CN111527108A - 制导和导航控制蛋白的制造和使用方法 - Google Patents

制导和导航控制蛋白的制造和使用方法 Download PDF

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CN111527108A
CN111527108A CN201980006977.5A CN201980006977A CN111527108A CN 111527108 A CN111527108 A CN 111527108A CN 201980006977 A CN201980006977 A CN 201980006977A CN 111527108 A CN111527108 A CN 111527108A
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gly
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cells
leu
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朱义
欧勒·奥尔森
贾汉·哈利利
夏冬
大卫·耶利曼
卡特里娜·贝科娃
安妮玛丽·卢梭
王宇燕
高泽人
黄辉
史蒂文·K·伦迪
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Chengdu Bailidote Biological Pharmaceutical Co ltd
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Sichuan Baili Pharmaceutical Co Ltd
Seattle Immunization Co
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Abstract

本申请提供了用于产生治疗组合物的方法。本方法包括以下步骤：提供包含细胞毒性细胞的细胞材料；将该细胞材料与第一GNC蛋白温育以提供活化的细胞组合物，其中该活化的细胞组合物包含第一治疗细胞；以及配制该活化的细胞组合物以提供治疗组合物，其中该治疗组合物基本上不含外源病毒和非病毒DNA或RNA。该第一GNC蛋白包含第一细胞毒性结合部分和第一癌症靶向部分，其中该第一细胞毒性结合部分对第一细胞毒性细胞受体具有特异性并且被配置为活化该第一细胞毒性细胞，并且其中该第一癌症靶向部分对第一癌细胞受体具有特异性。该第一治疗细胞包含通过该第一细胞毒性细胞受体与该细胞毒性细胞结合的第一GNC蛋白。

Description

制导和导航控制蛋白的制造和使用方法
相关申请的交叉引用
本申请要求于2018年3月27日提交的美国临时专利申请No.62648888和于2018年3月27日提交的美国临时专利申请No.62648880的提交日的权益，其全部公开内容明确地以引用方式并入本文。
技术领域
本申请总体上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 Control,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。免疫逃逸的潜在机制之一是免疫系统对癌细胞的识别降低。癌症特异性抗原的缺陷性呈递或其缺乏导致免疫耐受和癌症进展。在存在有效的免疫识别时，肿瘤使用其他机制避免被免疫系统消除。免疫活性肿瘤产生抑制性微环境以下调免疫应答。多个参与者参与形成抑制性肿瘤微环境，包括肿瘤细胞、调节性T细胞、髓系衍生的抑制细胞、基质细胞和其他细胞类型。免疫应答的抑制可以以细胞接触依赖性的形式以及以接触非依赖性的方式，经由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来执行。细胞接触依赖性抑制依靠在细胞表面表达的分子，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,Old等.2004,Adachi andTamada 2015)。
随着肿瘤逃避免疫系统识别的机制继续被更好地了解，最近出现了靶向这些机制的新治疗方式。2011年3月25日，美国食品和药品管理局(FDA)批准了用于治疗不可切除或转移性黑素瘤的易普利姆玛单抗(ipilimumab)注射剂(Yervoy，Bristol-Myers Squibb)。Yrevoy与活化T细胞上表达的细胞毒性T淋巴细胞相关蛋白4(CTLA-4)结合并阻断抗原呈递细胞上CTLA-4与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，这在许多患者中导致肿瘤的根除。2014年几年后，FDA批准Keytruda(派姆单抗(Pembrolizumab)，默克公司)和Opdivo(纳武单抗(Nivolumab)，百时美施贵宝)用于治疗晚期黑素瘤。这些单克隆抗体结合在活化和/或耗尽的T细胞上表达的PD-1，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，这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Yervoy和Opdivo的组合在晚期黑素瘤的治疗中进行比较，其显示在用抗体组合治疗的患者中总体存活和无进展存活的改善。(Hodi,Chesney等.2016,Hellmann,Callahan等.2018)。然而，由于许多临床试验已经显示出使用对一种或多种免疫检查点分子具有特异性的单克隆抗体治疗癌症患者的极大益处，数据已经显示出只有那些具有产生被抗原特异性T细胞识别的新T细胞表位的高突变负荷的患者显示出临床应答(Snyder,Makarov等.2014)。具有低肿瘤突变负荷的那些患者通常不显示客观的临床应答(Snyder,Makarov等.2014,Hellmann,Callahan等.2018)。
近年来，其他组已经开发了不需要存在通过抗原呈递细胞的新表位呈递来活化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如CD19有特异性的抗体的结合结构域与T细胞上CD3特异的抗体结合结构域连接，从而产生双特异性T细胞结合剂或咬合分子。在2014年，FDA批准了称为Blinatumumab的双特异性抗体用于治疗前体B细胞急性成淋巴细胞白血病。Blinatumumab将对白血病细胞上表达的CD19有特异性的单链可变片段(scFv)与对T细胞上表达的CD3有特异性的scFv连接(Benjamin and Stein2016)。然而，尽管复发或顽固性急性淋巴细胞白血病(ALL)患者的初始应答率>50％，但许多患者在用Blinatumumab成功治疗后对Blinatumumab治疗有耐药性或复发。有证据表明，对Blinatumomab的耐药性或Blinatumomab治疗后的复发归因于在肿瘤细胞上表达的免疫检查点抑制分子的表达，如PD-L1，其通过在活化的T细胞上表达的PD-1驱动抑制信号(Feucht,Kayser等.2016)。在对用Blinatumumab治疗有抗性的患者的病例研究中，进行第二轮Blinatumumab治疗，但添加单克隆抗体pembrolizumab(Keytruda,Merck)。Pembrolizumab与PD-1特异性结合并阻断T细胞表达的PD-1与肿瘤细胞表达的PD-L1的相互作用，这在这一位患者中导致显著的反应和骨髓中肿瘤细胞从45％减少至小于5％(Feucht,Kayser等.2016)。这些结果表明，与任一单独的试剂相比，将双特异性咬合分子与一种或多种单克隆抗体组合可显著增加临床活性。尽管有希望的结果，但由于多个临床试验和招募代表性群体的难度，导致组合治疗的成本必定高。
采用嵌合抗原受体T细胞(CAR-T)的过继性细胞治疗是另一种有前景的用于治疗癌症的免疫治疗。CAR-T治疗的临床成功显示了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延长的存活(Gill and June 2015)。然而，与制造个性化和遗传修饰的CAR-T免疫治疗相关联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，被认为是在工程化CAR-T细胞输注后的主要副作用(Bonifant,Jackson等.2016)。在许多情况下，CRS的发作和严重程度似乎是患者个人特异性的。目前减轻CRS的选项主要集中在快速反应和管理护理上，因为在T细胞输注之前控制CRS的选项是有限的。
虽然针对CD19阳性B细胞恶性肿瘤的CAR-T治疗的功效现在清楚地确定，但是针对实体瘤的CAR-T治疗的功效迄今尚未明确地证明。目前，许多临床试验正在进行中，以探索用于CAR-T治疗的多种实体瘤相关抗原(TAA)。目前认为，无效的T细胞运输进入肿瘤、免疫抑制性肿瘤微环境、次优抗原识别特异性和缺乏对治疗相关不良事件的控制是实体瘤CAR-T治疗中的主要障碍(Li,Li等.2018)。管理治疗效果以及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
本申请尤其提供用于产生含有引导和导航(GNC)蛋白的治疗组合物的方法，用于使用制导和导航控制(GNC)蛋白治疗癌症病症的方法，以及含有GNC蛋白或具有用GNC蛋白包被(或与之结合)的细胞毒性细胞的治疗细胞的治疗组合物。
在一个方面，本申请提供治疗组合物。在一个实施方案中，治疗组合物包含细胞毒性细胞、GNC蛋白和治疗细胞。该治疗细胞包含通过与细胞毒性细胞受体的结合相互作用与细胞毒性细胞结合的GNC蛋白，并且该治疗细胞组合物基本上不含外源病毒和非病毒DNA和RNA。
在一个实施方案中，该治疗组合物可还包含第二GNC蛋白、第二治疗细胞或其组合，其中该第二治疗细胞包含细胞毒性细胞，该细胞毒性细胞具有结合于其上的第二GNC蛋白或具有结合于其上的第一GNC蛋白和第二GNC蛋白两者。
GNC蛋白包括细胞毒性结合部分和癌症靶向部分。该细胞毒性结合部分对细胞毒性细胞受体具有结合特异性并且被配置成通过与该细胞毒性细胞受体的结合来活化该细胞毒性细胞。该癌症靶向部分对癌细胞受体具有结合特异性。
在一个实施方案中，GNC蛋白包括T细胞受体的结合结构域。T细胞受体的实例包括但不限于CD3、CD28、PD-L1、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蛋白能够通过将T细胞结合部分与T细胞上的T细胞受体结合来活化T细胞。在一个实施方案中，GNC蛋白能够通过结合在T细胞上的多个T细胞结合部分来活化T细胞。
在一个实施方案中，GNC蛋白包括NK细胞受体的结合结构域。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蛋白包括巨噬细胞受体的结合结构域。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；和其他表面受体，例如CSF-1R、LOX-1、CCR2、FRβ、CD163、CR3、DC-SIGN、CD206、SR-A、CD36、MARCO。
在一个实施方案中，GNC蛋白包括树突细胞受体的结合结构域。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；和其他表面受体，例如CSF-1R、LOX-1、CCR7、DC-SIGN、GM-CSF-R、IL-4R、IL-10R、CD36、CD206、DCIR、RIG-1、CLEC9A、CXCR4。
在一个实施方案中，GNC蛋白可以包括T细胞结合部分和癌症靶向部分。在一个实施方案中，该T细胞结合部分对包括以下的T细胞受体具有结合特异性：CD3、CD28、PD-L1、PDL2、PD1、OX40、4-1BB、GITR、TIGIT、TIM-3、LAG-3、CTLA4、CD40L、VISTA、ICOS、BTLA、Light、CD30、CD27、或其组合。在一个实施方案中，癌症靶向部分对癌细胞受体具有结合特异性。在一个实施方案中，该癌细胞受体可包括BCMA、CD19、CD20、CD33、CD123、CD22、CD30、ROR1、CEA、HER2、EGFR、EGFRvIII、LMP1、LMP2A、间皮素、PSMA、EpCAM、磷脂酰肌醇聚糖-3、gpA33、GD2、TROP2，尚未发现的肿瘤相关抗原或其组合。
在一个实施方案中，GNC蛋白可以对T细胞和肿瘤细胞的表面分子具有多特异性抗原结合活性。在一个实施方案中，制导和导航控制(GNC)蛋白包含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。免疫检查点受体可包括但不限于PD-L1、PD-1、TIGIT、TIM-3、LAG-3、CTLA4、BTLA、VISTA、PDL2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、PSMA、EpCAM、磷脂酰肌醇聚糖-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或其片段或其组合的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，GNC蛋白包括在GNC蛋白上产生多达八个结合基序的双特异性抗体、三特异性抗体、四特异性抗体或其组合。本文公开了抗体、抗体单体、其抗原结合片段的实例。在一个实施方案中，GNC蛋白可以包括具有两条重链和两条轻链的免疫球蛋白G(IgG)部分，并且至少两个scFv部分共价连接至重链或轻链的C或N末端。IgG部分可以为scFv部分提供稳定性，并且三特异性GNC蛋白可以具有用于结合T细胞上的表面分子的两个部分。
在一个实施方案中，制导和导航控制(GNC)蛋白可以是抗体。在一个实施方案中，肿瘤相关抗原包含ROR1、CD19或EGRFVIII。在一个实施方案中，T细胞活化受体包含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，IgGFc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。
该接头可以是共价键或肽接头。在一个实施方案中，肽接头可具有约2至约100个氨基酸残基。
在一个实施方案中，制导和导航控制(GNC)蛋白具有N末端和C末端，从N末端到C末端依次包含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41-BB结合结构域。在一个实施例中，制导和导航控制(GNC)蛋白具有N末端和C末端，从N末端到C末端串联地包含4-1BB的结合结构域、PD-L1的结合结构域、IgG Fc域、ROR1的结合结构域和CD3的结合结构域。在一个实施方案中，制导和导航控制(GNC)蛋白具有N末端和C末端，从N末端到C末端依次包含CD3结合结构域、CD19结合结构域、IgGFc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蛋白包含与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。百分比同源性不低于70％、80％、90％、95％、98％或99％。
另一方面，本申请提供了编码该GNC蛋白或其片段的核酸序列。在一个实施方案中，该核酸与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。百分比同源性不低于70％、80％、90％、95％、98％或99％。
在另一方面，本申请提供用于产生治疗组合物的方法。在一个实施方案中，该方法可包括以下步骤：提供包含细胞毒性细胞的细胞材料，将该细胞材料与第一GNC蛋白温育以提供活化的细胞组合物，以及配制该活化的细胞组合物以提供治疗组合物。该活化的细胞组合物含有第一治疗细胞。该第一治疗细胞包含通过与该第一细胞毒性细胞受体的结合相互作用与该细胞毒性细胞结合的第一GNC蛋白。该治疗组合物基本上不含外源病毒和非病毒DNA或RNA。
在一个实施方案中，该细胞材料可包含或衍生自PBMC。
该第一GNC蛋白可以包括第一细胞毒结合部分和第一癌症靶向部分。该第一细胞毒性结合部分对第一细胞毒性细胞受体具有特异性并且被配置成通过与该第一细胞毒性细胞受体的结合来活化该第一细胞毒性细胞。该第一癌症靶向部分对第一癌细胞受体具有特异性。
在一个实施方案中，该方法可通过将第二GNC蛋白与活化的细胞组合物温育来重复温育步骤。该第二GNC蛋白包含第二细胞毒性结合部分和第二癌症靶向部分，该第二细胞毒性结合部分对第二细胞毒性细胞受体具有特异性，并且该第二癌症靶向部分对第二癌细胞受体具有特异性。该活化的细胞组合物包含第二治疗细胞，并且该第二治疗细胞包含通过与该第二细胞毒性细胞受体的结合相互作用与该细胞毒性细胞或该第一治疗细胞结合的第二GNC蛋白。
在一个实施方案中，第一和第二癌症靶向部分独立地对CD19、PD-L1、或其组合具有特异性。在一个实施方案中，第一和第二细胞毒性结合部分独立地对CD3、PD-L1、4-1BB、或其组合具有特异性。
该方法可以进一步包括通过将另外的GNC蛋白与活化的组合物温育来重复温育步骤。另外的GNC蛋白可以是第三GNC蛋白、第四GNC蛋白等，以提供另外的治疗细胞，每个具有结合至细胞毒性细胞的另外的蛋白。
第一、第二和另外的GNC蛋白可以相同或可以不同。治疗细胞可以具有结合于其上的一种GNC蛋白、多个相同的GNC蛋白或多个不同的GNC蛋白。在一个实施方案中，治疗细胞可具有与其结合的第一GNC蛋白。在一个实施方案中，治疗细胞可具有结合于其上的第一和第二GNC蛋白。在一个实施方案中，治疗细胞可具有结合于其上的第一、第二和另外的GNC蛋白。
在一个实施方案中，治疗细胞包含具有至少一种结合的GNC蛋白的细胞毒性细胞。在一个实施方案中，治疗细胞包含具有至少10、20、50、100、200、300、400个结合的GNC蛋白的细胞毒性细胞。
该治疗组合物可以包括第一治疗细胞、第一GNC蛋白、细胞毒性细胞或其组合。在一个实施方案中，治疗组合物可包括第二治疗细胞，第二GNC蛋白，包括第一治疗细胞，第一GNC蛋白，细胞毒性细胞或其组合。在一个实施方案中，治疗组合物可包括另外的GNC蛋白和另外的治疗细胞。
在一个实施方案中，温育步骤可以用于扩增治疗细胞。在一个实施方案中，扩增治疗细胞可包括将治疗细胞与额外量的GNC蛋白温育以提供扩增的细胞群。在一个实施方案中，扩增的细胞群包含每毫升至少102、至少103、至少104、至少105、至少106、至少107、至少108、至少109、至少1010个细胞。在一个实施方案中，扩增的细胞群包含GNC结合细胞、GNC蛋白、细胞毒性细胞或其组合。在一个实施方案中，为了耗竭PD-1+T细胞，可以向扩增培养物中加入GNC蛋白，其将杀伤重定向至PD-1+T细胞，因此导致PD-1+耗尽的T细胞减少。在一个实施方案中，为了优先支持PD-1+T细胞，可以向扩增培养物中加入GNC蛋白，其通过PD-1缓解T细胞上的检查点信号传导，因此导致PD-1+T细胞的功能改善。在一个实施方案中，为了通过第3代CAR-T分离4-1BB介导的共刺激，可以将GNC蛋白加入到扩增培养物中，该扩增培养物重定向杀伤至4-1BB+T细胞或产生在诸如CAR-T细胞的治疗细胞中具有控制水平的4-1BB刺激的治疗组合物。
在一个实施方案中，癌症靶向部分具有针对B细胞的特异性，并且治疗组合物基本上不含B细胞。因此，本文公开的方法结合了治疗细胞的活化和纯化功能，这允许该方法产生不含B细胞的治疗组合物，而不需要引入任何外来物质(例如珠子)或任何外来遗传物质(例如病毒和非病毒DNA或RNA载体)。
在一个实施方案中，当将细胞材料与GNC蛋白温育时，GNC蛋白与细胞毒性细胞的比率为至少30比1。
在一个实施方案中，治疗组合物每毫升可以包括至少107个细胞。
在进一步的方面，本申请提供使用用于癌症治疗的制导和导航控制(GNC)蛋白的方法。在一个实施方案中，治疗患有癌症的受试者的方法包含提供细胞毒性细胞；将GNC蛋白与细胞毒性细胞组合以提供治疗细胞；任选地扩增治疗细胞以提供扩增的细胞群；以及向受试者施用治疗细胞或扩增的细胞群。
在一个实施方案中，该方法包括以下步骤：提供包含细胞毒性细胞的细胞材料；将该细胞材料与第一GNC蛋白温育以提供活化的细胞组合物，其中该活化的细胞组合物包含第一治疗细胞；配制该活化的细胞组合物以提供治疗组合物，其中该治疗组合物基本上不含病毒和非病毒DNA或RNA的外源物；以及将该治疗组合物向该受试者施用。
在一个实施方案中，该方法可进一步包括将第二GNC蛋白与活化的细胞组合物温育以提供还包含第二治疗细胞的活化的细胞组合物的步骤。在一个实施方案中，该方法可以进一步包括将另外的GNC蛋白与活化的细胞组合物温育以提供还包含另外的治疗细胞的活化的细胞组合物的步骤。
在一个实施方案中，该方法可还包含在提供细胞毒性细胞之前从外周血单个核细胞(PBMC)分离细胞毒性细胞。在一个实施方案中，该方法可进一步包括从血液分离外周血单个核细胞(PBMC)。在一个实施方案中，血液来自受试者。在一个实施方案中，血液不是来自受试者。在一个实施方案中，细胞毒性细胞可以来自接受治疗的患者或不同的个体，例如通用供体。
在一个实施方案中，细胞毒性细胞可以是自体T细胞，同种异体反应性T细胞或通用供体T细胞。在一个实施方案中，当使用自体供体T细胞时，为了防止污染癌细胞的输注，可将GNC蛋白添加至使杀伤重定向至肿瘤抗原的扩增培养物，例如肿瘤抗原可包括针对B细胞恶性肿瘤的CD19、针对乳腺癌的Epcam、针对黑素瘤的MCPl。
在一个实施方案中，该方法包括以下步骤：提供来自该受试者的血液，从该血液分离外周血单个核细胞(PBMC)，从该PBMC分离细胞毒性细胞，将GNC蛋白与该细胞毒性细胞结合以提供治疗细胞，任选地扩增该治疗细胞以提供扩增的细胞群，和向该受试者施用该治疗细胞或该扩增的细胞群。
在一个实施方案中，该方法还包含在向受试者施用治疗组合物后向受试者施用另外的GNC蛋白。在一个实施方案中，细胞毒性细胞可包括CD3+T细胞、NK细胞或其组合。
在一个实施方案中，细胞毒性细胞的分离包含分离至少一个细胞毒性细胞亚群以提供治疗T细胞。在一个实施方案中，细胞毒性细胞亚群包含CD4+细胞、CD8+细胞、CD56+细胞、CD69+细胞、CD107a+细胞、CD45RA+细胞、CD45RO+细胞、CD2+细胞、CD178+细胞、粒酶+细胞或其组合。
在一个实施方案中，GNC蛋白与细胞毒性细胞的结合包括将GNC蛋白与细胞毒性细胞温育约2小时至约14天、约1天至约7天、约8小时至约24小时、约4天至约7天、或约10天至约14天的时间段。在一个实施方案中，温育期可以超过14天。在一个实施方案中，温育期可以小于2小时。
在一个实施方案中，GNC蛋白与细胞毒性细胞之间的比率为至少600比1、500比1、400比1、300比1、200比1、100比1或1比1。在一个实施方案中，GNC蛋白与细胞毒性细胞之间的比率为约1比1、10比1、100比1、或至约1000比1的比率。
在一个实施例中，该方法可以还包含在施用步骤之后评估治疗功效。在一个实施方案中，评价治疗功效包含检查癌症的一种或多种生物标记物，监测治疗细胞的寿命，或其组合。在一个实施方案中，评价治疗功效包含检查癌症的一种或多种生物标记物，监测治疗细胞的寿命，或其组合。在一个实施方案中，该生物标记物包含肿瘤抗原；在死亡时由肿瘤释放到血流中的例如γ干扰素、IL-2、IL-8和/或趋化因子的细胞因子的释放，和/或各种细胞类型的表面上例如CD69、PD-1、TIGIT的CD标记物，和/或突变核酸；循环肿瘤细胞及其相关核酸；或外来体相关核酸；宿主炎性介质；或肿瘤衍生分析物；或其组合。在一个实施方案中，生物标记物包含肿瘤抗原、肿瘤相关凋亡体、小分子代谢物、细胞因子的释放、淋巴细胞表面标记物表达、磷酸化/去磷酸化信号传导分子、转录因子或其组合。
本文公开的方法不含用DNA载体或病毒载体转染细胞毒性细胞的步骤。在一个实施方案中，治疗细胞或扩增的细胞群基本上不含DNA载体或病毒载体。
该方法可用于治疗患有癌症的人类受试者。在一个实施方案中，该癌症包含表达ROR1、CEA、HER2、EGFR、EGFR vIII、LMP1、LMP2A、间皮素、PSMA、EpCAM、磷脂酰肌醇蛋白聚糖-3、gpA33、GD2、TROP2、BCMA、CD20、CD33、CD123、CD22、CD30、CD19、尚未被鉴定的肿瘤相关抗原或其组合的细胞。在一个实施方案中，该方法可用于治疗哺乳动物。
可以使用本文公开的方法治疗多种癌症。癌症的实例包括但不限于乳腺癌、结肠直肠癌、肛门癌、胰腺癌、胆囊癌、胆管癌、头颈癌、鼻咽癌、皮肤癌、黑素瘤、卵巢癌、前列腺癌、尿道癌、肺癌、非小细胞肺癌、小细胞肺癌、脑肿瘤、神经胶质瘤、成神经细胞瘤、食道癌、胃癌、肝癌、肾癌、膀胱癌、宫颈癌、子宫内膜癌、甲状腺癌、眼癌、肉瘤、骨癌、白血病、骨髓瘤或淋巴瘤。
在一个实施方案中，该方法可以进一步包括在向受试者施用治疗细胞或扩增的细胞群之后施用有效量的治疗剂。在一个实施方案中，治疗剂包含单克隆抗体、化学治疗剂、酶、蛋白质、共刺激物或其组合。在一个实施方案中，共刺激因子被配置为增加受试者中细胞毒性T细胞的量。
本申请还提供了包含有效浓度的GNC蛋白的溶液。在一个实施方案中，该溶液是接受治疗的受试者中的血浆。在一个实施方案中，溶液包括GNC蛋白结合的细胞。在一个实施方案中，溶液包括包含GNC蛋白的GNC簇、与GNC蛋白的T细胞结合部分结合的T细胞、和与GNC蛋白的肿瘤靶向部分结合的癌细胞。
通过以下结合附图对本发明的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，根据以下描述和所附权利要求书，本发明的前述和其他特征将变得更加完全显而易见。应理解，这些附图仅描绘了根据本公开安排的多个实施例，并且因此不应被认为是对其范围的限制，将通过使用附图以附加的特性和细节来描述本公开，在附图中：
图1显示一种GNC蛋白，其在对CD19阳性细胞具有靶向特异性的抗体结构中包含四个抗原特异性结合结构域；
图2说明四特异性GNC抗体介导T细胞和肿瘤细胞之间的多特异性结合；
图3是比较GNC-T细胞治疗(左)和CAR-T细胞治疗(右)的制造过程的流程图；
图4是显示用于制备GNC活化的治疗细胞组合物的细胞材料来源的图；
图5是显示用于制备GNC活化的治疗组合物的选择的T细胞的来源的图；
图6是显示GNC活化的治疗T细胞组合物的制备的图；
图7是显示制备用于GNC-T细胞治疗的第一GNC活化的T细胞的温育和配制步骤的图；
图8显示GNC蛋白(SI-35E类)诱导来自PBMC的IL-2分泌；
图9显示GNC蛋白(SI-35E类)诱导来自PBMC的粒酶B分泌；
图10显示GNC蛋白(SI-35E类)诱导活化标记物CD69在CD4+T细胞上的表达；
图11显示GNC蛋白(SI-35E类)诱导活化标记物CD69在CD8+T细胞上的表达；
图12显示GNC蛋白(SI-35E类)诱导活化标记物CD69在CD56+NK细胞上的表达；
图13显示GNC蛋白(SI-35E类)诱导细胞毒脱粒标记物CD107a在CD4+T细胞上的表达；
图14显示GNC蛋白(SI-35E类)诱导细胞毒脱粒标记物CD107a在CD8+T细胞上的表达；
图15显示GNC蛋白(SI-35E类)诱导细胞毒脱粒标记物CD107a在CD56+NK细胞上的表达；
图16显示GNC蛋白(SI-35E类)活化CD3+T细胞增殖；
图17显示GNC蛋白(SI-35E类)活化CD3+T细胞以分泌γ干扰素；
图18显示GNC蛋白(SI-35E类)活化幼稚CD8+/CD45RA+T细胞增殖；
图19显示GNC蛋白(SI-35E类)活化幼稚CD8+/CD45RA+T细胞以分泌γ干扰素；
图20显示6孔G-Rex板中GNC活化细胞生长随时间变化的图像；
图21显示了制备如本文所公开的治疗组合物的示例性方法(A)，以及解冻后PBMC、GET和GNC-T细胞的细胞活力(B)；
图22显示了PBMC衍生的第一GNC(SI-38E17)活化的治疗细胞组合物(产品A)(22A)和第二GNC(SI-38E17)包被的治疗细胞组合物(产品B)(22B)和输入PBMC细胞材料(22C)的流式细胞分析结果。
图23显示解冻后来自G-Rex 100M生物反应器的GET细胞和配制的GNC-T细胞的GNC-T治疗细胞组合物；
图24显示了通过使用GNC(SI-35E类)包被的PBMC细胞对CHO-ROR1细胞的RTCC的结果。
图25显示了PBMC衍生的SI-38E17 GNC活化的治疗细胞随着时间杀死前体B细胞白血病Kasumi的动力学；
图26显示通过使用PMBC衍生的SI-38E17 GNC活化的治疗细胞杀死Nalm-6、MEC-1、Daudi和Jurkat细胞的功效；以及
图27显示在加标(spike-in)模型中使用PBMC衍生的SI-38E17 GNC活化的治疗细胞杀死Nalm-6、MEC-1、Daudi和Jurkat白血病细胞。
具体实施方式
在以下详细描述中，参考了构成本文一部分的附图。在附图中，除非上下文另有说明，否则类似的符号通常标识类似的成分。在具体实施方式、附图和权利要求中描述的说明性实施方式并不意味着是限制性的。可利用其他实施方案，且可作出其他改变，而不背离本文所呈现的标的物的精神或范围。将容易理解的是，如在此总体描述的并且在附图中示出的本公开的这些方面可以被安排、替代、组合、分开，并且被设计成多种不同的构型，所有这些在此明确地预期。
在一个实施方案中，制导导航控制(GNC)蛋白的特征在于其多个抗原特异性结合结构域(AgBD)的组成和其通过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)定向至癌细胞(或其他靶细胞，例如旁观者抑制细胞)的能力。在一个实施方案中，GNC蛋白由表1所示的用于结合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。图1显示了包含用于结合表达CD3、PD-L1和/或4-1BB的T细胞和表达CD19的靶B细胞的AgBD的示例性四特异性GNC抗体的结构，如图2所示。
在T细胞治疗中，细胞毒性T细胞由T细胞受体复合物蛋白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蛋白调节。为了调节这种信号传导以及T细胞和癌细胞之间的相互作用，多个AgBD可分别组成部分1和部分2。可被部分1和2中的激动性或拮抗性结合结构域靶向的分子的实例示于表1中。在一个实施方案中，GNC蛋白可具有至少一个连接部分1和部分2的接头。在GNC蛋白的一个实例中，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-抗生物素蛋白、亮氨酸-拉链和任何双杂交阳性蛋白的互补接头。在一些实施方案中，接头可以是抗体骨架结构或抗体片段，使得GNC蛋白和GNC抗体可以具有相同的含义，例如图1中的示例性四特异性GNC抗体的结构。
GNC蛋白或抗体能够通过多个AgBD的结合功能在体内或体外将T细胞定向至癌细胞(图2)。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细胞治疗中的主要试剂，即GNC-T细胞治疗，用于在过继转移之前离体活化和控制细胞毒性T细胞。
本申请涉及制备GNC活化的治疗细胞组合物的方法。多个AgBD由于其分别与T细胞和癌细胞的界面而可分为部分1和部分2(表1)。具有两个AgBD的GNC蛋白可同时与T细胞上的表面分子(例如CD3)和肿瘤细胞上的肿瘤抗原(例如ROR1)结合，以将T细胞重定向至肿瘤细胞。
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，所以例如与4-1BB特异性结合的第三激动剂的添加可以帮助增强抗CD3诱导的T细胞活化。向GNC蛋白(例如，与肿瘤细胞上的PD-L1特异性结合的GNC蛋白)添加第四AGbd可以阻断肿瘤细胞上的PD-L1的抑制途径或通过其与T细胞上的PD-1的结合来介导。
在一些实施方案中，利用这些基本原理，GNC蛋白被构建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，在一些实施方案中，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，本申请涉及GNC-T细胞治疗，其中GNC蛋白用于在过继转移之前离体扩增T细胞(图3)。自主T细胞的体外致敏(priming)提供了细胞毒T细胞的制导和导航控制。例如，可以通过GNC蛋白离体分离和致敏(prime)外周血单个核细胞(PBMC)或PBMC内的特定类型的细胞群，例如，CD8+、CD45RO+记忆T细胞。可以配制这些扩增的细胞毒性T细胞并通过过继转移将其输注回患者。当在体内攻击癌症时，可将另外的GNC蛋白注入患者以控制细胞毒性的功效和寿命。因此，GNC-T细胞治疗不同于基于GNC蛋白的免疫治疗，其中GNC蛋白直接施用到患者中。然而，GNC-T细胞治疗不排除以受控方式直接施用GNC蛋白以管理体内注入的细胞毒性T细胞的功效。另外的GNC蛋白可以促进细胞裂解活性并且促进依赖于AgBD构型的T细胞增殖。
在一个方面，本申请涉及治疗性GNC-T细胞的生产。与治疗性CAR-T细胞的产生相比较并且为了与治疗性CAR-T细胞的产生相区别，出于比较目的，它们的一般过程示于图3中。在CAR-T治疗中，通过单采血液成分术(apheresis)收集细胞材料，例如患者白细胞，并且，选择并活化CD3+T细胞的亚单位以促进基因转移至细胞材料，然后通过引入外来物质支架以支持T细胞群，例如通过使用抗-CD3/抗-CD28抗体包被的珠子来扩大细胞材料的数量。有利地，GNC-T细胞材料不需要引入支架杂质以从患者白细胞扩增T细胞。
CAR-T治疗细胞材料必须经历涉及CAR-T载体DNA制备和转染的基因转移，这导致T细胞基因组的遗传修饰。此外，这些遗传修饰的T细胞可以在被转移回患者之前经历另一轮T细胞扩增。CAR-T载体DNA的随机整合携带T细胞转化的风险，导致原发性白血病发生或将CAR-T载体引入白血病细胞，通过CAR靶抗原的内部隔离机制增加复发的风险(Zhang,Liu等.2017)。
相反，GNC-T细胞治疗具有不涉及任何载体DNA转染的优点，因此在过继转移之前没有遗传修饰的风险，这提供了相对于现有CAR-T治疗的显著优点和技术改进之一。除了GNC-T细胞治疗没有外源性遗传物质污染和癌症风险的优点之外，当PBMC或不同的T细胞亚单位如图5和6所示在体外被引发和活化时，GNC-T细胞治疗的功效可以提高。在CAR-T治疗的使用中已经探索了类似的方法，其中可以将选定的特定比率的一些T细胞亚单位转移回患者(Turtle,Hanafi等.2016,Turtle,Hanafi等.2016)。
在一些实施方案中，在细胞扩增之前从细胞材料中除去白血病或其他癌细胞可能是有益的(图7)。具有循环白血病细胞，特别是B细胞恶性肿瘤的患者的PBMC可以深刻地改变细胞组成并因此影响最终治疗细胞产品的适用性。例如，高水平的循环白血病母细胞(leukemic blasts)(大于WBC的10％)可能需要在GNC介导的细胞扩增之前耗竭白血病细胞。通过使用细胞分级分离方法可以降低得自患者的PBMC中白血病细胞的百分比。这些方法可以包括涉及密度梯度分离或免疫荧光细胞分离或荧光活化细胞分选、免疫磁性细胞分离或微流体流动室方法的步骤。这些方法可以在离心、细胞洗涤、温育或温度调节之前或之后进行。这些方法可利用非细胞底物(磁珠、塑料、聚合物等)，对非细胞底物的修饰(蛋白质、抗体、电荷状态)，抗体处理，多重抗体处理，多特异性抗原结合蛋白和基于细胞表面抗原的细胞偶联。这些方法可以使用酶消化或离子螯合或机械搅拌或细胞容器旋转。减少白血病母细胞的方法可利用抗体药物缀合物或白血病敏化剂。该方法可以由这些方法的组合组成。
在一个实施方案中，为了能够产生用GNC蛋白致敏(或包被或结合)的治疗T细胞，产生四特异性抗体并将其用作GNC蛋白。在一个实施方案中，四特异性抗体/GNC蛋白包含通过抗体片段连接的4个不同结合结构域作为其主链。一种结合结构域对T细胞上的CD3有特异性，第二结合结构域对肿瘤相关抗原有特异性，包括但不限于ROR1、CEA、HER2、EGFR、EGFRvIII、LMP1、LMP2A、间皮素、PSMA、EpCAM、磷脂酰肌醇聚糖-3、gpA33、GD2、TROP2、BCMA、CD19、CD20、CD33、CD123、CD22、CD30，并且第三和第四结合结构域对两种不同的免疫检查点调节剂有特异性，例如PD-L1、PD-L2、PD-1、OX40、4-1BB、GITR、TIGIT、TIM-3、LAG-3、CTLA4、CD40L、VISTA、ICOS、BTLA、Light等。
不受理论限制，GNC蛋白介导的GNC-T细胞治疗相对于常规CAR-T治疗的优点包括但不限于，第一，包含IgGFc结构域可以赋予与双特异性咬合(BiTe)分子相比更长的血清半衰期的特性；第二，包含对免疫检查点调节剂有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重定向了T细胞的方向并引导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遗传修饰使其对肿瘤细胞有特异性(这也称为嵌合抗原受体T细胞(CAR-T)治疗)；以及第四，GNC蛋白介导的抗体治疗或T细胞治疗不涉及T细胞的基因修饰，后者可能具有将修饰的T细胞转化为克隆扩增即T细胞白血病的风险。
通过参考本文包括的特定实施方案和实施例的以下详细描述，可以更容易地理解本公开。尽管已经参考本发明的某些实施例的具体细节描述了本发明，但是并不意味着这些细节应当被认为是对本发明范围的限制。
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：GNC蛋白和四特异性GNC抗体
在本申请中，GNC蛋白的实例是四特异性GNC抗体类，其中4个AgBD以IgG抗体作为骨架共价连接(图1)。从该蛋白的N末端开始，第一scFv与IgG抗体的恒定结构域CH 1、2和3的Fab结构域连接，然后在C末端与另一scFv连接。因为每个scFv结构域显示独立的结合特异性，所以不需要使用IgG抗体的恒定结构域进行这些AgBD的连接。GNC蛋白被构建为四特异性GNC抗体，其可以直接结合肿瘤相关抗原(TAA)并接合宿主内源性T细胞以杀死肿瘤细胞，而不依赖于MHC将肿瘤抗原呈递给抗原特异性T细胞受体(图2)。如图1所示，CD19是靶向CD19阳性B细胞和肿瘤细胞的TAA。此外，PD-L1是四特异性GNC抗体的免疫检查点调节组分的实例，其可以克服免疫抑制性肿瘤微环境并完全活化肿瘤微环境内耗尽的T细胞。
在四特异性GNC抗体中，SI-35E类包含靶向抗人CD3结合结构域(SEQ ID 1-4)，抗人PD-L1(SEQ ID 5-12)，抗人4-1BB(SEQ ID 13-24)和靶向人ROR1(SEQ ID 25-32)，即TAA。在本文中，SI-38E和SI-39E的类别分别靶向CD19(SEQ ID 47-50)和EGFR(SEQ ID 51-54)。
为了构建四特异性GNC抗体，将AgBD转化为scFv和VLVH以置于GNC蛋白的N末端结构域1(D1)或scFv和VHVL，以置于C末端结构域3(D3)和4(D4)。本文所述所有的scFv分子含有20个氨基酸的柔性gly-gly-gly-gly-ser(G4S)X4接头，其可操作地连接VH和VL，而与V区取向(LH或HL)无关。四特异性GNC抗体中的剩余位置，结构域2(D2)，由IgG1重链VH-CH1-铰链-CH2-CH3及其相应的轻链VL-CL组成，其可以是κ链或λ链。D1和D2通过10个氨基酸(G4S)×2接头基因连接，D2和D3同样产生连续的～150kDa重链肽。当与合适的轻链共转染时，可以通过IgG1Fc(蛋白A/蛋白G)纯化最终的对称四特异性GNC肽并分析以评估功能活性。预先构建重链和轻链基因“盒”，使得可以使用限制性酶切位点(重链的HindIII/NheI和轻链的HindIII/BsiWI)或诸如Gibson装配的“无限制性克隆”(SGI-DNA，拉荷亚，加利福尼亚州)，输注(Takara Bio美国)或NEBuilder(NEB，伊普斯威奇，马萨诸塞州)轻易地克隆V区，后者在此使用。
四特异性GNC抗体通过包括设计完整分子、合成和克隆每个结构域的核苷酸序列，在哺乳动物细胞中表达和纯化终产物的方法产生。这里，使用Geneous 10.2.3软件包(生物材料(Biomaterials)，奥克兰，新西兰州)装配核苷酸序列，并将其分解成其用于基因合成的组成结构域(金唯智(Genewiz)，南普莱恩菲尔德，新泽西州)。在该实施例中，将SI-35E18(SEQ ID 65和67)分成其组分结构域，其中抗-4-1BB scFv VL-VH占据D1，抗人PD-L1克隆PL230C6占据D2(Fab位置)，抗人ROR1 Ig结构域特异性克隆323H7 VHVL scFv占据D3，以及抗人CD3scFv VHVL占据C-末端D4。使用基于NEBuilder Web的工具，根据其在较大蛋白质中的位置将5’和3’核苷酸附加到每个结构域上，使得每个结构域与它的侧翼结构域重叠20-30个核苷酸，这些核苷酸指导位点特异性重组，从而在单个基因装配步骤中基因融合每个结构域。由于四特异性核苷酸序列中有大量同源区，N-末端结构域1和2与C-末端D3和D4分开装配。然后在第二个NEBuilder反应中将N-和C-末端片段组装在一起。将一小等分试样转化到大肠杆菌(E.coli)DH10b(英杰(Invitrogen)，卡尔斯巴德，加利福尼亚州)中并铺在TB+羧苄青霉素100μg/ml平板(天惠华(Teknova)，12/5000霍利斯特，加利福尼亚州)上并在37℃温育过夜。选择所得菌落并将2ml过夜培养物接种于TB+羧苄青霉素中。从过夜培养物中制备DNA(Thermo-Fisher，卡尔斯巴德，加利福尼亚州)，随后使用侧翼于每个结构域的测序引物(Sigma，圣路易，密苏里州)测序(Genewiz，南普莱恩菲尔德，新泽西州)。所有DNA序列在Geneous中装配和分析。
在另一种靶向人CD19的四特异性GNC蛋白SI-38E17(SEQ ID 47-50)中，多个AgBD携带抗人4-1BB(scFv 466F6，SEQ ID 17-20)以及抗人PD-L1(scFv PL221G5 SEQ ID 9-13)和抗人CD3结合结构域(SEQ ID 1-4)。制备该四特异性抗体的方法和步骤是相同的。
GNC蛋白由用于结合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)。四特异性GNC抗体可用于直接与机体的内源性T细胞接合以杀死肿瘤细胞，而不依赖于由MHC向抗原特异性T细胞受体呈递的肿瘤抗原。这与仅基于免疫检查点阻断的治疗相反，后者受抗原识别的限制。在上下文中，免疫检查点调节组分可以被构建为四特异性GNC抗体的一部分，其可以提供类似于标准检查点阻断治疗中的益处。
除了T细胞之外，其他细胞毒性细胞也可以被GNC蛋白靶向用于杀死癌症或预防癌症的目的。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。
GNC蛋白被构建以获得与不等数目的T细胞拮抗剂和激动剂特异性地结合的多个AgBD。以这种方式，GNC蛋白可以将活化的T细胞重新定向肿瘤细胞，对它们的体内活性具有一定水平的控制(表2)。因此，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。在本发明中，有三类四特异性GNC抗体，即创建SI-39E、SI-35E和SI-38E以实现GNC-T细胞治疗，其抗体结构域及其特异性列于表3中。表4中列出了靶向EGFRvIII的四特异性GNC抗体(SI-39E)、ROR1(SI-35E)和CD19(SI-38E)的结构。
实例2：GNC活化的，PBMS衍生的细胞组合物。
测试表4中所列的SI-35类活化和诱导PBMC内不同细胞类型增殖的能力，例如CD4+和/或CD8+T细胞和/或CD56+天然杀伤细胞(NK)。以2X最终浓度制备四特异性GNC抗体，并以1:10系列稀释液在200ul RPMI+10％FBS中的96孔板的6孔中滴定。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白细胞单采产物。在最终目的地96孔板中，通过向测定的各孔中加入100μL PBMC(100,000)和100μL的每种抗体稀释液来组合PBMC和连续滴定的GNC蛋白。将测定板在37℃下温育约72小时，然后收获每个测定孔的内容物并通过FACS分析CD4+T细胞、CD8+T细胞和CD56+NK细胞的数目。从各孔中收获细胞并转移到新的96孔V-底板中，然后在400×g下离心3分钟。将上清液转移至96孔板用于分析IL-2和粒酶B。将细胞重悬于200μL的FACS抗体的2％FBS/PBS中并在冰上温育30分钟。将板在400×g下离心3分钟并抽吸上清液。将该洗涤步骤再重复一次，然后将细胞重悬于100μL 2％FBS/PBS中并在BD LSR FORTESSA上分析。
如图8所示，除了scFv结合结构域在位置2(SI-35E37)和4(SI-35E39)被FITC替代的那些抗体之外，所有SI-35E四特异性GNC抗体诱导从PBMC产生IL-2。这两种蛋白分别缺失了PD-L1或CD3的结合结构域。粒酶B分泌到培养物上清液中遵循与IL-2产生相似的模式，如图9所示。SI-35E37和SI-35E3在PBMC培养物中诱导CD4+(图10)、CD8+(图11)、和CD56+(图12)细胞上的活化标记物CD69的细胞表面表达的效力也低得多。细胞毒脱粒标记物CD107a(LAMP-1)的表面表达由所有测试的GNC蛋白诱导，除了在培养物中在CD4+(图13)、CD8+(图14)上的位置2和4处缺乏结合，但在CD56+(图15)上较不一致。在较低浓度下，3种GNC蛋白(SI-35E42、SI-35E43、和SI-35E46)诱导CD69在CD4+T细胞、CD8+T细胞和CD56+NK细胞上的表达，这与这些GNC诱导的IL-2和粒酶B分泌水平(图8和9)非常相关。
用一组SI-35类抗体从刺激5天的CD3+或幼稚CD8+T细胞(70,000个细胞/孔)的培养物中测量γ干扰素的增殖和产生。根据制造商的方案，使用EasySepTM人CD3+或幼稚CD8+T细胞分离试剂盒(干细胞技术(StemCell Technologies)，从来自正常供体的外周血单个核细胞富集人CD3+、或CD8+CD45RA+幼稚T细胞。通过流式细胞仪测定>98％CD3+或CD8+CD45RA+T细胞。在37℃下用Alamar蓝(Thermo Fisher，目录号DAL1100)染色1小时后，测量培养物中的增殖，然后在Spectramax plus 384孔读数器(美国分子仪器(Molecular Devices))上读数。在没有GNC的细胞培养物中，GNC扩增的CD3+T细胞的增殖被表示为细胞数目相对于CD3+T细胞背景的倍数增加(图16)。除了缺少CD3结合结构域的构建体之外，所有测试的构建体均诱导增殖。还从这些培养物中收集培养物上清液，并通过ELISA分析γ干扰素的存在。除非GNC构建体中CD3或ROR1结合结构域变成FITC，否则γ干扰素的分泌(图17)高。与总CD3+T细胞相比，幼稚CD8+CD45RA+T细胞的增殖(图18)对存在或不存在4-1BB结合结构域更敏感，如通过向培养物中加入可溶性抗4-1BB单克隆抗体(其中4-1BB结合在GNC上不存在)所示。发现从幼稚CD8+T细胞分泌γ干扰素的类似模式(图19)。
实施例3：按比例放大并配制第一GNC活化的治疗细胞组合物。
培养7天后，以临床上显着的剂量10E9获得了GNC活化的和包被的T细胞。通过来自白细胞单采术产物(leukopaks)的标准Ficoll密度梯度从LRS锥形白细胞中分离人PBMC，所述白细胞单采术产物是收集自正常人外周血的富集的去白细胞术产物(leukapheresisproduct)。收集后，将细胞在-80℃下冷冻，然后在放入培养物之前解冻。使用G-Rex板和生物反应器培养系统，监测SI-38E17 GNC刺激的PBMC培养物的生长达14天。培养基由RPMI1640，10％胎牛血清、1％非必需氨基酸、1％GlutaMAX、0.6％谷氨酰胺-丙氨酸补充剂、15ng/mL人IL-2和1nMGNC蛋白组成。6孔G-Rex培养物耐受25-100百万PBMC/孔的接种密度持续6天，其大大超过推荐量，但在第7天具有单个50％培养基变化的系统中的细胞耐受。细胞群集指示它们在培养物中的活化(图20)。将来自一个去白细胞术供体的至少250百万个细胞接种到两个G-Rex 100M生物反应器中，并在1升培养基中培养7天。较大体积的培养基允许继续培养而不需要更换培养基。每个100M生物反应器中的细胞产量在1.2-1.4十亿个细胞之间，其活力大于88％。
实施例4：第二GNC活化的治疗细胞组合物。
从生物反应器中收获细胞作为第一GNC活化的治疗细胞组合物，任选地使用LOVO自动细胞处理系统(Fresenius Kabi)浓缩。将一个样品(产物B)暴露于1nM SI-38E17，其在用于制备第二GNC活化的治疗细胞组合物的情况下与第一GNC相同，可能用于靶向治疗携带CD19阳性恶性肿瘤的患者(图21A)。
在LOVO系统中的处理中的第二浓缩步骤(100mL体积)之后，将第二GNC活化的治疗细胞洗涤两次，然后在无菌处理袋中洗脱至终体积为54mL。另一样品(产物A)仅在培养阶段暴露于第一GNC蛋白，而在LOVO系统中的处理中没有再暴露(图21A)。将细胞从袋中取出，与CryoStor CS10试剂1:1混合，并冷冻至-80℃。将处理后的细胞解冻，并与来自培养前相同供体的解冻的未刺激的PBMC进行比较。
来自GNC扩增的T细胞(GET)培养物的细胞活力>75％，并且不受处理中暴露于另外的GNC试剂(GNC-T，产物B)的影响(图21B)。在培养期间细胞的平均直径增加，指示细胞活化。对输入PBMC细胞材料和解冻后的两种制剂进行流式细胞术，使用多色抗体组染色：活/死(e 780)、CD45、TCRα/β、CD56、CD4、CD8、CD14、TCRγ/δ和CD20。在GNC活化的T细胞(产物A)和另外的GNC包被的GNC-T细胞(产物B)上显示用于定量不同细胞亚单位的门控(图22A和图22B)。产物A和产物B之间每个细胞亚群的百分比相似，但与输入PBMC的百分比有很大不同(图22C)。图23总结了每个细胞亚群的总数和百分比。与输入PBMC细胞材料相比，当白细胞总数从250百万个增加到1000百万个或4倍时，T细胞的每个亚群的总数对于α/βT细胞显著增加55倍，对于CD4+T细胞显著增加45倍，且对于CD8+T细胞显著增加78倍。在这种情况下，γ/δT细胞的5倍增加是温和的，而TCRα/β-lo、γ/δ+、CD8+T细胞似乎是最丰富的。最后，产物A和产物B细胞组合物的特征性特征在于没有可检测的B细胞。
本实施例说明了GNC-T细胞与CAR-T细胞制剂相比的许多优点。首先，起始材料的细胞组合物是来自供体的新鲜PBMC，并且不需要针对特定细胞亚单位进行预先选择或需要加入饲养细胞或合成珠子。GNC蛋白是100％的非核苷酸生物材料，并且不需要将RNA或DNA转移到细胞中，或用病毒载体转染。与CAR-T细胞扩增的平均40天相比，GNC诱导的扩增在9天内产生治疗剂量。所得细胞缺乏B细胞，并高度富集活化的CD4+和CD8+T细胞，所述CD4+和CD8+T细胞具有针对其特异性靶标的有效杀伤潜能。GNC治疗组合物在从-80℃解冻后是有活力的和生物活性的。预期这些优点一起显著降低等待时间、成本和与基础结构相关的问题以及与CAR-T细胞治疗相关的训练。最终产物的纯度、安全性和数量的改进将对患者具有显著的益处。
实施例5：用GNC蛋白预活化的PBMC被重新定向以有效地杀死肿瘤细胞。
测试了表4中列出的GNC SI-35类蛋白质中的6种针对人ROR1转导的CHO细胞系激活PBMC的重定向T细胞细胞毒性(RTCC)活性的能力(图24)。以2X终浓度制备GNC蛋白，并在200μl RPMI+10％FBS中在96孔板的10个孔中按1:3滴定。在最终目的地96孔板中，通过向测定的各孔中加入100μL PBMC(200,000)和100μL的每种抗体稀释液来组合PBMC和连续滴定的抗体。在加入CFSE-标记的CHO-ROR1细胞之前，将测定板在37℃下温育约72小时。用CFSE(Invitrogen，#C34554)以0.5-M在10mL培养基中在37℃标记5×10e6个CHO-ROR1靶细胞，持续20分钟。用50mL培养基洗涤CHO-ROR1细胞3次，然后重悬浮于10mL中，再次计数，然后将5,000CFSE标记的CHO-ROR1细胞加入至GNC活化的PBMC的各孔中。将细胞再温育72小时，然后收获每个测定孔的内容物，并分析剩余的CFSE标记的靶细胞的数量。如图24所示，所有GNC蛋白测试了定向RTCC活性，其中SI-35E42、SI-35E43和SI-35E46在减少孔中CHO-ROR1细胞的数目方面是最有效的。
为了进一步证明GNC-标记的PBMC对人肿瘤细胞的杀伤作用，使用IncuCyte S3活细胞分析系统(Sartorius/Essen Biosciences)进行GNC-剂量和效应物：靶标比率递增实验以监测细胞随时间的变化。来自健康供体的PBMC用GNC蛋白SI-38E17以0.01-100nM的10倍系列剂量在37℃下标记30分钟，然后在培养前洗涤。GNC SI-38E17靶向B细胞表面表达的CD19抗原，因此选择Kasumi-2前体B细胞白血病系作为靶细胞。将所使用的Kasumi-2细胞转导以表达绿色荧光蛋白(GFP)，并且因此通过测量在6天的时间段内收集9次的4个图像/孔中的平均绿色荧光来追踪肿瘤细胞的存在。通过将GNC-标记的PBMC以5,000(1:1)到160,000(32:1)个细胞的连续2倍稀释方式加入复孔中，来增加效应物:靶标(E:T)比率。如图25所示，Kasumi-2细胞在具有1:1-8:1E:T比例的未标记PBMC的孔中数量增加。暴露于低至0.1nM GNC导致Kasumi-2在1:1培养物中的生长降低，其中E:T比率每增加2倍抑制增加。用1nM或更高浓度的GNC包被PBMC导致在所有E:T比率下培养42小时后Kasumi-2细胞几乎完全消除。
作为跟踪实验，其他3个转化的B细胞系：NALM-6、MEC-1和Daudi以及急性T细胞白血病系Jurkat用作靶细胞。这些靶细胞先前用慢病毒转导以组成型表达NucRed 647分子。在该测定中，PBMC在37℃暴露于10倍剂量的GNC蛋白SI-38E17持续30分钟，然后如前洗涤。将PBMC以1.2×106细胞/孔铺板并加入50,000个靶肿瘤细胞。将细胞置于诱导细胞IncuCyte S3组中，以收集在5.5天时间内在10个时间点收集的红色荧光图像(4个图像/孔)(图26)。在没有PBMC的情况下建立所有4个肿瘤细胞系的生长曲线(空)。用1nM或更高的GNC蛋白SI-38E17标记PBMC导致所有三种B细胞系的停滞生长，而不是Jurkat T细胞白血病。B细胞系对预暴露于0.1nM GNC蛋白的PBMC细胞的敏感性不同。
作为定量GNC-T细胞与肿瘤细胞培养物结果的不同方法，我们建立了通过流式细胞术检测的定量限(LOQ)曲线。将Daudi-Red细胞在200,000至20个细胞的范围内连续稀释10倍，然后与1百万PBMC 1:1混合以产生10％、1.0％、0.1％、0.01％和0.001％肿瘤细胞的样品，然后通过流式细胞术分析(图27)。接下来，从1nM GNC扩增的T细胞的15天6孔G-Rex培养物中收获细胞，所述GNC扩增的T细胞在0时间点已经用10％、1％或0.1％的NALM-6、MEC-1、Daudi或Jurkat(全部被NucRed转导)肿瘤细胞进行了加标，并且使用与上述相同的流式细胞仪设置进行分析。在所有条件下肿瘤细胞减少到小于0.001％，除了在其中MEC-1肿瘤系以10％加标的培养物中检测到44个细胞。在这种条件下，MEC-1细胞在培养物中降低至<0.01％。
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含在本公开的范围内。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。
表格
表1A.实例GNC蛋白与T细胞结合结构域的组合物。
Figure BDA0002558885220000191
表2.单个GNC蛋白中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可能组合的示例。
Figure BDA0002558885220000192
表3.GNC蛋白中使用的抗体结合结构域的特异性。
Figure BDA0002558885220000193
Figure BDA0002558885220000201
表4.靶向EGFRvIII的四特异性GNC抗体(SI-39E)、ROR1(SI-35E)和CD19(SI-38E)的类别。
Figure BDA0002558885220000211
制导和导航控制蛋白的制造和使用方法
序列表
Figure BDA0002558885220000221
Figure BDA0002558885220000231
Figure BDA0002558885220000241
Figure BDA0002558885220000251
Figure BDA0002558885220000261
四特异性GNC抗体的GNC-T序列表
氨基酸序列中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
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIK
>SEQ ID 05抗-PD-L1 PL230C6 VHv3 nt
CAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCCAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTAGT
>SEQ ID 06抗-PD-L1 PL230C6 VHv3 aa
QSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSS
>SEQ ID 07抗-PD-L1 PL230C6 VLv2 nt
GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 08抗-PD-L1 PL230C6 VLv2 aa
AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIK
>SEQ ID 09抗-PD-L1 PL221G5 VHv1 nt
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
>SEQ ID 10抗-PD-L1 PL221G5 VHv1 aa
EVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSS
>SEQ ID 11抗-PD-L1 PL221G5 VLv1 nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 12抗-PD-L1 PL221G5 VLv1 aa
DIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIK
>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 323H7 VHv4 nt
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA
>SEQ ID 26抗-ROR1 323H7 VHv4 aa
EVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSS
>SEQ ID 27抗-ROR1 323H7 VLv1 nt
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 28抗-ROR1 323H7 VLv1 aa
DIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIK
>SEQ ID 29抗-ROR1 338H4 VHv3 nt
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCTCCCTCAGTAGCTATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAGGGGGCTGGAGTGGATCGGAATCATTTATGCTAGTGGTAGCACATACTACGCGAGCTCGGCGAAAGGCAGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAATTTATGACGGCATGGACCTCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA
>SEQ ID 30抗-ROR1 338H4 VHv3 aa
EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMSWVRQAPGRGLEWIGIIYASGSTYYASSAKGRFTISKDNTKNTVDLQMNSLRAEDTAVYYCARIYDGMDLWGQGTLVTVSS
>SEQ ID 31抗-ROR1 338H4 VLv4 nt
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTCAGAACATTTACAGCTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCGCCTGATCTATCTGGCATCTACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTACACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAAAGCAATTATAACGGTAATTATGGTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 32抗-ROR1 338H4 VLv4 aa
DIQMTQSPSSLSASVGDRVTINCQASQNIYSYLSWYQQKPGKVPKRLIYLASTLASGVPSRFSGSGSGTDYTLTISSLQPEDVATYYCQSNYNGNYGFGGGTKVEIK
>SEQ ID 33抗-FITC 4420VH nt
GAGGTGAAGCTGGATGAGACTGGAGGAGGCTTGGTGCAACCTGGGAGGCCCATGAAACTCTCCTGTGTTGCCTCTGGATTCACTTTTAGTGACTACTGGATGAACTGGGTCCGCCAGTCTCCAGAGAAAGGACTGGAGTGGGTAGCACAAATTAGAAACAAACCTTATAATTATGAAACATATTATTCAGATTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGTAGTGTCTACCTGCAAATGAACAACTTAAGAGTTGAAGACATGGGTATCTATTACTGTACGGGTTCTTACTATGGTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA
>SEQ ID 34抗-FITC 4420VH aa
EVKLDETGGGLVQPGRPMKLSCVASGFTFSDYWMNWVRQSPEKGLEWVAQIRNKPYNYETYYSDSVKGRFTISRDDSKSSVYLQMNNLRVEDMGIYYCTGSYYGMDYWGQGTSVTVSS
>SEQ ID 35抗-FITC 4420VL nt
GATGTCGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTGTACACAGTAATGGAAACACCTATTTACGTTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGGTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA
>SEQ ID 36抗-FITC 4420VL aa
DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLRWYLQKPGQSPKVLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIK
>SEQ ID 37人IgG1缺失(具有ADCC/CDC缺失突变的G1m-fa)nt
GCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT
>SEQ ID 38人IgG1缺失(具有ADCC/CDC缺失突变的G1m-fa)aa
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
>SEQ ID 39人Ig Kappa nt
CGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 40人Ig Kappa aa
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 41SI-35E18(460C3-L1H1-scFv×PL230C6-Fab×323H7-H4L1-scFv×284A10-H1L1-scFv)重链nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTACAATACTGTTATTGATACTTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCGACTTCAGTAGGAGATACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATATATACTGGTAGCCGCGATACTCCTCACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGAAGGTAGCCTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCCAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTAGTGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 42 SI-35E18(460C3-L1H1-scFv×PL230C6-Fab×323H7-H4L1-scFv×284A10-H1L1-scFv)重链aa
DIQMTQSPSTLSASVGDRVTITCQSSQSVYSNWFSWYQQKPGKAPKLLIYSASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGYNTVIDTFAFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGIDFSRRYYMCWVRQAPGKGLEWIACIYTGSRDTPHYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGSLWGQGTLVTVSSGGGGSGGGGSQSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIY VNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIKGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINCQASESISSW LAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIK
>SEQ ID 43SI-35E18(460C3-L1H1-scFv×PL230C6-Fab×323H7-H4L1-scFv×284A10-H1L1-scFv)轻链nt
GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 44SI-35E18(460C3-L1H1-scFv×PL230C6-Fab×323H7-H4L1-scFv×284A10-H1L1-scFv)轻链aa
AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 45抗-CD3 284A10 VHv1b nt
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACA
>SEQ ID 46抗-CD3 284A10 VHv1b aa
EVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVST
>SEQ ID 47抗-huCD19 21D4 VH nt
GAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAGAAACCAGGAGAGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGTTCATGGATCGGCTGGGTGCGCCAGGCACCTGGGAAAGGCCTGGAATGGATGGGGATCATCTATCCTGATGACTCTGATACCAGATACAGTCCATCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGGACTGCCTACCTGCAGTGGAGTAGCCTGAAGGCCTCGGACACCGCTATGTATTACTGTGCGAGACATGTTACTATGATTTGGGGAGTTATTATTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
>SEQ ID 48抗-huCD19 21D4 VH aa
EVQLVQSGAEVKKPGESLKISCKGSGYSFSSSWIGWVRQAPGKGLEWMGIIYPDDSDTRYSPSFQGQVTISADKSIRTAYLQWSSLKASDTAMYYCARHVTMIWGVIIDFWGQGTLVTVSS
>SEQ ID 49抗-huCD19 21D4 VL nt
GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAATAGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA
>SEQ ID 50抗-huCD19 21D4 VL aa
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIK
>SEQ ID 51抗-huEGFRvIII 806VH nt
GATGTGCAGCTTCAGGAGTCGGGACCTAGCCTGGTGAAACCTTCTCAGTCTCTGTCCCTCACCTGCACTGTCACTGGCTACTCAATCACCAGTGATTTTGCCTGGAACTGGATTCGGCAGTTTCCAGGAAACAAGCTGGAGTGGATGGGCTACATAAGTTATAGTGGTAACACTAGGTACAACCCATCTCTCAAAAGTCGAATCTCTATCACTCGCGACACATCCAAGAACCAATTCTTCCTGCAGTTGAACTCTGTGACTATTGAGGACACAGCCACATATTACTGTGTAACGGCGGGACGCGGGTTTCCTTATTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA
>SEQ ID 52抗-huEGFRvIII 806VH aa
DVQLQESGPSLVKPSQSLSLTCTVTGYSITSDFAWNWIRQFPGNKLEWMGYISYSGNTRYNPSLKSRISITRDTSKNQFFLQLNSVTIEDTATYYCVTAGRGFPYWGQGTLVTVSA
>SEQ ID 53抗-huEGFRvIII 806VL nt
GACATCCTGATGACCCAATCTCCATCCTCCATGTCTGTATCTCTGGGAGACACAGTCAGCATCACTTGCCATTCAAGTCAGGACATTAACAGTAATATAGGGTGGTTGCAGCAGAGACCAGGGAAATCATTTAAGGGCCTGATCTATCATGGAACCAACTTGGACGATGAAGTTCCATCAAGGTTCAGTGGCAGTGGATCTGGAGCCGATTATTCTCTCACCATCAGCAGCCTGGAATCTGAAGATTTTGCAGACTATTACTGTGTACAGTATGCTCAGTTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA
>SEQ ID 54抗-huEGFRvIII 806VL aa
DILMTQSPSSMSVSLGDTVSITCHSSQDINSNIGWLQQRPGKSFKGLIYHGTNLDDEVPSRFSGSGSGADYSLTISSLESEDFADYYCVQYAQFPWTFGGGTKLEIK
>SEQ ID 55GGGGSGGGGSG接头nt
GGCGGTGGAGGGTCCGGCGGTGGTGGCTCCGGA
>SEQ ID 56GGGGSGGGGSG接头aa
GGGGSGGGGSG
>SEQ ID 57GGGGSGGGGS接头01nt
GGCGGTGGAGGGTCCGGCGGTGGTGGATCA
>SEQ ID 58GGGGSGGGGS接头01aa
GGGGSGGGGS
>SEQ ID 59GGGGSGGGGS接头02nt
GGCGGTGGAGGGTCCGGCGGTGGTGGATCC
>SEQ ID 60GGGGSGGGGS接头02aa
GGGGSGGGGS
>SEQ ID 61GGGGSGGGGSGGGGSGGGGS接头nt
GGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCA
>SEQ ID 62GGGGSGGGGSGGGGSGGGGS接头aa
GGGGSGGGGSGGGGSGGGGS
>SEQ ID 63SI-39E18(284A10-L1H1-scFv×806-Fab×PL221G5-H1L1-scFv×420H5-H3L3-scFv)重链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGATGTGCAGCTTCAGGAGTCGGGACCTAGCCTGGTGAAACCTTCTCAGTCTCTGTCCCTCACCTGCACTGTCACTGGCTACTCAATCACCAGTGATTTTGCCTGGAACTGGATTCGGCAGTTTCCAGGAAACAAGCTGGAGTGGATGGGCTACATAAGTTATAGTGGTAACACTAGGTACAACCCATCTCTCAAAAGTCGAATCTCTATCACTCGCGACACATCCAAGAACCAATTCTTCCTGCAGTTGAACTCTGTGACTATTGAGGACACAGCCACATATTACTGTGTAACGGCGGGACGCGGGTTTCCTTATTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCAACTACTGGATATGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGTATTTATGTTGGTAGTAGTGGTGACACTTACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGATAGTAGTAGTTATTATATGTTTAACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGCCCTTGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATACCTATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTTACGCATCCGATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCGGTTACTATACTAGTAGTGCTGATACGAGGGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 64SI-39E18(284A10-L1H1-scFv×806-Fab×PL221G5-H1L1-scFv×420H5-H3L3-scFv)重链aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSGGGGSGGGGSDVQLQESGPSLVKPSQSLSLTCTVTGYSITSDFAWNWIRQFPGNKLEWMGYISYSGNTRYNPSLKSRISITRDTSKNQFFLQLNSVTIEDTATYYCVTAGRGFPYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIKGGGGSGGGGSQSLVESGGGLVQPGGSLRLSCAASGFSFSSNYWICWVRQAPGKGLEWIACIYVGSSGDTYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSSSYYMFNLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSALVMTQSPSTLSASVGDRVTINCQASED IDTYLAWYQQKPGKAPKLLIFYASDLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGGYYTSSADTRGAFGGGTKVEIK
>SEQ ID 65SI-39E18(284A10-L1H1-scFv×806-Fab×PL221G5-H1L1-scFv×420H5-H3L3-scFv)轻链nt
GACATCCTGATGACCCAATCTCCATCCTCCATGTCTGTATCTCTGGGAGACACAGTCAGCATCACTTGCCATTCAAGTCAGGACATTAACAGTAATATAGGGTGGTTGCAGCAGAGACCAGGGAAATCATTTAAGGGCCTGATCTATCATGGAACCAACTTGGACGATGAAGTTCCATCAAGGTTCAGTGGCAGTGGATCTGGAGCCGATTATTCTCTCACCATCAGCAGCCTGGAATCTGAAGATTTTGCAGACTATTACTGTGTACAGTATGCTCAGTTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 66SI-39E18(284A10-L1H1-scFv×806-Fab×PL221G5-H1L1-scFv×420H5-H3L3-scFv)轻链aa
DILMTQSPSSMSVSLGDTVSITCHSSQDINSNIGWLQQRPGKSFKGLIYHGTNLDDEVPSRFSGSGSGADYSLTISSLESEDFADYYCVQYAQFPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 67SI-39E29(806-LH-scFv×284A10-Fab×PL221G5-H1L1-scFv×420H5-H3L3-scFv)重链nt
GACATCCTGATGACCCAATCTCCATCCTCCATGTCTGTATCTCTGGGAGACACAGTCAGCATCACTTGCCATTCAAGTCAGGACATTAACAGTAATATAGGGTGGTTGCAGCAGAGACCAGGGAAATCATTTAAGGGCCTGATCTATCATGGAACCAACTTGGACGATGAAGTTCCATCAAGGTTCAGTGGCAGTGGATCTGGAGCCGATTATTCTCTCACCATCAGCAGCCTGGAATCTGAAGATTTTGCAGACTATTACTGTGTACAGTATGCTCAGTTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGATGTGCAGCTTCAGGAGTCGGGACCTAGCCTGGTGAAACCTTCTCAGTCTCTGTCCCTCACCTGCACTGTCACTGGCTACTCAATCACCAGTGATTTTGCCTGGAACTGGATTCGGCAGTTTCCAGGAAACAAGCTGGAGTGGATGGGCTACATAAGTTATAGTGGTAACACTAGGTACAACCCATCTCTCAAAAGTCGAATCTCTATCACTCGCGACACATCCAAGAACCAATTCTTCCTGCAGTTGAACTCTGTGACTATTGAGGACACAGCCACATATTACTGTGTAACGGCGGGACGCGGGTTTCCTTATTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCAACTACTGGATATGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGTATTTATGTTGGTAGTAGTGGTGACACTTACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGATAGTAGTAGTTATTATATGTTTAACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGCCCTTGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATACCTATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTTACGCATCCGATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCGGTTACTATACTAGTAGTGCTGATACGAGGGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 68SI-39E29(806-LH-scFv×284A10-Fab×PL221G5-H1L1-scFv×420H5-H3L3-scFv)重链aa
DILMTQSPSSMSVSLGDTVSITCHSSQDINSNIGWLQQRPGKSFKGLIYHGTNLDDEVPSRFSGSGSGADYSLTISSLESEDFADYYCVQYAQFPWTFGGGTKLEIKGGGGSGGGGSGGGGSGGGGSDVQLQESGPSLVKPSQSLSLTCTVTGYSITSDFAWNWIRQFPGNKLEWMGYISYSGNTRYNPSLKSRISITRDTSKNQFFLQLNSVTIEDTATYYCVTAGRGFPYWGQGTLVTVSAGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIKGGGGSGGGGSQSLVESGGGLVQPGGSLRLSCAASGFSFSSNYWICWVRQAPGKGLEWIACIYVGSSGDTYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSSSYYMFNLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSALVMTQSPSTLSASVGDRVTINCQASEDIDTYL AWYQQKPGKAPKLLIFYASDLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGGYYTSSADTRGAFGGGTKVEIK
>SEQ ID 69SI-39E29(806-LH-scFv×284A10-Fab×PL221G5-H1L1-scFv×420H5-H3L3-scFv)轻链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 70SI-39E29(806-LH-scFv×284A10-Fab×PL221G5-H1L1-scFv×420H5-H3L3-scFv)轻链aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 71SI-35E20(466F6-L5H2-scFv×PL230C6-Fab×323H7-H4L1-scFv×284A10-H1L1-scFv)重链nt
GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCGAGCTCCGCGAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCCAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTAGTGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 72SI-35E20(466F6-L5H2-scFv×PL230C6-Fab×323H7-H4L1-scFv×284A10-H1L1-scFv)重链aa
DVVMTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSQSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIY VNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIKGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINCQASESISSW LAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIK
>SEQ ID 73SI-35E20(466F6-L5H2-scFv×PL230C6-Fab×323H7-H4L1-scFv×284A10-H1L1-scFv)轻链nt
GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 74SI-35E20(466F6-L5H2-scFv×PL230C6-Fab×323H7-H4L1-scFv×284A10-H1L1-scFv)轻链aa
AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 75SI-35E58(284A10-L1H1-scFv×PL230C6-Fab×323H7-H4L1-scFv×466F6-H2L5-scFv)重链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACCGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGGTCCGGAGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGGTCCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 76SI-35E58(284A10-L1H1-scFv×PL230C6-Fab×323H7-H4L1-scFv×466F6-H2L5-scFv)重链aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGGSGGGGSQSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLA SGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQASQNI RTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK
>SEQ ID 77SI-35E58(284A10-L1H1-scFv×PL230C6-Fab×323H7-H4L1-scFv×466F6-H2L5-scFv)轻链nt
GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 78SI-35E58(284A10-L1H1-scFv×PL230C6-Fab×323H7-H4L1-scFv×466F6-H2L5-scFv)轻链aa
AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 79SI-35E88(284A10-L1H1-scFv×323H7-Fab×PL230C6-H3L2-scFv×466F6-H2L5-scFv)重链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACCGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCCGGTGGAGGCGGTTCAGGCGGAGGTGGAAGTGGTGGTGGCGGCTCTGGAGGCGGCGGATCTGCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGGTCCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 80SI-35E88(284A10-L1H1-scFv×323H7-Fab×PL230C6-H3L2-scFv×466F6-H2L5-scFv)重链aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSAYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQASQNIRTYL SWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK
>SEQ ID 81SI-35E88(284A10-L1H1-scFv×323H7-Fab×PL230C6-H3L2-scFv×466F6-H2L5-scFv)轻链nt
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCATCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 82SI-35E88(284A10-L1H1-scFv×323H7-Fab×PL230C6-H3L2-scFv×466F6-H2L5-scFv)轻链aa
DIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 83SI-35E99(284A10-L1H1-scFv×323H7-Fab×PL221G5-H1L1-scFv×466F6-H2L5-scFv)重链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACAGGCGGTGGAGGGTCCGGCGGTGGTGGATCAGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGCTCCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 84SI-35E99(284A10-L1H1-scFv×323H7-Fab×PL221G5-H1L1-scFv×466F6-H2L5-scFv)重链aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKA STLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQAS QNIRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK
>SEQ ID 85SI-35E99(284A10-L1H1-scFv×323H7-Fab×PL221G5-H1L1-scFv×466F6-H2L5-scFv)轻链nt
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCATCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 86SI-35E99(284A10-L1H1-scFv×323H7-Fab×PL221G5-H1L1-scFv×466F6-H2L5-scFv)轻链aa
DIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 87SI-38E17(284A10-L1H1-scFv×21D4-Fab×PL221G5-H1L1-scFv×466F6-H2L5-scFv)重链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAGAAACCAGGAGAGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGTTCATGGATCGGCTGGGTGCGCCAGGCACCTGGGAAAGGCCTGGAATGGATGGGGATCATCTATCCTGATGACTCTGATACCAGATACAGTCCATCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGGACTGCCTACCTGCAGTGGAGTAGCCTGAAGGCCTCGGACACCGCTATGTATTACTGTGCGAGACATGTTACTATGATTTGGGGAGTTATTATTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCGAGCTCCGCGAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 88SI-38E17(284A10-L1H1-scFv×21D4-Fab×PL221G5-H1L1-scFv×466F6-H2L5-scFv)重链aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGESLKISCKGSGYSFSSSWIGWVRQAPGKGLEWMGIIYPDDSDTRYSPSFQGQVTISADKSIRTAYLQWSSLKASDTAMYYCARHVTMIWGVIIDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKAS TLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIKGGGGSGGGGSRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQASQN IRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK
>SEQ ID 89SI-38E17(284A10-L1H1-scFv×21D4-Fab×PL221G5-H1L1-scFv×466F6-H2L5-scFv)轻链nt
GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAATAGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>SEQ ID 90SI-38E17(284A10-L1H1-scFv×21D4-Fab×PL221G5-H1L1-scFv×466F6-H2L5-scFv)轻链aa
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID 91SI-38E33(21D4-LH-scFv×284A10-Fab×PL221G5-H1L1-scFv×466F6-H2L5-scFv)重链nt
GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAATAGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAGAAACCAGGAGAGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGTTCATGGATCGGCTGGGTGCGCCAGGCACCTGGGAAAGGCCTGGAATGGATGGGGATCATCTATCCTGATGACTCTGATACCAGATACAGTCCATCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGGACTGCCTACCTGCAGTGGAGTAGCCTGAAGGCCTCGGACACCGCTATGTATTACTGTGCGAGACATGTTACTATGATTTGGGGAGTTATTATTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCGAGCTCCGCGAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>SEQ ID 92SI-38E33(21D4-LH-scFv×284A10-Fab×PL221G5-H1L1-scFv×466F6-H2L5-scFv)重链aa
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIKGGGGSGGGGSGGGGSGGGGSEVQLVQSGAEVKKPGESLKISCKGSGYSFSSSWIGWVRQAPGKGLEWMGIIYPDDSDTRYSPSFQGQVTISADKSIRTAYLQWSSLKASDTAMYYCARHVTMIWGVIIDFWGQGTLVTVSSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIKGGGGSGGGGSRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQASQNIRTYL SWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK
SEQ ID 93SI-38E33(21D4-LH-scFv×284A10-Fab×PL221G5-H1L1-scFv×466F6-H2L5-scFv)轻链nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
SEQ ID 94SI-38E33(21D4-LH-scFv×284A10-Fab×PL221G5-H1L1-scFv×466F6-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的制造和使用方法
<130> SIBA104PCT
<141> 2019-03-26
<150> US62648888
<151> 2018-03-27
<150> US62648880
<151> 2018-03-27
<160> 94
<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> 345
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 5
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> 6
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 6
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> 7
<211> 330
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 7
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> 8
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 8
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> 9
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 9
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> 10
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 10
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> 11
<211> 330
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 11
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> 12
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 12
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> 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> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 25
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> 26
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 26
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> 27
<211> 339
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 27
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> 28
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 28
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> 29
<211> 345
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 29
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> 30
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 30
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> 31
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 31
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> 32
<211> 107
<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 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> 33
<211> 354
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 33
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> 34
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 34
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> 35
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 35
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> 36
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 36
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> 37
<211> 987
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 37
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> 38
<211> 329
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 38
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> 39
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 39
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> 40
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 40
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> 41
<211> 3681
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 41
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> 42
<211> 1227
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 42
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> 43
<211> 651
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 43
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> 44
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 44
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> 45
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 45
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> 46
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 46
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> 47
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 47
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> 48
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 48
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> 49
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 49
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> 50
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 50
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> 51
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 51
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> 52
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 52
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> 53
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 53
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> 54
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 54
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> 55
<211> 33
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 55
ggcggtggag ggtccggcgg tggtggctcc gga 33
<210> 56
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 56
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10
<210> 57
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 57
ggcggtggag ggtccggcgg tggtggatca 30
<210> 58
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 58
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 59
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 59
ggcggtggag ggtccggcgg tggtggatcc 30
<210> 60
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 60
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 61
<211> 60
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 61
ggcggtggcg gtagtggggg aggcggttct ggcggcggag ggtccggcgg tggaggatca 60
<210> 62
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 62
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> 63
<211> 3693
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 63
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> 64
<211> 1231
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 64
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> 65
<211> 642
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 65
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> 66
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 66
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> 67
<211> 3678
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 67
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> 68
<211> 1226
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 68
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> 69
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 69
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> 70
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 70
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> 71
<211> 3681
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 71
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> 72
<211> 1227
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 72
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> 73
<211> 651
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 73
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> 74
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 74
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> 75
<211> 3687
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 75
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> 76
<211> 1229
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 76
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> 77
<211> 651
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 77
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> 78
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 78
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> 79
<211> 3675
<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 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> 80
<211> 1225
<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 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> 81
<211> 660
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 81
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> 82
<211> 220
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 82
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> 83
<211> 3696
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 83
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> 84
<211> 1232
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 84
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> 85
<211> 660
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 85
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> 86
<211> 220
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 86
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys 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> 87
<211> 3690
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 87
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> 88
<211> 1230
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 88
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> 89
<211> 642
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 89
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> 90
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 90
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> 91
<211> 3675
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 91
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> 92
<211> 1225
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 92
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
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Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
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Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
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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
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Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
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His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
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Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
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His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
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Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
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Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
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Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro
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Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
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Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
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Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
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Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
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Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
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Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
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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
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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
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Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
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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
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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
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Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
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Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln
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Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
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Cys Gln Ala Ser Gln Asn Ile Arg Thr Tyr Leu Ser Trp Tyr Gln Gln
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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> 93
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
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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> 94
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 94
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
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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 (39)

1.一种用于产生治疗组合物的方法，其包含
提供包含细胞毒性细胞的细胞材料，
将所述细胞材料与第一制导和导航控制(GNC)蛋白温育以提供活化的细胞组合物，其中所述活化的细胞组合物包含第一治疗细胞，
其中所述第一GNC蛋白包含第一细胞毒性结合部分和第一癌症靶向部分，其中所述第一细胞毒性结合部分对第一细胞毒性细胞受体具有特异性并且被配置为通过与所述第一细胞毒性细胞受体结合来活化所述第一细胞毒性细胞，并且其中所述第一癌症靶向部分对第一癌细胞受体具有特异性，并且
其中所述第一治疗细胞包含通过与所述第一细胞毒性细胞受体的结合相互作用与所述细胞毒性细胞结合的第一GNC蛋白，以及
配制所述活化的细胞组合物以提供治疗组合物，其中所述治疗组合物基本上不含外源病毒和非病毒DNA或RNA。
2.根据权利要求1所述的方法，其中通过温育第二GNC蛋白与所述活化的细胞组合物来重复所述温育步骤，
其中所述第二GNC蛋白包含第二细胞毒性结合部分和第二癌症靶向部分，其中所述第二细胞毒性结合部分对第二细胞毒性细胞受体具有特异性，并且其中所述第二癌症靶向部分对第二癌细胞受体具有特异性，
其中所述活化细胞组合物还包含第二治疗细胞，以及
其中所述第二治疗细胞包含通过与所述第二细胞毒性细胞受体的结合相互作用与所述细胞毒性细胞或所述第一治疗细胞结合的第二GNC蛋白。
3.根据权利要求2所述的方法，其中所述第二GNC蛋白与所述第一GNC蛋白相同。
4.根据权利要求2所述的方法，其中所述第二GNC蛋白不同于所述第一GNC蛋白。
5.根据权利要求1或2所述的方法，其中所述第一或第二癌症靶向部分具有针对B细胞的特异性，并且其中所述治疗组合物基本上不含B细胞。
6.根据权利要求1所述的方法，其中所述细胞毒性细胞受体包含T细胞受体、NK细胞受体、巨噬细胞受体、树突细胞受体或其组合。
7.根据权利要求1所述的方法，其中当温育所述细胞材料与所述第一GNC蛋白时，所述第一GNC蛋白与所述细胞毒性细胞之间的摩尔比为至少30比1。
8.根据权利要求1所述的方法，其中所述治疗组合物每毫升包含至少106个细胞。
9.根据权利要求1所述的方法，其中所述治疗组合物包含所述第一治疗细胞、所述第一GNC蛋白、所述细胞毒性细胞、或其组合。
10.根据权利要求2所述的方法，其中所述治疗组合物包含所述第二治疗细胞、所述第二GNC蛋白，所述第一治疗细胞、所述第一GNC蛋白、所述细胞毒性细胞、或其组合。
11.根据权利要求1所述的方法，其中所述细胞材料包含外周血单个核细胞(PBMC)。
12.根据权利要求1所述的方法，其中所述第一和第二癌症靶向部分独立地对CD19、PD-L1、或其组合具有特异性。
13.根据权利要求1所述的方法，其中所述第一和第二细胞毒性结合部分独立地对CD3、PD-L1、4-1BB、或其组合具有特异性。
14.一种治疗患有癌症的受试者的方法，包含
提供包含细胞毒性细胞的细胞材料，
将所述细胞材料与第一制导和导航控制(GNC)蛋白温育以提供活化的细胞组合物，其中所述活化的细胞组合物包含第一治疗细胞，
其中所述第一GNC蛋白包含第一细胞毒性结合部分和第一癌症靶向部分，其中所述第一细胞毒性结合部分对第一细胞毒性细胞受体具有特异性并且被配置为通过与所述第一细胞毒性细胞受体结合来活化所述第一细胞毒性细胞，并且其中所述第一癌症靶向部分对第一癌细胞受体具有特异性，并且
其中所述第一治疗细胞包含通过与所述第一细胞毒性细胞受体的结合相互作用与所述细胞毒性细胞结合的第一GNC蛋白，以及
配制所述活化的细胞组合物以提供治疗组合物，其中所述治疗组合物基本上不含外源病毒和非病毒DNA或RNA，和
将所述治疗组合物向所述受试者施用。
15.根据权利要求14所述的方法，其中通过温育第二GNC蛋白与所述活化的细胞组合物来重复所述温育步骤，
其中所述第二GNC蛋白包含第二细胞毒性结合部分和第二癌症靶向部分，其中所述第二细胞毒性结合部分对第二细胞毒性细胞受体具有特异性，并且其中所述第二癌症靶向部分对第二癌细胞受体具有特异性，
其中所述活化的细胞组合物还包含第二治疗细胞，以及
其中所述第二治疗细胞包含通过与所述第二细胞毒性细胞受体的结合相互作用与所述细胞毒性细胞或所述第一治疗细胞结合的第二GNC蛋白。
16.根据权利要求14所述的方法，其中所述第二GNC蛋白与所述第一GNC蛋白相同。
17.根据权利要求14所述的方法，其中所述第二GNC蛋白与所述第一GNC蛋白不同。
18.根据权利要求14或15所述的方法，其中所述第一或第二癌症靶向部分具有针对B细胞的特异性，并且其中所述治疗组合物基本上不含B细胞。
19.根据权利要求14所述的方法，还包含在提供所述细胞材料之前从外周血单个核细胞(PBMC)中分离所述细胞毒性细胞。
20.根据权利要求19所述的方法，还包含从血液中分离所述外周血单个核细胞(PBMC)。
21.根据权利要求20所述的方法，其中所述血液来自所述受试者。
22.根据权利要求20所述的方法，其中所述血液不是来自所述受试者。
23.根据权利要求14所述的方法，还包含在向所述受试者施用所述治疗组合物之后向所述受试者施用另外的GNC蛋白。
24.根据权利要求14所述的方法，其中所述细胞毒性细胞包含T细胞、NK细胞或其组合。
25.根据权利要求19所述的方法，其中所述分离细胞毒性细胞包含分离至少一个细胞毒性细胞亚群以提供治疗T细胞。
26.根据权利要求25所述的方法，其中所述细胞毒性细胞亚群包含CD3+细胞、CD4+细胞、CD8+细胞、CD56+细胞、CD28+细胞、CD69+细胞、CD107a+细胞、CD45RA+细胞、CD45RO+细胞、γδTCR+细胞、αβTCR+细胞、CD25+细胞、CD127lo/-细胞、CCR7+细胞、PD-1+细胞或其组合。
27.根据权利要求14所述的方法，其还包含在所述施用步骤后评价治疗功效。
28.根据权利要求26所述的方法，其中所述评价治疗功效包含检查所述癌症的一种或多种生物标记物、监测所述治疗细胞的寿命、或其组合。
29.根据权利要求28所述的方法，其中所述生物标记物包括肿瘤抗原；在死亡时由肿瘤释放到血流中的例如γ干扰素、IL-2、IL-8和/或趋化因子的细胞因子的释放，和/或各种细胞类型的表面上例如CD69、PD-1、TIGIT的CD标记物，和/或突变核酸；循环肿瘤细胞及其相关核酸；或外来体相关核酸；宿主炎性介质；或肿瘤衍生分析物；或其组合。
30.根据权利要求14所述的方法，其中所述受试者是人。
31.根据权利要求14所述的方法，其中所述癌症包含表达ROR1、CEA、HER2、EGFR、EGFRVIII、LMP1、LMP2A、间皮素、PSMA、EpCAM、磷脂酰肌醇蛋白聚糖-3、gpA33、GD2、TROP2、BCMA、CD19、CD20、CD33、CD123、CD22、CD30或其组合的细胞。
32.根据权利要求14所述的方法，其中所述癌症包含乳腺癌、结肠直肠癌、肛门癌、胰腺癌、胆囊癌、胆管癌、头颈癌、鼻咽癌、皮肤癌、黑素瘤、卵巢癌、前列腺癌、尿道癌、肺癌、非小细胞肺癌、小细胞肺癌、脑肿瘤、神经胶质瘤、成神经细胞瘤、食道癌、胃癌、肝癌、肾癌、膀胱癌、宫颈癌、子宫内膜癌、甲状腺癌、眼癌、肉瘤、骨癌、白血病、骨髓瘤或淋巴瘤。
33.根据权利要求14的方法，其中所述癌症是CD19阳性的。
34.根据权利要求14所述的方法，还包含在向所述受试者施用所述治疗组合物之后施用有效量的治疗剂。
35.根据权利要求34所述的方法，其中所述治疗剂包含单克隆抗体、多特异性抗体、化疗剂、酶、蛋白质、共刺激剂、细胞凋亡敏化剂、肿瘤血管破裂剂或其组合。
36.根据权利要求35所述的方法，其中所述共刺激因子被配置为增加所述受试者中细胞毒性T细胞的量。
37.一种治疗组合物，其包含细胞毒性细胞、GNC蛋白和治疗细胞，
其中所述GNC蛋白包含细胞毒性结合部分和癌症靶向部分，其中所述细胞毒性结合部分对细胞毒性细胞受体具有特异性，其中所述癌症靶向部分对癌细胞受体具有特异性，并且其中所述细胞毒性结合部分被配置为通过与所述细胞毒性细胞受体的结合活化所述细胞毒性细胞，
其中所述治疗细胞包含通过与所述细胞毒性细胞受体的结合相互作用与所述细胞毒性细胞结合的GNC蛋白，以及
其中所述治疗细胞组合物基本上不含外源病毒和非病毒DNA和RNA。
38.根据权利要求37所述的治疗组合物，其中所述癌症靶向部分对B细胞具有特异性，并且所述治疗组合物基本上不含B细胞。
39.根据权利要求37所述的治疗组合物，其还包含第二GNC蛋白、第二治疗细胞或其组合，其中所述第二治疗细胞包含与所述细胞毒性细胞或所述第一治疗细胞结合的所述第二GNC蛋白。
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