CN107206074A - 双特异性四价抗体及其制备和使用方法 - Google Patents

双特异性四价抗体及其制备和使用方法 Download PDF

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CN107206074A
CN107206074A CN201580073430.9A CN201580073430A CN107206074A CN 107206074 A CN107206074 A CN 107206074A CN 201580073430 A CN201580073430 A CN 201580073430A CN 107206074 A CN107206074 A CN 107206074A
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CN107206074B (zh
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高泽人
朱义
菲尔·谭
布莱尔·伦肖
布莱恩·科瓦切维奇
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Chengdu Bailidote Biological Pharmaceutical Co ltd
Seattle Immunization Co
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Abstract

一种双特异性四价抗体，其包含具有一对重链和一对轻链的IgG，并且两个scFv组分连接至重链或轻链的C端或N端。双特异性四价抗体可以对HER2受体上的两种不同表位具有结合特异性。

Description

双特异性四价抗体及其制备和使用方法
相关专利申请的交叉引用
本申请要求于2014年12月22日提交的题为“BISPECIFIC ANTIBODIES(双特异性抗体)”的美国第62095348号临时申请的优先权，其通过引用整体并入本文。
序列表
与本申请相关的序列表以文本格式提供，代替纸质副本，并通过引用并入说明书中。包含序列表的文本文件名为Sequence Listing_ST25_0003PCT2.txt。文本文件约为164KB，于2015年12月18日创建，并经由EFS-Web提交电子版。
技术领域
本公开总体上涉及抗体的技术领域，更具体地涉及双特异性抗体。
背景技术
HER2是ErbB/HER受体家族的成员，在乳腺和卵巢的几种癌症中过表达和/或失调(King,Kraus and Aaronson,Science 1985；229:974-976；Slamon et al.,Science 1989；244:707-712)。HER2靶向治疗药物已经在临床上成功使用，并已被美国FDA批准。这样的抗体治疗药物包括曲妥珠单抗(Horton,Cancer Control 2001:8(1),103-110)和帕妥珠单抗(Badache and Hynes,Cancer Cell；5(4):299-301)。一些研究表明，与单一抗体单药治疗相比，可以通过组合两种或多种表位不同的抗HER2抗体(诸如曲妥珠单抗和帕妥珠单抗)来实现增强治疗(Kasprzyk et al.,Cancer Res 1992；52:2771-2776,Ben-Kasus et al.,Proc Natl Acad Sci USA,106(9)3294-3329)。结合HER2细胞外结构域4的曲妥珠单抗抑制非配体依赖性信号传导、刺激ADCC、阻断HER2脱落但不抑制HER2二聚化。与细胞外结构域2结合的帕妥珠单抗抑制HER2二聚化和与其他HER家族受体的二聚化，抑制多种配体依赖性HER介导的信号通路并刺激ADCC(O'Sullivan and Connolly,Oncology 2014；28(3):186-194)。
基于单独使用曲妥珠单抗的显著临床益处，FDA已经于2013年批准了曲妥珠单抗和帕妥珠单抗组合治疗HER2阳性转移性癌症作为HER2阳性乳腺癌的新治疗方法，(Baselgaet al.N Engl J Med.2012Jan 12；366(2):109-19)。然而，使用两种或多种单克隆抗体的简单组合的功效是次优的。此外，单独生产两种或多种单克隆抗体的成本高。
因此，需要通过组合单克隆抗体来改善癌症治疗的功效并降低与单克隆抗体生产相关的成本。
发明内容
本公开提供双特异性四价抗体。双特异性四价抗体可以包括两条IgGl重链；两条kappa轻链；以及两个单链Fv(scFv)结构域。两条IgGl重链和kappa轻链可以形成对HER2的第一结构域具有结合特异性的IgG部分。两个scFv结构域可以对HER2的第二结构域具有结合特异性。IgG部分和两个scFv结构域共价连接，作为双特异性四价抗体起作用。从以下结合附图对其优选实施例的详细描述中，本公开的目的和优点可变得显而易见。
附图说明
现在可以参考附图来描述根据本公开的优选实例，其中相同的附图标记表示相同的元件。
图1示出了根据本发明一实例的四价双特异性抗体结构。
图2示出了根据本发明的实例的示例性四价双特异性抗体4X1、4X2、4X3和4X4的功能框图。
图3示出了示例性单特异性抗体4C1和4C2的功能框图。
图4示出了示例性Fc-scFv抗体4C3、4C4、4C5、4C6、4C7、4C8、4C10和4C11的功能框图。
图5示出了SI-4X和SI-4C抗体对BT-474细胞增殖的作用。
图6示出了将连接体长度从10个氨基酸扩展到30个氨基酸对BT-474细胞增殖的作用。
图7示出了将连接体长度扩展到40个氨基酸对BT-474细胞增殖的作用。
图8示出了SI-4X抗体对BT-474细胞上HER2内化的作用。
具体实施方式
本公开提供了双特异性四价抗体。该抗体可以具有同时靶向HER2的细胞外结构域2和4的优点。
必须注意的是，如本文和所附权利要求中所使用的，除非上下文另有明确规定，否则在整个本说明书和权利要求书中，单数形式“一”、“和”以及“该”，词语“包含”或诸如“包含”或“包含……的”将被理解为暗示包含所述整数或整数组，但不排除任何其他整数或整数组，包括复数对象。
“抗体片段”包含完整抗体的一部分，优选是完整抗体的抗原结合区或可变区。抗体片段的实例包括Fv、Fab、Fab'、F(ab')2、Fab'-SH；双抗体；线性抗体(参见美国专利第5,641,870号，实例2；Zapata et al.,Protein Eng.8(10):1057-1062(1995))；单链抗体分子(例如，scFv)。尽管在本说明书中并且在整个说明书中，提及抗体和抗体的各种性质，但是相同的公开内容也适用于功能性抗体片段，例如，双重作用Fab片段。
一方面，双特异性四价抗体可以包括两条IgGl重链；两条kappa轻链；以及两个单链Fv(scFv)结构域。两条IgGl重链和kappa轻链可以形成对HER2的第一结构域具有结合特异性的IgG部分。两个scFv结构域可以对HER2的第二结构域具有结合特异性。每个scFv结构域可以通过具有氨基酸序列(gly-gly-gly-gly-ser)n((G4S)n)的连接体与任一个IgGl重链的C端残基连接。每个scFv结构域可以具有N端-可变重链-接头-可变轻链-C端或N端-可变轻链-接头-可变重链-C端的结构顺序，并且接头可以包括(gly-gly-gly-gly-ser)m((G4S)m)氨基酸序列。n和m均为整数，n可以是至少为2的整数。在一实施例中，n为1至10或2至9。在一些实施例中，n至少为9。在一些实施例中，n为2至20。m可以是至少为2的整数。在一些实施例中，m可以是2、3、4或5。在一些实施例中，m可以是选自2、3、4、5、6、7、8、9和10的整数。
在一些实施例中，IgGl重链或kappa轻链中的至少一个是人源化的或人的。在一些实施例中，两条IgGl重链均是人源化的或人的。在一些实施例中，两条kappa轻链均是人源化的或人的。
在一些实施例中，HER2的结构域独立地选自HER2的结构域2和结构域4。在一些实施例中，双特异性四价抗体可以包括具有经由肽接头连接到重链或轻链的C端或N端的scFv的IgG部分。IgG部分可以对HER2(人表皮生长因子2)表达细胞的细胞外结构域2或4具有结合特异性，而scFv结构域可以分别对HER2表达细胞的胞外域4或2具有结合特异性。结合可以是二价的。
肽接头的长度可能不同。在一些实施例中，肽接头可包括约15至约45个氨基酸。在一些实施例中，肽接头可包括约20至约50个氨基酸。在一些实施例中，肽接头可包括约10至约30个氨基酸。
在一些实施例中，IgG部分可以对HER2的结构域2具有结合特异性。在一些实施例中，scFv结构域可以对HER2的结构域4具有结合特异性。在一些实施例中，IgG部分可以对HER2的结构域4具有结合特异性。在一些实施例中，scFv结构域可以对HER2的结构域2具有结合特异性。
在一些实施例中，IgGl重链中的至少一个或两个包含SEQ ID NO 7、15、30、40、50和58的氨基酸序列或与SEQ ID NO 7、15、30、40、50和58具有至少95％、98％或99％相似性的氨基酸序列。在一些实施例中，IgGl重链、连接体以及scFv结构域具有SEQ ID NO 30、50、40和58的氨基酸序列或与SEQ ID NO 30、50、40和58具有至少95％、98％或99％相似性的氨基酸序列。在一些实施例中，kappa轻链中的至少一个或两个包含SEQ ID NO 3、11、25、35、45和53的氨基酸序列或与SEQ ID NO 3、11、25、35、45和53具有至少95％、98％或99％相似性的氨基酸序列。在一些实施例中，可变轻链中的至少一个或两个包含SEQ ID NO 4、12、26、36、46和54的氨基酸序列或与SEQ ID NO 4、12、26、36、46和54具有至少95％、98％或99％相似性的氨基酸序列。在一些实施例中，可变重链中的至少一个或两个包含SEQ ID NO8、16、31、41、79和59的氨基酸序列或与SEQ ID NO 8、16、31、41、79和59具有至少95％、98％或99％相似性的氨基酸序列。在一些实施例中，至少一个或两个scFv结构域包含SEQ ID NO19、22、32、42、80、60、63、66、69、72、75、78的氨基酸序列或与SEQ ID NO 19、22、32、42、80、60、63、66、69、72、75、78具有至少95％、98％或99％相似性的氨基酸序列。
在一些实施例中，IgG部分可以对HER2的结构域2具有结合特异性，并且scFv结构域可以对HER2的结构域4具有结合特异性。在一实施例中，IgGl重链、连接体以及scFv结构域可以具有SEQ ID NO 30的氨基酸序列或与SEQ ID NO 30具有至少95％相似性的氨基酸序列，并且kappa轻链可以具有SEQ ID NO 25的氨基酸序列或与SEQ ID NO 25具有至少95％相似性的氨基酸序列。在一实施例中，IgGl重链、连接体以及scFv结构域可以具有SEQID NO 50的氨基酸序列或与SEQ ID NO 50具有至少95％相似性的氨基酸序列，并且kappa轻链可以具有SEQ ID NO 45的氨基酸序列或与SEQ ID NO 45具有至少95％相似性的氨基酸序列。
在一些实施例中，IgG部分可以对HER2的结构域4具有结合特异性，并且scFv结构域可以对HER2的结构域2具有结合特异性。在一实施例中，IgGl重链、连接体以及scFv结构域可以具有SEQ ID NO 40的氨基酸序列或与SEQ ID NO 40具有至少95％相似性的氨基酸序列，并且kappa轻链可以具有SEQ ID NO 35的氨基酸序列或与SEQ ID NO 35具有至少95％相似性的氨基酸序列。在一实施例中，IgGl重链、连接体以及scFv结构域可以具有SEQID NO 58的氨基酸序列或与SEQ ID NO 58具有至少95％相似性的氨基酸序列，并且kappa轻链可以具有SEQ ID NO 53的氨基酸序列或与SEQ ID NO 53具有至少95％相似性的氨基酸序列。
双特异性四价抗体具有抑制癌细胞生长的活性。在某些实施例中，本发明的抗体对于其靶标EGRF或HER3的解离常数(Kd)≤80nM、≤50nM、≤30nM、≤20nM、≤10nM或≤0.1nM。抗体可以同时与两个靶标结合。在一些实施例中，抗体可以以小于1nM、10nM、20nM、50nM或100nM的Kd与HER2的结构域2结合。在一些实施例中，抗体可以以小于5nM、10nM、20nM、50nM或100nM的Kd与HER2的结构域4结合。在一些实施例中，抗体可以以小于30nM的Kd与HER2的结构域4结合，并以小于30nM的Kd与HER2的结构域2结合。在一些实施例中，抗体可以以小于50nM的Kd与HER2的结构域4结合，并同时以小于20nM的Kd与HER2的结构域2结合。
在一些实施例中，IgG部分可以为scFv结构域提供稳定性。另外可选地，IgG部分可以提供对表位的特异性。在一些实施例中，双特异性抗体可介导对表达HER2的细胞的ADCC(抗体依赖性细胞介导的细胞毒性)。在一些实施例中，抗体可能能够结合HER2抗原上的至少两个结构域(即表位)。在一些实施例中，抗体可以同时结合HER2抗原上的多个结构域。
在一些实施例中，抗体可以在体外和体内增殖试验中提供比单特异性抗体亲本对照或单特异性抗体亲本对照的组合更强的肿瘤抑制。不希望被理论限制，据信通过对两种不同表位的相同抗原作用，本文公开的双特异性四价抗体可以增强受体(HER2)的内化，并且比单独单特异性抗体或两种单特异性抗体的组合之一更有效地下调信号通路。
在一些实施例中，双特异性四价抗体可抑制癌细胞生长。在一些实施例中，癌细胞可以表达HER2。在一些实施例中，双特异性四价抗体可抑制癌细胞生长。在一些实施例中，癌细胞可以表达HER2+。
在另一方面，本公开提供了编码本文公开的双特异性四价抗体、片段或亚组分的分离的核酸。
在另一方面，本公开提供了具有编码本文公开的双特异性四价抗体、片段或亚组分的分离的核酸的表达载体。载体可在宿主细胞中表达。宿主细胞可以是原核的或真核的。
在另一方面，本公开提供具有本文公开的双特异性四价抗体、片段或亚组分的分离的核酸的宿主细胞，或包括该核酸序列的表达载体。
在另一方面，本公开提供了制备双特异性四价抗体的方法。在一实施例中，该方法可以包括培养上述宿主细胞，使得产生抗体。
在另一方面，本公开提供了免疫交联物，包括本文所述的双特异性四价抗体和细胞毒性剂。
在另一方面，本公开提供了药物组合物。药物组合物可以包括双特异性四价抗体或本文所述的免疫交联物和药学上可接受的载体。在一些实施例中，组合物还可包括放射性同位素、放射性核素、毒素、治疗剂、化学治疗剂或其组合。
在另一方面，本公开提供了治疗癌症患者的方法。在一实施例中，该方法包括对患者施用有效量的本文所述的双特异性四价抗体的步骤。癌症可以包括表达HER2、结构域、表位、片段或其衍生物的细胞。癌症可能是HER2+乳腺癌、结肠直肠癌、卵巢癌、胃癌、食管癌、头颈癌以及非小细胞肺癌。
在一实施例中，该方法还可包括共同施用有效量的治疗剂。治疗剂可以是例如抗体、化疗剂、酶或其组合。在一些实施例中，治疗剂可以是抗雌激素剂，受体酪氨酸抑制剂或其组合。在一些实施例中，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、睾丸酯、伏氯唑、福美斯坦、法倔唑、来曲唑、厄洛替尼、阿法替尼、达沙替尼、吉非替尼、伊马替尼、帕唑帕尼、拉帕替尼、舒尼替尼、尼罗替尼、索拉非尼、白蛋白结合型紫杉醇。在一些实施例中，需要这种治疗的患者是人。在一些实施例中，治疗剂可以是生物制剂。在一些实施例中，治疗剂可以是检查点抑制剂，包括但不限于PDl、PDLl、CTLA4、4-lBB、OX40、GITR、TIM3、LAG 3、TIGIT、CD40、CD27、HVEM、BTLA、VISTA和B7H4。
在一实施例中，本公开提供了通过向患者施用有效量的双特异性四价抗体以抑制HER2受体的生物学活性来治疗患者的方法。
在一实施例中，本公开提供了具有有效浓度的双特异性四价抗体的溶液。在一实施例中，该溶液是患者中的血浆。
双特异性四价抗体的一般结构示意图如图1所示。在一实施例中，双特异性四价抗体包括两条人IgGl重链、两条人kappa轻链以及两个单链Fv(scFv)结构域。两条人IgGl重链和人kappa轻链形成IgG部分。两个scFv结构域分别连接到具有连接体的人IgGl重链的C端残基，该连接体具有gly-gly-gly-gly-ser-重复(也被称为(G4S)n)的氨基酸序列。n可以是整数。在一实施例中，n为2至10。在一些实施例中，n可以是1至15。scFv可以为顺序：N端-可变重链-接头-可变轻链-C端。scFv接头可以包括Gly-gly-gly-gly-ser重复(也被称为(G4S)m)的氨基酸序列。m为整数。例如，m可以是3或4。对于所有构建体，CHI、CH2、CH3和CL氨基酸序列可以相同。有4个双特异性抗体，称为4X1、4X2、4X3和4X4。这些在图2中示出。
每个双特异性四价抗体可以在一端与HER2的细胞外结构域2特异性结合，在另一端与HER2的细胞外结构域4特异性结合。这2种抗-HER2结合结构域分别称为4C1和4C2。结构4X1在双特异性抗体的氨基末端具有常规IgGl/kappa重链和轻链形式的4C1结合结构域，在羧基末端加入4C2作为单链Fv。4X2方向相反，4C2位于氨基末端，4C1为羧基末端单链Fv。存在可以使用这些结合对创建的多种其他类型的双特异性抗体结构，包括接头和连接体序列的改变以及这些结合结构域的可选位置和/或形式。例如，通过将4X1的连接体从(G4S)x2扩展到(G4S)x6可以创建4X3，并且可以通过将4X2的连接体从(G4S)x2扩展到(G4S)x6来创建4X4。
为了研究连接体长度的作用，已经生成了称为4C3、4C4、4C5、4C6、4C7、4C8、4C10和4C11的多个Fc-scFv构建体。4C3包含来自4C1的scFv，而4C4包含来自4C2的scFv。为4C4生成(G4S)x3至(G4S)x8的连接体变体，如图4所示，例如，4C5具有15个氨基酸(G4S)x3的连接体长度，而4C11具有40个氨基酸(G4S)x8的连接体长度。表1示出了不同变体的连接体长度。
表1.变体名称和连接体长度
变体名称 连接体长度
4C4 (G4S)x2
4C5 (G4S)x3
4C6 (G4S)x4
4C7 (G4S)x 5
4C8 (G4S)x 6
4C10 (G4S)x 7
4C11 (G4S)x 8
可变轻链，可变重链和单链Fv(scFv)DNA片段通过基因合成生成。通过基因合成生成人Gamma-1重链和人kappa轻链DNA片段。通过使用限制性位点的DNA连接将片段组装在一起，并克隆到设计用于哺乳动物细胞中瞬时表达的载体中。载体含有强CMV衍生的启动子，以及瞬时表达所需的其他上游和下游元件。通过DNA测序验证所得IgG表达质粒含有预期的DNA序列。按CSH手册所述(CSH Protocols；2008；doi:10.1101/pdb.prot4977)，用线性PEI转染悬浮适应的HEK293F细胞来实现抗体构建体的瞬时表达。简言之，将DNA加入每个含有F17表达培养基的管中，该培养基已在37℃预热，然后加入PEI。在室温下孵育15分钟，并将DNA/PEI混合物加入含有HEK293细胞(在F17完全培养基中HEK293细胞密度为约1x106细胞/ml)的烧瓶中。在37℃下振荡孵育5天，然后将样品离心，收集上清液并在4℃下储存以进行纯化。
需要时使用蛋白质亲和层析和尺寸排阻色谱法从所得转染上清液中纯化抗体。蛋白质质量用Superdex 200柱分析。用于所有试验的蛋白质纯度大于90％。
对HER2两个不同表位特异的双特异性抗体可用于治疗许多HER2表达的癌症，诸如乳腺癌、卵巢癌、胃癌、食道癌、前列腺癌、肺癌以及神经内分泌癌。
在一实施例中，双重特异性抗体具有四价双特异性。其包括IgG和两个scFv，其与单特异性抗体IgG相比提供两种不同的结合特异性。IgG组分提供了优于仅使用scFv(诸如BiTE技术(Lutterbuese et al,Proceedings of the National Academy of Sciences ofthe United States of America107.28(2010):12605-12610.PMC.Web.2Dec.2014)和其他(美国专利第7332585号))的其他双特异性抗体的稳定性。其也能够介导ADCC，而无Fc组分的那些则不能(美国专利第7332585号)。四价双重特异性性质为双特异性抗体提供了优于一些其他双特异性抗体的同时结合能力，其可以一次仅结合一种抗原(Kontermann,MAbs.2012Mar-Apr；4(2):182-97；Schanzer et al,Antimicrob.Agents Chemother.2011,55(5):2369；EP272942)。
为了便于叙述，双特异性抗体的序列或与双特异性抗体相关的序列总结在下面的表2中。
表2.双特异性抗体或与之相关的核苷酸和氨基酸序列的总结
实例
实例1
为了评估抗HER2抗体的生长抑制潜力，测试了对作为乳腺导管癌肿瘤细胞系的BT-474细胞(ATCC HTB-20,Manassas,Va.)增殖的作用。将细胞用含有1％胎牛血清的100μlRPMI-1640培养基以6000细胞/孔的密度接种到96孔组织培养板中。4小时后，以0.0061nM至400nM的不同浓度加入试验抗体。在试验抗体存在下培养细胞7天。向每个孔中加入20μlMTS试剂(Promega,Madison,Wl)，将细胞在37℃下孵育2小时。MTS容易被活跃增殖的细胞吸收，还原成甲腊(其易吸收490nm的光)，然后分泌到培养基中。孵育后，使用BioTek(Winooski,VT)ELx800吸光度读数器测量OD490值。在抗体添加时也以这种方式获得对照细胞(仅用培养基处理)的OD490值，以确立基线代谢活性。可以通过从72小时OD490中减去对照基线OD490来计算增殖。来自抗体滴定的数据根据以下公式以对照群体的百分比表示：对照增殖的百分比＝(试验增殖/对照增殖)*100。
SI-4X1和SI-4X2对BT-474增殖的作用如图5所示。这两种分子均具有抗增殖作用，但两者均不如对照抗体SI-4C2或对照抗体SI-4C1和SI-4C2的组合有效。从SI-4X3可以看出，将C端scFv与hulgG分开的连接体G4S接头的长度从2个重复增加到6个重复增加了功效。怀疑双特异性抗体的较低功效可能是C端scFv提供的促增殖活性的结果。之前有抗-Her2抗体显示出依赖其结构的激动活性的文献。为了研究这一点，我们创建了一系列含有相同抗-Her2scFv的对照分子，但是具有逐渐变长的G4S接头。如图6中所示，抗增殖作用与接头中G4S元件的数量直接成正比，其中SI-4C8(6个重复)显示出最高的抗增殖活性，而SI-4C4(2个重复)则表现出激动活性。当接头增加到7(SI-4C10)和8(SI-4C11)个重复时，该作用甚至更明显，在图7中示出。
实例2
测试抗-Her2抗体被BT-474细胞内化的能力。使1mg等分试样的抗体标准PBS溶液与Alexa Fluor 488羧酸、TFP酯(Thermo Fisher#A-10235,Waltham,MA)在室温下反应1小时。使用Bio-Gel P-30柱通过凝胶过滤除去未结合的染料。偶联后，将3x10 5BT-474细胞的等分试样在37℃或4℃(冰)下，在完全培养基(RPMI-1640+10％FBS)中与50nM每种Alexa488标记的抗体一起孵育1小时。孵育后，将细胞在冷的离心机中用冰冷的PBS洗涤两次。然后将细胞重悬于500nM淬灭兔-抗-Alexa488抗体(Thermo Fisher#A-11094,Waltham,MA)或500nM兔IgG同种型对照抗体(Jackson ImmunoResearch Laboratories#011-000-003,WestGrove,PA)任一者中，并在冰上孵育30分钟。向每种样品中加入两倍体积的2％多聚甲醛，并在室温下孵育10分钟。然后将细胞用1ml冰冷的PBS洗涤一次，重悬于200μl PBS中，并使用FACScalibur流式细胞仪分析。使用每个样品2x10 4个事件的几何平均荧光强度(GMFI)来计算内化抗体的百分比。由于在4℃不会发生内化，所以在冰上孵育随后与抗-Alexa488抗体孵育的样品中测量的荧光被认为是不可淬灭的背景表面荧光，并在淬灭前从37℃孵育的样品所得GMFI值中扣除。内化如下计算：内化百分比＝(GMFI淬灭/GMFI未淬灭)*100。
结果在图8中示出。双特异性抗体SI-4X2(39.3％)比单特异性对照抗体SI-4C1(18.29％)和SI-4C2(14.97％)以及SI-4C1+SI-4C2的组合(29.19％)更大程度地内化。
药物组合物
词语“有效量”是指有效实现期望效果的药物的量，例如改善患者的疾病。其中该疾病是癌症，有效量的药物可以抑制(例如，在一定程度上减缓、抑制或停止)以下一个或多个示例性特征，包括但不限于癌细胞生长、癌细胞增殖、癌细胞运动、癌细胞浸润到周围器官、肿瘤转移以及肿瘤生长。其中该疾病是癌症，当对患者施药时，有效量的药物可以可选地进行以下一种或多种：减缓或停止肿瘤生长、减小肿瘤尺寸(例如体积或质量)、在一定程度上缓解一种或多种与癌相关的症状、延长无进展生存期、产生客观疗效(包括例如部分疗效或完全疗效)，以及增加卵巢生存时间。在药物可以预防生长和/或杀死现有癌细胞的程度上，其是抑制细胞生长和/或细胞毒性的。
关于给诸如需要治疗的人类患者的患者施用合适的组合物的制剂，本文公开的抗体可以根据所选择的施药途径与本领域已知的药学上可接受的载体混合或组合。对本文公开的抗体的应用模式没有特别限制，并且合适的施药途径和合适的组合物的选择在本领域中是已知的而无需过多的实验。
虽然许多施药形式是可能的，但是示例性施药形式将是注射溶液，具体用于静脉内或动脉内注射。通常，用于注射的合适的药物组合物可以包括药学上合适的载体或赋形剂，诸如但不限于缓冲液、表面活性剂或稳定剂。示例性缓冲液可以包括但不限于乙酸盐，磷酸盐或柠檬酸盐缓冲液。示例性表面活性剂可以包括但不限于聚山梨醇酯。示例性稳定剂可以包括但不限于人白蛋白。
类似地，本领域技术人员有能力确定其中公开的抗体的有效量或浓度以有效治疗诸如癌症的病症。其他参数，诸如药物组合物中各种组分的比例、施药剂量以及频率可由本领域技术人员获得，而无需过多的实验。例如，合适的注射溶液可以包含但不限于约1至约20，约1至约10mg抗体/ml。示例性剂量可以是但不限于约0.1至约20，约1至约5mg/Kg体重。示例性施药频率可以是但不限于每天一次或每周三次。
虽然已经参考特定实施例或示例描述了本公开，但是可以理解，实施例是说明性的，并且公开范围不受此限制。本公开的可选实施例对于本公开所属领域的普通技术人员来说可以变得显而易见。这些可选实施例被认为包含在本公开的范围内。因此，本公开的范围由所附权利要求限定，并且由前述描述支持。
序列表
<110> 西雅图免疫公司
<120> 双特异性四价抗体及其制备和使用方法
<130> EM01.0003PCT2
<150> US 62095348
<151> 2014-12-22
<160> 80
<170> PatentIn version 3.5
<210> 1
<211> 642
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 1
gacatccaga tgacacaatc tcctagcagt ctgagcgcaa gtgttggaga tcgtgtcacc 60
atcacatgca aggccagcca ggatgtgagc attggagtcg cctggtatca gcagaaaccc 120
ggcaaggcac ccaagctgct gatctactcg gccagttaca gatacactgg cgtaccttcg 180
aggtttagtg gtagcggttc tggaaccgat ttcaccctca ccattagctc cctccaaccc 240
gaggacttcg ccacctacta ctgccagcaa tactacatct acccttacac gttcggccaa 300
ggcactaagg tcgagattaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 2
<211> 324
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 2
gacatccaga tgacacaatc tcctagcagt ctgagcgcaa gtgttggaga tcgtgtcacc 60
atcacatgca aggccagcca ggatgtgagc attggagtcg cctggtatca gcagaaaccc 120
ggcaaggcac ccaagctgct gatctactcg gccagttaca gatacactgg cgtaccttcg 180
aggtttagtg gtagcggttc tggaaccgat ttcaccctca ccattagctc cctccaaccc 240
gaggacttcg ccacctacta ctgccagcaa tactacatct acccttacac gttcggccaa 300
ggcactaagg tcgagattaa acgt 324
<210> 3
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 3
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 4
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 4
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 5
<211> 1347
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 5
gaagtgcagc tcgtcgaaag cggtggcgga ctggttcagc ccggtggttc tctgcggctg 60
tcttgtgctg cctcgggttt cacgttcact gactacacaa tggactgggt gcgtcaggct 120
cctggaaagg gattggagtg ggtagccgac gttaatccaa actccggcgg gagcatctac 180
aaccagaggt tcaaggggag gttcactctg agcgtggatc gctccaagaa cacgctgtac 240
ctccagatga actctctcag ggccgaggac acggctgttt actattgcgc gaggaacctg 300
ggtccttcct tctacttcga ctactgggga cagggaaccc tggtgaccgt cagctccgct 360
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagagagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtaaa 1347
<210> 6
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 6
gaagtgcagc tcgtcgaaag cggtggcgga ctggttcagc ccggtggttc tctgcggctg 60
tcttgtgctg cctcgggttt cacgttcact gactacacaa tggactgggt gcgtcaggct 120
cctggaaagg gattggagtg ggtagccgac gttaatccaa actccggcgg gagcatctac 180
aaccagaggt tcaaggggag gttcactctg agcgtggatc gctccaagaa cacgctgtac 240
ctccagatga actctctcag ggccgaggac acggctgttt actattgcgc gaggaacctg 300
ggtccttcct tctacttcga ctactgggga cagggaaccc tggtgaccgt cagctcc 357
<210> 7
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 7
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 8
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 8
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 9
<211> 642
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 9
gatatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggtcacc 60
atcacctgcc gtgccagtca ggatgtgaat actgctgtag cctggtatca acagaaacca 120
ggaaaagctc cgaaactact gatttactcg gcatccttcc tctactctgg agtcccttct 180
cgcttctctg gctccagatc tgggacggat ttcactctga ccatcagcag tctgcagccg 240
gaagacttcg caacttatta ctgtcagcaa cattatacta ctcctcccac gttcggacag 300
ggtaccaagg tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 10
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 10
gatatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggtcacc 60
atcacctgcc gtgccagtca ggatgtgaat actgctgtag cctggtatca acagaaacca 120
ggaaaagctc cgaaactact gatttactcg gcatccttcc tctactctgg agtcccttct 180
cgcttctctg gctccagatc tgggacggat ttcactctga ccatcagcag tctgcagccg 240
gaagacttcg caacttatta ctgtcagcaa cattatacta ctcctcccac gttcggacag 300
ggtaccaagg tggagatcaa a 321
<210> 11
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 11
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 12
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 12
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 13
<211> 1350
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 13
gaggttcagc tggtggagtc tggcggtggc ctggtgcagc cagggggctc actccgtttg 60
tcctgtgcag cttctggctt caacattaaa gacacctata tacactgggt gcgtcaggcc 120
ccgggtaagg gcctggaatg ggttgcaagg atttatccta cgaatggtta tactagatat 180
gccgatagcg tcaagggccg tttcactata agcgcagaca catccaaaaa cacagcctac 240
ctgcagatga acagcctgcg tgctgaggac actgccgtct attattgttc tagatgggga 300
ggggacggct tctatgctat ggactactgg ggtcaaggaa ccctggtcac cgtctcctcg 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 cacctgaact cctgggggga 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 gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1080
atgaccaaga 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 tccgggtaaa 1350
<210> 14
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 14
gaggttcagc tggtggagtc tggcggtggc ctggtgcagc cagggggctc actccgtttg 60
tcctgtgcag cttctggctt caacattaaa gacacctata tacactgggt gcgtcaggcc 120
ccgggtaagg gcctggaatg ggttgcaagg atttatccta cgaatggtta tactagatat 180
gccgatagcg tcaagggccg tttcactata agcgcagaca catccaaaaa cacagcctac 240
ctgcagatga acagcctgcg tgctgaggac actgccgtct attattgttc tagatgggga 300
ggggacggct tctatgctat ggactactgg ggtcaaggaa ccctggtcac cgtctcctcg 360
<210> 15
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met 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 Lys
450
<210> 16
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 16
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 17
<211> 1450
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 17
gagcccaaat cttgtgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 60
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 120
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 180
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 240
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 300
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 360
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 420
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 480
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 540
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 600
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 660
tacacgcaga agagcctctc cctgtctccg ggtaaaggcg gtggaggatc cggcggtggt 720
ggatcagaag tgcagctcgt cgaaagcggt ggcggactgg ttcagcccgg tggttctctg 780
cggctgtctt gtgctgcctc gggtttcacg ttcactgact acacaatgga ctgggtgcgt 840
caggctcctg gaaagggatt ggagtgggta gccgacgtta atccaaactc cggcgggagc 900
atctacaacc agaggttcaa ggggaggttc actctgagcg tggatcgctc caagaacacg 960
ctgtacctcc agatgaactc tctcagggcc gaggacacgg ctgtttacta ttgcgcgagg 1020
aacctgggtc cttccttcta cttcgactac tggggacagg gaaccctggt gaccgtcagc 1080
tccggtggag gcggttcagg cggaggtggt tccggcggtg gcggctccga catccagatg 1140
acacaatctc ctagcagtct gagcgcaagt gttggagatc gtgtcaccat cacatgcaag 1200
gccagccagg atgtgagcat tggagtcgcc tggtatcagc agaaacccgg caaggcaccc 1260
aagctgctga tctactcggc cagttacaga tacactggcg taccttcgag gtttagtggt 1320
agcggttctg gaaccgattt caccctcacc attagctccc tccaacccga ggacttcgcc 1380
acctactact gccagcaata ctacatctac ccttacacgt tcggccaagg cactaaggtc 1440
gagattaaat 1450
<210> 18
<211> 483
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 18
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
245 250 255
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr
260 265 270
Asp Tyr Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
275 280 285
Trp Val Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln
290 295 300
Arg Phe Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr
305 310 315 320
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
325 330 335
Tyr Cys Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly
340 345 350
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
355 360 365
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
370 375 380
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
385 390 395 400
Ala Ser Gln Asp Val Ser Ile Gly Val Ala Trp Tyr Gln Gln Lys Pro
405 410 415
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr
420 425 430
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
435 440 445
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
450 455 460
Gln Gln Tyr Tyr Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val
465 470 475 480
Glu Ile Lys
<210> 19
<211> 241
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 19
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser
145 150 155 160
Gln Asp Val Ser Ile Gly Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
165 170 175
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val
180 185 190
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
210 215 220
Tyr Tyr Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
225 230 235 240
Lys
<210> 20
<211> 1452
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 20
gagcccaaat cttgtgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 60
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 120
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 180
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 240
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 300
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 360
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 420
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 480
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 540
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 600
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 660
tacacgcaga agagcctctc cctgtctccg ggtaaaggcg gtggaggatc cggcggtggt 720
ggatcagagg ttcagctggt ggagtctggc ggtggcctgg tgcagccagg gggctcactc 780
cgtttgtcct gtgcagcttc tggcttcaac attaaagaca cctatataca ctgggtgcgt 840
caggccccgg gtaagggcct ggaatgggtt gcaaggattt atcctacgaa tggttatact 900
agatatgccg atagcgtcaa gggccgtttc actataagcg cagacacatc caaaaacaca 960
gcctacctgc agatgaacag cctgcgtgct gaggacactg ccgtctatta ttgttctaga 1020
tggggagggg acggcttcta tgctatggac tactggggtc aaggaaccct ggtcaccgtc 1080
tcctcgggtg gaggcggttc aggcggaggt ggttccggcg gtggcggctc cgatatccag 1140
atgacccagt ccccgagctc cctgtccgcc tctgtgggcg atagggtcac catcacctgc 1200
cgtgccagtc aggatgtgaa tactgctgta gcctggtatc aacagaaacc aggaaaagct 1260
ccgaaactac tgatttactc ggcatccttc ctctactctg gagtcccttc tcgcttctct 1320
ggctccagat ctgggacgga tttcactctg accatcagca gtctgcagcc ggaagacttc 1380
gcaacttatt actgtcagca acattatact actcctccca cgttcggaca gggtaccaag 1440
gtggagatca aa 1452
<210> 21
<211> 484
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 21
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
245 250 255
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys
260 265 270
Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
275 280 285
Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp
290 295 300
Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr
305 310 315 320
Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
325 330 335
Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp
340 345 350
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
355 360 365
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
370 375 380
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
385 390 395 400
Arg Ala Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys
405 410 415
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr
420 425 430
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe
435 440 445
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
450 455 460
Cys Gln Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys
465 470 475 480
Val Glu Ile Lys
<210> 22
<211> 242
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 22
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu
225 230 235 240
Ile Lys
<210> 23
<211> 642
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 23
gacatccaga tgacacaatc tcctagcagt ctgagcgcaa gtgttggaga tcgtgtcacc 60
atcacatgca aggccagcca ggatgtgagc attggagtcg cctggtatca gcagaaaccc 120
ggcaaggcac ccaagctgct gatctactcg gccagttaca gatacactgg cgtaccttcg 180
aggtttagtg gtagcggttc tggaaccgat ttcaccctca ccattagctc cctccaaccc 240
gaggacttcg ccacctacta ctgccagcaa tactacatct acccttacac gttcggccaa 300
ggcactaagg tcgagattaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 24
<211> 324
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 24
gacatccaga tgacacaatc tcctagcagt ctgagcgcaa gtgttggaga tcgtgtcacc 60
atcacatgca aggccagcca ggatgtgagc attggagtcg cctggtatca gcagaaaccc 120
ggcaaggcac ccaagctgct gatctactcg gccagttaca gatacactgg cgtaccttcg 180
aggtttagtg gtagcggttc tggaaccgat ttcaccctca ccattagctc cctccaaccc 240
gaggacttcg ccacctacta ctgccagcaa tactacatct acccttacac gttcggccaa 300
ggcactaagg tcgagattaa acgt 324
<210> 25
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 25
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 26
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 26
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 27
<211> 2103
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 27
gaagtgcagc tcgtcgaaag cggtggcgga ctggttcagc ccggtggttc tctgcggctg 60
tcttgtgctg cctcgggttt cacgttcact gactacacaa tggactgggt gcgtcaggct 120
cctggaaagg gattggagtg ggtagccgac gttaatccaa actccggcgg gagcatctac 180
aaccagaggt tcaaggggag gttcactctg agcgtggatc gctccaagaa cacgctgtac 240
ctccagatga actctctcag ggccgaggac acggctgttt actattgcgc gaggaacctg 300
ggtccttcct tctacttcga ctactgggga cagggaaccc tggtgaccgt cagctccgct 360
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagagagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtaaaggc ggtggaggat ccggcggtgg tggatcagag 1380
gttcagctgg tggagtctgg cggtggcctg gtgcagccag ggggctcact ccgtttgtcc 1440
tgtgcagctt ctggcttcaa cattaaagac acctatatac actgggtgcg tcaggccccg 1500
ggtaagggcc tggaatgggt tgcaaggatt tatcctacga atggttatac tagatatgcc 1560
gatagcgtca agggccgttt cactataagc gcagacacat ccaaaaacac agcctacctg 1620
cagatgaaca gcctgcgtgc tgaggacact gccgtctatt attgttctag atggggaggg 1680
gacggcttct atgctatgga ctactggggt caaggaaccc tggtcaccgt ctcctcgggt 1740
ggaggcggtt caggcggagg tggttccggc ggtggcggct ccgatatcca gatgacccag 1800
tccccgagct ccctgtccgc ctctgtgggc gatagggtca ccatcacctg ccgtgccagt 1860
caggatgtga atactgctgt agcctggtat caacagaaac caggaaaagc tccgaaacta 1920
ctgatttact cggcatcctt cctctactct ggagtccctt ctcgcttctc tggctccaga 1980
tctgggacgg atttcactct gaccatcagc agtctgcagc cggaagactt cgcaacttat 2040
tactgtcagc aacattatac tactcctccc acgttcggac agggtaccaa ggtggagatc 2100
aaa 2103
<210> 28
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 28
gaagtgcagc tcgtcgaaag cggtggcgga ctggttcagc ccggtggttc tctgcggctg 60
tcttgtgctg cctcgggttt cacgttcact gactacacaa tggactgggt gcgtcaggct 120
cctggaaagg gattggagtg ggtagccgac gttaatccaa actccggcgg gagcatctac 180
aaccagaggt tcaaggggag gttcactctg agcgtggatc gctccaagaa cacgctgtac 240
ctccagatga actctctcag ggccgaggac acggctgttt actattgcgc gaggaacctg 300
ggtccttcct tctacttcga ctactgggga cagggaaccc tggtgaccgt cagctcc 357
<210> 29
<211> 726
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 29
gaggttcagc tggtggagtc tggcggtggc ctggtgcagc cagggggctc actccgtttg 60
tcctgtgcag cttctggctt caacattaaa gacacctata tacactgggt gcgtcaggcc 120
ccgggtaagg gcctggaatg ggttgcaagg atttatccta cgaatggtta tactagatat 180
gccgatagcg tcaagggccg tttcactata agcgcagaca catccaaaaa cacagcctac 240
ctgcagatga acagcctgcg tgctgaggac actgccgtct attattgttc tagatgggga 300
ggggacggct tctatgctat ggactactgg ggtcaaggaa ccctggtcac cgtctcctcg 360
ggtggaggcg gttcaggcgg aggtggttcc ggcggtggcg gctccgatat ccagatgacc 420
cagtccccga gctccctgtc cgcctctgtg ggcgataggg tcaccatcac ctgccgtgcc 480
agtcaggatg tgaatactgc tgtagcctgg tatcaacaga aaccaggaaa agctccgaaa 540
ctactgattt actcggcatc cttcctctac tctggagtcc cttctcgctt ctctggctcc 600
agatctggga cggatttcac tctgaccatc agcagtctgc agccggaaga cttcgcaact 660
tattactgtc agcaacatta tactactcct cccacgttcg gacagggtac caaggtggag 720
atcaaa 726
<210> 30
<211> 701
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 30
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
450 455 460
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
465 470 475 480
Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val
485 490 495
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Tyr Pro
500 505 510
Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
515 520 525
Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser
530 535 540
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly
545 550 555 560
Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
565 570 575
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
580 585 590
Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
595 600 605
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn
610 615 620
Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
625 630 635 640
Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe
645 650 655
Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
660 665 670
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr
675 680 685
Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
690 695 700
<210> 31
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 31
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 32
<211> 242
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 32
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu
225 230 235 240
Ile Lys
<210> 33
<211> 642
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 33
gatatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggtcacc 60
atcacctgcc gtgccagtca ggatgtgaat actgctgtag cctggtatca acagaaacca 120
ggaaaagctc cgaaactact gatttactcg gcatccttcc tctactctgg agtcccttct 180
cgcttctctg gctccagatc tgggacggat ttcactctga ccatcagcag tctgcagccg 240
gaagacttcg caacttatta ctgtcagcaa cattatacta ctcctcccac gttcggacag 300
ggtaccaagg tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 34
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 34
gatatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggtcacc 60
atcacctgcc gtgccagtca ggatgtgaat actgctgtag cctggtatca acagaaacca 120
ggaaaagctc cgaaactact gatttactcg gcatccttcc tctactctgg agtcccttct 180
cgcttctctg gctccagatc tgggacggat ttcactctga ccatcagcag tctgcagccg 240
gaagacttcg caacttatta ctgtcagcaa cattatacta ctcctcccac gttcggacag 300
ggtaccaagg tggagatcaa a 321
<210> 35
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 35
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 36
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 36
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 37
<211> 2103
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 37
gaggttcagc tggtggagtc tggcggtggc ctggtgcagc cagggggctc actccgtttg 60
tcctgtgcag cttctggctt caacattaaa gacacctata tacactgggt gcgtcaggcc 120
ccgggtaagg gcctggaatg ggttgcaagg atttatccta cgaatggtta tactagatat 180
gccgatagcg tcaagggccg tttcactata agcgcagaca catccaaaaa cacagcctac 240
ctgcagatga acagcctgcg tgctgaggac actgccgtct attattgttc tagatgggga 300
ggggacggct tctatgctat ggactactgg ggtcaaggaa ccctggtcac cgtctcctcg 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 cacctgaact cctgggggga 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 gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1080
atgaccaaga 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 tccgggtaaa ggcggtggag gatccggcgg tggtggatca 1380
gaagtgcagc tcgtcgaaag cggtggcgga ctggttcagc ccggtggttc tctgcggctg 1440
tcttgtgctg cctcgggttt cacgttcact gactacacaa tggactgggt gcgtcaggct 1500
cctggaaagg gattggagtg ggtagccgac gttaatccaa actccggcgg gagcatctac 1560
aaccagaggt tcaaggggag gttcactctg agcgtggatc gctccaagaa cacgctgtac 1620
ctccagatga actctctcag ggccgaggac acggctgttt actattgcgc gaggaacctg 1680
ggtccttcct tctacttcga ctactgggga cagggaaccc tggtgaccgt cagctccggt 1740
ggaggcggtt caggcggagg tggttccggc ggtggcggct ccgacatcca gatgacacaa 1800
tctcctagca gtctgagcgc aagtgttgga gatcgtgtca ccatcacatg caaggccagc 1860
caggatgtga gcattggagt cgcctggtat cagcagaaac ccggcaaggc acccaagctg 1920
ctgatctact cggccagtta cagatacact ggcgtacctt cgaggtttag tggtagcggt 1980
tctggaaccg atttcaccct caccattagc tccctccaac ccgaggactt cgccacctac 2040
tactgccagc aatactacat ctacccttac acgttcggcc aaggcactaa ggtcgagatt 2100
aaa 2103
<210> 38
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 38
gaggttcagc tggtggagtc tggcggtggc ctggtgcagc cagggggctc actccgtttg 60
tcctgtgcag cttctggctt caacattaaa gacacctata tacactgggt gcgtcaggcc 120
ccgggtaagg gcctggaatg ggttgcaagg atttatccta cgaatggtta tactagatat 180
gccgatagcg tcaagggccg tttcactata agcgcagaca catccaaaaa cacagcctac 240
ctgcagatga acagcctgcg tgctgaggac actgccgtct attattgttc tagatgggga 300
ggggacggct tctatgctat ggactactgg ggtcaaggaa ccctggtcac cgtctcctcg 360
<210> 39
<211> 723
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 39
gaagtgcagc tcgtcgaaag cggtggcgga ctggttcagc ccggtggttc tctgcggctg 60
tcttgtgctg cctcgggttt cacgttcact gactacacaa tggactgggt gcgtcaggct 120
cctggaaagg gattggagtg ggtagccgac gttaatccaa actccggcgg gagcatctac 180
aaccagaggt tcaaggggag gttcactctg agcgtggatc gctccaagaa cacgctgtac 240
ctccagatga actctctcag ggccgaggac acggctgttt actattgcgc gaggaacctg 300
ggtccttcct tctacttcga ctactgggga cagggaaccc tggtgaccgt cagctccggt 360
ggaggcggtt caggcggagg tggttccggc ggtggcggct ccgacatcca gatgacacaa 420
tctcctagca gtctgagcgc aagtgttgga gatcgtgtca ccatcacatg caaggccagc 480
caggatgtga gcattggagt cgcctggtat cagcagaaac ccggcaaggc acccaagctg 540
ctgatctact cggccagtta cagatacact ggcgtacctt cgaggtttag tggtagcggt 600
tctggaaccg atttcaccct caccattagc tccctccaac ccgaggactt cgccacctac 660
tactgccagc aatactacat ctacccttac acgttcggcc aaggcactaa ggtcgagatt 720
aaa 723
<210> 40
<211> 701
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 40
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met 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 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
450 455 460
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
465 470 475 480
Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr Thr Met Asp Trp
485 490 495
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Asp Val Asn
500 505 510
Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe Lys Gly Arg Phe
515 520 525
Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn
530 535 540
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Leu
545 550 555 560
Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
565 570 575
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
580 585 590
Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
595 600 605
Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser
610 615 620
Ile Gly Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
625 630 635 640
Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe
645 650 655
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
660 665 670
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr
675 680 685
Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
690 695 700
<210> 41
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 41
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 42
<211> 241
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 42
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser
145 150 155 160
Gln Asp Val Ser Ile Gly Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
165 170 175
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val
180 185 190
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
210 215 220
Tyr Tyr Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
225 230 235 240
Lys
<210> 43
<211> 642
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 43
gacatccaga tgacacaatc tcctagcagt ctgagcgcaa gtgttggaga tcgtgtcacc 60
atcacatgca aggccagcca ggatgtgagc attggagtcg cctggtatca gcagaaaccc 120
ggcaaggcac ccaagctgct gatctactcg gccagttaca gatacactgg cgtaccttcg 180
aggtttagtg gtagcggttc tggaaccgat ttcaccctca ccattagctc cctccaaccc 240
gaggacttcg ccacctacta ctgccagcaa tactacatct acccttacac gttcggccaa 300
ggcactaagg tcgagattaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 44
<211> 324
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 44
gacatccaga tgacacaatc tcctagcagt ctgagcgcaa gtgttggaga tcgtgtcacc 60
atcacatgca aggccagcca ggatgtgagc attggagtcg cctggtatca gcagaaaccc 120
ggcaaggcac ccaagctgct gatctactcg gccagttaca gatacactgg cgtaccttcg 180
aggtttagtg gtagcggttc tggaaccgat ttcaccctca ccattagctc cctccaaccc 240
gaggacttcg ccacctacta ctgccagcaa tactacatct acccttacac gttcggccaa 300
ggcactaagg tcgagattaa acgt 324
<210> 45
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 45
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 46
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 46
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 47
<211> 2163
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 47
gaagtgcagc tcgtcgaaag cggtggcgga ctggttcagc ccggtggttc tctgcggctg 60
tcttgtgctg cctcgggttt cacgttcact gactacacaa tggactgggt gcgtcaggct 120
cctggaaagg gattggagtg ggtagccgac gttaatccaa actccggcgg gagcatctac 180
aaccagaggt tcaaggggag gttcactctg agcgtggatc gctccaagaa cacgctgtac 240
ctccagatga actctctcag ggccgaggac acggctgttt actattgcgc gaggaacctg 300
ggtccttcct tctacttcga ctactgggga cagggaaccc tggtgaccgt cagctccgct 360
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagagagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtaaagga ggcgggggtt ccggcggagg tggctcagga 1380
ggcggagggt cagggggagg tggctccggc ggtggaggat ccggcggtgg tggatcagag 1440
gttcagctgg tggagtctgg cggtggcctg gtgcagccag ggggctcact ccgtttgtcc 1500
tgtgcagctt ctggcttcaa cattaaagac acctatatac actgggtgcg tcaggccccg 1560
ggtaagggcc tggaatgggt tgcaaggatt tatcctacga atggttatac tagatatgcc 1620
gatagcgtca agggccgttt cactataagc gcagacacat ccaaaaacac agcctacctg 1680
cagatgaaca gcctgcgtgc tgaggacact gccgtctatt attgttctag atggggaggg 1740
gacggcttct atgctatgga ctactggggt caaggaaccc tggtcaccgt ctcctcgggt 1800
ggaggcggtt caggcggagg tggttccggc ggtggcggct ccgatatcca gatgacccag 1860
tccccgagct ccctgtccgc ctctgtgggc gatagggtca ccatcacctg ccgtgccagt 1920
caggatgtga atactgctgt agcctggtat caacagaaac caggaaaagc tccgaaacta 1980
ctgatttact cggcatcctt cctctactct ggagtccctt ctcgcttctc tggctccaga 2040
tctgggacgg atttcactct gaccatcagc agtctgcagc cggaagactt cgcaacttat 2100
tactgtcagc aacattatac tactcctccc acgttcggac agggtaccaa ggtggagatc 2160
aaa 2163
<210> 48
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 48
gaagtgcagc tcgtcgaaag cggtggcgga ctggttcagc ccggtggttc tctgcggctg 60
tcttgtgctg cctcgggttt cacgttcact gactacacaa tggactgggt gcgtcaggct 120
cctggaaagg gattggagtg ggtagccgac gttaatccaa actccggcgg gagcatctac 180
aaccagaggt tcaaggggag gttcactctg agcgtggatc gctccaagaa cacgctgtac 240
ctccagatga actctctcag ggccgaggac acggctgttt actattgcgc gaggaacctg 300
ggtccttcct tctacttcga ctactgggga cagggaaccc tggtgaccgt cagctcc 357
<210> 49
<211> 726
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 49
gaggttcagc tggtggagtc tggcggtggc ctggtgcagc cagggggctc actccgtttg 60
tcctgtgcag cttctggctt caacattaaa gacacctata tacactgggt gcgtcaggcc 120
ccgggtaagg gcctggaatg ggttgcaagg atttatccta cgaatggtta tactagatat 180
gccgatagcg tcaagggccg tttcactata agcgcagaca catccaaaaa cacagcctac 240
ctgcagatga acagcctgcg tgctgaggac actgccgtct attattgttc tagatgggga 300
ggggacggct tctatgctat ggactactgg ggtcaaggaa ccctggtcac cgtctcctcg 360
ggtggaggcg gttcaggcgg aggtggttcc ggcggtggcg gctccgatat ccagatgacc 420
cagtccccga gctccctgtc cgcctctgtg ggcgataggg tcaccatcac ctgccgtgcc 480
agtcaggatg tgaatactgc tgtagcctgg tatcaacaga aaccaggaaa agctccgaaa 540
ctactgattt actcggcatc cttcctctac tctggagtcc cttctcgctt ctctggctcc 600
agatctggga cggatttcac tctgaccatc agcagtctgc agccggaaga cttcgcaact 660
tattactgtc agcaacatta tactactcct cccacgttcg gacagggtac caaggtggag 720
atcaaa 726
<210> 50
<211> 721
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 50
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
465 470 475 480
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
485 490 495
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr
500 505 510
Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala
515 520 525
Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys
530 535 540
Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu
545 550 555 560
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser
565 570 575
Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly
580 585 590
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
595 600 605
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
610 615 620
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
625 630 635 640
Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
645 650 655
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
660 665 670
Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr
675 680 685
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
690 695 700
His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
705 710 715 720
Lys
<210> 51
<211> 642
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 51
gatatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggtcacc 60
atcacctgcc gtgccagtca ggatgtgaat actgctgtag cctggtatca acagaaacca 120
ggaaaagctc cgaaactact gatttactcg gcatccttcc tctactctgg agtcccttct 180
cgcttctctg gctccagatc tgggacggat ttcactctga ccatcagcag tctgcagccg 240
gaagacttcg caacttatta ctgtcagcaa cattatacta ctcctcccac gttcggacag 300
ggtaccaagg tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 52
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 52
gatatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggtcacc 60
atcacctgcc gtgccagtca ggatgtgaat actgctgtag cctggtatca acagaaacca 120
ggaaaagctc cgaaactact gatttactcg gcatccttcc tctactctgg agtcccttct 180
cgcttctctg gctccagatc tgggacggat ttcactctga ccatcagcag tctgcagccg 240
gaagacttcg caacttatta ctgtcagcaa cattatacta ctcctcccac gttcggacag 300
ggtaccaagg tggagatcaa a 321
<210> 53
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 53
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 54
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 54
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 55
<211> 2163
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 55
gaggttcagc tggtggagtc tggcggtggc ctggtgcagc cagggggctc actccgtttg 60
tcctgtgcag cttctggctt caacattaaa gacacctata tacactgggt gcgtcaggcc 120
ccgggtaagg gcctggaatg ggttgcaagg atttatccta cgaatggtta tactagatat 180
gccgatagcg tcaagggccg tttcactata agcgcagaca catccaaaaa cacagcctac 240
ctgcagatga acagcctgcg tgctgaggac actgccgtct attattgttc tagatgggga 300
ggggacggct tctatgctat ggactactgg ggtcaaggaa ccctggtcac cgtctcctcg 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 cacctgaact cctgggggga 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 gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1080
atgaccaaga 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 tccgggtaaa ggaggcgggg gttccggcgg aggtggctca 1380
ggaggcggag ggtcaggggg aggtggctcc ggcggtggag gatccggcgg tggtggatca 1440
gaagtgcagc tcgtcgaaag cggtggcgga ctggttcagc ccggtggttc tctgcggctg 1500
tcttgtgctg cctcgggttt cacgttcact gactacacaa tggactgggt gcgtcaggct 1560
cctggaaagg gattggagtg ggtagccgac gttaatccaa actccggcgg gagcatctac 1620
aaccagaggt tcaaggggag gttcactctg agcgtggatc gctccaagaa cacgctgtac 1680
ctccagatga actctctcag ggccgaggac acggctgttt actattgcgc gaggaacctg 1740
ggtccttcct tctacttcga ctactgggga cagggaaccc tggtgaccgt cagctccggt 1800
ggaggcggtt caggcggagg tggttccggc ggtggcggct ccgacatcca gatgacacaa 1860
tctcctagca gtctgagcgc aagtgttgga gatcgtgtca ccatcacatg caaggccagc 1920
caggatgtga gcattggagt cgcctggtat cagcagaaac ccggcaaggc acccaagctg 1980
ctgatctact cggccagtta cagatacact ggcgtacctt cgaggtttag tggtagcggt 2040
tctggaaccg atttcaccct caccattagc tccctccaac ccgaggactt cgccacctac 2100
tactgccagc aatactacat ctacccttac acgttcggcc aaggcactaa ggtcgagatt 2160
aaa 2163
<210> 56
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 56
gaggttcagc tggtggagtc tggcggtggc ctggtgcagc cagggggctc actccgtttg 60
tcctgtgcag cttctggctt caacattaaa gacacctata tacactgggt gcgtcaggcc 120
ccgggtaagg gcctggaatg ggttgcaagg atttatccta cgaatggtta tactagatat 180
gccgatagcg tcaagggccg tttcactata agcgcagaca catccaaaaa cacagcctac 240
ctgcagatga acagcctgcg tgctgaggac actgccgtct attattgttc tagatgggga 300
ggggacggct tctatgctat ggactactgg ggtcaaggaa ccctggtcac cgtctcctcg 360
<210> 57
<211> 723
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 57
gaagtgcagc tcgtcgaaag cggtggcgga ctggttcagc ccggtggttc tctgcggctg 60
tcttgtgctg cctcgggttt cacgttcact gactacacaa tggactgggt gcgtcaggct 120
cctggaaagg gattggagtg ggtagccgac gttaatccaa actccggcgg gagcatctac 180
aaccagaggt tcaaggggag gttcactctg agcgtggatc gctccaagaa cacgctgtac 240
ctccagatga actctctcag ggccgaggac acggctgttt actattgcgc gaggaacctg 300
ggtccttcct tctacttcga ctactgggga cagggaaccc tggtgaccgt cagctccggt 360
ggaggcggtt caggcggagg tggttccggc ggtggcggct ccgacatcca gatgacacaa 420
tctcctagca gtctgagcgc aagtgttgga gatcgtgtca ccatcacatg caaggccagc 480
caggatgtga gcattggagt cgcctggtat cagcagaaac ccggcaaggc acccaagctg 540
ctgatctact cggccagtta cagatacact ggcgtacctt cgaggtttag tggtagcggt 600
tctggaaccg atttcaccct caccattagc tccctccaac ccgaggactt cgccacctac 660
tactgccagc aatactacat ctacccttac acgttcggcc aaggcactaa ggtcgagatt 720
aaa 723
<210> 58
<211> 721
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 58
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met 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 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
485 490 495
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
500 505 510
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
515 520 525
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
530 535 540
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
545 550 555 560
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
565 570 575
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
580 585 590
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
595 600 605
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
610 615 620
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser
625 630 635 640
Gln Asp Val Ser Ile Gly Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
645 650 655
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val
660 665 670
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
675 680 685
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
690 695 700
Tyr Tyr Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
705 710 715 720
Lys
<210> 59
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 59
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 60
<211> 241
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 60
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser
145 150 155 160
Gln Asp Val Ser Ile Gly Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
165 170 175
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val
180 185 190
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
210 215 220
Tyr Tyr Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
225 230 235 240
Lys
<210> 61
<211> 1467
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 61
gagcccaaat cttgtgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 60
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 120
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 180
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 240
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 300
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 360
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 420
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 480
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 540
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 600
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 660
tacacgcaga agagcctctc cctgtctccg ggtaaagggg gaggtggctc cggcggtgga 720
ggatccggcg gtggtggatc agaggttcag ctggtggagt ctggcggtgg cctggtgcag 780
ccagggggct cactccgttt gtcctgtgca gcttctggct tcaacattaa agacacctat 840
atacactggg tgcgtcaggc cccgggtaag ggcctggaat gggttgcaag gatttatcct 900
acgaatggtt atactagata tgccgatagc gtcaagggcc gtttcactat aagcgcagac 960
acatccaaaa acacagccta cctgcagatg aacagcctgc gtgctgagga cactgccgtc 1020
tattattgtt ctagatgggg aggggacggc ttctatgcta tggactactg gggtcaagga 1080
accctggtca ccgtctcctc gggtggaggc ggttcaggcg gaggtggttc cggcggtggc 1140
ggctccgata tccagatgac ccagtccccg agctccctgt ccgcctctgt gggcgatagg 1200
gtcaccatca cctgccgtgc cagtcaggat gtgaatactg ctgtagcctg gtatcaacag 1260
aaaccaggaa aagctccgaa actactgatt tactcggcat ccttcctcta ctctggagtc 1320
ccttctcgct tctctggctc cagatctggg acggatttca ctctgaccat cagcagtctg 1380
cagccggaag acttcgcaac ttattactgt cagcaacatt atactactcc tcccacgttc 1440
ggacagggta ccaaggtgga gatcaaa 1467
<210> 62
<211> 489
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 62
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr
290 295 300
Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp
305 310 315 320
Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
325 330 335
Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr
340 345 350
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
355 360 365
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
370 375 380
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
385 390 395 400
Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala Val Ala
405 410 415
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser
420 425 430
Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg
435 440 445
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
450 455 460
Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro Thr Phe
465 470 475 480
Gly Gln Gly Thr Lys Val Glu Ile Lys
485
<210> 63
<211> 242
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu
225 230 235 240
Ile Lys
<210> 64
<211> 1482
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 64
gagcccaaat cttgtgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 60
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 120
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 180
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 240
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 300
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 360
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 420
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 480
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 540
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 600
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 660
tacacgcaga agagcctctc cctgtctccg ggtaaaggag gcggagggtc agggggaggt 720
ggctccggcg gtggaggatc cggcggtggt ggatcagagg ttcagctggt ggagtctggc 780
ggtggcctgg tgcagccagg gggctcactc cgtttgtcct gtgcagcttc tggcttcaac 840
attaaagaca cctatataca ctgggtgcgt caggccccgg gtaagggcct ggaatgggtt 900
gcaaggattt atcctacgaa tggttatact agatatgccg atagcgtcaa gggccgtttc 960
actataagcg cagacacatc caaaaacaca gcctacctgc agatgaacag cctgcgtgct 1020
gaggacactg ccgtctatta ttgttctaga tggggagggg acggcttcta tgctatggac 1080
tactggggtc aaggaaccct ggtcaccgtc tcctcgggtg gaggcggttc aggcggaggt 1140
ggttccggcg gtggcggctc cgatatccag atgacccagt ccccgagctc cctgtccgcc 1200
tctgtgggcg atagggtcac catcacctgc cgtgccagtc aggatgtgaa tactgctgta 1260
gcctggtatc aacagaaacc aggaaaagct ccgaaactac tgatttactc ggcatccttc 1320
ctctactctg gagtcccttc tcgcttctct ggctccagat ctgggacgga tttcactctg 1380
accatcagca gtctgcagcc ggaagacttc gcaacttatt actgtcagca acattatact 1440
actcctccca cgttcggaca gggtaccaag gtggagatca aa 1482
<210> 65
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 65
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Tyr
290 295 300
Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe
305 310 315 320
Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn
325 330 335
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly
340 345 350
Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
385 390 395 400
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val
405 410 415
Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
420 425 430
Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg
435 440 445
Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
450 455 460
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr
465 470 475 480
Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
485 490
<210> 66
<211> 242
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 66
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu
225 230 235 240
Ile Lys
<210> 67
<211> 1497
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 67
gagcccaaat cttgtgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 60
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 120
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 180
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 240
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 300
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 360
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 420
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 480
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 540
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 600
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 660
tacacgcaga agagcctctc cctgtctccg ggtaaaggcg gaggtggctc aggaggcgga 720
gggtcagggg gaggtggctc cggcggtgga ggatccggcg gtggtggatc agaggttcag 780
ctggtggagt ctggcggtgg cctggtgcag ccagggggct cactccgttt gtcctgtgca 840
gcttctggct tcaacattaa agacacctat atacactggg tgcgtcaggc cccgggtaag 900
ggcctggaat gggttgcaag gatttatcct acgaatggtt atactagata tgccgatagc 960
gtcaagggcc gtttcactat aagcgcagac acatccaaaa acacagccta cctgcagatg 1020
aacagcctgc gtgctgagga cactgccgtc tattattgtt ctagatgggg aggggacggc 1080
ttctatgcta tggactactg gggtcaagga accctggtca ccgtctcctc gggtggaggc 1140
ggttcaggcg gaggtggttc cggcggtggc ggctccgata tccagatgac ccagtccccg 1200
agctccctgt ccgcctctgt gggcgatagg gtcaccatca cctgccgtgc cagtcaggat 1260
gtgaatactg ctgtagcctg gtatcaacag aaaccaggaa aagctccgaa actactgatt 1320
tactcggcat ccttcctcta ctctggagtc ccttctcgct tctctggctc cagatctggg 1380
acggatttca ctctgaccat cagcagtctg cagccggaag acttcgcaac ttattactgt 1440
cagcaacatt atactactcc tcccacgttc ggacagggta ccaaggtgga gatcaaa 1497
<210> 68
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 68
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp
275 280 285
Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
290 295 300
Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser
305 310 315 320
Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala
325 330 335
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
340 345 350
Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
385 390 395 400
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
405 410 415
Ala Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val
485 490 495
Glu Ile Lys
<210> 69
<211> 242
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 69
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu
225 230 235 240
Ile Lys
<210> 70
<211> 1512
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 70
gagcccaaat cttgtgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 60
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 120
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 180
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 240
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 300
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 360
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 420
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 480
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 540
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 600
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 660
tacacgcaga agagcctctc cctgtctccg ggtaaaggag gcgggggttc cggcggaggt 720
ggctcaggag gcggagggtc agggggaggt ggctccggcg gtggaggatc cggcggtggt 780
ggatcagagg ttcagctggt ggagtctggc ggtggcctgg tgcagccagg gggctcactc 840
cgtttgtcct gtgcagcttc tggcttcaac attaaagaca cctatataca ctgggtgcgt 900
caggccccgg gtaagggcct ggaatgggtt gcaaggattt atcctacgaa tggttatact 960
agatatgccg atagcgtcaa gggccgtttc actataagcg cagacacatc caaaaacaca 1020
gcctacctgc agatgaacag cctgcgtgct gaggacactg ccgtctatta ttgttctaga 1080
tggggagggg acggcttcta tgctatggac tactggggtc aaggaaccct ggtcaccgtc 1140
tcctcgggtg gaggcggttc aggcggaggt ggttccggcg gtggcggctc cgatatccag 1200
atgacccagt ccccgagctc cctgtccgcc tctgtgggcg atagggtcac catcacctgc 1260
cgtgccagtc aggatgtgaa tactgctgta gcctggtatc aacagaaacc aggaaaagct 1320
ccgaaactac tgatttactc ggcatccttc ctctactctg gagtcccttc tcgcttctct 1380
ggctccagat ctgggacgga tttcactctg accatcagca gtctgcagcc ggaagacttc 1440
gcaacttatt actgtcagca acattatact actcctccca cgttcggaca gggtaccaag 1500
gtggagatca aa 1512
<210> 71
<211> 504
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 71
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
260 265 270
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
275 280 285
Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly
290 295 300
Lys Gly Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr
305 310 315 320
Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr
325 330 335
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
340 345 350
Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala
355 360 365
Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
385 390 395 400
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
405 410 415
Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala Val Ala Trp
420 425 430
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala
435 440 445
Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser
450 455 460
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
465 470 475 480
Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro Thr Phe Gly
485 490 495
Gln Gly Thr Lys Val Glu Ile Lys
500
<210> 72
<211> 242
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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 Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu
225 230 235 240
Ile Lys
<210> 73
<211> 1527
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 73
gagcccaaat cttgtgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 60
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 120
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 180
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 240
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 300
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 360
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 420
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 480
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 540
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 600
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 660
tacacgcaga agagcctctc cctgtctccg ggtaaaggcg gtggagggtc cggaggcggg 720
ggttccggcg gaggtggctc aggaggcgga gggtcagggg gaggtggctc cggcggtgga 780
ggatccggcg gtggtggatc agaggttcag ctggtggagt ctggcggtgg cctggtgcag 840
ccagggggct cactccgttt gtcctgtgca gcttctggct tcaacattaa agacacctat 900
atacactggg tgcgtcaggc cccgggtaag ggcctggaat gggttgcaag gatttatcct 960
acgaatggtt atactagata tgccgatagc gtcaagggcc gtttcactat aagcgcagac 1020
acatccaaaa acacagccta cctgcagatg aacagcctgc gtgctgagga cactgccgtc 1080
tattattgtt ctagatgggg aggggacggc ttctatgcta tggactactg gggtcaagga 1140
accctggtca ccgtctcctc gggtggaggc ggttcaggcg gaggtggttc cggcggtggc 1200
ggctccgata tccagatgac ccagtccccg agctccctgt ccgcctctgt gggcgatagg 1260
gtcaccatca cctgccgtgc cagtcaggat gtgaatactg ctgtagcctg gtatcaacag 1320
aaaccaggaa aagctccgaa actactgatt tactcggcat ccttcctcta ctctggagtc 1380
ccttctcgct tctctggctc cagatctggg acggatttca ctctgaccat cagcagtctg 1440
cagccggaag acttcgcaac ttattactgt cagcaacatt atactactcc tcccacgttc 1500
ggacagggta ccaaggtgga gatcaaa 1527
<210> 74
<211> 509
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 74
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
260 265 270
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
275 280 285
Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val
290 295 300
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Tyr Pro
305 310 315 320
Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
325 330 335
Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser
340 345 350
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly
355 360 365
Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
370 375 380
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
385 390 395 400
Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
405 410 415
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn
420 425 430
Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
435 440 445
Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe
450 455 460
Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
465 470 475 480
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr
485 490 495
Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
500 505
<210> 75
<211> 242
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 75
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu
225 230 235 240
Ile Lys
<210> 76
<211> 1542
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 76
gagcccaaat cttgtgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 60
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 120
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 180
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 240
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 300
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 360
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 420
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 480
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 540
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 600
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 660
tacacgcaga agagcctctc cctgtctccg ggtaaagggg gaggtggctc cggcggtgga 720
gggtccggag gcgggggttc cggcggaggt ggctcaggag gcggagggtc agggggaggt 780
ggctccggcg gtggaggatc cggcggtggt ggatcagagg ttcagctggt ggagtctggc 840
ggtggcctgg tgcagccagg gggctcactc cgtttgtcct gtgcagcttc tggcttcaac 900
attaaagaca cctatataca ctgggtgcgt caggccccgg gtaagggcct ggaatgggtt 960
gcaaggattt atcctacgaa tggttatact agatatgccg atagcgtcaa gggccgtttc 1020
actataagcg cagacacatc caaaaacaca gcctacctgc agatgaacag cctgcgtgct 1080
gaggacactg ccgtctatta ttgttctaga tggggagggg acggcttcta tgctatggac 1140
tactggggtc aaggaaccct ggtcaccgtc tcctcgggtg gaggcggttc aggcggaggt 1200
ggttccggcg gtggcggctc cgatatccag atgacccagt ccccgagctc cctgtccgcc 1260
tctgtgggcg atagggtcac catcacctgc cgtgccagtc aggatgtgaa tactgctgta 1320
gcctggtatc aacagaaacc aggaaaagct ccgaaactac tgatttactc ggcatccttc 1380
ctctactctg gagtcccttc tcgcttctct ggctccagat ctgggacgga tttcactctg 1440
accatcagca gtctgcagcc ggaagacttc gcaacttatt actgtcagca acattatact 1500
actcctccca cgttcggaca gggtaccaag gtggagatca aa 1542
<210> 77
<211> 514
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 77
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
260 265 270
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
275 280 285
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
290 295 300
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
305 310 315 320
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
325 330 335
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
340 345 350
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
355 360 365
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
370 375 380
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
385 390 395 400
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
405 410 415
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
420 425 430
Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly
435 440 445
Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly
450 455 460
Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu
465 470 475 480
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
485 490 495
Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu
500 505 510
Ile Lys
<210> 78
<211> 242
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 78
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu
225 230 235 240
Ile Lys
<210> 79
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 79
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 80
<211> 242
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 80
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
145 150 155 160
Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu
195 200 205
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu
225 230 235 240
Ile Lys

Claims (64)

1.一种双特异性四价抗体，所述双特异性四价抗体包含：
两条IgGl重链；
两条kappa轻链；以及
两个单链Fv(scFv)结构域。
其中所述两条IgGl重链和kappa轻链形成对HER2的第一结构域具有结合特异性的IgG部分；
其中所述两个scFv结构域对HER2的第二结构域具有结合特异性，并且每个scFv结构域通过具有氨基酸序列(gly-gly-gly-gly-ser)n((G4S)n)的连接体与任一个IgGl重链的C端残基连接；其中n是至少为2的整数；并且
其中每个scFv结构域具有N端-可变重链结构域-接头-可变轻链结构域-C端或N端-可变轻链结构域-接头-可变重链结构域-C端的结构顺序，并且其中所述接头可以由(gly-gly-gly-gly-ser)m((G4S)m)氨基酸序列组成。其中m是至少为3的整数。
2.根据权利要求1所述的双特异性四价抗体，其中，n为小于20的整数。
3.根据权利要求1所述的双特异性四价抗体，其中，n为1至15的整数。
4.根据权利要求1所述的双特异性四价抗体，其中，n为1至9的整数。
5.根据权利要求1所述的双特异性四价抗体，其中，m为小于10的整数。
6.根据权利要求1所述的双特异性四价抗体，其中，m为小于7的整数。
7.根据权利要求1所述的双特异性四价抗体，其中，m为3、4、5或6。
8.根据权利要求1所述的双特异性四价抗体，其中，所述IgGl重链中的至少一个是人源化的或人IgGl重链。
9.根据权利要求1所述的双特异性四价抗体，其中，两条IgGl重链是人源化的或人IgGl重链。
10.根据权利要求1所述的双特异性四价抗体，其中，所述kappa轻链中的至少一个是人源化的或人kappa轻链。
11.根据权利要求1所述的双特异性四价抗体，其中，两条kappa轻链是人源化的或人kappa轻链。
12.根据权利要求1所述的双特异性四价抗体，其中，HER2的所述第一或所述第二结构域独立地选自HER2的结构域2和结构域4。
13.根据权利要求1所述的双特异性四价抗体，其中，所述IgG部分对HER2的结构域2具有结合特异性。
14.根据权利要求1所述的双特异性四价抗体，其中，所述scFv结构域对HER2的结构域4具有结合特异性。
15.根据权利要求1所述的双特异性四价抗体，其中，所述IgG部分对HER2的结构域2具有结合特异性，并且同时所述scFv结构域对HER2的结构域4具有结合特异性。
16.根据权利要求1所述的双特异性四价抗体，其中，所述IgG部分对HER2的结构域4具有结合特异性。
17.根据权利要求1所述的双特异性四价抗体，其中，所述scFv结构域对HER2的结构域2具有结合特异性。
18.根据权利要求1所述的双特异性四价抗体，其中，所述IgG部分对HER2的结构域4具有结合特异性，并且同时所述scFv结构域对HER2的结构域2具有结合特异性。
19.根据权利要求1所述的双特异性四价抗体，其中，所述IgGl重链中的至少一个包含选自SEQ ID NO 7、15、30、40、50和58的氨基酸序列。
20.根据权利要求1所述的双特异性四价抗体，其中，所述IgGl重链、连接体以及scFv结构域具有选自SEQ ID NO：30、50、40和58的氨基酸序列。
21.根据权利要求1所述的双特异性四价抗体，其中，所述kappa轻链中的至少一个包含选自SEQ ID NO 3、11、25、35、45和53的氨基酸序列。
22.根据权利要求1所述的双特异性四价抗体，其中，可变轻链中的至少一个包含选自SEQ ID NO 4、12、26、36、46和54的氨基酸序列。
23.根据权利要求1所述的双特异性四价抗体，其中，可变重链中的至少一个包含选自SEQ ID NO 8、16、31、41、79和59的氨基酸序列。
24.根据权利要求1所述的双特异性四价抗体，其中，scFv结构域中的至少一个包含选自SEQ ID NO 19、22、32、42、60、63、66、69、72、75、78和80的氨基酸序列。
25.根据权利要求1所述的双特异性四价抗体，其中，所述IgG部分对HER2的结构域2具有结合特异性，并且所述scFv结构域对HER2的结构域4具有结合特异性；
其中所述IgGl重链、连接体以及scFv结构域具有SEQ ID NO 30的氨基酸序列，并且所述kappa轻链具有SEQ ID NO 25的氨基酸序列。
26.根据权利要求1所述的双特异性四价抗体，其中，所述IgG部分对HER2的结构域2具有结合特异性，并且所述scFv结构域对HER2的结构域4具有结合特异性；
其中所述IgGl重链、连接体以及scFv结构域具有SEQ ID NO 50的氨基酸序列，并且所述kappa轻链具有SEQ ID NO 45的氨基酸序列。
27.根据权利要求1所述的双特异性四价抗体，其中，所述IgG部分对HER2的结构域4具有结合特异性，并且所述scFv结构域对HER2的结构域2具有结合特异性；
其中所述IgGl重链、连接体以及scFv结构域具有SEQ ID NO 40的氨基酸序列，并且所述kappa轻链具有SEQ ID NO 35的氨基酸序列。
28.根据权利要求1所述的双特异性四价抗体，其中所述IgG部分对HER2的结构域4具有结合特异性，并且所述scFv结构域对HER2的结构域2具有结合特异性；
其中所述IgGl重链、连接体以及scFv结构域具有SEQ ID NO 58的氨基酸序列，并且所述kappa轻链具有SEQ ID NO 53的氨基酸序列。
29.根据权利要求1-10任一项所述的双特异性四价抗体，其中，所述抗体抑制癌细胞生长。
30.根据权利要求31所述的双特异性四价抗体，其中，所述癌细胞表达HER2。
31.根据权利要求1所述的双特异性四价抗体，其中，所述抗体以小于50nM的Kd与HER2的结构域2结合。
32.根据权利要求1所述的双特异性四价抗体，其中，所述抗体以小于50nM的Kd与HER2的结构域4结合。
33.根据权利要求1所述的双特异性四价抗体，其中，所述抗体以小于50nM的Kd与HER2的结构域4结合，并且同时以小于50nM的Kd与HER2的结构域2结合。
34.根据权利要求1所述的双特异性四价抗体，其中，所述抗体以小于30nM的Kd与HER2的结构域4结合，并以小于30nM的Kd与HER2的结构域2结合。
35.一种根据权利要求1所述的双特异性四价抗体的IgGl重链，其包含选自SEQ ID NO7、15、30、40、50和58的氨基酸序列。
36.一种根据权利要求1所述的双特异性四价抗体的kappa轻链，其包含选自SEQ ID NO3、11、25、35、45和53的氨基酸序列。
37.一种根据权利要求1所述的双特异性四价抗体的可变轻链，其包含选自SEQ ID NO4、12、26、36、46和54的氨基酸序列。
38.一种根据权利要求1所述的双特异性四价抗体的可变重链，其包含选自SEQ ID NO8、16、31、41、79和59的氨基酸序列。
39.一种根据权利要求1所述的双特异性四价抗体的scFv结构域，其包含选自SEQ IDNO 19、22、32、42、60、63、66、69、72、75、78和80的氨基酸序列。
40.一种编码根据权利要求1所述的抗体、根据权利要求35所述的IgGl重链、根据权利要求36所述的kappa轻链、根据权利要求37所述的可变轻链、根据权利要求38所述的可变重链或根据权利要求39所述的scFv结构域的分离的核酸。
41.一种包含根据权利要求40所述的分离的核酸的表达载体。
42.根据权利要求41所述的表达载体，其中，所述载体在细胞中是可表达的。
43.一种宿主细胞，其包含根据权利要求40所述的核酸。
44.一种宿主细胞，其包含根据权利要求41所述的表达载体。
45.根据权利要求43和44中任一项所述的宿主细胞，其中，所述宿主细胞是原核细胞或真核细胞。
46.一种产生抗体的方法，其包含培养根据权利要求43-45中任一项所述的宿主细胞，从而产生抗体。
47.一种免疫交联物，其包含根据权利要求1所述的抗体和细胞毒性剂。
48.一种药物组合物，其包含根据权利要求1所述的双特异性四价抗体和药学上可接受的载体。
49.根据权利要求48所述的药物组合物，其还包含放射性同位素、放射性核素、毒素、治疗剂、化学治疗剂或其组合。
50.一种药物组合物，其包含根据权利要求47所述的免疫交联物和药学上可接受的载体。
51.一种治疗癌症患者的方法，其包含向患者施用有效量的根据权利要求1所述的双特异性四价抗体。
52.根据权利要求51所述的方法，其中，所述癌症包含在其表面上表达HER2的细胞。
53.根据权利要求51所述的方法，其中，所述癌症包含在其表面上表达HER2+的细胞。
54.根据权利要求51所述的方法，其中，所述癌症是选自由以下各项组成的群组中的一种：HER2+乳腺癌、结肠直肠癌、卵巢癌、头颈癌、胃癌、食道癌以及非小细胞肺癌。
55.根据权利要求51所述的方法，其还包含共同施用有效量的治疗剂。
56.根据权利要求55所述的方法，其中，所述治疗剂包含抗体、化疗剂、酶或其组合。
57.根据权利要求55所述的方法，其中，所述治疗剂包含抗雌激素剂、受体酪氨酸抑制剂或其组合。
58.根据权利要求55所述的方法，其中，所述治疗剂包括卡培他滨、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、睾丸酯、伏氯唑、福美斯坦、法倔唑、来曲唑、厄洛替尼、阿法替尼、达沙替尼、吉非替尼、伊马替尼、帕唑帕尼、拉帕替尼、舒尼替尼、尼罗替尼、索拉非尼、白蛋白结合型紫杉醇、衍生物或其组合。
59.根据权利要求55所述的方法，其中，所述治疗剂包含生物制剂。
60.根据权利要求55所述的方法，其中，所述治疗剂包含检查点抑制剂。
61.根据权利要求55所述的方法，其中，治疗剂包括PDl、PDLl、CTLA4、4-lBB、OX40、GITR、TIM 3、LAG 3、TIGIT、CD40、CD27、HVEM、BTLA、VISTA、B7H4、衍生物或其组合。
62.根据权利要求51所述的方法，其中，所述患者是人。
63.一种抑制患者中HER2受体的生物学活性的方法，其包含向所述患者施用有效量的根据权利要求1所述的抗体以抑制HER2受体的生物学活性。
64.一种包含有效浓度的根据权利要求1所述的双特异性四价抗体的溶液，其中，所述溶液是患者中的血浆。
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