 295 300
Lys Gly Leu Glu Trp Ile Gly His Ile Tyr Val Asn Asn Asp Asp Thr
305 310 315 320
Asp Tyr Ala Ser Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
325 330 335
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
340 345 350
Thr Ala Thr Tyr Phe Cys Ala Arg Leu Asp Val Gly Gly Gly Gly Ala
355 360 365
Tyr Ile Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
370 375 380
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
385 390 395 400
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
405 410 415
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
420 425 430
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
435 440 445
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
450 455 460
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
465 470 475 480
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
485 490 495
Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
500 505 510
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
515 520 525
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
530 535 540
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
545 550 555 560
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
565 570 575
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn
580 585 590
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
595 600 605
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
610 615 620
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
625 630 635 640
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
645 650 655
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
660 665 670
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
675 680 685
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
690 695 700
Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly
705 710 715 720
Gly Gly Ser Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro
725 730 735
Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ile Asp Leu Asn
740 745 750
Thr Tyr Asp Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
755 760 765
Trp Val Gly Ile Ile Thr Tyr Ser Gly Ser Arg Tyr Tyr Ala Asn Trp
770 775 780
Ala Lys Gly Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Val
785 790 795 800
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
805 810 815
Cys Ala Arg Asp Tyr Met Ser Gly Ser His Leu Trp Gly Gln Gly Thr
820 825 830
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
835 840 845
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Tyr Asp Met Thr Gln
850 855 860
Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Lys
865 870 875 880
Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe Leu Ala Trp Tyr Gln Gln
885 890 895
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile His Ser Ala Ser Ser Leu
900 905 910
Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
915 920 925
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
930 935 940
Tyr Cys Gln Gln Gly Tyr Gly Lys Asn Asn Val Asp Asn Ala Phe Gly
945 950 955 960
Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly
965 970 975
Gly Ser Gly Arg Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
980 985 990
Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Ile Ser
995 1000 1005
Ser Tyr His Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
1010 1015 1020
Tyr Ile Gly Thr Ile Ser Ser Gly Gly Asn Val Tyr Tyr Ala Ser Ser
1025 1030 1035 1040
Ala Arg Gly Arg Phe Thr Ile Ser Arg Pro Ser Ser Lys Asn Thr Val
1045 1050 1055
Asp Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
1060 1065 1070
Cys Ala Arg Asp Ser Gly Tyr Ser Asp Pro Met Trp Gly Gln Gly Thr
1075 1080 1085
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1090 1095 1100
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln
1105 1110 1115 1120
Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
1125 1130 1135
Cys Gln Ala Ser Gln Asn Ile Arg Thr Tyr Leu Ser Trp Tyr Gln Gln
1140 1145 1150
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ala Asn Leu
1155 1160 1165
Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
1170 1175 1180
Phe Thr Leu Thr Ile Ser Asp Leu Glu Pro Gly Asp Ala Ala Thr Tyr
1185 1190 1195 1200
Tyr Cys Gln Ser Thr Tyr Leu Gly Thr Asp Tyr Val Gly Gly Ala Phe
1205 1210 1215
Gly Gly Gly Thr Lys Val Glu Ile Lys
1220 1225
<210> 97
<211> 660
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 97
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc agtccagtca gagtgtttat aacaacaacg acttagcctg gtatcagcag 120
aaaccaggga aagttcctaa gctcctgatc tattatgcat ccactctggc atctggggtc 180
ccatctcggt tcagtggcag tggatctggg acagatttca ctctcaccat cagcagcctg 240
cagcctgaag atgttgcaac ttattactgt gcaggcggtt atgatacgga tggtcttgat 300
acgtttgctt tcggcggagg gaccaaggtg gagatcaaac gtacggtggc tgcaccatct 360
gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420
ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480
caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540
ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600
gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660
<210> 98
<211> 220
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 98
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 Gln Ser Ser Gln Ser Val Tyr Asn Asn
20 25 30
Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu
35 40 45
Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
65 70 75 80
Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Asp Thr
85 90 95
Asp Gly Leu Asp Thr Phe Ala Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 99
<211> 3696
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 99
gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300
aattctttcg gcggagggac caaggtggag atcaaaggcg gtggcggtag tgggggaggc 360
ggttctggcg gcggagggtc cggcggtgga ggatcagagg tgcagctggt ggagtctggg 420
ggaggcttgg tccagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480
atcagtacca atgcaatgag ctgggtccgc caggctccag ggaaggggct ggagtggatc 540
ggagtcatta ctggtcgtga tatcacatac tacgcgagct gggcgaaagg cagattcacc 600
atctccagag acaattccaa gaacacgctg tatcttcaaa tgaacagcct gagagccgag 660
gacacggctg tgtattactg tgcgagagac ggtggttctt ctgctattac tagtaacaac 720
atttggggcc agggaaccct ggtcaccgtg tcgacaggcg gtggagggtc cggcggtggt 780
ggatcagagg tgcagctgtt ggagtctggg ggaggcttgg tacagcctgg ggggtccctg 840
agactctcct gtgcagcctc tggattcacc atcagtcgct accacatgac ttgggtccgc 900
caggctccag ggaaggggct ggagtggatc ggacatattt atgttaataa tgatgacaca 960
gactacgcga gctccgcgaa aggccggttc accatctcca gagacaattc caagaacacg 1020
ctgtatctgc aaatgaacag cctgagagcc gaggacacgg ccacctattt ctgtgcgaga 1080
ttggatgttg gtggtggtgg tgcttatatt ggggacatct ggggccaggg aactctggtt 1140
accgtctctt cagctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 1200
agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 1260
gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 1320
ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 1380
ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 1440
agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 1500
gccgcggggg caccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 1560
tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 1620
aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 1680
gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 1740
ctgaatggca aggagtacaa gtgcgcggtc tccaacaaag ccctcccagc ccccatcgag 1800
aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 1860
tcccgggatg agctgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 1920
cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1980
acgcctcccg tgctggactc cgacggctcc ttcttcctct atagcaagct caccgtggac 2040
aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 2100
aaccactaca cgcagaagag cctctccctg tctccgggtg gcggtggagg gtccggcggt 2160
ggtggatccg aggtgcagct gttggagtct gggggaggct tggtacagcc tggggggtcc 2220
ctgagactct cctgtgcagc ctctggattc tccttcagta gcgggtacga catgtgctgg 2280
gtccgccagg ctccagggaa ggggctggag tggatcgcat gcattgctgc tggtagtgct 2340
ggtatcactt acgacgcgaa ctgggcgaaa ggccggttca ccatctccag agacaattcc 2400
aagaacacgc tgtatctgca aatgaacagc ctgagagccg aggacacggc cgtatattac 2460
tgtgcgagat cggcgttttc gttcgactac gccatggacc tctggggcca gggaaccctg 2520
gtcaccgtct cgagcggtgg aggcggatct ggcggaggtg gttccggcgg tggcggctcc 2580
ggtggaggcg gctctgacat ccagatgacc cagtctcctt ccaccctgtc tgcatctgta 2640
ggagacagag tcaccatcac ttgccaggcc agtcagagca ttagttccca cttaaactgg 2700
tatcagcaga aaccagggaa agcccctaag ctcctgatct ataaggcatc cactctggca 2760
tctggggtcc catcaaggtt cagcggcagt ggatctggga cagaatttac tctcaccatc 2820
agcagcctgc agcctgatga ttttgcaact tattactgcc aacagggtta tagttggggt 2880
aatgttgata atgttttcgg cggagggacc aaggtggaga tcaaaggcgg tggagggtcc 2940
ggcggtggtg gctccggacg gtcgctggtg gagtctgggg gaggcttggt ccagcctggg 3000
gggtccctga gactctcctg tactgcctct ggattcacca tcagtagcta ccacatgcag 3060
tgggtccgcc aggctccagg gaaggggctg gagtacatcg gaaccattag tagtggtggt 3120
aatgtatact acgcaagctc cgctagaggc agattcacca tctccagacc ctcgtccaag 3180
aacacggtgg atcttcaaat gaacagcctg agagccgagg acacggctgt gtattactgt 3240
gcgagagact ctggttatag tgatcctatg tggggccagg gaaccctggt caccgtctct 3300
tcaggcggtg gcggtagtgg gggaggcggt tctggcggcg gagggtccgg cggtggagga 3360
tcagacgttg tgatgaccca gtctccatct tccgtgtctg catctgtagg agacagagtc 3420
accatcacct gtcaggccag tcagaacatt aggacttact tatcctggta tcagcagaaa 3480
ccagggaaag cccctaagct cctgatctat gctgcagcca atctggcatc tggggtccca 3540
tcaaggttca gcggcagtgg atctgggaca gatttcactc tcaccatcag cgacctggag 3600
cctggcgatg ctgcaactta ctattgtcag tctacctatc ttggtactga ttatgttggc 3660
ggtgctttcg gcggagggac caaggtggag atcaaa 3696
<210> 100
<211> 1232
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 100
Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
145 150 155 160
Ile Ser Thr Asn Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
165 170 175
Leu Glu Trp Ile Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala
180 185 190
Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn
225 230 235 240
Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Thr Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
260 265 270
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
275 280 285
Phe Thr Ile Ser Arg Tyr His Met Thr Trp Val Arg Gln Ala Pro Gly
290 295 300
Lys Gly Leu Glu Trp Ile Gly His Ile Tyr Val Asn Asn Asp Asp Thr
305 310 315 320
Asp Tyr Ala Ser Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
325 330 335
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
340 345 350
Thr Ala Thr Tyr Phe Cys Ala Arg Leu Asp Val Gly Gly Gly Gly Ala
355 360 365
Tyr Ile Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
370 375 380
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
385 390 395 400
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
405 410 415
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
420 425 430
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
435 440 445
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
450 455 460
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
465 470 475 480
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
485 490 495
Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
500 505 510
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
515 520 525
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
530 535 540
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
545 550 555 560
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
565 570 575
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn
580 585 590
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
595 600 605
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
610 615 620
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
625 630 635 640
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
645 650 655
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
660 665 670
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
675 680 685
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
690 695 700
Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly
705 710 715 720
Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
725 730 735
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe
740 745 750
Ser Ser Gly Tyr Asp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly
755 760 765
Leu Glu Trp Ile Ala Cys Ile Ala Ala Gly Ser Ala Gly Ile Thr Tyr
770 775 780
Asp Ala Asn Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
785 790 795 800
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
805 810 815
Ala Val Tyr Tyr Cys Ala Arg Ser Ala Phe Ser Phe Asp Tyr Ala Met
820 825 830
Asp Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
835 840 845
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
850 855 860
Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val
865 870 875 880
Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser
885 890 895
His Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
900 905 910
Ile Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
915 920 925
Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln
930 935 940
Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Trp Gly
945 950 955 960
Asn Val Asp Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly
965 970 975
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Arg Ser Leu Val Glu Ser
980 985 990
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr
995 1000 1005
Ala Ser Gly Phe Thr Ile Ser Ser Tyr His Met Gln Trp Val Arg Gln
1010 1015 1020
Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly Thr Ile Ser Ser Gly Gly
1025 1030 1035 1040
Asn Val Tyr Tyr Ala Ser Ser Ala Arg Gly Arg Phe Thr Ile Ser Arg
1045 1050 1055
Pro Ser Ser Lys Asn Thr Val Asp Leu Gln Met Asn Ser Leu Arg Ala
1060 1065 1070
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Gly Tyr Ser Asp
1075 1080 1085
Pro Met Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
1090 1095 1100
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1105 1110 1115 1120
Ser Asp Val Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val
1125 1130 1135
Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Arg Thr
1140 1145 1150
Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
1155 1160 1165
Ile Tyr Ala Ala Ala Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
1170 1175 1180
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asp Leu Glu
1185 1190 1195 1200
Pro Gly Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Leu Gly Thr
1205 1210 1215
Asp Tyr Val Gly Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1220 1225 1230
<210> 101
<211> 660
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 101
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc agtccagtca gagtgtttat aacaacaacg acttagcctg gtatcagcag 120
aaaccaggga aagttcctaa gctcctgatc tattatgcat ccactctggc atctggggtc 180
ccatctcggt tcagtggcag tggatctggg acagatttca ctctcaccat cagcagcctg 240
cagcctgaag atgttgcaac ttattactgt gcaggcggtt atgatacgga tggtcttgat 300
acgtttgctt tcggcggagg gaccaaggtg gagatcaaac gtacggtggc tgcaccatct 360
gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420
ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480
caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540
ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600
gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660
<210> 102
<211> 220
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 102
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 Gln Ser Ser Gln Ser Val Tyr Asn Asn
20 25 30
Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu
35 40 45
Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
65 70 75 80
Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Asp Thr
85 90 95
Asp Gly Leu Asp Thr Phe Ala Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 103
<211> 3690
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 103
gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300
aattctttcg gcggagggac caaggtggag atcaaaggcg gtggcggtag tgggggaggc 360
ggttctggcg gcggagggtc cggcggtgga ggatcagagg tgcagctggt ggagtctggg 420
ggaggcttgg tccagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480
atcagtacca atgcaatgag ctgggtccgc caggctccag ggaaggggct ggagtggatc 540
ggagtcatta ctggtcgtga tatcacatac tacgcgagct gggcgaaagg cagattcacc 600
atctccagag acaattccaa gaacacgctg tatcttcaaa tgaacagcct gagagccgag 660
gacacggctg tgtattactg tgcgcgcgac ggtggatcat ctgctattac tagtaacaac 720
atttggggcc aaggaactct ggtcaccgtt tcttcaggcg gtggagggtc cggcggtggt 780
ggatccgagg tgcagctggt gcagtctgga gcagaggtga agaaaccagg agagtctctg 840
aagatctcct gtaagggttc tggatacagc tttagcagtt catggatcgg ctgggtgcgc 900
caggcacctg ggaaaggcct ggaatggatg gggatcatct atcctgatga ctctgatacc 960
agatacagtc catccttcca aggccaggtc accatctcag ccgacaagtc catcaggact 1020
gcctacctgc agtggagtag cctgaaggcc tcggacaccg ctatgtatta ctgtgcgaga 1080
catgttacta tgatttgggg agttattatt gacttctggg gccagggaac cctggtcacc 1140
gtctcctcag ctagcaccaa gggcccatcg gtcttccccc tggcaccctc ctccaagagc 1200
acctctgggg gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 1260
acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 1320
cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag cagcttgggc 1380
acccagacct acatctgcaa cgtgaatcac aagcccagca acaccaaggt ggacaagaga 1440
gttgagccca aatcttgtga caaaactcac acatgcccac cgtgcccagc acctgaagcc 1500
gcgggggcac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 1560
cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 1620
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1680
cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1740
aatggcaagg agtacaagtg cgcggtctcc aacaaagccc tcccagcccc catcgagaaa 1800
accatctcca aagccaaagg gcagccccga gaaccacagg tgtataccct gcccccatcc 1860
cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1920
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1980
cctcccgtgc tggactccga cggctccttc ttcctctata gcaagctcac cgtggacaag 2040
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 2100
cactacacgc agaagagcct ctccctgtct ccgggtggcg gtggagggtc cggcggtggt 2160
ggatccgagg tgcagctgtt ggagtctggg ggaggcttgg tacagcctgg ggggtccctg 2220
agactctcct gtgcagcctc tggattctcc ttcagtagcg ggtacgacat gtgctgggtc 2280
cgccaggctc cagggaaggg gctggagtgg atcgcatgca ttgctgctgg tagtgctggt 2340
atcacttacg acgcgaactg ggcgaaaggc cggttcacca tctccagaga caattccaag 2400
aacacgctgt atctgcaaat gaacagcctg agagccgagg acacggccgt atattactgt 2460
gcgagatcgg cgttttcgtt cgactacgcc atggacctct ggggccaggg aaccctggtc 2520
accgtctcga gcggtggagg cggatctggc ggaggtggtt ccggcggtgg cggctccggt 2580
ggaggcggct ctgacatcca gatgacccag tctccttcca ccctgtctgc atctgtagga 2640
gacagagtca ccatcacttg ccaggccagt cagagcatta gttcccactt aaactggtat 2700
cagcagaaac cagggaaagc ccctaagctc ctgatctata aggcatccac tctggcatct 2760
ggggtcccat caaggttcag cggcagtgga tctgggacag aatttactct caccatcagc 2820
agcctgcagc ctgatgattt tgcaacttat tactgccaac agggttatag ttggggtaat 2880
gttgataatg ttttcggcgg agggaccaag gtggagatca aaggcggtgg agggtccggc 2940
ggtggtggat cccggtcgct ggtggagtct gggggaggct tggtccagcc tggggggtcc 3000
ctgagactct cctgtacagc ctctggattc accatcagta gctaccacat gcagtgggtc 3060
cgccaggctc cagggaaggg gctggagtac atcggaacca ttagtagtgg tggtaatgta 3120
tactacgcga gctccgcgag aggcagattc accatctcca gaccctcgtc caagaacacg 3180
gtggatcttc aaatgaacag cctgagagcc gaggacacgg ctgtgtatta ctgtgcgaga 3240
gactctggtt atagtgatcc tatgtggggc cagggaaccc tggtcaccgt ctcgagcggc 3300
ggtggcggta gtgggggagg cggttctggc ggcggagggt ccggcggtgg aggatcagac 3360
gttgtgatga cccagtctcc atcttccgtg tctgcatctg taggagacag agtcaccatc 3420
acctgtcagg ccagtcagaa cattaggact tacttatcct ggtatcagca gaaaccaggg 3480
aaagccccta agctcctgat ctatgctgca gccaatctgg catctggggt cccatcaagg 3540
ttcagcggca gtggatctgg gacagatttc actctcacca tcagcgacct ggagcctggc 3600
gatgctgcaa cttactattg tcagtctacc tatcttggta ctgattatgt tggcggtgct 3660
ttcggcggag ggaccaaggt ggagatcaaa 3690
<210> 104
<211> 1230
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 104
Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
145 150 155 160
Ile Ser Thr Asn Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
165 170 175
Leu Glu Trp Ile Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala
180 185 190
Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn
225 230 235 240
Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu
260 265 270
Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly
275 280 285
Tyr Ser Phe Ser Ser Ser Trp Ile Gly Trp Val Arg Gln Ala Pro Gly
290 295 300
Lys Gly Leu Glu Trp Met Gly Ile Ile Tyr Pro Asp Asp Ser Asp Thr
305 310 315 320
Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys
325 330 335
Ser Ile Arg Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp
340 345 350
Thr Ala Met Tyr Tyr Cys Ala Arg His Val Thr Met Ile Trp Gly Val
355 360 365
Ile Ile Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
370 375 380
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
385 390 395 400
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
405 410 415
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
420 425 430
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
435 440 445
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
450 455 460
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg
465 470 475 480
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
485 490 495
Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys
500 505 510
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
515 520 525
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
530 535 540
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
545 550 555 560
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
565 570 575
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys
580 585 590
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
595 600 605
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
610 615 620
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
625 630 635 640
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
645 650 655
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
660 665 670
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
675 680 685
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
690 695 700
Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly
705 710 715 720
Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
725 730 735
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser
740 745 750
Ser Gly Tyr Asp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
755 760 765
Glu Trp Ile Ala Cys Ile Ala Ala Gly Ser Ala Gly Ile Thr Tyr Asp
770 775 780
Ala Asn Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
785 790 795 800
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
805 810 815
Val Tyr Tyr Cys Ala Arg Ser Ala Phe Ser Phe Asp Tyr Ala Met Asp
820 825 830
Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
835 840 845
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
850 855 860
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
865 870 875 880
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser His
885 890 895
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
900 905 910
Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
915 920 925
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
930 935 940
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Trp Gly Asn
945 950 955 960
Val Asp Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
965 970 975
Gly Gly Ser Gly Gly Gly Gly Ser Arg Ser Leu Val Glu Ser Gly Gly
980 985 990
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser
995 1000 1005
Gly Phe Thr Ile Ser Ser Tyr His Met Gln Trp Val Arg Gln Ala Pro
1010 1015 1020
Gly Lys Gly Leu Glu Tyr Ile Gly Thr Ile Ser Ser Gly Gly Asn Val
1025 1030 1035 1040
Tyr Tyr Ala Ser Ser Ala Arg Gly Arg Phe Thr Ile Ser Arg Pro Ser
1045 1050 1055
Ser Lys Asn Thr Val Asp Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
1060 1065 1070
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Gly Tyr Ser Asp Pro Met
1075 1080 1085
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
1090 1095 1100
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
1105 1110 1115 1120
Val Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp
1125 1130 1135
Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Arg Thr Tyr Leu
1140 1145 1150
Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
1155 1160 1165
Ala Ala Ala Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
1170 1175 1180
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asp Leu Glu Pro Gly
1185 1190 1195 1200
Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Leu Gly Thr Asp Tyr
1205 1210 1215
Val Gly Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1220 1225 1230
<210> 105
<211> 642
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 105
gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120
gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag tttaatagtt acccattcac tttcggccct 300
gggaccaaag tggatatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 106
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 106
Ala Ile Gln Leu 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 Gly Ile Ser Ser Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu 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 Phe Asn Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp 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> 107
<211> 3675
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 107
gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120
gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag tttaatagtt acccattcac tttcggccct 300
gggaccaaag tggatatcaa aggcggtggc ggtagtgggg gaggcggttc tggcggcgga 360
gggtccggcg gtggaggatc agaggtgcag ctggtgcagt ctggagcaga ggtgaagaaa 420
ccaggagagt ctctgaagat ctcctgtaag ggttctggat acagctttag cagttcatgg 480
atcggctggg tgcgccaggc acctgggaaa ggcctggaat ggatggggat catctatcct 540
gatgactctg ataccagata cagtccatcc ttccaaggcc aggtcaccat ctcagccgac 600
aagtccatca ggactgccta cctgcagtgg agtagcctga aggcctcgga caccgctatg 660
tattactgtg cgagacatgt tactatgatt tggggagtta ttattgactt ctggggccag 720
ggaaccctgg tcaccgtctc ctcaggcggt ggagggtccg gcggtggtgg atccgaggtg 780
cagctggtgg agtctggggg aggcttggtc cagcctgggg ggtccctgag actctcctgt 840
gcagcctctg gattcaccat cagtaccaat gcaatgagct gggtccgcca ggctccaggg 900
aaggggctgg agtggatcgg agtcattact ggtcgtgata tcacatacta cgcgagctgg 960
gcgaaaggca gattcaccat ctccagagac aattccaaga acacgctgta tcttcaaatg 1020
aacagcctga gagccgagga cacggctgtg tattactgtg cgcgcgacgg tggatcatct 1080
gctattacta gtaacaacat ttggggccaa ggaactctgg tcaccgtttc ttcagctagc 1140
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 1200
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 1260
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 1320
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 1380
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 1440
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aagccgcggg ggcaccgtca 1500
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 1560
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 1620
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 1680
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 1740
aagtgcgcgg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1800
aaagggcagc cccgagaacc acaggtgtat accctgcccc catcccggga tgagctgacc 1860
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1920
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1980
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 2040
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 2100
agcctctccc tgtctccggg tggcggtgga gggtccggcg gtggtggatc cgaggtgcag 2160
ctgttggagt ctgggggagg cttggtacag cctggggggt ccctgagact ctcctgtgca 2220
gcctctggat tctccttcag tagcgggtac gacatgtgct gggtccgcca ggctccaggg 2280
aaggggctgg agtggatcgc atgcattgct gctggtagtg ctggtatcac ttacgacgcg 2340
aactgggcga aaggccggtt caccatctcc agagacaatt ccaagaacac gctgtatctg 2400
caaatgaaca gcctgagagc cgaggacacg gccgtatatt actgtgcgag atcggcgttt 2460
tcgttcgact acgccatgga cctctggggc cagggaaccc tggtcaccgt ctcgagcggt 2520
ggaggcggat ctggcggagg tggttccggc ggtggcggct ccggtggagg cggctctgac 2580
atccagatga cccagtctcc ttccaccctg tctgcatctg taggagacag agtcaccatc 2640
acttgccagg ccagtcagag cattagttcc cacttaaact ggtatcagca gaaaccaggg 2700
aaagccccta agctcctgat ctataaggca tccactctgg catctggggt cccatcaagg 2760
ttcagcggca gtggatctgg gacagaattt actctcacca tcagcagcct gcagcctgat 2820
gattttgcaa cttattactg ccaacagggt tatagttggg gtaatgttga taatgttttc 2880
ggcggaggga ccaaggtgga gatcaaaggc ggtggagggt ccggcggtgg tggatcccgg 2940
tcgctggtgg agtctggggg aggcttggtc cagcctgggg ggtccctgag actctcctgt 3000
acagcctctg gattcaccat cagtagctac cacatgcagt gggtccgcca ggctccaggg 3060
aaggggctgg agtacatcgg aaccattagt agtggtggta atgtatacta cgcgagctcc 3120
gcgagaggca gattcaccat ctccagaccc tcgtccaaga acacggtgga tcttcaaatg 3180
aacagcctga gagccgagga cacggctgtg tattactgtg cgagagactc tggttatagt 3240
gatcctatgt ggggccaggg aaccctggtc accgtctcga gcggcggtgg cggtagtggg 3300
ggaggcggtt ctggcggcgg agggtccggc ggtggaggat cagacgttgt gatgacccag 3360
tctccatctt ccgtgtctgc atctgtagga gacagagtca ccatcacctg tcaggccagt 3420
cagaacatta ggacttactt atcctggtat cagcagaaac cagggaaagc ccctaagctc 3480
ctgatctatg ctgcagccaa tctggcatct ggggtcccat caaggttcag cggcagtgga 3540
tctgggacag atttcactct caccatcagc gacctggagc ctggcgatgc tgcaacttac 3600
tattgtcagt ctacctatct tggtactgat tatgttggcg gtgctttcgg cggagggacc 3660
aaggtggaga tcaaa 3675
<210> 108
<211> 1225
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 108
Ala Ile Gln Leu 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 Gly Ile Ser Ser Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu 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 Phe Asn Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser
130 135 140
Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Ser Ser Trp
145 150 155 160
Ile Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly
165 170 175
Ile Ile Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln
180 185 190
Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Arg Thr Ala Tyr Leu
195 200 205
Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala
210 215 220
Arg His Val Thr Met Ile Trp Gly Val Ile Ile Asp Phe Trp Gly Gln
225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
260 265 270
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser
275 280 285
Thr Asn Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
290 295 300
Trp Ile Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp
305 310 315 320
Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
325 330 335
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
340 345 350
Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
370 375 380
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
385 390 395 400
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
405 410 415
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
420 425 430
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
435 440 445
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
450 455 460
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
465 470 475 480
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
485 490 495
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
500 505 510
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
515 520 525
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
530 535 540
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
545 550 555 560
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
565 570 575
Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro
580 585 590
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
595 600 605
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
610 615 620
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
625 630 635 640
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
645 650 655
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
660 665 670
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
675 680 685
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
690 695 700
Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln
705 710 715 720
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
725 730 735
Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Gly Tyr Asp Met
740 745 750
Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala Cys
755 760 765
Ile Ala Ala Gly Ser Ala Gly Ile Thr Tyr Asp Ala Asn Trp Ala Lys
770 775 780
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
785 790 795 800
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
805 810 815
Arg Ser Ala Phe Ser Phe Asp Tyr Ala Met Asp Leu Trp Gly Gln Gly
820 825 830
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
835 840 845
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
850 855 860
Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
865 870 875 880
Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser His Leu Asn Trp Tyr Gln
885 890 895
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Thr
900 905 910
Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
915 920 925
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr
930 935 940
Tyr Tyr Cys Gln Gln Gly Tyr Ser Trp Gly Asn Val Asp Asn Val Phe
945 950 955 960
Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly
965 970 975
Gly Gly Ser Arg Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
980 985 990
Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Ile Ser
995 1000 1005
Ser Tyr His Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
1010 1015 1020
Tyr Ile Gly Thr Ile Ser Ser Gly Gly Asn Val Tyr Tyr Ala Ser Ser
1025 1030 1035 1040
Ala Arg Gly Arg Phe Thr Ile Ser Arg Pro Ser Ser Lys Asn Thr Val
1045 1050 1055
Asp Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
1060 1065 1070
Cys Ala Arg Asp Ser Gly Tyr Ser Asp Pro Met Trp Gly Gln Gly Thr
1075 1080 1085
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1090 1095 1100
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln
1105 1110 1115 1120
Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
1125 1130 1135
Cys Gln Ala Ser Gln Asn Ile Arg Thr Tyr Leu Ser Trp Tyr Gln Gln
1140 1145 1150
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ala Asn Leu
1155 1160 1165
Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
1170 1175 1180
Phe Thr Leu Thr Ile Ser Asp Leu Glu Pro Gly Asp Ala Ala Thr Tyr
1185 1190 1195 1200
Tyr Cys Gln Ser Thr Tyr Leu Gly Thr Asp Tyr Val Gly Gly Ala Phe
1205 1210 1215
Gly Gly Gly Thr Lys Val Glu Ile Lys
1220 1225
<210> 109
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 109
gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300
aattctttcg gcggagggac caaggtggag atcaaacgta cggtggctgc accatctgtc 360
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657
<210> 110
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 110
Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215

Claims (8)

1.一种制导和导航控制蛋白，由
T细胞活化受体的结合结构域，
肿瘤相关抗原的结合结构域，
免疫检查点受体的结合结构域，和
T细胞共刺激受体的结合结构域组成，
其中，所述肿瘤相关抗原的所述结合结构域不与所述T细胞共刺激受体的所述结合结构域相邻，其中所述蛋白是包括Fc结构域的四特异性抗体单体，其中所述T细胞活化受体为CD3，并且其中CD3的所述结合结构域通过肽接头与所述肿瘤相关抗原的所述结合结构域连接以形成CD3-TAA对，其中所述肽接头具有不超过100个氨基酸的长度，该制导和导航控制蛋白具有N端和C端，从所述N端到所述C端相继为：
CD3的所述结合结构域，
CD19的所述结合结构域，
IgG Fc结构域，
PD-L1的所述结合结构域，和
41-BB的所述结合结构域，
并且，所述制导和导航控制蛋白为对称的四特异性抗体，其包含两条相同的重链和两条相同的轻链，该四特异性抗体的重链从N端到C端为结合CD3的scFv、结合CD19的Fab重链部分、IgG Fc结构域、结合PD-L1的scFv、结合4-1BB的scFv，轻链从N端到C端为结合CD19的Fab轻链部分，
其中，该制导和导航控制蛋白包括如SEQ ID NO.104和106所示的重链和轻链氨基酸序列。
2.一种核酸，其编码根据权利要求1所述的制导和导航控制蛋白。
3.根据权利要求2所述的核酸，其包括SEQ ID NO.103和105所示的核苷酸序列。
4.一种细胞毒性细胞，包括：
具有T细胞活化受体和T细胞共刺激受体的T细胞，和
根据权利要求1所述的制导和导航控制蛋白，其通过与所述T细胞活化受体、所述T细胞共刺激受体或其组合相互作用而结合至所述T细胞。
5.一种癌细胞，包括：
具有肿瘤相关抗原的癌细胞，和
根据权利要求1所述的制导和导航控制蛋白通过与所述肿瘤相关抗原的相互作用与癌细胞结合。
6.一种生物复合体，包括：
具有T细胞活化受体和T细胞共刺激受体的T细胞，
具有肿瘤相关抗原的癌细胞，和
根据权利要求1所述的制导和导航控制蛋白，其中所述制导和导航控制蛋白通过与所述T细胞活化受体、所述T细胞共刺激受体或其组合的相互作用结合至所述T细胞，并且其中所述制导和导航控制蛋白通过与所述肿瘤相关抗原的相互作用结合至所述癌细胞。
7.一种药物组合物，包括根据权利要求1所述的制导和导航控制蛋白，和/或根据权利要求4所述的细胞毒性细胞，和药学上可接受的载体。
8.根据权利要求7所述的药物组合物在制备治疗患有癌症的受试者的药物中的用途。
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