CN110799538B - 抗cd3抗体及其制备和使用方法 - Google Patents

抗cd3抗体及其制备和使用方法 Download PDF

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CN110799538B
CN110799538B CN201880038306.2A CN201880038306A CN110799538B CN 110799538 B CN110799538 B CN 110799538B CN 201880038306 A CN201880038306 A CN 201880038306A CN 110799538 B CN110799538 B CN 110799538B
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奥勒·奥尔森
菲尔·谭
夏冬
大卫·耶利曼
布莱恩·科瓦切维奇
比尔·布雷迪
布莱尔·伦肖
高泽人
朱义
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Seattle Immunization Co
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Abstract

本申请提供了抗CD3单克隆抗体、其抗原结合部分、其治疗组合物和/或编码其的核酸，以及它们在治疗癌症和其他T细胞功能障碍中激活CD3+T细胞以增强细胞介导的免疫应答的用途。

Description

抗CD3抗体及其制备和使用方法
相关申请的交叉引用
本申请要求于2017年8月27日提交的美国临时专利申请No.62551032的权益，其全部内容通过引用明确地并入本文。
技术领域
本公开一般涉及抗体技术领域，更具体地涉及抗CD3抗体的制备和使用。
背景技术
癌症是全世界的主要健康问题。仅在美国，据估计，2016年就诊断出了1,685,210例新癌症病例，并有595,690例死亡(http:/www.cancer.gov)。因此，任何可降低癌症严重性或死亡率的药剂都是理想的。
在免疫系统中，通过由抗原呈递细胞(APC)呈递的外源抗原肽通过T细胞受体(TCR)递送的初级信号，可以活化静息T细胞以应答抗原。除了该初级信号之外，还存在进一步影响T细胞应答的次级正、负共刺激信号。完全T细胞活化需要次级正信号(Lafferty等人，Ausl.J.Exp.Biol.Med.Sci.5327-42(1975))。负的次级信号可导致T细胞抑制和耐受。
分化簇3(CD3)T细胞共受体有助于激活细胞毒性T细胞(CD8+初始T细胞)和T辅助细胞(CD4+初始T细胞)。它由蛋白质复合物组成并且由四条不同的链组成。在哺乳动物中，复合物含有CD3γ链、CD3δ链和两条CD3ε链。这些链与称为T细胞受体(TCR)和ζ链(zeta-chain)的分子结合以在T淋巴细胞中产生激活信号。TCR、ζ链和CD3分子一起构成TCR复合物。
因为T细胞活化需要CD3，所以靶向CD3的单克隆抗体(mAb)(例如，奥昔珠单抗(otelixizumab)、foralumab)作为1型糖尿病和其他自身免疫疾病的免疫抑制疗法进行研究。然而，尚不清楚特异性抗CD3 mAb是否能激活CD3+T细胞，从而增加宿主对癌性肿瘤的免疫应答。
发明内容
本发明尤其提供了抗CD3单克隆抗体、其抗原结合部分、其治疗组合物和/或编码其的核酸，以及它们在治疗癌症和其他T细胞功能障碍中激活CD3+T细胞并因此增强细胞介导的免疫应答的用途。在一个实施方案中，提供了特异性结合人CD3的分离的单克隆抗体(mAb)或其抗原结合片段。
在一个实施方案中，分离的mAb或抗原结合片段包含与SEQ ID NO:4、SEQ ID NO:8、SEQ ID NO:12、SEQ ID NO:16、SEQ ID NO:20、SEQ ID NO:24、SEQ ID NO:28、SEQ ID NO:32、SEQ ID NO:36、SEQ ID NO:40、SEQ ID NO:44、SEQ ID NO:48、SEQ ID NO:52、SEQ IDNO:56、SEQ ID NO:60、SEQ ID NO:64、SEQ ID NO:68或SEQ ID NO:72具有百分比同源性的氨基酸序列。在一个实施方案中，同源性百分比不小于70％、75％、80％、90％、95％、98％或99％。
在一个实施方案中，分离的mAb或抗原结合片段对CD3具有Kd不大于30nM、40nM或50nM的结合亲和力。在一个实施方案中，分离的mAb或抗原结合片段对CD3具有Kd不大于60nM的结合亲和力。在一个实施方案中，分离的mAb或抗原结合片段对CD3具有Kd不大于70nM的结合亲和力。在一个实施方案中，分离的mAb或抗原结合片段对CD3具有Kd不大于80nM的结合亲和力。在一个实施方案中，分离的mAb或抗原结合片段对CD3具有Kd不大于100nM的结合亲和力。
在一些实施方案中，分离的mAb或抗原结合片段可以表现出一种或多种功能特性，包括例如与CD3的高亲和力结合、增强T细胞活化、刺激抗体应答、逆转免疫抑制细胞的抑制功能或其组合。在一个实施方案中，分离的mAb或抗原结合片段可通过T细胞增殖、IFN-γ和/或IL-2分泌或其组合增强T细胞活化。在一个实施方案中，分离的mAb或抗原结合片段可以逆转T调节细胞的抑制功能。
在一些实施方案中，分离的mAb或抗原结合片段可包括人构架区。在一个实施方案中，分离的mAb或抗原结合片段可以包括人源化抗体、嵌合抗体或重组抗体。
在一个实施方案中，分离的mAb或抗原结合片段可以是属于IgG家族的抗体。在一个实施方案中，分离的mAb是IgG。在一个实施方案中，分离的mAb或抗原结合片段可以包括抗原结合片段，包括例如Fv、Fab、F(ab')2、scFV或scFV2片段。
在一个实施方案中，分离的mAb或抗原结合片段可以是双特异性抗体、三特异性抗体或多特异性抗体。
在一个实施方案中，分离的mAb或抗原结合片段可包括IgG1重链，其包含与SEQ IDNO:7、SEQ ID NO:15、SEQ ID NO:23、SEQ ID NO:31、SEQ ID NO:39、SEQ ID NO:47、SEQ IDNO:55、SEQ ID NO:63或SEQ IID NO:71具有百分比同源性的氨基酸序列。在一个实施方案中，同源性百分比不小于70％、75％、80％、90％、95％、98％或99％。
在一个实施方案中，分离的mAb或抗原结合片段可包括κ轻链，其包含与SEQ IDNO:3、SEQ ID NO:11、SEQ ID NO:19、SEQ ID NO:27、SEQ ID NO:35、SEQ ID NO:43、SEQ IDNO:51、SEQ ID NO:59或SEQ ID NO:67具有百分比同源性的氨基酸序列。在一个实施方案中，同源性百分比不小于70％、75％、80％、90％、95％、98％或99％。
在一个实施方案中，分离的mAb或抗原结合片段可包括可变轻链，其包含与SEQ IDNO:4、SEQ ID NO:12、SEQ ID NO:20、SEQ ID NO:28、SEQ ID NO:36、SEQ ID NO:44、SEQ IDNO:52、SEQ ID NO:60或SEQ ID NO:68具有至少70％、80％、90％、95％、98％或99％同一性的氨基酸序列。
在一个实施方案中，分离的mAb或抗原结合片段可包括可变重链，其包含与SEQ IDNO:8、SEQ ID NO:16、SEQ ID NO:24、SEQ ID NO:32、SEQ ID NO:40、SEQ ID NO:48、SEQ IDNO:56、SEQ ID NO:64或SEQ ID NO:72具有百分比同源性的氨基酸序列。在一个实施方案中，同源性百分比不小于70％、75％、80％、90％、95％、98％或99％。
本申请还提供了编码本文公开的氨基酸序列、分离的mAb或抗原结合片段的核酸序列。在一个实施方案中，分离的核酸编码IgG1重链，其与SEQ ID NO:5、SEQ ID NO:13、SEQID NO:21、SEQ ID NO:29、SEQ ID NO:37、SEQ ID NO:45、SEQ ID NO:53、SEQ ID NO:61或SEQ ID NO:69具有百分比同源性；κ轻链包含SEQ ID NO:1、SEQ ID NO:9、SEQ ID NO:17、SEQ ID NO:25、SEQ ID NO:33、SEQ ID NO:41、SEQ ID NO:49、SEQ ID NO:57或SEQ ID NO:65。在一个实施方案中，分离的核酸编码可变轻链，其与SEQ ID NO:2、SEQ ID NO:10、SEQID NO:18、SEQ ID NO:26、SEQ ID NO:34、SEQ ID NO:42、SEQ ID NO:50、SEQ ID NO:58或SEQ ID NO:66具有百分比同源性。在一个实施方案中，分离的核酸编码可变重链，其与SEQID NO:6、SEQ ID NO:14、SEQ ID NO:22、SEQ ID NO:30、SEQ ID NO:38、SEQ ID NO:46、SEQID NO:54、SEQ ID NO:62或SEQ ID NO:70具有百分比同源性。在一个实施方案中，同源性百分比不小于70％、75％、80％、90％、95％、98％或99％。
本申请还提供了含有本文公开的核酸序列的表达载体。在一个实施方案中，载体可在细胞中表达。在一个实施方案中，表达载体编码本文公开的分离的mAb或抗原结合片段。
在一个实施方案中，本文所述的表达载体可存在于细胞中并可表达。在一个实施方案中，本文所述的表达载体可存在于宿主细胞中并可表达。在一个实施方案中，提供了包含表达载体的宿主细胞，其中表达载体包含本文公开的核酸。宿主细胞可以是原核细胞或真核细胞。
提供了产生本文公开的抗体的方法。在一个实施方案中，所述方法包括以下步骤；提供含有可在宿主细胞中表达的表达载体的宿主细胞，该表达载体包含本文公开的核酸序列；以通过表达上述核酸序列产生抗体。
本申请还提供了免疫缀合物。在一个实施方案中，免疫缀合物包括与药物单元缀合的分离的mAb或其抗原结合片段。在一些实施方案中，药物单元通过接头与分离的mAb或抗原结合片段连接。
接头可以是共轭键。接头可以是可切割的或不可切割的。在一个实施方案中，接头是化学接头。在一个实施方案中，接头包含共价键，例如酯键、醚键、胺键、酰胺键、二硫键、酰亚胺键、砜键、磷酸键(phosphate bond)、磷酸酯键(phosphorus ester bond)、肽键、腙键或其组合。在一个实施方案中，接头包含疏水性聚(乙二醇)接头。在一个实施方案中，接头包含肽键。
在一个实施方案中，提供了免疫缀合物，其包含药物单元和特异性结合人CD3的分离的mAb或抗原结合片段。在一个实施方案中，免疫缀合物中的药物单元可以是化疗剂、生长抑制剂、毒素或放射性同位素。在一个实施方案中，药物单元可以是卡利奇霉素(calicheamicin)类药物单元、抗有丝分裂剂、毒素或放射性同位素。在一个实施方案中，药物单元包括卡利奇霉素类药物单元。卡利奇霉素类药物的实例包括奥佐米星(ozogamicin)。在一个实施方案中，药物单元包含抗有丝分裂剂。抗有丝分裂剂的实例包括单甲基澳瑞他汀E(monomethyl auristatin E)。在一个实施方案中，药物单元包含美坦新(emtansine，DM1)。
在一个实施方案中，药物单元选自细胞毒性剂、免疫调节剂、显像剂或其组合。在一个实施方案中，细胞毒性剂选自生长抑制剂或选自微管蛋白结合剂、DNA嵌入剂、DNA烷化剂、酶抑制剂、免疫调节剂、抗代谢剂、放射性同位素的化疗剂，或其组合。在一个实施方案中，细胞毒性剂选自卡利奇霉素、奥佐米星、单甲基澳瑞他汀E、美坦新(emtansine)、其衍生物或其组合。在一个实施方案中，免疫调节剂激活或抑制免疫细胞、T细胞、NK细胞、B细胞、巨噬细胞或树突细胞。
在一个实施方案中，成像剂可以是放射性核素、荧光剂、量子点或其组合。
本申请还提供了药物组合物。在一个实施方案中，药物组合物可包括本文公开的分离的mAb或抗原结合片段和药学上可接受的载体。在一个实施方案中，药物组合物可包括本文公开的免疫缀合物和药学上可接受的载体。
在一个实施方案中，药物组合物还包括放射性同位素、放射性核素、毒素、治疗剂、化疗剂、卡利奇霉素类药物单元、抗有丝分裂剂、放射性同位素、治疗剂或其组合。在一个实施方案中，治疗剂可包括抗体、酶、化疗剂、生长抑制剂或其组合。
本申请还提供了治疗患有癌症的受试者的方法。在一个实施方案中，该方法包括向受试者施用有效量的本文公开的分离的mAb或抗原结合片段的步骤。在一个实施方案中，分离的mAb或抗原结合片段特异性结合人CD3。
在一个实施方案中，治疗患有癌症的受试者的方法可包括将治疗剂与有效量的对人CD3具有结合特异性的分离的mAb或抗原结合片段共同施用。在一些实施方案中，治疗剂可以是抗体、化疗剂、酶或其组合。在一些实施方案中，治疗剂可以是卡培他滨、顺铂、曲妥珠单抗、氟维司群、他莫昔芬、来曲唑、依西美坦、阿那曲唑、氨鲁米特、睾内酯、伏氯唑、福美坦、法倔唑、来曲唑、埃罗替尼、拉法替尼、达沙替尼、吉非替尼、伊马替尼、帕唑帕尼(pazopanib)、拉帕替尼、舒尼替尼、尼洛替尼、索拉非尼、nab-紫杉醇、奥佐米星、单甲基奥瑞他汀E、美坦新(DM1)、其衍生物或组合。
可以使用公开的组合物、分离的mAb或抗原结合片段治疗多种癌症。在一个实施方案中，癌症可包括表达CD3的细胞。可以治疗的癌症的实例包括但不限于乳腺癌、结肠直肠癌、胰腺癌、头颈癌、黑色素瘤、卵巢癌、前列腺癌、非小细胞肺癌、神经胶质瘤、食管癌、鼻咽癌、肛门癌、直肠癌、胃癌、膀胱癌、宫颈癌或脑癌。
接受治疗的受试者可以是人。本申请还提供了包含有效浓度的特异性结合人CD3的分离的mAb或抗原结合片段的溶液。在一个实施方案中，溶液是受试者的血浆。
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。
应当理解，这些附图仅描绘了根据本公开安排的多个实施方案，并且因此不应被认为是对其范围的限制，将通过使用附图以额外的特性和细节来描述本公开，在附图中：
图1显示了用人或食蟹猴CD3免疫NZW兔(新西兰白兔)的策略；
图2显示了免疫前后兔血清中例如人和食蟹猴CD3γ/ε或CD3δ-εFc特异性IgG的分析；
图3总结了通过FACS筛选BCC上清液中结合人和食蟹猴T细胞的兔IgG以及总结了人CD3+T细胞的活化；
图4显示了示例性嵌合兔/人IgG抗体与食蟹猴CD3δ、γ或εFc融合蛋白和人T细胞系Jurkat的结合；
图5显示了示例性嵌合兔/人CD3特异性抗体与人T细胞系Jurkat结合的FACS分析；
图6显示了示例性嵌合兔/人CD3特异性抗体与人T细胞系Jurkat结合的FACS分析；
图7显示了示例性嵌合兔/人CD3特异性抗体对人CD3+T细胞的活化；以及
图8显示了示例性嵌合兔/人或人源化CD3特异性抗体的结合和解离速率分析。
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。在详细描述、附图和权利要求中描述的说明性实施方案并不意味着是限制性的。可利用其他实施方案，且可作出其他改变，而不背离本文所呈现的主题的精神或范围。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。
本申请尤其提供了分离的抗体、制备此类抗体、双特异性或多特异性分子、由此类抗体或抗原结合片段组成的抗体-药物缀合物和/或免疫缀合物、以及含有此类抗体、双特异性或多特异性分子、抗体-药物缀合物和/或免疫缀合物的药物组合物的方法，以及使用这些抗体、缀合物或组合物治疗癌症的方法。
在一方面，本申请提供了与人CD3结合的分离的单克隆抗体或其片段。抗体或其片段可以表现出一种或多种期望的功能特性，包括但不限于与CD3的高亲和力结合、与人T细胞系Jurkat结合的能力、增强人CD3+T细胞活化(包括增殖、IFN-γ和/或IL-2分泌)的能力、刺激抗体应答的能力和/或逆转免疫抑制细胞的抑制功能的能力，例如T调节细胞。抗体或其片段可衍生自特异性重链和轻链氨基酸序列和/或结构特征，例如由本文公开的特异性氨基酸序列组成的互补决定区(CDR)。
在一些实施方案中，通过用人CD3δ-εFc(“杵臼结构”(Knobs-into-hole)-KnH)和γ-εFc(KnH)融合蛋白或用人或食蟹猴“CD3复合物”(α和βT细胞受体，γ、δ和ε辅助链)瞬时转染的HEK293细胞免疫兔子产生抗体。已知兔子产生高亲和力、多样性和特异性的抗体(Weber等人，Exp.Mol.Med.49:e305，其全部内容通过引用并入本文)。体外培养来自免疫动物的B细胞并筛选产生抗CD3抗体。使用重组DNA技术分离抗体可变基因，重组表达所得抗体，并进一步筛选所需特征，例如结合人和食蟹猴CD3δ、γ或εFc融合蛋白、结合人T细胞系Jurkat和食蟹猴T细胞系HSC-F的能力，以及活化纯化的人CD3+T细胞的能力。这种抗体发现的一般方法类似于Seeber等人描述的方法，PLOS One.9:e86184(2014)，其全部内容通过引用并入本文。
术语“抗体”以最广泛的意义使用，具体包括单一单克隆抗体(包括激动剂和拮抗剂抗体)、具有多表位特异性的抗体组合物、以及抗体片段(例如Fab、F(ab')2和Fv)，只要它们表现出所需的生物活性。在一些实施方案中，抗体可以是单克隆抗体、多克隆抗体、嵌合抗体、单链抗体、双特异性抗体或双效抗体，以及人源化抗体及其活性片段。与已知抗原结合的分子的活性片段的实例包括Fab、F(ab')2、scFv和Fv片段，以及Fab免疫球蛋白表达文库的产物和任何上述抗体和片段的表位结合片段。在一些实施方案中，抗体可以包括免疫球蛋白分子和免疫球蛋白分子的免疫活性部分，即含有对抗原具有免疫结合特异性的结合位点的分子。免疫球蛋白可以是任何类型(IgG、IgM、IgD、IgE、IgA和IgY)或类别(IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或免疫球蛋白分子的亚类。在一个实施方案中，抗体可以是完整抗体和衍生自该完整抗体的任何抗原结合片段。典型的抗体是指典型地包含两条重(H)链和两条轻链的异四聚体蛋白。每条重链由重链可变区(缩写为VH)和重链恒定区组成。每条轻链由轻链可变区(缩写为VL)和轻链恒定区组成。VH和VL区可进一步细分为超变互补决定区(CDR)的结构域和称为构架区(FR)的更为保守的区域。每个可变区(VH或VL)通常由三个CDR和四个FR组成，按以下顺序排列：从氨基末端到羧基末端的FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。在轻链和重链的可变区内存在与抗原相互作用的结合区。
本文所用的术语“单克隆抗体”是指从基本上同质的抗体群体中获得的抗体，即包含该群体的单个抗体是相同的，除了可能以少量存在的天然存在的突变。单克隆抗体是针对单个抗原位点高度特异性的。此外，与通常包括针对不同决定簇(表位)的不同抗体的常规(多克隆)抗体制剂相反，每种单克隆抗体针对抗原上的单一决定簇(表位)。除了它们的特异性之外，单克隆抗体的优点在于它们由杂交瘤培养物制备，不被其他免疫球蛋白污染。修饰语“单克隆”表明抗体的特征是从基本上同质的抗体群体获得的，而不是被解释为需要通过任何特定方法产生抗体。例如，根据本公开内容使用的单克隆抗体可以通过首先由Kohler&Milstein,Nature,256:495(1975)描述的杂交瘤方法制备，其全部内容通过引用并入本文，或者可以通过重组DNA方法制备(参见，例如，美国专利No.4,816,567，其全部内容通过引用并入本文)。
单克隆抗体可以使用各种方法产生，包括小鼠杂交瘤或噬菌体展示(参见Siegel.Transfus.Clin.Biol.9:15-22(2002)，其全部内容通过引用并入本文)或直接来自原代B细胞的抗体的分子克隆(参见Tiller.新型生物技术(NewBiotechnol).28:453-7(2011)，其全部内容通过引用并入本文)。
在一些实施方案中，单克隆抗体可包括“嵌合”抗体(免疫球蛋白)，其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源，而链的其余部分与衍生自另一物种或属于另一抗体类别或亚类的抗体以及这些抗体的片段中的相应序列相同或同源，只要它们表现出所需的生物活性(美国专利No.4,816,567(Cabilly等人)；和Morrison等人，Proc.Natl.Acad.Sci.USA,81:6851-6855)。
术语“抗原或表位结合部分或片段”是指能够结合抗原(例如CD3)的抗体片段。这些片段可以具有完整抗体的抗原结合功能和其他功能。结合片段的实例包括但不限于单链Fv片段(scFv)或Fab片段，其中单链Fv片段由通过合成接头连接的单条多肽链中的抗体单臂的VL和VH结构域组成，Fab片段是由VL、恒定轻链(CL)、VH和恒定重链1(CH1)结构域组成的单价片段。抗体片段可以是甚至更小的亚片段并且可以由与单个CDR结构域一样小的结构域组成。在一个实施方案中，单个CDR结构域可以是来自VL和/或VH结构域的CDR3区域(例如，参见Beiboer等人，J.Mol.Biol.296:833-49(2000)，其全部内容通过引用并入本文)。使用本领域技术人员已知的常规方法产生抗体片段。可以使用与全抗体相同的技术筛选抗体片段的效用。
“抗原或表位结合部分或片段”可以通过多种本领域已知的技术衍生自本公开的抗体。例如，可以用酶如胃蛋白酶裂解纯化的单克隆抗体，并进行HPLC凝胶过滤。然后可收集含有Fab片段的适当级分并通过膜过滤等进行浓缩。关于分离抗体活性片段的一般技术的进一步描述，参见例如Khaw,B.A.等人，J.Nucl.Med.23:1011-1019(1982)；Rousseaux等人，Methods Enzymology,121:663-69,Academic Press,1986，其全部内容通过引用并入本文。
抗体的胃蛋白酶消化产生两个相同的抗原结合片段，称为“Fab”片段，每个片段具有单个抗原结合位点，和残余“Fc”片段，其名称反映其易于结晶的能力。胃蛋白酶处理产生具有两个抗原结合位点并且仍然能够交联抗原的F(ab')2片段。
Fab片段还可以含有轻链恒定区和重链第一恒定区(CH1)。Fab'片段与Fab片段的不同之处在于在重链CH1结构域的羧基末端添加了一些残基，包括来自抗体铰链区的一个或多个半胱氨酸。Fab'-SH在本文中是指其中恒定区的半胱氨酸残基带有游离巯基的Fab'。F(ab')2抗体片段最初是成对的Fab'片段，它们之间具有铰链半胱氨酸。本领域已知的抗体片段的其他化学偶联也可用于本申请。
“Fv”是含有完整抗原识别和结合位点的最小抗体片段。该区域由紧密非共价结合的一个重链和一个轻链可变区的二聚体组成。在这种构型中，每个可变区的三个CDR相互作用以限定VH-VL二聚体表面上的抗原结合位点。总起来说，六个CDR赋予抗体抗原结合特异性。然而，即使单个可变结构域(或仅包含对抗原具有特异性的三个CDR的Fv的一半)也具有识别和结合抗原的能力，尽管亲和力低于整个结合位点。
根据其恒定域的氨基酸序列，可以将来自任何脊椎动物的抗体(免疫球蛋白)的“轻链”分为两种明显不同的类型之一，称为κ和λ。
根据其重链恒定区的氨基酸序列，免疫球蛋白可分为不同的类别。免疫球蛋白有五大类别：IgA、IgD、IgE、IgG和IgM，其中一些可以进一步分为亚类(同种型)，例如IgG-1、IgG-2、IgG-3和IgG-4；IgA-1和IgA-2。对应于不同类别免疫球蛋白的重链恒定区分别称为α、δ、ε、γ和μ。不同类别免疫球蛋白的亚基结构和三维构型是众所周知的。
“人源化抗体”是指一类工程化抗体，其CDR衍生自非人供体免疫球蛋白，分子的其余免疫球蛋白衍生部分衍生自一种(或多种)人免疫球蛋白。此外，可以改变框架支持残基以保持结合亲和力。获得“人源化抗体”的方法是本领域技术人员熟知的(参见例如Queen等人，Proc.Natl Acad Sci USA,86:10029-10032(1989),Hodgson等人，Bio/Technology,9:421(1991))。在一个实施方案中，“人源化抗体”可以通过基因工程方法获得，该基因工程方法能够在大型动物例如兔子中产生亲和力成熟的类人多克隆抗体(参见，例如，美国专利No.7,129,084)。
如本文所用，术语“多肽”、“肽”和“蛋白质”是可互换的，并且定义为意指由通过肽键连接的氨基酸组成的生物分子。
除非上下文不适当，本文使用的术语“一个(a、an)”和“该(the)”定义为意指一个或多个并且包括复数。
“分离的”是指不含至少一些其天然存在的组分的生物分子。当用于描述本文公开的各种多肽时，“分离的”是指已经从其表达的细胞或细胞培养物中鉴定和分离和/或回收的多肽。通常，通过至少一个纯化步骤制备分离的多肽。“分离的抗体”是指基本上不含具有不同抗原特异性的其他抗体的抗体。
“重组”是指使用重组核酸技术在外源宿主细胞中产生抗体。
术语“抗原”是指可以在生物体，特别是动物，更特别是包括人在内的哺乳动物中诱导免疫应答的实体或其片段。该术语包括免疫原及其负责抗原性或抗原决定簇的区域。
同样如本文所用，术语“免疫原性”是指引发或增强针对免疫原性剂的抗体、T细胞或其他反应性免疫细胞的产生并有助于人或动物中的免疫应答的物质。当个体针对本公开的施用的免疫原性组合物产生足够的抗体、T细胞和其他反应性免疫细胞以缓和或减轻待治疗的病症时，发生免疫应答。
“特异性结合(specific binding、specifically binds to)”或“特异性针对(specific for)”特定抗原或表位是指与非特异性相互作用显著不同的结合。特异性结合可以例如通过测定与对照分子的结合相比的分子的结合来测量，所述对照分子通常是具有不含结合活性的类似结构的分子。例如，特异性结合可以通过与类似于靶标的对照分子竞争来确定。
对特定抗原或表位的特异性结合可以例如通过抗体对抗原或表位具有至少约10- 4M、至少约10-5M、至少约10-6M、至少约10-7M、至少约10-8M、至少约10-9M、或者至少约10-10M、至少约10-11M、至少约10-12M或更高KD来体现，其中KD是指特定抗体-抗原相互作用的解离速率。通常，与对照分子相比，特异性结合抗原的抗体对于抗原或表位会具有20、50、100、500、1000、5,000、10,000或更多倍的KD。
此外，对于特定抗原或表位的特异性结合可以例如通过抗体对抗原或表位的KA或Ka来体现，该抗体对于抗原或表位的KA或Ka相对于对照至少大20、50、100、500、1000、5,000、10,000或更多倍。其中KA或Ka是指特定抗体-抗原相互作用的结合速率。
两个序列之间的“同源性”通过序列同一性确定。如果相互比较的两个序列长度不同，则序列同一性优选涉及与较长序列的核苷酸残基相同的较短序列的核苷酸残基的百分比。可以使用计算机程序常规地确定序列同一性。在给定序列与本公开的上述序列之间的比较中出现的偏差可以由例如添加、缺失、取代、插入或重组引起。
本申请还提供了包含通过接头与本文公开的mAb或其片段连接的药物单元的免疫缀合物。接头可以是可切割的或不可切割的。在一个实施方案中，接头是化学接头。在一个实施方案中，接头包含共价键，例如酯键、醚键、酰胺键、二硫键、酰亚胺键、砜键、磷酸键、磷酸酯键、肽键或其组合。在一个实施方案中，接头包含疏水性聚(乙二醇)接头。在一个实施方案中，接头包含肽键。
药物单元可以包括化疗剂、生长抑制剂、一类来自卡利奇霉素、抗有丝分裂剂、毒素、放射性同位素、治疗剂或其组合的药物单元。在一个实施方案中，治疗剂包括抗体、化疗剂、酶或其组合。
本申请还提供了药物组合物。在一个实施方案中，药物组合物包含本文公开的mAb或其片段以及药学上可接受的载体。在一个实施方案中，药物组合物包含本文公开的免疫缀合物以及药学上可接受的载体。
抗体及其片段或免疫缀合物可以使用已知技术以生理学上可接受的制剂形式制备，并且其可包含药学上可接受的载体、稀释剂和/或赋形剂。例如，根据本公开的抗体可包括任何功能等效抗体或其功能部分，特别地，包括任何功能等效抗体或其功能部分的单克隆抗体与药学上可接受的载体、稀释剂和/或赋形剂组合以形成治疗组合物。
合适的药物载体、稀释剂和/或赋形剂是本领域熟知的，包括例如磷酸盐缓冲盐溶液、水、乳液如油/水乳液，各种类型的润湿剂、无菌溶液等。在一些实施方案中，可以根据本领域普通技术人员已知的标准方法得到根据本公开的药物组合物的制剂。
根据其预期用途，其他生物活性剂可以存在于本公开的药物组合物中。在一个实施方案中，生物活性剂可以包括卡培他滨、顺铂、曲妥珠单抗、氟维司群、他莫昔芬、来曲唑、依西美坦、阿那曲唑、氨鲁米特、睾内酯、伏氯唑、福美坦、法倔唑、来曲唑、埃罗替尼、拉法替尼、达沙替尼、吉非替尼、伊马替尼、帕唑帕尼(pazopanib)、拉帕替尼、舒尼替尼、尼洛替尼、索拉非尼、nab-紫杉醇、卡利奇霉素、抗有丝分裂剂、单甲基奥瑞他汀E、美坦新、奥佐米星或其衍生物或组合。
在另一方面，本申请提供了使用抗CD3抗体或含有抗CD3抗体的抗原结合部分的其他分子活化人CD3+T细胞来治疗受试者的方法。在一些实施方案中，该方法包括使用抗体刺激保护性自身免疫应答、修饰免疫应答或刺激抗原特异性免疫应答的步骤。在一些实施方案中，该方法包括向受试者施用所公开的组合物以治疗癌症。
在一些实施方案中，该方法包括向需要这种治疗的受试者施用有效量的其公开的药物组合物的步骤。组合物可以以固体、液体或气雾剂的形式以合适的药学有效剂量施用于受试者。固体组合物的实例包括丸剂、乳膏和可植入的剂量单位。丸剂可以口服施用。治疗乳膏可以局部施用。可植入的剂量单位可以局部施用，例如在肿瘤部位施用，或者可以植入用于治疗组合物的系统释放，例如皮下施用。液体组合物的实例包括适于肌内、皮下、静脉内、动脉内注射的制剂，以及用于局部和眼内施用的制剂。气溶胶制剂的实例包括用于向肺部施用的吸入剂制剂。
组合物可以通过标准施用途径施用。通常，组合物可以通过局部、口服、直肠、鼻、皮内、腹膜内或肠胃外(例如静脉内、皮下或肌内)途径施用。
在一个实施方案中，施用可以是肠胃外施用，例如静脉内施用。用于肠胃外施用的制剂包括无菌水性或非水性溶液、悬浮液和乳液。非水溶剂包括但不限于丙二醇、聚乙二醇、植物油如橄榄油和可注射有机酯如油酸乙酯。水性溶剂可以选自水、醇/水溶液、乳液或悬浮液(包括盐水和缓冲介质)。肠胃外载体包括氯化钠溶液、林格氏葡萄糖、葡萄糖和氯化钠、乳酸化林格氏液或不挥发性油。静脉内载体包括流体和营养补充剂、电解质补充剂(例如基于林格氏葡萄糖的那些)等。还可以存在防腐剂，例如抗菌剂、抗氧化剂、螯合剂、惰性气体等。
在一些实施方案中，可以将组合物掺入诸如生物可降解聚合物等缓释基质中，将聚合物植入需要递送的部位附近，例如肿瘤部位。在一个实施方案中，可以使用缓释基质。基质可由通常为可通过酶促或酸/碱水解或通过溶解降解的聚合物的材料制成。一旦插入体内，基质被酶和体液作用。期望通过生物相容性材料选择缓释基质，该生物相容性材料例如脂质体、聚丙交酯(聚丙交酯酸)、聚乙交酯(乙醇酸的聚合物)、聚丙交酯-乙交酯(乳酸和乙醇酸的共聚物)、聚酸酐、聚(原酸)酯、多肽、透明质酸、胶原蛋白、硫酸软骨素、羧酸、脂肪酸、磷脂、多糖、核酸、聚氨基酸、氨基酸(如苯丙氨酸、酪氨酸、异亮氨酸)、多核苷酸、聚乙烯丙烯、聚乙烯吡咯烷酮和硅酮。优选的生物可降解基质是聚丙交酯、聚乙交酯或聚丙交酯-乙交酯(乳酸和乙醇酸的共聚物)其中之一的基质。
药物组合物可进一步包含蛋白质载体，例如血清白蛋白或免疫球蛋白，特别是人源的。在一些实施方案中，蛋白质药物活性物质可以每剂1ng至10mg的量存在。在一些实施方案中，施用方案可以在根据本公开的抗体的0.1g至10mg的范围内，特别地在1.0g至1.0mg的范围内，并且更特别地在1.0g至100g的范围内，落入这些范围内的所有单个数值也是本公开的一部分。如果通过连续输注进行施用，则更合适的剂量可以在0.01g至10mg单位/千克体重/小时的范围内，并且落入这些范围内的所有单个数值也是本公开的一部分。
该方法可包括施用单剂量、以预定时间间隔施用重复剂量以及持续施用预定的时间。本领域普通技术人员众所周知，组合物的剂量将取决于各种因素，例如所治疗的病症、所使用的特定组合物以及其他临床因素，例如患者的体重、大小、性别和一般健康状况、体表面积、待施用的特定化合物或组合物、同时施用的其他药物和施用途径。
术语“治疗有效量”是指当施用于人或动物时引起足以在所述人或动物中产生治疗效果的应答的抗体的量。有效量易于由本领域普通技术人员按照常规方法确定。
组合物可以与包含生物活性物质或化合物的其他组合物组合施用。在一个实施方案中，生物活性物质或化合物可以包括抗氧化应激的化合物、抗凋亡化合物、金属螯合剂、DNA修复抑制剂例如哌仑西平及代谢物3-氨基-1-丙磺酸(3APS)和1,3-丙烷二磺酸盐(1,3PDS)、分泌酶活化剂、β和γ分泌酶抑制剂、tau蛋白、神经递质、β片层破坏剂、抗炎分子、非典型抗精神病药如氯氮平、齐拉西酮、利培酮、阿立哌唑或奥氮平、或胆碱酯酶抑制剂(ChEI)如他克林，利凡斯的明、多奈哌齐和/或加兰他敏以及其他药物和营养补充剂如维生素B12、半胱氨酸、乙酰胆碱的前体、卵磷脂、胆碱、银杏、乙酰基-L-肉碱、艾地苯醌、丙烯基可可碱或黄嘌呤衍生物。
通过参考以下包括在此的具体实施方案的详细描述，可以更容易地理解本公开。尽管已经公开了本发明参照其某些实施方案的具体细节进行描述，并不旨在将这些细节视为对本发明范围的限制。
实施例
实施例1：抗CD3抗体的产生
通过免疫新西兰白兔开发抗人CD3的单克隆抗体。如图1所示，用重组人CD3δ-εFc(“杵臼结构”-KnH)和γ-εFc(KnH)融合蛋白或HEK 293细胞免疫动物并通过皮下注射进行，其中，其中，HEK 293细胞用人或食蟹猴“CD3复合物”(α和βT细胞受体、γ、δ以及ε辅助链)瞬时转染，该复合物与以1：1v/v完全或不完全弗氏佐剂(第1组)或TiterMax Gold(第2组)混合，并交替添加铝胶2％(Alum)和CpG 2007。随后每7天进行一次加强，直到第51天(第1组)或第68天(第2组)。
在第5周，通过ELISA测试来自动物的血清的CD3δ-εFc(“杵臼结构”-KnH)和γ-εFc(KnH)融合蛋白滴度。免疫前，从每只兔获得的血清作为阴性对照。免疫后，再次从每只动物收集血清，并与来自相同动物的免疫前血清比较CD3δ、γ或ε特异性IgG抗体的存在。如图2所示，用人和食蟹猴CD3δ、γ或εFc融合蛋白免疫的所有动物都产生了对人CD3δ-εFc(板1)、人CD3γ-εFc(板2)、食蟹猴CD3δ-εFc(板3)、食蟹猴CD3γ-εFcCD3-Fc融合蛋白特异的可检测滴度的IgG。
用转染人或食蟹猴CD3的细胞免疫的No.2,6235R组中的一只兔子显示血清IgG结合人和食蟹猴CD3δ、γ或εFc融合蛋白，表明特异性针对Fc融合蛋白的δ、γ或ε部分。使用生物素化的食蟹猴CD3δ、γ或εFc融合蛋白富集抗原特异性B细胞，并以有限稀释度接种到多个96孔组织培养板中，并培养9天以使它们分化成浆细胞并分泌抗体。在如下列出的一系列测定中，通过ELISA、流式细胞术(FACS)和功能测定筛选了来自这些浆细胞培养物的上清液中CD3特异性抗体的存在：
1.结合人CD3δ、γ或εFc融合蛋白-检测δ、γ或ε特异性IgG ELISA
2.结合食蟹猴CD3δ、γ或εFc融合蛋白-检测δ、γ或ε特异性IgG ELISA
3.结合人IgG-反筛选检测人IgG Fc特异性IgG ELISA
4.结合人T细胞系Jurkat-检测CD3δ、γ或ε特异性IgG FACS
5.结合食蟹猴T细胞系HSC-F-检测CD3δ、γ或ε特异性IgG FACS
6.与未转染的人胚肾(HEK)293细胞结合-反筛选用于检测在不表达人或食蟹猴CD3δ、γ或ε的细胞上对未知靶标特异的IgG
7.活化纯化的人CD3+T细胞-检测IL-2分泌ELISA
在B细胞培养的第9天，将上清液从B细胞中分离并储存在单独的平板中用于以后的分析。将RNAlater组织储存试剂加入到B细胞培养板中的每个孔中，以保存B细胞中的RNA，用于抗体可变区的RT-PCR扩增。
在筛选BCC上清液如上述第1-3点的结合后，鉴定出含有特异性识别人和食蟹猴CD3ε的IgG的23个孔。然后筛选该组23个孔中结合人和食蟹猴T细胞以及活化人T细胞的结果，如图3所示。
通过ELISA和FACS筛选鉴定这组23个BCC孔具有所需抗体,我们进行了抗体可变区的分子“拯救”。使用简并引物通过多重RT-PCR扩增轻链和重链可变区序列，所述简并引物设计为与兔IgG和兔κ序列的前导序列和恒定区退火。
使用含有限制性位点的嵌套引物分别对轻链和重链进行第二次PCR。将来自可变重链PCR的扩增子克隆到含有人IgG1的表达载体中。将轻链扩增子克隆到含有人IgK的表达载体中。测序并分析所得克隆。
将从各孔产生的重链和轻链表达质粒瞬时共转染以产生兔/人嵌合抗体。使用Fortebio Octt Red 96仪器上的生物层干涉测量分析，证实重组抗体上清液含有食蟹猴CD3δ、γ或ε特异性的抗体。使用抗人Fc生物传感器(Pall Fortebio)捕获上清液中的抗体。通过将生物传感器置于含有重组人ROR1胞外结构域蛋白的孔中，通过实时干涉测量法观察与食蟹猴CD3δ、γ或ε的缔合。在将生物传感器转移到含有10X动力学缓冲液(PallFortebio)的孔中之后测量解离。制造商提供的软件用于分析干涉测量数据。
图4显示了22种重组嵌合兔/人IgG抗体的初级BCC筛选数据和相应筛选数据的总结。从最初的23个BCC孔拯救22个嵌合抗体，6个显示与食蟹猴CD3δ/εFc融合蛋白结合，6个中的5个显示与食蟹猴CD3γ/εFc融合蛋白结合，5个中的4个显示与人T细胞系Jurkat结合(图5和图4)。
用结合来自兔6235R的IgG+B细胞的食蟹猴CD3δ、γ或εFc融合蛋白，按每孔1个分选到多个96孔组织培养板中进行第二轮B细胞培养，并培养9天以使它们分化成浆细胞并分泌抗体。通过ELISA、流式细胞术(FACS)和功能性分析筛选来自这些浆细胞培养物的上清液中CD3特异性抗体的存在，如以上列表所示。如图6所示，测试5个嵌合兔/人抗体与人T细胞系Jurkat的结合，且5个中的3个显示结合。
来自第一BCC4嵌合兔/人抗体和来自第二BCC3嵌合兔/人抗体显示与人T细胞系Jurkat的结合总共有7种。分析这7种抗体和2种另外的非结合抗体对人CD3+T细胞的活化。如图7所示，测试的9种抗体中有7种激活人CD3+T细胞，其中6种强烈激活人CD3+T细胞，284A10、295E9、299F6、480A7、480C8、485H6。
上述6种嵌合兔/人IgG抗体的重链可变区和轻链可变区是人源化的。6种中的3种人源化变体通过八位位组分析(octet analysis)显示出与人CD3δ/εFc和/或γ/εFc融合蛋白相似的结合动力学，其总结于图8中。
序列表
SEQ ID NO:1
284A10嵌合轻链全长核苷酸序列
GATGTCGTGATGACCCAGACTCCTCCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACGAAGCATCCAAACTGGCATCTGGGGTCCCATCGCGGTTCAGTGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGTGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGCACCGAGGTGGAGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
SEQ ID NO:2
284A10嵌合轻链可变轻链核苷酸序列
GATGTCGTGATGACCCAGACTCCTCCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACGAAGCATCCAAACTGGCATCTGGGGTCCCATCGCGGTTCAGTGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGTGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGCACCGAGGTGGAGTTCAAA
SEQ ID NO:3
284A10嵌合轻链全长氨基酸序列。人κ恒定结构域用下划线标出
DVVMTQTPPSVSAAVGGTVTIKCQASESISSWLAWYQQKPGQPPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISDLECADAATYYCQGYFYFISRTYVNSFGGGTEVEFKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:4
284A10嵌合轻链可变轻链氨基酸序列。互补决定区用下划线标出
DVVMTQTPPSVSAAVGGTVTIKCQASESISSWLAWYQQKPGQPPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISDLECADAATYYCQGYFYFISRTYVNSFGGGTEVEFK
SEQ ID NO:5
284A10嵌合重链全长核苷酸序列
CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACGCCCCTGACACTCACCTGCACAGTCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGTTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGAGGACTCGGCCACCTATTTCTGTGCCAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCCAGGCACCCTCGTCACCGTCTCGAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT
SEQ ID NO:6
284A10嵌合重链可变重链核苷酸序列
CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACGCCCCTGACACTCACCTGCACAGTCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGTTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGAGGACTCGGCCACCTATTTCTGTGCCAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCCAGGCACCCTCGTCACCGTCTCGAGC
SEQ ID NO:7
284A10嵌合重链全长氨基酸序列。人γ-1恒定结构域用下划线标出
QSLEESGGRLVTPGTPLTLTCTVSGFTISTNAMSWVRQVPGKGLEWIGVITGRDITYYASWAKGRFTISKTSSTTVDLKMTSLTAEDSATYFCARDGGSSAITSNNIWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO:8
284A10嵌合重链可变重链氨基酸序列。互补决定区用下划线标出
QSLEESGGRLVTPGTPLTLTCTVSGFTISTNAMSWVRQVPGKGLEWIGVITGRDITYYASWAKGRFTISKTSSTTVDLKMTSLTAEDSATYFCARDGGSSAITSNNIWGPGTLVTVSS
SEQ ID NO:9
299F6嵌合轻链全长核苷酸序列
GATGTCGTGATGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACGAAGCATCCAAACTGGCATCTGGGGTCCCATCGCGGTTCAGTGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCTATTTTTATTTTATTAGTCGTAGTTATGTGAATGCTTTCGGCGGAGGGACCGAGGTGGGGGTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
SEQ ID NO:10
299F6嵌合轻链可变轻链核苷酸序列
GATGTCGTGATGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACGAAGCATCCAAACTGGCATCTGGGGTCCCATCGCGGTTCAGTGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCTATTTTTATTTTATTAGTCGTAGTTATGTGAATGCTTTCGGCGGAGGGACCGAGGTGGGGGTCAAA
SEQ ID NO:11
299F6嵌合轻链全长氨基酸序列。人κ恒定结构域用下划线标出
DVVMTQTPSSVSAAVGGTVTINCQASESISSWLAWYQQKPGQPPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISDLECADAATYYCQGYFYFISRSYVNAFGGGTEVVFKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:12
299F6嵌合轻链可变轻链氨基酸序列。互补决定区用下划线标出
DVVMTQTPSSVSAAVGGTVTINCQASESISSWLAWYQQKPGQPPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISDLECADAATYYCQGYFYFISRSYVNAFGGGTEVVFK
299F6嵌合重链全长核苷酸序列
CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACGCCCCTGACACTCACCTGCACAGTCTCTGGATTCACCATCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGAGGACTCGGCCACCTATTTCTGTGCCAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCCAGGGACCCTGGTCACCGTCTCGAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT
SEQ ID NO:14
299F6嵌合重链可变重链核苷酸序列
CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACGCCCCTGACACTCACCTGCACAGTCTCTGGATTCACCATCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGAGGACTCGGCCACCTATTTCTGTGCCAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCCAGGGACCCTGGTCACCGTCTCGAGC
SEQ ID NO:15
299F6嵌合重链全长氨基酸序列。人γ-1恒定结构域用下划线标出
QSLEESGGRLVTPGTPLTLTCTVSGFTISSNAMSWVRQAPGKGLEWIGVITGRDITYYANWAKGRFTISKTSSTTVDLKMTSLTAEDSATYFCARDGGSSAITSNNIWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO:16
299F6嵌合重链可变重链氨基酸序列。互补决定区用下划线标出
QSLEESGGRLVTPGTPLTLTCTVSGFTISSNAMSWVRQAPGKGLEWIGVITGRDITYYANWAKGRFTISKTSSTTVDLKMTSLTAEDSATYFCARDGGSSAITSNNIWGPGTLVTVSS
SEQ ID NO:17
480C8嵌合轻链全长核苷酸序列
GATGTCGTGATGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACGAAGCATCCAAACTGGCATCTGGGGTCCCATCGCGGTTCAGTGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATGCTTTCGGCGGAGGGACCGAGGTGGAGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
SEQ ID NO:18
480C8嵌合轻链可变轻链核苷酸序列
GATGTCGTGATGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACGAAGCATCCAAACTGGCATCTGGGGTCCCATCGCGGTTCAGTGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATGCTTTCGGCGGAGGGACCGAGGTGGAGTTCAAA
SEQ ID NO:19
480C8嵌合轻链全长氨基酸序列。人κ恒定结构域用下划线标出
DVVMTQTPSSVSAAVGGTVTINCQASESISSWLAWYQQKPGQPPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISDLECADAATYYCQGYFYFISRTYVNAFGGGTEVEFKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:20
480C8嵌合轻链可变轻链氨基酸序列。下划线部分是互补决定区
DVVMTQTPSSVSAAVGGTVTINCQASESISSWLAWYQQKPGQPPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISDLECADAATYYCQGYFYFISRTYVNAFGGGTEVEFK
SEQ ID NO:21
480C8嵌合重链全长核苷酸序列
CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACGCCCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGAGGACTCGGCCACCTATTTCTGTGCCAGAGACGGTGGTTCTTCTGCTATTAATAGTAAGAACATTTGGGGCCAAGGCACCCTGGTCACCGTCTCGAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT
SEQ ID NO:22
480C8嵌合重链可变重链核苷酸序列
CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACGCCCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGAGGACTCGGCCACCTATTTCTGTGCCAGAGACGGTGGTTCTTCTGCTATTAATAGTAAGAACATTTGGGGCCAAGGCACCCTGGTCACCGTCTCGAGC
SEQ ID NO:23
480C8嵌合重链全长氨基酸序列。人γ-1恒定结构域用下划线标出
QSLEESGGRLVTPGTPLTLTCTVSGIDLSSNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISKTSSTTVDLKMTSLTAEDSATYFCARDGGSSAINSKNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNG
KEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO:24
480C8嵌合重链可变重链氨基酸序列。互补决定区用下划线标出
QSLEESGGRLVTPGTPLTLTCTVSGIDLSSNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISKTSSTTVDLKMTSLTAEDSATYFCARDGGSSAINSKNIWGQGTLVTVSS
SEQ ID NO:25
295E9嵌合轻链全长核苷酸序列
GATGTCGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACAATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAGACCAGGGCAGCCTCCCAAACTCCTGATCTACGAAGCATCCAAACTGGCGTCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAGGCTATTTTTATTTTATTAGTCGTAGTTATGTAAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
SEQ ID NO:26
295E9嵌合轻链可变轻链核苷酸序列
GATGTCGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACAATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAGACCAGGGCAGCCTCCCAAACTCCTGATCTACGAAGCATCCAAACTGGCGTCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAGGCTATTTTTATTTTATTAGTCGTAGTTATGTAAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAA
SEQ ID NO:27
295E9嵌合轻链全长氨基酸序列。人κ恒定结构域用下划线标出
DVVMTQTPASVEAAVGGTVTINCQASESISSWLAWYQQRPGQPPKLLIYEASKLASGVPSRFKGSGSGTEFTLTISDLECADAATYYCQGYFYFISRSYVNAFGGGTEVVVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:28
295E9嵌合轻链可变轻链氨基酸序列。互补决定区用下划线标出
DVVMTQTPASVEAAVGGTVTINCQASESISSWLAWYQQRPGQPPKLLIYEASKLASGVPSRFKGSGSGTEFTLTISDLECADAATYYCQGYFYFISRSYVNAFGGGTEVVVK
SEQ ID NO:29
295E9嵌合重链全长核苷酸序列
CAGTCACTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTAGTAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATTAATTACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGAGGACTCGGCCACCTATTTCTGTGCCAGAGACGGTGGTTCTTCTGCTATTACTAGTAAGAACATTTGGGGCCCAGGCACCCTGGTCACCGTCTCGAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT
SEQ ID NO:30
295E9嵌合重链可变重链核苷酸序列
CAGTCACTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTAGTAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATTAATTACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGAGGACTCGGCCACCTATTTCTGTGCCAGAGACGGTGGTTCTTCTGCTATTACTAGTAAGAACATTTGGGGCCCAGGCACCCTGGTCACCGTCTCGAGC
SEQ ID NO:31
295E9嵌合重链全长氨基酸序列。人γ-1恒定结构域用下划线标出
QSLEESGGRLVTPGTPLTLTCTVSGIDLSSNAMSWVRQAPGKGLEWIGVITGRDINYYASWAKGRFTISKTSSTTVDLKMTSLTAEDSATYFCARDGGSSAITSKNIWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO:32
295E9嵌合重链可变重链氨基酸序列。互补决定区用下划线标出
QSLEESGGRLVTPGTPLTLTCTVSGIDLSSNAMSWVRQAPGKGLEWIGVITGRDINYYASWAKGRFTISKTSSTTVDLKMTSLTAEDSATYFCARDGGSSAITSKNIWGPGTLVTVSS
SEQ ID NO:33
480A7嵌合轻链全长核苷酸序列
GATGTCGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAGACCAGGGCAGCCTCCCAAGCTCCTGATCTACGAAGCATCCAAACTGGCATCTGGGGTCCCATCGCGGTTCAGTGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAGGGCTATTTTTATTTTATTAGTCGTAGTTATGTAAATGCTTTCGGCGGAGGGACCGAGGTGGTGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
SEQ ID NO:34
480A7嵌合轻链可变轻链核苷酸序列
GATGTCGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAGACCAGGGCAGCCTCCCAAGCTCCTGATCTACGAAGCATCCAAACTGGCATCTGGGGTCCCATCGCGGTTCAGTGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAGGGCTATTTTTATTTTATTAGTCGTAGTTATGTAAATGCTTTCGGCGGAGGGACCGAGGTGGTGTTCAAA
SEQ ID NO:35
480A7嵌合轻链全长氨基酸序列。人κ恒定结构域用下划线标出
DVVMTQTPASVEAAVGGTVTINCQASESISSWLAWYQQRPGQPPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISDLECADAATYYCQGYFYFISRSYVNAFGGGTEVVFKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:36
480A7嵌合轻链可变轻链氨基酸序列。互补决定区用下划线标出
DVVMTQTPASVEAAVGGTVTINCQASESISSWLAWYQQRPGQPPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISDLECADAATYYCQGYFYFISRSYVNAFGGGTEVVFK
SEQ ID NO:37
480A7嵌合重链全长核苷酸序列
CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGAGGACTCGGCCACCTATTTCTGTGCCAGAGACGGTGGTTCTTCTGCTATTACTAGTAAGAACATTTGGGGCCCGGGCACCCTGGTCACCGTCTCGAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT
SEQ ID NO:38
480A7嵌合重链可变重链核苷酸序列
CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACG
GTGGATCTGAAAATGACCAGTCTGACAGCCGAGGACTCGGCCACCTATTTCTGTGCCAGAGACGGTGGTTCTTCTGCTATTACTAGTAAGAACATTTGGGGCCCGGGCACCCTGGTCACCGTCTCGAGC
SEQ ID NO:39
480A7嵌合重链全长氨基酸序列。人γ-1恒定结构域用下划线标出
QSLEESGGRLVTPGTPLTLTCTVSGIDLSSNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISKTSSTTVDLKMTSLTAEDSATYFCARDGGSSAITSKNIWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO:40
480A7嵌合重链可变重链氨基酸序列。互补决定区用下划线标出
QSLEESGGRLVTPGTPLTLTCTVSGIDLSSNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISKTSSTTVDLKMTSLTAEDSATYFCARDGGSSAITSKNIWGPGTLVTVSS
SEQ ID NO:41
485H6嵌合轻链全长核苷酸序列
GATGTCGTGATGACCCAGACTCCAGCCTCCGTGTCTGAACCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGAGCATTAATAGTAATGTAGCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTATGATTCATCCACTCTGGAATCTGGGGTCCCATCGCGGTTCAAAGGCAGTAGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCCGCCACTTACTACTGTCAATGTAGTAGTTATGGTAGTAGTTATGTTGGTGGTTTCGGCGGAGGGACCGAGGTGGTGTTCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
SEQ ID NO:42
485H6嵌合轻链可变轻链核苷酸序列
GATGTCGTGATGACCCAGACTCCAGCCTCCGTGTCTGAACCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGAGCATTAATAGTAATGTAGCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTATGATTCATCCACTCTGGAATCTGGGGTCCCATCGCGGTTCAAAGGCAGTAGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCCGCCACTTACTACTGTCAATGTAGTAGTTATGGTAGTAGTTATGTTGGTGGTTTCGGCGGAGGGACCGAGGTGGTGTTCAAA
SEQ ID NO:43
485H6嵌合轻链全长氨基酸序列。人κ恒定结构域用下划线标出
DVVMTQTPASVSEPVGGTVTIKCQASESINSNVAWYQQKPGQRPKLLIYDSSTLESGVPSRFKGSRSGTEFTLTISDLECADAATYYCQCSSYGSSYVGGFGGGTEVVFKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:44
485H6嵌合轻链可变轻链氨基酸序列。用下划线标出了复杂度确定区域
DVVMTQTPASVSEPVGGTVTIKCQASESINSNVAWYQQKPGQRPKLLIYDSSTLESGVPSRFKGSRSGTEFTLTISDLECADAATYYCQCSSYGSSYVGGFGGGTEVVFK
SEQ ID NO:45
485H6嵌合重链全长核苷酸序列
CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATGCCCAGTCTGACAGCCGAGGACTCGGCCACCTATTTCTGTGCCAGAGACGGTGGTTCTTCTGCTATTACTAGTAAGAACATTTGGGGCCAGGGGACCCTCGTCACCGTCTCGAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT
SEQ ID NO:46
485H6嵌合重链可变重链核苷酸序列
CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATGCCCAGTCTGACAGCCGAGGACTCGGCCACCTATTTCTGTGCCAGAGACGGTGGTTCTTCTGCTATTACTAGTAAGAACATTTGGGGCCAGGGGACCCTCGTCACCGTCTCGAGC
SEQ ID NO:47
485H6嵌合重链全长氨基酸序列。人γ-1恒定结构域用下划线标出
QSLEESGGRLVTPGTPLTLTCTVSGIDLSSNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISKTSSTTVDLKMPSLTAEDSATYFCARDGGSSAITSKNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO:48
485H6嵌合重链可变重链氨基酸序列。互补决定区用下划线标出QSLEESGGRLVTPGTPLTLTCTVSGIDLSSNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISKTSSTTVDLKMPSLTAEDSATYFCARDGGSSAITSKNIWGQGTLVTVSS
SEQ ID NO:49
284A10人源化轻链全长核苷酸序列
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
SEQ ID NO:50
284A10人源化轻链可变轻链核苷酸序列
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAG
CATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
SEQ ID NO:51
284A10人源化轻链全长氨基酸序列。人κ恒定结构域用下划线标出
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:52
284A10人源化轻链可变轻链氨基酸序列。互补决定区用下划线标出
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIK
SEQ ID NO:53
284A10人源化重链全长核苷酸序列
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT
284A10人源化重链可变重链核苷酸序列
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
SEQ ID NO:55
284A10人源化重链全长氨基酸序列。人γ-1恒定结构域用下划线标出
EVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO:56
284A10人源化重链可变重链氨基酸序列。互补决定区用下划线标出
EVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSS
SEQ ID NO:57
299F6人源化轻链全长核苷酸序列
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTAGTTATGTAAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
SEQ ID NO:58
299F6人源化轻链可变轻链核苷酸序列
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTAGTTATGTAAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
SEQ ID NO:59
299F6人源化轻链全长氨基酸序列。人κ恒定结构域用下划线标出
DIQMTQSPSTLSASVGDRVTITCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRSYVNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:60
299F6人源化轻链可变轻链氨基酸序列。互补决定区用下划线标出
DIQMTQSPSTLSASVGDRVTITCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRSYVNAFGGGTKVEIK
SEQ ID NO:61
299F6人源化重链全长核苷酸序列
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAACTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGG
TGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT
SEQ ID NO:62
299F6人源化重链可变重链核苷酸序列
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAACTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
SEQ ID NO:63
299F6人源化重链全长氨基酸序列。人γ-1恒定结构域用下划线标出
EVQLVESGGGLVQPGGSLRLSCAASGFTISSNAMSWVRQAPGKGLEWIGVITGRDITYYANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO:64
299F6人源化重链可变重链氨基酸序列。互补决定区用下划线标出
EVQLVESGGGLVQPGGSLRLSCAASGFTISSNAMSWVRQAPGKGLEWIGVITGRDITYYANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSS
SEQ ID NO:65
480C8人源化轻链全长核苷酸序列
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACC
TACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
SEQ ID NO:66
480C8人源化轻链可变轻链核苷酸序列
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
SEQ ID NO:67
480C8人源化轻链全长氨基酸序列。人κ恒定结构域用下划线标出
DIQMTQSPSTLSASVGDRVTITCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:68
480C8人源化轻链可变轻链氨基酸序列。互补决定区用下划线标出
DIQMTQSPSTLSASVGDRVTITCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNAFGGGTKVEIK
SEQ ID NO:69
480C8人源化重链全长核苷酸序列
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCGACCTCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTAATAGTAAGAACATTTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAAC
AGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT
SEQ ID NO:70
480C8人源化重链可变重链核苷酸序列
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCGACCTCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTAATAGTAAGAACATTTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
SEQ ID NO:71
480C8人源化重链全长氨基酸序列。人γ-1恒定结构域用下划线标出
EVQLVESGGGLVQPGGSLRLSCAASGIDLSSNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAINSKNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO:72
480C8人源化重链可变重链氨基酸序列。互补决定区用下划线标出
EVQLVESGGGLVQPGGSLRLSCAASGIDLSSNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAINSKNIWGQGTLVTVSS
序列表
<110> 西雅图免疫公司
成都百利多特生物药业有限责任公司
<120> 抗CD3抗体及其制备和使用方法
<130> SIBA009PCT
<140> 2018800383062
<141> 2018-06-22
<150> US 62/551,032
<151> 2017-08-28
<160> 72
<170> SIPOSequenceListing 1.0
<210> 1
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 1
gatgtcgtga tgacccagac tcctccctcc gtgtctgcag ctgtgggagg cacagtcacc 60
atcaagtgcc aggccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggcagcctc ccaagctcct gatctacgaa gcatccaaac tggcatctgg ggtcccatcg 180
cggttcagtg gcagtggatc tgggacagag ttcactctca ccatcagtga cctggagtgt 240
gccgatgctg ccacttacta ctgtcaaggc tatttttatt ttattagtcg tacttatgta 300
aattctttcg gcggaggcac cgaggtggag ttcaaacgta 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> 2
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 2
gatgtcgtga tgacccagac tcctccctcc gtgtctgcag ctgtgggagg cacagtcacc 60
atcaagtgcc aggccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggcagcctc ccaagctcct gatctacgaa gcatccaaac tggcatctgg ggtcccatcg 180
cggttcagtg gcagtggatc tgggacagag ttcactctca ccatcagtga cctggagtgt 240
gccgatgctg ccacttacta ctgtcaaggc tatttttatt ttattagtcg tacttatgta 300
aattctttcg gcggaggcac cgaggtggag ttcaaa 336
<210> 3
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 3
Asp Val Val Met Thr Gln Thr Pro Pro Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro 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 Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala 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 Glu Val Glu Phe 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> 4
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 4
Asp Val Val Met Thr Gln Thr Pro Pro Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro 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 Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala 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 Glu Val Glu Phe Lys
100 105 110
<210> 5
<211> 1341
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 5
cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacgcccct gacactcacc 60
tgcacagtct ctggattcac catcagtacc aatgcaatga gctgggtccg ccaggttcca 120
gggaaggggc tggagtggat cggagtcatt actggtcgtg atatcacata ctacgcgagc 180
tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240
accagtctga cagccgagga ctcggccacc tatttctgtg ccagagacgg tggttcttct 300
gctattacta gtaacaacat ttggggccca ggcaccctcg tcaccgtctc gagcgctagc 360
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aagccgcggg ggcaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcgcgg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg t 1341
<210> 6
<211> 354
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 6
cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacgcccct gacactcacc 60
tgcacagtct ctggattcac catcagtacc aatgcaatga gctgggtccg ccaggttcca 120
gggaaggggc tggagtggat cggagtcatt actggtcgtg atatcacata ctacgcgagc 180
tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240
accagtctga cagccgagga ctcggccacc tatttctgtg ccagagacgg tggttcttct 300
gctattacta gtaacaacat ttggggccca ggcaccctcg tcaccgtctc gagc 354
<210> 7
<211> 447
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 7
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Thr Ile Ser Thr Asn Ala
20 25 30
Met Ser Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Thr Ser Leu Thr Ala Glu Asp Ser Ala Thr Tyr Phe Cys Ala Arg Asp
85 90 95
Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp Gly Pro Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 8
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 8
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Thr Ile Ser Thr Asn Ala
20 25 30
Met Ser Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Thr Ser Leu Thr Ala Glu Asp Ser Ala Thr Tyr Phe Cys Ala Arg Asp
85 90 95
Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp Gly Pro Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 9
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 9
gatgtcgtga tgacccagac tccatcctcc gtgtctgcag ctgtgggagg cacagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggcagcctc ccaagctcct gatctacgaa gcatccaaac tggcatctgg ggtcccatcg 180
cggttcagtg gcagtggatc tgggacagag ttcactctca ccatcagcgg cgtgcagtgt 240
gacgatgctg ccacttacta ctgtcaaggc tatttttatt ttattagtcg tagttatgtg 300
aatgctttcg gcggagggac cgaggtgggg gtcaaacgta 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> 10
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 10
gatgtcgtga tgacccagac tccatcctcc gtgtctgcag ctgtgggagg cacagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggcagcctc ccaagctcct gatctacgaa gcatccaaac tggcatctgg ggtcccatcg 180
cggttcagtg gcagtggatc tgggacagag ttcactctca ccatcagcgg cgtgcagtgt 240
gacgatgctg ccacttacta ctgtcaaggc tatttttatt ttattagtcg tagttatgtg 300
aatgctttcg gcggagggac cgaggtgggg gtcaaa 336
<210> 11
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 11
Asp Val Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr 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 Gln Pro 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 Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Ser Tyr Val Asn Ala Phe Gly Gly Gly Thr Glu Val Val Phe 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> 12
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 12
Asp Val Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr 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 Gln Pro 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 Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Ser Tyr Val Asn Ala Phe Gly Gly Gly Thr Glu Val Val Phe Lys
100 105 110
<210> 13
<211> 1341
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 13
cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacgcccct gacactcacc 60
tgcacagtct ctggattcac catcagtagc aatgcaatga gctgggtccg ccaggctcca 120
gggaaggggc tggagtggat cggagtcatt actggtcgtg atatcacata ctacgcgaac 180
tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240
accagtctga cagccgagga ctcggccacc tatttctgtg ccagagacgg tggttcttct 300
gctattacta gtaacaacat ttggggccca gggaccctgg tcaccgtctc gagcgctagc 360
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aagccgcggg ggcaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcgcgg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg t 1341
<210> 14
<211> 354
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 14
cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacgcccct gacactcacc 60
tgcacagtct ctggattcac catcagtagc aatgcaatga gctgggtccg ccaggctcca 120
gggaaggggc tggagtggat cggagtcatt actggtcgtg atatcacata ctacgcgaac 180
tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240
accagtctga cagccgagga ctcggccacc tatttctgtg ccagagacgg tggttcttct 300
gctattacta gtaacaacat ttggggccca gggaccctgg tcaccgtctc gagc 354
<210> 15
<211> 447
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 15
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Thr Ile Ser Ser Asn Ala
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Asn Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Thr Ser Leu Thr Ala Glu Asp Ser Ala Thr Tyr Phe Cys Ala Arg Asp
85 90 95
Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp Gly Pro Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 16
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 16
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Thr Ile Ser Ser Asn Ala
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Asn Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Thr Ser Leu Thr Ala Glu Asp Ser Ala Thr Tyr Phe Cys Ala Arg Asp
85 90 95
Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp Gly Pro Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 17
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 17
gatgtcgtga tgacccagac tccatcctcc gtgtctgcag ctgtgggagg cacagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggcagcctc ccaagctcct gatctacgaa gcatccaaac tggcatctgg ggtcccatcg 180
cggttcagtg gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240
gccgatgctg ccacttacta ctgtcaaggc tatttttatt ttattagtcg tacttatgta 300
aatgctttcg gcggagggac cgaggtggag ttcaaacgta 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> 18
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 18
gatgtcgtga tgacccagac tccatcctcc gtgtctgcag ctgtgggagg cacagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120
gggcagcctc ccaagctcct gatctacgaa gcatccaaac tggcatctgg ggtcccatcg 180
cggttcagtg gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240
gccgatgctg ccacttacta ctgtcaaggc tatttttatt ttattagtcg tacttatgta 300
aatgctttcg gcggagggac cgaggtggag ttcaaa 336
<210> 19
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 19
Asp Val Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr 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 Gln Pro 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 Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Thr Tyr Val Asn Ala Phe Gly Gly Gly Thr Glu Val Glu Phe 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> 20
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 20
Asp Val Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr 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 Gln Pro 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 Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Thr Tyr Val Asn Ala Phe Gly Gly Gly Thr Glu Val Glu Phe Lys
100 105 110
<210> 21
<211> 1341
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 21
cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacgcccct gacactcacc 60
tgcacagtct ctggaatcga cctcagtagc aatgcaatga gctgggtccg ccaggctcca 120
gggaaggggc tggagtggat cggagtcatt actggtcgtg atatcacata ctacgcgagc 180
tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240
accagtctga cagccgagga ctcggccacc tatttctgtg ccagagacgg tggttcttct 300
gctattaata gtaagaacat ttggggccaa ggcaccctgg tcaccgtctc gagcgctagc 360
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aagccgcggg ggcaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcgcgg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg t 1341
<210> 22
<211> 354
<212> DNA
<213> Artificial Sequence
<220>
<223> sunthesized
<400> 22
cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacgcccct gacactcacc 60
tgcacagtct ctggaatcga cctcagtagc aatgcaatga gctgggtccg ccaggctcca 120
gggaaggggc tggagtggat cggagtcatt actggtcgtg atatcacata ctacgcgagc 180
tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240
accagtctga cagccgagga ctcggccacc tatttctgtg ccagagacgg tggttcttct 300
gctattaata gtaagaacat ttggggccaa ggcaccctgg tcaccgtctc gagc 354
<210> 23
<211> 447
<212> PRT
<213> Artificial Sequence
<220>
<223> sunthesized
<400> 23
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Asn Ala
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Thr Ser Leu Thr Ala Glu Asp Ser Ala Thr Tyr Phe Cys Ala Arg Asp
85 90 95
Gly Gly Ser Ser Ala Ile Asn Ser Lys Asn Ile Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 24
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 24
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Asn Ala
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Thr Ser Leu Thr Ala Glu Asp Ser Ala Thr Tyr Phe Cys Ala Arg Asp
85 90 95
Gly Gly Ser Ser Ala Ile Asn Ser Lys Asn Ile Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 25
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 25
gatgtcgtga tgacccagac tccagcctcc gtggaggcag ctgtgggagg cacagtcaca 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagagacca 120
gggcagcctc ccaaactcct gatctacgaa gcatccaaac tggcgtctgg ggtcccatcg 180
cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240
gccgatgctg ccacttacta ctgtcaaggc tatttttatt ttattagtcg tagttatgta 300
aatgctttcg gcggagggac cgaggtggtg gtcaaacgta 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> 26
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 26
gatgtcgtga tgacccagac tccagcctcc gtggaggcag ctgtgggagg cacagtcaca 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagagacca 120
gggcagcctc ccaaactcct gatctacgaa gcatccaaac tggcgtctgg ggtcccatcg 180
cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240
gccgatgctg ccacttacta ctgtcaaggc tatttttatt ttattagtcg tagttatgta 300
aatgctttcg gcggagggac cgaggtggtg gtcaaa 336
<210> 27
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 27
Asp Val Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Ser Tyr Val Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val 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> 28
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 28
Asp Val Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Ser Tyr Val Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 29
<211> 1341
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 29
cagtcactgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60
tgcacagtct ctggaatcga cctcagtagt aatgcaatga gctgggtccg ccaggctcca 120
gggaaggggc tggagtggat cggagtcatt actggtcgtg atattaatta ctacgcgagc 180
tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240
accagtctga cagccgagga ctcggccacc tatttctgtg ccagagacgg tggttcttct 300
gctattacta gtaagaacat ttggggccca ggcaccctgg tcaccgtctc gagcgctagc 360
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aagccgcggg ggcaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcgcgg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg t 1341
<210> 30
<211> 354
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 30
cagtcactgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60
tgcacagtct ctggaatcga cctcagtagt aatgcaatga gctgggtccg ccaggctcca 120
gggaaggggc tggagtggat cggagtcatt actggtcgtg atattaatta ctacgcgagc 180
tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240
accagtctga cagccgagga ctcggccacc tatttctgtg ccagagacgg tggttcttct 300
gctattacta gtaagaacat ttggggccca ggcaccctgg tcaccgtctc gagc 354
<210> 31
<211> 447
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 31
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Asn Ala
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Val Ile Thr Gly Arg Asp Ile Asn Tyr Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Thr Ser Leu Thr Ala Glu Asp Ser Ala Thr Tyr Phe Cys Ala Arg Asp
85 90 95
Gly Gly Ser Ser Ala Ile Thr Ser Lys Asn Ile Trp Gly Pro Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 32
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthesized
<400> 32
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Asn Ala
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Val Ile Thr Gly Arg Asp Ile Asn Tyr Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Thr Ser Leu Thr Ala Glu Asp Ser Ala Thr Tyr Phe Cys Ala Arg Asp
85 90 95
Gly Gly Ser Ser Ala Ile Thr Ser Lys Asn Ile Trp Gly Pro Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 33
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 33
gatgtcgtga tgacccagac tccagcctcc gtggaggcag ctgtgggagg cacagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagagacca 120
gggcagcctc ccaagctcct gatctacgaa gcatccaaac tggcatctgg ggtcccatcg 180
cggttcagtg gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240
gccgatgctg ccacttacta ctgtcagggc tatttttatt ttattagtcg tagttatgta 300
aatgctttcg gcggagggac cgaggtggtg ttcaaacgta 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> 34
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 34
gatgtcgtga tgacccagac tccagcctcc gtggaggcag ctgtgggagg cacagtcacc 60
atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagagacca 120
gggcagcctc ccaagctcct gatctacgaa gcatccaaac tggcatctgg ggtcccatcg 180
cggttcagtg gcagtggatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240
gccgatgctg ccacttacta ctgtcagggc tatttttatt ttattagtcg tagttatgta 300
aatgctttcg gcggagggac cgaggtggtg ttcaaa 336
<210> 35
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 35
Asp Val Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Pro 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 Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Ser Tyr Val Asn Ala Phe Gly Gly Gly Thr Glu Val Val Phe 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> 36
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 36
Asp Val Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Pro 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 Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Ser Tyr Val Asn Ala Phe Gly Gly Gly Thr Glu Val Val Phe Lys
100 105 110
<210> 37
<211> 1341
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 37
cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60
tgcacagtct ctggaatcga cctcagtagc aatgcaatga gctgggtccg ccaggctcca 120
gggaaggggc tggagtggat cggagtcatt actggtcgtg atatcacata ctacgcgagc 180
tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240
accagtctga cagccgagga ctcggccacc tatttctgtg ccagagacgg tggttcttct 300
gctattacta gtaagaacat ttggggcccg ggcaccctgg tcaccgtctc gagcgctagc 360
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aagccgcggg ggcaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcgcgg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg t 1341
<210> 38
<211> 354
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 38
cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60
tgcacagtct ctggaatcga cctcagtagc aatgcaatga gctgggtccg ccaggctcca 120
gggaaggggc tggagtggat cggagtcatt actggtcgtg atatcacata ctacgcgagc 180
tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240
accagtctga cagccgagga ctcggccacc tatttctgtg ccagagacgg tggttcttct 300
gctattacta gtaagaacat ttggggcccg ggcaccctgg tcaccgtctc gagc 354
<210> 39
<211> 447
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 39
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Asn Ala
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Thr Ser Leu Thr Ala Glu Asp Ser Ala Thr Tyr Phe Cys Ala Arg Asp
85 90 95
Gly Gly Ser Ser Ala Ile Thr Ser Lys Asn Ile Trp Gly Pro Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 40
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 40
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Asn Ala
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Thr Ser Leu Thr Ala Glu Asp Ser Ala Thr Tyr Phe Cys Ala Arg Asp
85 90 95
Gly Gly Ser Ser Ala Ile Thr Ser Lys Asn Ile Trp Gly Pro Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 41
<211> 651
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 41
gatgtcgtga tgacccagac tccagcctcc gtgtctgaac ctgtgggagg cacagtcacc 60
atcaagtgcc aggccagtga gagcattaat agtaatgtag cctggtatca gcagaaacca 120
gggcagcgtc ccaagctcct gatctatgat tcatccactc tggaatctgg ggtcccatcg 180
cggttcaaag gcagtagatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240
gccgatgccg ccacttacta ctgtcaatgt agtagttatg gtagtagtta tgttggtggt 300
ttcggcggag ggaccgaggt ggtgttcaaa 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> 42
<211> 330
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 42
gatgtcgtga tgacccagac tccagcctcc gtgtctgaac ctgtgggagg cacagtcacc 60
atcaagtgcc aggccagtga gagcattaat agtaatgtag cctggtatca gcagaaacca 120
gggcagcgtc ccaagctcct gatctatgat tcatccactc tggaatctgg ggtcccatcg 180
cggttcaaag gcagtagatc tgggacagag ttcactctca ccatcagcga cctggagtgt 240
gccgatgccg ccacttacta ctgtcaatgt agtagttatg gtagtagtta tgttggtggt 300
ttcggcggag ggaccgaggt ggtgttcaaa 330
<210> 43
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 43
Asp Val Val Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly
1 5 10 15
Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Asn Ser Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ser Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Lys Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Tyr Val Gly Gly Phe Gly Gly Gly Thr Glu Val Val Phe 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> 44
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 44
Asp Val Val Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly
1 5 10 15
Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Asn Ser Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ser Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Lys Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asp Leu Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Cys Ser Ser Tyr Gly Ser Ser
85 90 95
Tyr Val Gly Gly Phe Gly Gly Gly Thr Glu Val Val Phe Lys
100 105 110
<210> 45
<211> 1341
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 45
cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60
tgcacagtct ctggaatcga cctcagtagc aatgcaatga gctgggtccg ccaggctcca 120
gggaaggggc tggagtggat cggagtcatt actggtcgtg atatcacata ctacgcgagc 180
tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240
cccagtctga cagccgagga ctcggccacc tatttctgtg ccagagacgg tggttcttct 300
gctattacta gtaagaacat ttggggccag gggaccctcg tcaccgtctc gagcgctagc 360
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aagccgcggg ggcaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcgcgg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg t 1341
<210> 46
<211> 354
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 46
cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60
tgcacagtct ctggaatcga cctcagtagc aatgcaatga gctgggtccg ccaggctcca 120
gggaaggggc tggagtggat cggagtcatt actggtcgtg atatcacata ctacgcgagc 180
tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240
cccagtctga cagccgagga ctcggccacc tatttctgtg ccagagacgg tggttcttct 300
gctattacta gtaagaacat ttggggccag gggaccctcg tcaccgtctc gagc 354
<210> 47
<211> 447
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 47
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Asn Ala
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Pro Ser Leu Thr Ala Glu Asp Ser Ala Thr Tyr Phe Cys Ala Arg Asp
85 90 95
Gly Gly Ser Ser Ala Ile Thr Ser Lys Asn Ile Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 48
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 48
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Asn Ala
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Pro Ser Leu Thr Ala Glu Asp Ser Ala Thr Tyr Phe Cys Ala Arg Asp
85 90 95
Gly Gly Ser Ser Ala Ile Thr Ser Lys Asn Ile Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 49
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 49
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> 50
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 50
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 atcaaa 336
<210> 51
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 51
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> 52
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 52
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> 53
<211> 1347
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 53
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccatcagt accaatgcaa tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg gatcggagtc attactggtc gtgatatcac atactacgcg 180
agctgggcga aaggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agacggtggt 300
tcttctgcta ttactagtaa caacatttgg ggccagggaa ccctggtcac cgtctcgagc 360
gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 660
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaagc cgcgggggca 720
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 900
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960
gagtacaagt gcgcggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 1080
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200
ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 1260
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320
cagaagagcc tctccctgtc tccgggt 1347
<210> 54
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 54
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 cgtctcgagc 360
<210> 55
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 55
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 Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 56
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 56
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> 57
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 57
gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc 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 tagttatgta 300
aatgctttcg 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> 58
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 58
gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc 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 tagttatgta 300
aatgctttcg gcggagggac caaggtggag atcaaa 336
<210> 59
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 59
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Ser Tyr Val Asn Ala 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> 60
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 60
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Ser Tyr Val Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 61
<211> 1347
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 61
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccatcagt agcaatgcaa tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg gatcggagtc attactggtc gtgatatcac atactacgcg 180
aactgggcga aaggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agacggtggt 300
tcttctgcta ttactagtaa caacatttgg ggccagggaa ccctggtcac cgtctcgagc 360
gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 660
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaagc cgcgggggca 720
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 900
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960
gagtacaagt gcgcggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 1080
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200
ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 1260
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320
cagaagagcc tctccctgtc tccgggt 1347
<210> 62
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 62
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccatcagt agcaatgcaa tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg gatcggagtc attactggtc gtgatatcac atactacgcg 180
aactgggcga aaggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agacggtggt 300
tcttctgcta ttactagtaa caacatttgg ggccagggaa ccctggtcac cgtctcgagc 360
<210> 63
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 63
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 Ser Asn
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Asn 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 Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 64
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 64
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 Ser Asn
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Asn 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> 65
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 65
gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc 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
aatgctttcg 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> 66
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 66
gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc 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
aatgctttcg gcggagggac caaggtggag atcaaa 336
<210> 67
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 67
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Thr Tyr Val Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
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> 68
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 68
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser
85 90 95
Arg Thr Tyr Val Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 69
<211> 1347
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 69
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggaat cgacctcagt agcaatgcaa tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg gatcggagtc attactggtc gtgatatcac atactacgcg 180
agctgggcga aaggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agacggtggt 300
tcttctgcta ttaatagtaa gaacatttgg ggccagggaa ccctggtcac cgtctcgagc 360
gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 660
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaagc cgcgggggca 720
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 900
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960
gagtacaagt gcgcggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 1080
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200
ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 1260
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320
cagaagagcc tctccctgtc tccgggt 1347
<210> 70
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> synthesized
<400> 70
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggaat cgacctcagt agcaatgcaa tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg gatcggagtc attactggtc gtgatatcac atactacgcg 180
agctgggcga aaggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agacggtggt 300
tcttctgcta ttaatagtaa gaacatttgg ggccagggaa ccctggtcac cgtctcgagc 360
<210> 71
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 71
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Asp Leu Ser Ser Asn
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Gly Gly Ser Ser Ala Ile Asn Ser Lys Asn Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 72
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 72
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Asp Leu Ser Ser Asn
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Gly Gly Ser Ser Ala Ile Asn Ser Lys Asn Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120

Claims (30)

1.一种对人CD3具有结合特异性的分离的单克隆抗体（mAb）或其抗原结合片段，其中所述分离的mAb或抗原结合片段包含可变轻链氨基酸序列和可变重链氨基酸序列，其中所述可变轻链氨基酸序列包含如下互补决定区（CDR）序列：如QASESISSWLA所示的CDR1氨基酸序列、如EASKLAS所示的CDR2氨基酸序列和如QGYFYFISRTYVNS所示的CDR3氨基酸序列，所述可变重链氨基酸序列包含如下互补决定区序列：如TNAMS所示的CDR1氨基酸序列、如VITGRDITYYASWAKG所示的CDR2氨基酸序列和如DGGSSAITSNNI所示的CDR3氨基酸序列。
2. 根据权利要求1所述的分离的mAb或抗原结合片段，其包含SEQ ID NO:52所示的人源化轻链可变轻链氨基酸序列和SEQ ID NO:56所示的人源化重链可变重链氨基酸序列，或包含SEQ ID NO:4所示的嵌合轻链可变轻链氨基酸序列和SEQ ID NO:8所示的嵌合重链可变重链氨基酸序列， 或包含与上述轻链可变轻链氨基酸序列之一具有同一性不小于98%的轻链可变轻链氨基酸序列和与上述重链可变重链氨基酸序列之一具有同一性不小于98%的重链可变重链氨基酸序列。
3. 根据权利要求2所述的分离的mAb或抗原结合片段，其包含SEQ ID NO:51所示的人源化轻链全长氨基酸序列和SEQ ID NO:55所示的人源化重链全长氨基酸序列，或包含SEQID NO:3所示的嵌合轻链全长氨基酸和SEQ ID NO:7所示的嵌合重链全长氨基酸序列，或包含与上述轻链全长氨基酸序列之一具有同一性不小于98%的轻链全长氨基酸序列和与上述重链全长氨基酸序列之一具有同一性不小于98%的重链全长氨基酸序列。
4.根据权利要求1所述的分离的mAb或抗原结合片段，其对人CD3具有Kd不大于70 nM的结合亲和力。
5.根据权利要求1所述的分离的mAb或其抗原结合片段，其中所述分离的mAb是重组抗体。
6.根据权利要求5所述的分离的mAb或其抗原结合片段，其中所述重组抗体是人源化抗体或嵌合抗体。
7.根据权利要求1所述的分离的mAb或其抗原结合片段，其中所述分离的mAb是IgG。
8.根据权利要求1所述的分离的mAb或其抗原结合片段，其中所述抗原结合片段是Fv、Fab、F(ab')2、scFV或其组合。
9.根据权利要求1所述的分离的mAb或其抗原结合片段，其中所述分离的mAb是双特异性抗体或三特异性抗体。
10.根据权利要求1所述的分离的mAb或其抗原结合片段，其中所述分离的mAb是多特异性抗体。
11.一种分离的核酸，其编码根据权利要求1-10任一项所述的分离的mAb或抗原结合片段。
12.一种包含权利要求11所述的分离的核酸的表达载体。
13.一种包含权利要求11所述的核酸的宿主细胞，其中所述宿主细胞是原核细胞或真核细胞。
14.一种产生抗体的方法，包括培养根据权利要求13所述的宿主细胞以产生抗体。
15.一种免疫缀合物，其包含根据权利要求1-10任一项所述的分离的mAb或其抗原结合片段和药物单元，其中所述药物单元通过接头与所述分离的mAb或抗原结合片段连接，并且其中所述接头包含共价键，该共价键选自酯键、醚键、胺键、酰胺键、二硫键、酰亚胺键、砜键、磷酸键、磷酸酯键、肽键、腙键或其组合。
16.根据权利要求15所述的免疫缀合物，其中所述药物单元包含细胞毒性剂、免疫调节剂、显像剂或其组合。
17.根据权利要求16所述的免疫缀合物，其中所述细胞毒性剂为生长抑制剂。
18.根据权利要求16所述的免疫缀合物，其中所述细胞毒性剂为化疗剂，所述化疗剂选自微管蛋白结合剂、DNA嵌入剂、DNA烷化剂、酶抑制剂、免疫调节剂、抗代谢剂、或其组合。
19.根据权利要求16所述的免疫缀合物，其中所述细胞毒性剂为放射性同位素。
20.根据权利要求16所述的免疫缀合物，其中所述细胞毒性剂选自卡利奇霉素、奥佐米星、单甲基澳瑞他汀E、emtansine或其组合。
21.根据权利要求16所述的免疫缀合物，其中所述显像剂是放射性核素、荧光剂、量子点或其组合。
22.一种药物组合物，其包含根据权利要求1-10任一项所述的分离的mAb或其抗原结合片段和药学上可接受的载体。
23.根据权利要求22所述的药物组合物，其还包含化疗剂、放射性同位素或其组合。
24.根据权利要求23所述的药物组合物，其中所述化疗剂为生长抑制剂。
25.根据权利要求24所述的药物组合物，其中所述生长抑制剂为来自卡利奇霉素类细胞毒性剂、抗有丝分裂剂或其组合。
26.根据权利要求23所述的药物组合物，其中所述化疗剂为毒素。
27.一种药物组合物，其包含权利要求15所述的免疫缀合物和药学上可接受的载体。
28.权利要求1-10任一项所述的分离的mAb或其抗原结合片段在制备治疗患有癌症的受试者的药物中的用途。
29.根据权利要求28所述的用途，其中所述药物还包括治疗剂，其中所述治疗剂包括抗体、化疗剂、酶或其组合。
30.一种包含有效浓度的根据权利要求1-10任一项所述的分离的mAb或其抗原结合片段的溶液，其中所述溶液是受试者的血浆。
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