CN115703839A - 特异性结合vegf和pk的双特异性结合分子及其用途 - Google Patents
特异性结合vegf和pk的双特异性结合分子及其用途 Download PDFInfo
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Abstract
本发明涉及能够同时结合VEGF和PK的双特异性结合分子及其用途。
Description
技术领域
本发明涉及生物技术领域,具体涉及一种特异性结合VEGF和PK的双特异性结合分子及其用途。
背景技术
血浆激肽释放酶(plasma kallikrein,PK)属丝氨酸蛋白酶家族的一员,最早是在哺乳动物的血浆中被发现。它由位于4q35染色体上单个基因(KLKB1)编码,主要在肝脏中合成。PK是激肽释放酶-激肽系统(KKS)的一个关键酶,可作用于高分子量激肽原(KH),从而使其活化释放小分子缓激肽(BK),进而通过作用于缓激肽受体参与凝血、纤维蛋白溶解、补体激活以及炎症发生等生物学过程。而血浆前激肽释放酶(plasma prekallikrein,PPK)是血浆激肽释放酶的前体,血浆激肽释放酶以血浆前激肽释放酶(PPK)形式大量存在于血液循环中,并进一步通过凝血因子XIIa剪切其内在的Arg-IIe键激活转化成PK。
近年来,随着对血浆激肽释放酶的基因学、分子学和药理学的研究更加深入,人们对其生理和病理角色有了深入的认识。研究表明,血浆激肽释放酶与炎症性疾病、肿瘤、心血管疾病、肾病、中枢神经系统疾病、视网膜病以及糖尿病视网膜疾病等多种疾病密切相关(Costa-Neto,C.M.et al.Participation of kallikrein-kinin system in differentpathologies.Int.Immunopharmacol.2008,8,135-142)。例如遗传性血管水肿(HAE),它是一种常染色体显性遗传性,主要是由于患者体内C1-INH缺乏,导致其对血浆激肽释放酶的抑制作用减弱,不受控制的激活KKS系统,释放血管活性物质,使血管通透性增加引起典型的肿胀(Farkas,H.Orphan drugs for the treatment of hereditaryangioedema.Expert Opinion on Orphan Drugs,2015,1,141-156)。又例如,在糖尿病黄斑水肿患者眼部玻璃体中,发现其KKS系统过度激活,导致视网膜血管通透性增加和视网膜增厚。近年来已公开多项资料表明血浆激肽释放酶抑制剂可以降低视网膜血管通透性,用于治疗糖尿病视网膜疾病和糖尿病黄斑水肿(Feener,E.P.Plasma kallikrein anddiabetic macular edema.Curr.Diab.Rep.2010,10,270-275;Liu J.et al.Plasmakallikrein-kinin system and diabetic retinopathy.Biol.Chem.2013,394,319-328)。
人血管内皮生长因子(vascular endothelial growth factor,VEGF)早在LeungD.W.等的文献中描述是一种对血管内皮具有特异性的肝素结合生长因子(Leung D.W.etal.VEGF is a secreted angiogenic mitogen.Science,1989,246:1306~1309),能够在体内诱导血管生成。VEGF受体是血管内皮生长因子的受体。VEGF受体有三种主要的亚型,分别为VEGFR-1(也称为FLT-1)、VEGFR-2(也称为KDR或者FLK-1)、VEGFR-3。VEGFR-1具有最高的VEGF亲和力,而VEGFR-2则具有稍低的VEGF亲和力。VEGF受体具有由7个免疫球蛋白样结构域(如细胞外结构域1-7),单个跨膜跨越区域和包含分裂的酪氨酸激酶结构域的细胞内部分组成的细胞外部分。进一步研究证明血管内皮细胞生长因子是调节血管新生的最重要的因子(Ferrara N.VEGF and the quest for tumor angiogenesisfactor.Nat.Rev.Cancer,2002,2(10):795-803)。VEGF参与调节正常及非正常的肿瘤和眼内病症的血管新生,例如眼部的许多疾病都涉及血管发生,包括年龄相关性黄斑变性(AMD)、视网膜静脉阻塞(RVO)、糖尿病视网膜病变(DR)和病理性近视等。由于VEGF信号传递对血管新生的重要性,阻断VEGF或VEGF受体从而达到抑制血管新生,对包括癌症、视网膜血管病变等与血管新生相关的疾病有着重要的治疗作用。在过去的十多年,诞生了一些用于治疗眼部新生血管性眼病的抗VEGF药物,如哌加他尼(Macugen)、贝伐单抗(Avastin)、雷珠单抗(Lucentis)、阿柏西普(Eylea)等。
虽然对于肿瘤或眼部疾病的单克隆抗体的开发方面已经取得了显著的成效,但是对于进一步的改进仍然存在需求。双特异性的抗体或蛋白分子对于提高的活性或降低的副作用提供了一种新的选择。目前还没有能够同时结合PK和VEGF的研究报道。
发明内容
发明简述
本发明第一方面是提供一种双特异性结合分子,包含特异性结合人VEGF的抗原结合位点和特异性结合人PK的抗原结合位点。
在本发明的一个实施方案中,根据本发明所述的双特异性结合分子,所述特异性结合人VEGF的抗原结合位点包含VEGFR-1的胞外结构域2和VEGFR-2的胞外结构域3,在某些优选的实施例中,所述特异性结合人VEGF的抗原结合位点进一步包含VEGFR-2的胞外结构域4;更优选地,所述特异性结合人VEGF的抗原结合位点还包含免疫球蛋白Fc片段。
在本发明的一个实施方案中,根据本发明所述的双特异性结合分子,所述特异性结合人VEGF的抗原结合位点包含VEGFR-1的胞外结构域2、VEGFR-2的胞外结构域3和免疫球蛋白Fc片段;其中所述VEGFR-1的胞外结构域2包含SEQ ID NO:7所述的氨基酸序列;所述VEGFR-2的胞外结构域3包含SEQ ID NO:8所述的氨基酸序列;所述免疫球蛋白Fc片段包含SEQ ID NO:9所述的氨基酸序列。
在本发明的一个实施方案中,根据本发明所述的双特异性结合分子,所述特异性结合人VEGF的抗原结合位点包含VEGFR-1的胞外结构域2、VEGFR-2的胞外结构域3和4,以及免疫球蛋白Fc片段;其中所述VEGFR-1的胞外结构域2包含SEQ ID NO:7所述的氨基酸序列;所述VEGFR-2的胞外结构域3包含SEQ ID NO:8所述的氨基酸序列;所述VEGFR-2的胞外结构域4具有如SEQ ID NO:51所述的氨基酸序列;
所述免疫球蛋白Fc片段具有如SEQ ID NO:52所述的氨基酸序列。
在某些具体的实施方案中,根据本发明所述的双特异性结合分子,所述特异性结合人VEGF的抗原结合位点包含SEQ ID NO:10或SEQ ID NO:53所述的氨基酸序列。
在本发明的一个实施方案中,根据本发明所述的双特异性结合分子,所述特异性结合人PK的抗原结合位点包含PK结合性免疫球蛋白单一可变域,并具有SEQ ID NO:1-3所述的CDR1-3区,或者SEQ ID NO:1、SEQ ID NO:4和SEQ ID NO:3所述的CDR1-3区。
在某些具体的实施方案中,根据本发明所述的双特异性结合分子,所述PK结合性免疫球蛋白单一可变域为VHH域。
在某些具体的实施方案中,根据本发明所述的双特异性结合分子,所述PK结合性的VHH域包含SEQ ID NO:5、SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16、SEQ ID NO:18和SEQ ID NO:20中任一所述的氨基酸序列。
在某些具体的实施方案中,根据本发明所述的双特异性结合分子具有如SEQ IDNO:22、SEQ ID NO:24、SEQ ID NO:26、SEQ ID NO:28、SEQ ID NO:30、SEQ ID NO:32、SEQ IDNO:34、SEQ ID NO:36、SEQ ID NO:38和SEQ ID NO:40中任一所述的氨基酸序列。
本发明所述的双特异性结合分子至少是二价的,并且可以是三价、四价或多价,优选的,本发明所述的双特异性结合分子为二价、三价或者四价结合分子,优选二价结合分子。
本发明另一方面在于提供一种分离的核酸,其编码本发明所述的双特异性结合分子。
本发明的另一方面还在于提供包含本发明所述核酸的载体,优选地所述载体是表达载体。其能够在原核或真核宿主细胞表达所述核酸。
本发明的另一方面还在于提供包含本发明所述核酸或载体的宿主细胞,优选地,所述宿主细胞是原核细胞或真核细胞。
本发明的另一方面还在于提供一种药物组合物,其包含本发明所述的结合分子,和药学上可接受的赋形剂。
本发明的另一方面还在于提供本发明所述的结合分子在制备用于预防或治疗血管疾病的药物中的用途。
本发明的另一方面还在于提供一种预防或治疗受试者中血管疾病的方法,包括给予本发明所述的结合分子。
在某些具体的实施方式中,本发明所述血管疾病为水肿、类风湿性关节炎、痛风、肠道疾病、口腔粘膜炎、神经性疼痛、炎性疼痛、椎管狭窄-退行性脊柱疾病、糖尿病、动脉或静脉血栓形成、主动脉瘤、骨关节炎、脉管炎、肺栓塞、中风、败血病、系统性红斑狼疮性肾炎和烧伤、眼部疾病。
优选的,在某些实施例中,本发明所述水肿优选自遗传性血管性水肿、脑水肿或头部外伤。
优选的,在某些实施例中,本发明所述眼部疾病优选自糖尿病性黄斑水肿,视网膜静脉阻塞,年龄相关性黄斑变性,继发于视网膜静脉阻塞的黄斑水肿,葡萄膜炎、眼内炎或息肉状脉络膜血管病变。
发明详述
本发明的一个实施方案是特异性结合人血管内皮生长因子(VEGF)和人血浆激肽释放酶(PK)双特异性结合分子,其包含特异性结合人VEGF的抗原结合位点和特异性结合人PK的抗原结合位点。
在一种实施方式中,本发明所述的双特异性结合分子,所述特异性结合人VEGF的抗原结合位点是人VEGF受体或受体的一部分。其能够识别并结合VEGF配体但不能激活受体复合物,起到抑制作用,与配体结合并阻止配体与常规受体结合。例如,本发明的VEGF抗原结合位点是人VEGF受体1(VEGFR-1)的细胞外结构域1-7中的任一个结构域,或者多个结构域的组合。再例如,本发明的VEGF拮抗剂是人VEGF受体2(VEGFR-2)的细胞外结构域1-7中的任一个结构域,或者多个结构域的组合。再例如,本发明的VEGF拮抗剂是人VEGF受体3(VEGFR-3)的细胞外结构域1-7中的任一个结构域,或者多个结构域的组合。再例如,本发明的VEGF拮抗剂是人VEGF受体1,和/或VEGF受体2,和/或VEGF受体3中1-7个结构域中的一个或多个细胞外结构域的组合。
在一些实施例中,本发明所述的双特异性结合分子中,所述特异性结合人VEGF的抗原结合位点包含VEGFR-1的细胞外结构域2和VEGFR-2的细胞外结构域3。胞外结构域之间通过接头彼此连接,或者直接彼此连接。
在一些实施例中,本发明所述的双特异性结合分子中,所述特异性结合人VEGF的抗原结合位点包含VEGFR-1的细胞外结构域2、VEGFR-2的细胞外结构域3和VEGFR-2的细胞外结构域4。各胞外结构域之间通过接头彼此连接,或者直接彼此连接。
在一些实施例中,本发明所述的双特异性结合分子中,所述特异性结合人VEGF的抗原结合位点包含VEGFR-1的胞外第2结构域,其含有SEQ ID NO:7所述的氨基酸序列。
在一些实施例中,本发明所述的双特异性结合分子中,所述特异性结合人VEGF的抗原结合位点包含VEGFR-2的胞外结构域3,其含有SEQ ID NO:8所述的氨基酸序列。
在一些实施例中,本发明所述的双特异性结合分子中,所述特异性结合人VEGF的抗原结合位点包括VEGFR-2的胞外结构域4,其含有SEQ ID NO:51所述的氨基酸序列。
在一些实施例中,本发明所述的双特异性结合分子中,所述特异性结合人VEGF的抗原结合位点包含人VEGF受体的任一胞外结构域融合至免疫球蛋白Fc。优选的,所述免疫球蛋白Fc为人免疫球蛋白Fc片段。优选的,所述人免疫球蛋白Fc片段选自如下片段之一:IgG1Fc、IgG2Fc、IgG3Fc和IgG4Fc。更优选的,人免疫球蛋白Fc为IgG1Fc或其突变体。在某些实施例中,人免疫球蛋白Fc具有SEQ ID NO:9或SEQ ID NO:52所述的氨基酸序列。
在一个优选实施例中,本发明所述的特异性结合人VEGF的抗原结合位点包含VEGFR-1的细胞外结构域2,VEGFR-2的细胞外结构域3和免疫球蛋白IgG1Fc。优选的,所述融合蛋白含有SEQ ID NO:10(阿柏西普)所述的氨基酸序列。
在一个优选实施例中,本发明所述的特异性结合人VEGF的抗原结合位点包含VEGFR-1的细胞外结构域2,VEGFR-2的细胞外结构域3,VEGFR-2的细胞外结构域4和免疫球蛋白IgG1Fc。优选的,所述融合蛋白含有SEQ ID NO:53(康柏西普)所述的氨基酸序列。
在另一种实施方式中,本发明所述的特异性结合人VEGF的抗原结合位点也可选自根据本领域的常规方式(如杂交瘤技术、噬菌体展示技术等)获得的,或者现有已报道的特异性结合VEGF的抗体(示例性如贝伐单抗、雷珠单抗)的一条重链、轻链、重链可变结构域(重链Fab)、轻链可变结构域(重链Fab)或Fv片段(其中Fv通过如二硫键等连接肽进行稳定和链接),或其他的VEGF结合性片段。在一些优选的实施例中,本发明所述的特异性结合人VEGF的抗原结合位点选自现有报道的VEGF结合性片段,如Brolucizumab,其重链可变结构域具有如SEQ ID NO:42-44所述的CDRH1-3,轻链可变结构域具有如SEQ ID NO:45-47所述的CDRL1-3;进一步其具有SEQ ID NO:48所述的重链可变结构域和SEQ ID NO:49所述的轻链可变结构域,重链可变结构域和轻链可变结构域通过连接肽进行连接;更进一步地其具有SEQ ID NO:50所述的氨基酸序列。
在一种实施方式中,根据本发明所述的双特异性结合分子,所述PK结合性免疫球蛋白单一可变域为VHH域。
在某些实施方式中,根据本发明所述的双特异性结合分子,所述PK结合性的VHH域包含SEQ ID NO:5、SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16、SEQ ID NO:18和SEQ IDNO:20中任一所述的氨基酸序列。
在某些实施方式中,根据本发明所述的双特异性结合分子,其中结合人VEGF的抗原结合位点和结合人PK的抗原结合位点之间彼此直接连接,或通过连接肽进行连接。
在某些实施方式中,根据本发明所述的特异性结合人VEGF的抗原结合位点和特异性结合人PK的抗原结合位点的双特异性结合分子,所述结合分子具有如SEQ ID NO:22、SEQID NO:24、SEQ ID NO:26、SEQ ID NO:28、SEQ ID NO:30、SEQ ID NO:32、SEQ ID NO:34、SEQID NO:36、SEQ ID NO:38和SEQ ID NO:40中任一所述的氨基酸序列。
在本申请中使用的术语“双特异性结合分子”是指包含一个第一抗原结合分子和至少一个第二抗原结合分子的分子。双特异性结合分子可包含多余一个第一抗原结合分子和/或多于一个第二抗原结合分子。本发明的“双特异性”并不解释为从双特异性结合分子中排除对第一抗原和第二抗原以外的分子具有结合特异性的其他结合组分,示例性地如结合血清白蛋白的结合组分。通常来说,本发明的第一抗原不同于第二抗原。在本发明的一些具体实施例中,本发明的第一抗原为VEGF,第二抗原为PK;或者第一抗原为PK,第二抗原为VEGF。
在本申请中使用的术语“结合”或“特异性结合”指在体外测定法中,抗原结合分子与抗原(如人VEGF或人PK)的表位进行结合。结合的亲和力由Ka(结合速率)或Kd(解离常数)进行表征。结合或特异性结合Kd在10-8mol/L以下,优选10-9mol/L到10-13mol/L。
在本申请中使用的术语“表位”意指抗原的与抗体特异性结合的部分。表位通常由部分(moiety)(诸如氨基酸或多糖侧链)的化学活性(诸如,极性、非极性或疏水性)表面基团构成,并且可以具有特定三维结构特征以及特定电荷特征。表位可由形成构象空间单元的连续和/或不连续氨基酸构成。对于不连续表位,来自抗原的线性序列的不同部分的氨基酸因蛋白质分子的折叠而在三维空间上靠近。
在本申请中使用的术语“结合位点”或“抗原结合位点”指配体实际上结合的抗原结合分子的区域。例如如本发明所述的特异性结合人VEGF的抗原结合位点或特异性结合人PK的抗原结合位点包括抗VEGF或抗PK的抗体、抗体片段或抗体样分子。抗体包括但不限于单克隆抗体及嵌合单克隆抗体。抗体涵盖通过宿主细胞重组表达产生的完全免疫球蛋白(如单克隆抗体)、抗体片段或抗体样分子,包括单链抗体及线型抗体;抗体样分子包括本发明所述的免疫球蛋白单一可变域。抗体样分子的其他实例还包括免疫球蛋白超家族抗体(IgSF)或CDR移植分子。
在本申请中使用的术语“免疫球蛋白”及“免疫球蛋白序列”是指无论是重链抗体还是常规4链抗体,均包括其全长抗体、其单个的链以及其所有部分、域或片段(包括但不限于抗原结合域或片段,分别例如VHH域或VH/VL域)。
在本申请中使用的术语“序列”一般应理解为既包括相关氨基酸序列,又包括编码所述序列的核酸序列或核苷酸序列。
在本申请中使用的术语“域”是指折叠蛋白结构,其能够独立于蛋白的其余部分维持其三级结构。一般而言,域负责蛋白的单个的功能性质,且在许多情况下可添加、移除或转移至其他蛋白而不损失蛋白的其余部分和/或域的功能。
在本申请中使用的术语“免疫球蛋白可变域”是指基本上由“框架区1”或“FR1”、“框架区2”或“FR2”、“框架区3”或“FR3”、及“框架区4”或“FR4”的四个“框架区”组成的免疫球蛋白域;所述框架区被“互补决定区1”或“CDR1”、“互补决定区2”或“CDR2”、及“互补决定区3”或“CDR3”的三个“互补决定区”或“CDR”间隔开来。因此,免疫球蛋白可变域的一般结构或序列可如下表示为:FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。免疫球蛋白可变域因具有抗原结合位点而赋予抗体对抗原的特异性。对于常规4链抗体,其包括免疫球蛋白轻链可变结构域(VL),和免疫球蛋白重链可变结构域(VH),并且由轻链和重链对直接参与抗体与抗原结合。所述构架区的序列普遍保守,其通过3个“高变区”(或互补性决定区,CDRs)相连接。每条链中的CDR通过框架区以其三维结构保持并与来自另一条链的CDR一起形成抗原结合位点。
在本申请中使用的术语“免疫球蛋白单一可变域”是指能够在不与其他可变的免疫球蛋白域配对的情况下特异性结合抗原表位的免疫球蛋白可变域。本发明含义中的免疫球蛋白单一可变域的一个实例为“域抗体”,例如免疫球蛋白单一可变域VH及VL(VH域及VL域)。免疫球蛋白单一可变域的另一实例为如下文定义的来自骆驼科的“VHH域”(或简称为“VHH”)。
在本申请中使用的术语“高变区”指负责抗原结合的抗体的氨基酸残基。高变区包括来自“互补性决定区”或“CDRs”的氨基酸残基。“构架”或“FR”区是除本文中定义的高变区残基之外的那些可变结构域区域。因此,抗体的轻链或重链可变结构域从N端到C端包括结构域FR1,CDR1、FR2、CDR2、FR3、CDR3和FR4。各条链上的CDR通过所述框架氨基酸分开。
常规4链抗体(例如本领域中已知的IgG、IgM、IgA、IgD或IgE分子)或源自所述常规4链抗体的Fab片段、F(ab′)2片段、Fv片段(例如二硫键连接的Fv或scFv片段)或双特异抗体(均为本领域中已知)的抗原结合域,通常不视为免疫球蛋白单一可变域,因为他们并非通过一个(单一)免疫球蛋白域与抗原的各别表位发生结合,而是通过共同结合抗原表位的一对(缔合)免疫球蛋白域(例如轻链及重链可变域),即通过免疫球蛋白域的VH-VL对进行结合。其中“Fab”指包含抗体重链可变结构域(VH),抗体恒定结构域1(CH1),抗体轻链可变结构域(VL)和抗体轻链恒定结构域(CL)的多肽,重链和轻链结构域之间通过二硫键稳定。一个Fab可形成一个抗原结合位点,两个“Fab”可通过二硫键形成“(Fab)2”,因此具有两个抗原结合位点。“scFv”指包含抗体重链可变结构域(VH)、抗体恒定结构域1(CH1)的多肽,重链和轻链结构域之间通过二硫键稳定,scFv是常规4链抗体抗原结合的关键区域。
在本申请中使用的术语“VHH域”,也称为VHH、VHH抗体片段和VHH抗体,最初被描述为“重链抗体”(即“缺乏轻链的抗体”)的抗原结合免疫球蛋白(可变)域。术语“VHH域”与存在于常规4链抗体中的重链可变域(其在本文中称为“VH”或“VH”)以及存在于常规4链抗体中的轻链可变域(其在本文中称为“VL”或“VL”)进行区分。VHH域可在无其他抗原结合域的情况下特异性结合表位(此与常规4链抗体中的VH或VL域相反,在该情况下表位由VL域与VH域一起识别)。VHH域为由单一免疫球蛋白域形成的小型稳定及高效的抗原识别单元。
在本发明的上下文中,术语VHH域、VHH、VHH抗体片段、VHH抗体可互换使用,且表示免疫球蛋白单一可变域(具有FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4结构,并且特异性结合表位而无需存在另一免疫球蛋白可变域)。
本发明的免疫球蛋白单一可变域的生物来源或具体制备方法不受限制。例如,获得VHH可包括以下方法:分离天然存在的重链抗体的VHH域;或筛选包含重链抗体或VHH的文库且从中分离VHH;)表达编码具有天然存在序列的VHH的核酸分子;在亲和力成熟之后使具有天然存在序列的VHH“人源化”,或表达编码这类人源化VHH的核酸;使动物物种(特别是哺乳动物物种,例如人)天然存在抗体的免疫球蛋白单一可变重域“骆驼化”,或表达编码这类骆驼化域的核酸分子;使VH“骆驼化”,或表达编码这类骆驼化VH的核酸分子;使用以合成方式或半合成方式制备蛋白、多肽或其他氨基酸序列的技术等。
本发明的蛋白或多肽中的免疫球蛋白单一可变域为氨基酸序列基本上对应于天然存在VHH域的氨基酸序列的VHH域,但其已经“人源化”或“序列最优化”(任选在亲和力成熟之后),即通过以人的常规4链抗体可变重域中相应位置处存在的一个或多个氨基酸残基置换该天然存在VHH序列的氨基酸序列中的一个或多个氨基酸残基,例如人源化的VHH域可含有一个或多个完全人框架区序列。这可使用本领域中已知的方法进行。此外,本领域技术人员还有可能将一个或多个VHH的CDR“移植”于其他“支架”(包括但不限于人支架或非免疫球蛋白支架)上。用于这种CDR移植的适合支架及技术在本领域中是已知的。
在本申请中使用的术语“价”指抗原结合位点在双特异性结合分子上存在的具体数量。例如,术语“二价”、“四价”、“六价”指在抗体分子上分别存在两个、四个和六个抗原结合位点。本发明所述的双特异性结合分子是至少“二价的”,并且可以是“三价”、“四价”或更多价。优选地、本发明所述的双特异性结合分子是二价、三价或四价。在一个实施方案中,所述双特异性结合分子是二价的。在一个实施方案中,所述双特异性结合分子是三价的。在一个实施方案中,所述双特异性结合分子是四价的。
根据本发明所述的双特异性结合分子还包括具有“保守序列修饰”的结合分子或抗体(“变体”)。这意味着不影响或改变上述特征的核苷酸和氨基酸序列修饰。可以通过本领域已知的技术对核苷酸或氨基酸进行修饰,如位点定向诱变和PCR介导的诱变。在双特异性结合分子中的非必需氨基酸残基可以优选地被来自相同侧链家族的另一种氨基酸残基置换。因此,“变体”双特异性结合分子是指其氨基酸序列与“母体”氨基酸序列相比,具有一个或多个氨基酸的添加、缺失和/或置换。根据本发明所述的“变体”双特异性结合分子也包括接头(如果存在)被修饰或被另一个接头替换的情形。因此本发明所述双特异性结合分子的核苷酸或氨基酸序列均包括具有“保守序列修饰”与母体核苷酸或氨基酸具有至少80%、85%、90%、95%、98%、99%或以上同源性的序列。
在某些实施方式中,本发明所述的双特异性结合分子是具有两种不同特异性的二价双特异性结合分子,其包括一条特异性结合PK的蛋白或多肽链,和一条特异性结合VEGF的蛋白或多肽链,其中两条链通过肽连接头进行连接,或者直接连接。
在某些实施方式中,本发明所述的双特异性结合分子是具有两种不同特异性的三价或更多价的结合分子,其中在前述二价双特异性结合分子的基础上,还具有一个或多个特异性结合VEGF或PK的蛋白或多肽链,通过肽连接头进行连接。其中特异性结合VEGF或PK的蛋白或多肽链可以是免疫球蛋白单一可变域(例如VH、VL、VHH)、scFv或其他具有抗原结合能力的蛋白或多肽片段(例如融合蛋白)。
在本申请中使用的术语“肽连接头”指具有氨基酸序列的肽,优选地肽连接头通过合成获得。根据本发明所述的肽接头用于连接不同的抗原结合位点的蛋白或多肽片段,或者用于连接结合于同一抗原结合位点内不同的蛋白或多肽片段(如形成融合蛋白),从而一起形成本发明所述的二价、三价、四价或更多价的双特异性结合分子。所述肽接头具有至少5个氨基酸长度,优选地至少10个氨基酸长度,更优选地10-50个氨基酸长度。在一个实施方案中,所述肽接头是(GxS)n,其中G=甘氨酸,S=丝氨酸,(x=3和n=3,4,5或6)或(x=4和n=2,3,4或5),优选地x=4和n=2或3,更优选地x=4,n=2((G4S)2)。还可以将另外的G=甘氨酸,例如GG,或GGG加入所述(GxS)n肽接头。
在本申请中使用的术语“宿主细胞”指可以被改造从而产生根据本发明所述的双特异性结合分子的任何细胞系。在一个实施方案中,将HEK293细胞和CHO细胞用作宿主细胞。在本申请中,表述“细胞”、“细胞系”和“细胞培养物”可交替使用,且包括他们的后代。
本发明的另一个方面在于提供包含本发明所述的双特异性结合分子的药物组合物,所述药物组合物包含本发明所述的双特异性结合分子和药学上可接受的赋形剂。
在本申请中使用的术语“药学上可接受的赋形剂”是指能够递送本发明有效量活性分子、不干扰活性分子生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质,包括任何本领域普通技术人员已知的溶剂、分散介质、表面活性剂、抗氧剂、防腐剂(例如抗菌剂、抗真菌剂)、等张剂、吸收延迟剂、盐、防腐剂、药物、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、矫味剂、染料等及其组合。优选地,所述赋形剂适合用于眼内、静脉内、肌内、皮下、肠胃外、关节内等方式给药。
本发明本发明的另一个方面在于提供本发明所述的双特异性结合分子在制备用于预防或治疗血管疾病的药物中的用途。
本发明本发明的另一个方面在于提供一种预防或治疗受试者中血管疾病的方法,包括给予本发明所述的双特异性结合分子。
本发明结合分子可以通过本领域已知的方式施用,例如肠胃外施用,包括但不限于肌肉内、静脉内、动脉内、腹膜内、大脑内、眼内、关节内、囊下、脊柱内、硬膜外、胸骨内注射或输注。
本发明的“血管疾病”包括水肿、类风湿性关节炎、痛风、肠道疾病、口腔粘膜炎、神经性疼痛、炎性疼痛、椎管狭窄-退行性脊柱疾病、糖尿病、动脉或静脉血栓形成、主动脉瘤、骨关节炎、脉管炎、肺栓塞、中风、败血病、系统性红斑狼疮性肾炎和烧伤、眼部疾病等。在一些优选实施方案中,所述水肿选自遗传性血管性水肿、脑水肿或头部外伤等。在另一些优选实施方案中,所述眼部疾病选自糖尿病性黄斑水肿,视网膜静脉阻塞,年龄相关性黄斑变性,继发于视网膜静脉阻塞的黄斑水肿,葡萄膜炎、眼内炎或息肉状脉络膜血管病变等。
本发明示例给出的本发明所述的双特异性结合分子的氨基酸和核苷酸序列对应关系分别见表1和表2:
表1部分双特异性结合分子的氨基酸序列
表2部分双特异性结合分子的核苷酸序列
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。
实施例一双特异性抗体的制备
1、双特异性结合分子的构建
制备和鉴定本发明的双特异性结合分子过程中需要用到多种抗体,包括特异性结合VEGF的蛋白,如阿柏西普(商品名Eylea,蛋白及其序列在WO0075319A中有所描述),和特异性结合PK的重链单域抗体(VHH)。
1)结合PK的重链单域抗体(VHH)文库构建
利用购自Enzyme research laboratories公司的血浆激态释放酶抗原分别对2只羊驼(alpaca)进行4次免疫。免疫结束评估免疫反应效果后,取50mL羊驼外周血淋巴细胞并提取Total RNA,并反转录成cDNA,通过2轮PCR扩增羊驼重链抗体的可变区片段VHH。将VHH片段构建入噬菌体展示载体中,并通过电转化将携带有单域抗体基因片段的产物转入感受态大肠杆菌中,从而获得单域抗体免疫文库2个,计算库容大小均约5*108。为检测文库的插入率,随机选取100个克隆做菌落PCR,结果显示插入率大于85%。
2)单域抗体库海选
将来自上述文库制备的噬菌体悬液用2%的BSA稀释封闭,与Dynabeads共孵育,收集负筛孵育后的噬菌体,将该噬菌体悬液与抗原生物素包被且封闭后的Dynabeads孵育,按照磁珠筛选系统方法进行结合和清洗,使用trypsin洗脱噬菌体。洗脱后的噬菌体溶液与对数期SS320细胞充分混合后37℃静置培养30分钟,涂布抗性平板,同时进行噬菌体滴度检测,37℃培养过夜,计算噬菌体输入和输出等,刮板制备输入噬菌体并进行2-3轮筛选,每次筛选降低抗原使用浓度,以增加筛选亲和力较好的抗体。然后使用ELISA方法对获得的克隆进行筛选获得候选克隆,再经过进一步蛋白纯化表达,进行活性验证分析,最终获得候选克隆,选择其中一个分子进行亲和力成熟和采用通用纳米人源化策略(参考文献:Vinckeet.al.,J.Biol.Chem.2009,284:3273-3284)对候选克隆进行人源化改造。
3)纳米抗体双特异性结合分子构建
以pcDNA3.4载体为基本表达框架,通过常规分子生物学技术方法,例如通过基因合成目的片段作为模版,然后通过PCR对Eylea和纳米抗体目的片段分别进行扩增,最后通过重叠PCR方法或者直接通过多片段Infusion连接的方式将包含不同纳米抗体和Eylea分子的序列连接进酶切载体pcDNA3.4中,其中纳米抗体可以在Eylea序列的N端,也可以在Eylea序列的C端,中间连接部分的Linker为3个柔性G4S重复序列,连接产物通过热激转化进感受态DH5ɑ细胞,进行菌落PCR鉴定,将阳性克隆进行培养,提取少量质粒送检测和测序验证,酶切和测序正确即构建完成。
2、双特异性结合分子的表达和纯化
将测序正确的轻重链质粒转染expiCHO或HEK293细胞中进行表达,7-10天后,细胞上清利用AKTA蛋白纯化仪进行亲和纯化(例如protein A填料),得到双特异结合分子蛋白,用于后续亲和力及其它生物学活性实验。
实施例二、与人VEGF结合亲和力测试
使用高通量分子互作检测系统(Biacore 8K),选用Protein A芯片进行检测;先进行抗原抗体浓度摸索,选择适合浓度的抗体和适合浓度范围的抗原,芯片先偶联不同浓度抗体(一般3个不同浓度),结合时间30s,流速为10ul/min,分别结合一个浓度抗原,流速为30ul/min,时间约120s,进行结合解离初步检测,根据结果显示的RU值选择最适合抗体浓度,并设计合适的抗原浓度(至少6个浓度);然后开始亲和力检测,芯片先藕联适合抗体浓度,结合时间90s,流速为10ul/min,再与不同浓度的抗原进行结合(时间约120s)解离(时间约300s)检测,流速为30ul/min;结果用分析软件进行分析,获得亲和力数据。
表3双特异性结合分子与人VEGF结合亲和力参数
实施例三、与人PK结合亲和力测试
使用高通量分子互作检测系统(Biacore 8K),选用Protein A芯片进行检测;先进行抗原抗体浓度摸索,选择适合浓度的抗体和适合浓度范围的抗原,芯片先偶联不同浓度抗体(一般3个不同浓度),结合时间30s,流速为10ul/min,分别结合一个浓度抗原,流速为30ul/min,时间约120s,进行结合解离初步检测,根据结果显示的RU值选择最适合抗体浓度,并设计合适的抗原浓度(至少6个浓度);然后开始亲和力检测,芯片先藕联适合抗体浓度,结合时间90s,流速为10ul/min,再与不同浓度的抗原进行结合(时间约120s)解离(时间约300s)检测,流速为30ul/min;结果用分析软件进行分析,获得亲和力数据。结果如表4。
表4双特异性结合分子与人PK结合亲和力参数
其中MHL(Lanadelumab)可参见现有技术(如专利WO2011085103A、WO2014113701A、WO2017100679A等),并可根据本领域的常规技术手段进行构建及制备。
实施例四、血管内皮生长因子(VEGF)生物学活性检测
将生长良好的人脐带静脉血管内皮细胞(HUVEC,ScienCell公司)接种于96孔培养板中,2×103细胞/孔,100μl/孔,37℃,5%CO2培养20h;用含2%胎牛血清的ECM培养基(内皮细胞培养基,货号1001,Sciencell公司)配制不同摩尔浓度(0.2、2、17.56、26.34、39.51、59.26、88.89、133.33、200、2000ng/ml)的双特异性结合分子,分别与40ng/ml的VEGF(R&D公司)混匀,孵育2h;再加至接种有HUVEC细胞的96孔板上,100μl/孔,每组3复孔,5%CO2继续孵育96h,加入CCK-8试剂(Dojindo公司),以EC50表示本发明的抑制作用。结果如表5所示,本发明的双特异性结合分子均可有效抑制VEGF刺激的HUVEC细胞增殖作用,表明本发明的双特异性结合分子具有较好抑制VEGF的生物学活性。
表5:双特异性结合分子抑制VEGF诱导HUVEC细胞增殖作用
样品 | EC50(nM) |
KH01 | 0.49 |
KH02 | 0.508 |
KH03 | 0.49 |
KH04 | 0.45 |
KH05 | 0.50 |
KH06 | 0.52 |
KH07 | 0.429 |
KH08 | 0.333 |
KH09 | 0.427 |
KH10 | 1.31 |
实施例五、人血浆活性检测
人血浆中存在PPK、PK等蛋白,但通过检测发现人血浆原液或稀释液中PK并不显现出活性,可能是一个酶活抑制的平衡状态。如果额外加入Factor XIIa因子将打破平衡,产生具有酶活性的PK蛋白,以此原理检测PK抑制剂的活性。首先是蛋白样品准备,用检测缓冲液(20mM Tris-HCl,PH=7.50、150mM NaCl、1mM EDTA、0.1%PEG-8000和0.1%Triton X-100)将结合分子蛋白进行稀释至200μg/ml作为起始浓度,进行4倍梯度稀释,共11个浓度梯度,稀释好后待用。用检测缓冲液将人血浆稀释40倍,Factor XIIa因子稀释至100ng/ml,底物肽(H-Pro-Phe-Arg-AMC)稀释至1000μM备用。分别吸取50μl检测缓冲液及稀释后的各个浓度梯度结合分子蛋白溶液加至96孔不透光酶标板;另取20μl人血浆40倍稀释样至上述96孔板中,37℃孵育30min;再加入浓度为100ng/ml Factor XIIa 20μl,37℃孵育45min;最后向上述96孔不透光酶标板各孔中加入浓度1000μM底物肽(H-Pro-Phe-Arg-AMC)10μl。将准备好的96孔板放入多功能酶标仪(Spectra Max i3X)进行检测,检测参数:激发光360nm、发射光480nm,每60s读一次,共读10min。将酶反应速率(斜率)进行归一化处理后与浓度(nM)进行四参数曲线拟合,计算出IC50(nM),具体结果见表6。
表6双特异性结合分子的人血浆活性检测结果
样品 | EC50(nM) |
KH01 | 0.391 |
KH02 | 0.503 |
KH03 | 0.794 |
KH04 | 0.569 |
KH05 | 1.084 |
KH06 | 0.894 |
KH07 | 0.813 |
KH08 | 1.314 |
KH09 | 1.21 |
KH10 | 0.312 |
序列表
<110> 成都康弘生物科技有限公司
<120> 特异性结合VEGF和PK的双特异性结合分子及其用途
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Cys Ile Ser Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
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Gly
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Cys Ile Ser Ser Ser Gly Trp Ile Thr Asn Tyr Ala Asp Ser Val Lys
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Gly
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Ile Lys Tyr Tyr
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Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
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<210> 6
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<213> 人工序列(artifical sequence)
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caggtgcagc tggttgaatc tggcggagga ctcgttagac ctggcggctc tctgagactg 60
tcttgtgccg cctctggctt ctccattaag tactatgtga tcggctggtt cagacaggcc 120
cctggcaaag agagagaggg cgtcagctgc atctcttcct ctggcggatc taccaactac 180
gccgactccg tgaagggcag attcaccatc tccagagaca acgccaagaa caccgtgtac 240
ctgcagatga actccctgaa gcctgaggac accgccgtgt actactgtgc cgctgattct 300
ggcctgtccg actacgcctg ttgggctgat acaagaggcg tgcggagagg ctacctggaa 360
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<210> 7
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<212> PRT
<213> 人工序列(artifical sequence)
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Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
1 5 10 15
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
20 25 30
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
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Gln Thr Asn Thr Ile Ile
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Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu
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20 25 30
Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu
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Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe
50 55 60
Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu
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Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr
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Phe Val Arg Val His Glu Lys
100
<210> 9
<211> 227
<212> PRT
<213> 人工序列(artifical sequence)
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Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 10
<211> 432
<212> PRT
<213> 人工序列(artifical sequence)
<400> 10
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
1 5 10 15
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
20 25 30
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
35 40 45
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
50 55 60
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
65 70 75 80
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
85 90 95
Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile
100 105 110
Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr
115 120 125
Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys
130 135 140
His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly
145 150 155 160
Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr
165 170 175
Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met
180 185 190
Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Asp Lys Thr
195 200 205
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
210 215 220
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
225 230 235 240
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
245 250 255
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
260 265 270
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
275 280 285
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
290 295 300
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
305 310 315 320
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
325 330 335
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
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Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
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Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
370 375 380
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
385 390 395 400
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
405 410 415
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
420 425 430
<210> 11
<211> 1296
<212> DNA
<213> 人工序列(artifical sequence)
<400> 11
agcgacaccg gtagaccttt cgtagagatg tacagtgaaa tccccgaaat tatacacatg 60
actgaaggaa gggagctcgt cattccctgc cgggttacgt cacctaacat cactgttact 120
ttaaaaaagt ttccacttga cactttgatc cctgatggaa aacgcataat ctgggacagt 180
agaaagggct tcatcatatc aaatgcaacg tacaaagaaa tagggcttct gacctgtgaa 240
gcaacagtca atgggcattt gtataagaca aactatctca cacatcgaca aaccaataca 300
atcatagatg tggttctgag tccgtctcat ggaattgaac tatctgttgg agaaaagctt 360
gtcttaaatt gtacagcaag aactgaacta aatgtgggga ttgacttcaa ctgggaatac 420
ccttcttcga agcatcagca taagaaactt gtaaaccgag acctaaaaac ccagtctggg 480
agtgagatga agaaattttt gagcacctta actatagatg gtgtaacccg gagtgaccaa 540
ggattgtaca cctgtgcagc atccagtggg ctgatgacca agaagaacag cacatttgtc 600
agggtccatg aaaaagacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 660
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 720
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 780
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 840
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 900
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 960
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1020
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 1080
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1140
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 1200
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1260
tacacgcaga agagcctctc cctgtctccg ggtaaa 1296
<210> 12
<211> 132
<212> PRT
<213> 人工序列(artifical sequence)
<400> 12
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Val Asp Tyr Tyr
20 25 30
Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Gly Trp Ile Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
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Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg
100 105 110
Gly Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val
115 120 125
Thr Val Ser Ser
130
<210> 13
<211> 396
<212> DNA
<213> 人工序列(artifical sequence)
<400> 13
caggtgcagc tggttgaatc tggcggagga ctcgttagac ctggcggctc tctgagactg 60
tcttgtgccg cctctggctt ctccgtggac tactatgtga tcggctggtt cagacaggcc 120
cctggcaaag agagagaggg cgtcagctgc atctcttcct ctggctggat taccaactac 180
gccgactccg tgaagggcag attcaccatc tccagagaca acgccaagaa caccgtgtac 240
ctgcagatga actccctgaa gcctgaggac accgccgtgt actactgtgc cgctgattct 300
ggcctgtccg actacgcctg ttgggctgat acaagaggcg tgcggagagg ctacctggaa 360
gtttggggac agggcaccct ggtcacagtg tcatct 396
<210> 14
<211> 132
<212> PRT
<213> 人工序列(artifical sequence)
<400> 14
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Ala Asp Tyr Tyr
20 25 30
Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg
100 105 110
Gly Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val
115 120 125
Thr Val Ser Ser
130
<210> 15
<211> 396
<212> DNA
<213> 人工序列(artifical sequence)
<400> 15
caggtgcagc tggttgaatc tggcggagga ctcgttagac ctggcggctc tctgagactg 60
tcttgtgccg cctctggctt caaggcggac tactatgtga tcggctggtt cagacaggcc 120
cctggcaaag agagagaggg cgtcagctgc atctcttcct ctggcggatc taccaactac 180
gccgactccg tgaagggcag attcaccatc tccagagaca acgccaagaa caccgtgtac 240
ctgcagatga actccctgaa gcctgaggac accgccgtgt actactgtgc cgctgattct 300
ggcctgtccg actacgcctg ttgggctgat acaagaggcg tgcggagagg ctacctggaa 360
gtttggggac agggcaccct ggtcacagtg tcatct 396
<210> 16
<211> 132
<212> PRT
<213> 人工序列(artifical sequence)
<400> 16
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Ile Lys Tyr Tyr
20 25 30
Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala 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 Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg
100 105 110
Gly Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val
115 120 125
Thr Val Ser Ser
130
<210> 17
<211> 396
<212> DNA
<213> 人工序列(artifical sequence)
<400> 17
caagtgcaac tagtggaaag tggtggtggt ctcgtgaagc ccggcggatc tctgcggctg 60
tcttgtgctg cttctggctt ctccatcaag tactacgtga tcggctggtt tagacaggcc 120
cctggcaagg gcctggaggg cgtcagctgc atctcctcct ctggcggctc taccaactac 180
gctgattccg tgaaaggcag attcaccatc tctcgggaca atgccaagaa caccctgtac 240
ctgcagatga actccctgag agccgaggac acagccgtgt actactgcgc cgctgactcc 300
ggactgtccg actacgcctg ctgggccgat accagaggcg tgcggcgcgg atatctggaa 360
gtgtggggcc agggcaccct ggtgaccgtg tccagc 396
<210> 18
<211> 132
<212> PRT
<213> 人工序列(artifical sequence)
<400> 18
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Ile Lys Tyr Tyr
20 25 30
Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val 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 Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg
100 105 110
Gly Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val
115 120 125
Thr Val Ser Ser
130
<210> 19
<211> 396
<212> DNA
<213> 人工序列(artifical sequence)
<400> 19
caagtgcaac tagtggaaag tggtggtggt ctcgtgcggc ctggcggaag cctgcggctg 60
tcttgtgctg cttctggctt ctccatcaag tactacgtga tcggctggtt tagacaggct 120
cccggcaaag gactggaggg cgtttcttgc atcagctcct ctggcggctc taccaactac 180
gctgattccg tgaagggcag attcaccatc tctcgcgaca acgccaagaa caccgtgtat 240
ctgcagatga attccctgag agccgaggac accgccgtgt actactgcgc cgccgactcc 300
ggcctgtccg actacgcctg ctgggccgat acaagaggcg tcagacgggg ctacctggaa 360
gtgtggggcc agggtaccct ggtgaccgtg tccagc 396
<210> 20
<211> 132
<212> PRT
<213> 人工序列(artifical sequence)
<400> 20
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Ile Lys Tyr Tyr
20 25 30
Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg
100 105 110
Gly Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val
115 120 125
Thr Val Ser Ser
130
<210> 21
<211> 396
<212> DNA
<213> 人工序列(artifical sequence)
<400> 21
caagtgcaac tagtggaaag tggtggtggt ctggtccggc ctggcggaag cctgagactg 60
tcttgcgccg cttctggctt ttccatcaag tactacgtga tcggctggtt ccggcaggcc 120
cctggaaaag gactcgaggg cgtgtcctgc atctcctctt ctggcggctc caccaactac 180
gctgattccg tgaagggcag attcaccatc tctagagaca acgccaagaa tacagtgtat 240
ctgcagatga actccctgaa gcccgaggac accgccgtgt actactgcgc tgctgactcc 300
ggcctgtccg actacgcctg ttgggccgat accagaggcg tgcggcgcgg ctacctggaa 360
gtgtggggcc agggcaccct ggtgaccgtg tctagc 396
<210> 22
<211> 579
<212> PRT
<213> 人工序列(artifical sequence)
<400> 22
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Ile Lys Tyr Tyr
20 25 30
Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg
100 105 110
Gly Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val
115 120 125
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu
145 150 155 160
Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro
165 170 175
Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro
180 185 190
Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg
195 200 205
Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu
210 215 220
Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu
225 230 235 240
Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser
245 250 255
His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr
260 265 270
Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro
275 280 285
Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr
290 295 300
Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp
305 310 315 320
Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser
325 330 335
Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
340 345 350
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
355 360 365
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
370 375 380
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
385 390 395 400
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
405 410 415
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
420 425 430
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
435 440 445
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
450 455 460
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
465 470 475 480
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
485 490 495
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
500 505 510
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
515 520 525
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
530 535 540
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
545 550 555 560
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
565 570 575
Pro Gly Lys
<210> 23
<211> 1737
<212> DNA
<213> 人工序列(artifical sequence)
<400> 23
caggtgcagc tggttgaatc tggcggagga ctcgttagac ctggcggctc tctgagactg 60
tcttgtgccg cctctggctt ctccattaag tactatgtga tcggctggtt cagacaggcc 120
cctggcaaag agagagaggg cgtcagctgc atctcttcct ctggcggatc taccaactac 180
gccgactccg tgaagggcag attcaccatc tccagagaca acgccaagaa caccgtgtac 240
ctgcagatga actccctgaa gcctgaggac accgccgtgt actactgtgc cgctgattct 300
ggcctgtccg actacgcctg ttgggctgat acaagaggcg tgcggagagg ctacctggaa 360
gtttggggac agggcaccct ggtcacagtg tcatctggtg gcggcggttc cggtggcggt 420
ggctctggcg gcggtggttc cagcgacacc ggtagacctt tcgtagagat gtacagtgaa 480
atccccgaaa ttatacacat gactgaagga agggagctcg tcattccctg ccgggttacg 540
tcacctaaca tcactgttac tttaaaaaag tttccacttg acactttgat ccctgatgga 600
aaacgcataa tctgggacag tagaaagggc ttcatcatat caaatgcaac gtacaaagaa 660
atagggcttc tgacctgtga agcaacagtc aatgggcatt tgtataagac aaactatctc 720
acacatcgac aaaccaatac aatcatagat gtggttctga gtccgtctca tggaattgaa 780
ctatctgttg gagaaaagct tgtcttaaat tgtacagcaa gaactgaact aaatgtgggg 840
attgacttca actgggaata cccttcttcg aagcatcagc ataagaaact tgtaaaccga 900
gacctaaaaa cccagtctgg gagtgagatg aagaaatttt tgagcacctt aactatagat 960
ggtgtaaccc ggagtgacca aggattgtac acctgtgcag catccagtgg gctgatgacc 1020
aagaagaaca gcacatttgt cagggtccat gaaaaagaca aaactcacac atgcccaccg 1080
tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 1140
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1200
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1260
acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1320
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1380
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1440
tacaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gacctgcctg 1500
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1560
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctatagc 1620
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1680
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 1737
<210> 24
<211> 579
<212> PRT
<213> 人工序列(artifical sequence)
<400> 24
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Val Asp Tyr Tyr
20 25 30
Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Gly Trp Ile Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg
100 105 110
Gly Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val
115 120 125
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu
145 150 155 160
Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro
165 170 175
Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro
180 185 190
Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg
195 200 205
Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu
210 215 220
Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu
225 230 235 240
Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser
245 250 255
His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr
260 265 270
Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro
275 280 285
Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr
290 295 300
Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp
305 310 315 320
Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser
325 330 335
Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
340 345 350
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
355 360 365
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
370 375 380
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
385 390 395 400
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
405 410 415
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
420 425 430
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
435 440 445
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
450 455 460
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
465 470 475 480
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
485 490 495
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
500 505 510
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
515 520 525
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
530 535 540
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
545 550 555 560
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
565 570 575
Pro Gly Lys
<210> 25
<211> 1737
<212> DNA
<213> 人工序列(artifical sequence)
<400> 25
caggtgcagc tggttgaatc tggcggagga ctcgttagac ctggcggctc tctgagactg 60
tcttgtgccg cctctggctt ctccgtggac tactatgtga tcggctggtt cagacaggcc 120
cctggcaaag agagagaggg cgtcagctgc atctcttcct ctggctggat taccaactac 180
gccgactccg tgaagggcag attcaccatc tccagagaca acgccaagaa caccgtgtac 240
ctgcagatga actccctgaa gcctgaggac accgccgtgt actactgtgc cgctgattct 300
ggcctgtccg actacgcctg ttgggctgat acaagaggcg tgcggagagg ctacctggaa 360
gtttggggac agggcaccct ggtcacagtg tcatctggtg gcggcggttc cggtggcggt 420
ggctctggcg gcggtggttc cagcgacacc ggtagacctt tcgtagagat gtacagtgaa 480
atccccgaaa ttatacacat gactgaagga agggagctcg tcattccctg ccgggttacg 540
tcacctaaca tcactgttac tttaaaaaag tttccacttg acactttgat ccctgatgga 600
aaacgcataa tctgggacag tagaaagggc ttcatcatat caaatgcaac gtacaaagaa 660
atagggcttc tgacctgtga agcaacagtc aatgggcatt tgtataagac aaactatctc 720
acacatcgac aaaccaatac aatcatagat gtggttctga gtccgtctca tggaattgaa 780
ctatctgttg gagaaaagct tgtcttaaat tgtacagcaa gaactgaact aaatgtgggg 840
attgacttca actgggaata cccttcttcg aagcatcagc ataagaaact tgtaaaccga 900
gacctaaaaa cccagtctgg gagtgagatg aagaaatttt tgagcacctt aactatagat 960
ggtgtaaccc ggagtgacca aggattgtac acctgtgcag catccagtgg gctgatgacc 1020
aagaagaaca gcacatttgt cagggtccat gaaaaagaca aaactcacac atgcccaccg 1080
tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 1140
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1200
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1260
acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1320
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1380
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1440
tacaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gacctgcctg 1500
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1560
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctatagc 1620
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1680
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 1737
<210> 26
<211> 579
<212> PRT
<213> 人工序列(artifical sequence)
<400> 26
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Ala Asp Tyr Tyr
20 25 30
Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg
100 105 110
Gly Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val
115 120 125
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu
145 150 155 160
Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro
165 170 175
Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro
180 185 190
Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg
195 200 205
Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu
210 215 220
Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu
225 230 235 240
Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser
245 250 255
His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr
260 265 270
Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro
275 280 285
Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr
290 295 300
Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp
305 310 315 320
Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser
325 330 335
Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
340 345 350
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
355 360 365
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
370 375 380
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
385 390 395 400
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
405 410 415
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
420 425 430
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
435 440 445
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
450 455 460
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
465 470 475 480
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
485 490 495
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
500 505 510
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
515 520 525
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
530 535 540
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
545 550 555 560
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
565 570 575
Pro Gly Lys
<210> 27
<211> 1737
<212> DNA
<213> 人工序列(artifical sequence)
<400> 27
caggtgcagc tggttgaatc tggcggagga ctcgttagac ctggcggctc tctgagactg 60
tcttgtgccg cctctggctt caaggcggac tactatgtga tcggctggtt cagacaggcc 120
cctggcaaag agagagaggg cgtcagctgc atctcttcct ctggcggatc taccaactac 180
gccgactccg tgaagggcag attcaccatc tccagagaca acgccaagaa caccgtgtac 240
ctgcagatga actccctgaa gcctgaggac accgccgtgt actactgtgc cgctgattct 300
ggcctgtccg actacgcctg ttgggctgat acaagaggcg tgcggagagg ctacctggaa 360
gtttggggac agggcaccct ggtcacagtg tcatctggtg gcggcggttc cggtggcggt 420
ggctctggcg gcggtggttc cagcgacacc ggtagacctt tcgtagagat gtacagtgaa 480
atccccgaaa ttatacacat gactgaagga agggagctcg tcattccctg ccgggttacg 540
tcacctaaca tcactgttac tttaaaaaag tttccacttg acactttgat ccctgatgga 600
aaacgcataa tctgggacag tagaaagggc ttcatcatat caaatgcaac gtacaaagaa 660
atagggcttc tgacctgtga agcaacagtc aatgggcatt tgtataagac aaactatctc 720
acacatcgac aaaccaatac aatcatagat gtggttctga gtccgtctca tggaattgaa 780
ctatctgttg gagaaaagct tgtcttaaat tgtacagcaa gaactgaact aaatgtgggg 840
attgacttca actgggaata cccttcttcg aagcatcagc ataagaaact tgtaaaccga 900
gacctaaaaa cccagtctgg gagtgagatg aagaaatttt tgagcacctt aactatagat 960
ggtgtaaccc ggagtgacca aggattgtac acctgtgcag catccagtgg gctgatgacc 1020
aagaagaaca gcacatttgt cagggtccat gaaaaagaca aaactcacac atgcccaccg 1080
tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 1140
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1200
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1260
acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1320
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1380
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1440
tacaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gacctgcctg 1500
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1560
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctatagc 1620
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1680
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 1737
<210> 28
<211> 579
<212> PRT
<213> 人工序列(artifical sequence)
<400> 28
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Ile Lys Tyr Tyr
20 25 30
Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala 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 Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg
100 105 110
Gly Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val
115 120 125
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu
145 150 155 160
Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro
165 170 175
Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro
180 185 190
Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg
195 200 205
Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu
210 215 220
Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu
225 230 235 240
Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser
245 250 255
His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr
260 265 270
Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro
275 280 285
Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr
290 295 300
Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp
305 310 315 320
Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser
325 330 335
Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
340 345 350
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
355 360 365
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
370 375 380
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
385 390 395 400
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
405 410 415
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
420 425 430
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
435 440 445
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
450 455 460
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
465 470 475 480
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
485 490 495
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
500 505 510
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
515 520 525
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
530 535 540
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
545 550 555 560
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
565 570 575
Pro Gly Lys
<210> 29
<211> 1737
<212> DNA
<213> 人工序列(artifical sequence)
<400> 29
caagtgcaac tagtggaaag tggtggtggt ctcgtgaagc ccggcggatc tctgcggctg 60
tcttgtgctg cttctggctt ctccatcaag tactacgtga tcggctggtt tagacaggcc 120
cctggcaagg gcctggaggg cgtcagctgc atctcctcct ctggcggctc taccaactac 180
gctgattccg tgaaaggcag attcaccatc tctcgggaca atgccaagaa caccctgtac 240
ctgcagatga actccctgag agccgaggac acagccgtgt actactgcgc cgctgactcc 300
ggactgtccg actacgcctg ctgggccgat accagaggcg tgcggcgcgg atatctggaa 360
gtgtggggcc agggcaccct ggtgaccgtg tccagcggtg gcggcggttc cggtggcggt 420
ggctctggcg gcggtggttc cagcgacacc ggtagacctt tcgtagagat gtacagtgaa 480
atccccgaaa ttatacacat gactgaagga agggagctcg tcattccctg ccgggttacg 540
tcacctaaca tcactgttac tttaaaaaag tttccacttg acactttgat ccctgatgga 600
aaacgcataa tctgggacag tagaaagggc ttcatcatat caaatgcaac gtacaaagaa 660
atagggcttc tgacctgtga agcaacagtc aatgggcatt tgtataagac aaactatctc 720
acacatcgac aaaccaatac aatcatagat gtggttctga gtccgtctca tggaattgaa 780
ctatctgttg gagaaaagct tgtcttaaat tgtacagcaa gaactgaact aaatgtgggg 840
attgacttca actgggaata cccttcttcg aagcatcagc ataagaaact tgtaaaccga 900
gacctaaaaa cccagtctgg gagtgagatg aagaaatttt tgagcacctt aactatagat 960
ggtgtaaccc ggagtgacca aggattgtac acctgtgcag catccagtgg gctgatgacc 1020
aagaagaaca gcacatttgt cagggtccat gaaaaagaca aaactcacac atgcccaccg 1080
tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 1140
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1200
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1260
acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1320
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1380
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1440
tacaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gacctgcctg 1500
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1560
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctatagc 1620
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1680
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 1737
<210> 30
<211> 579
<212> PRT
<213> 人工序列(artifical sequence)
<400> 30
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Ile Lys Tyr Tyr
20 25 30
Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val 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 Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg
100 105 110
Gly Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val
115 120 125
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu
145 150 155 160
Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro
165 170 175
Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro
180 185 190
Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg
195 200 205
Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu
210 215 220
Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu
225 230 235 240
Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser
245 250 255
His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr
260 265 270
Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro
275 280 285
Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr
290 295 300
Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp
305 310 315 320
Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser
325 330 335
Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
340 345 350
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
355 360 365
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
370 375 380
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
385 390 395 400
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
405 410 415
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
420 425 430
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
435 440 445
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
450 455 460
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
465 470 475 480
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
485 490 495
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
500 505 510
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
515 520 525
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
530 535 540
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
545 550 555 560
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
565 570 575
Pro Gly Lys
<210> 31
<211> 1737
<212> DNA
<213> 人工序列(artifical sequence)
<400> 31
caagtgcaac tagtggaaag tggtggtggt ctcgtgcggc ctggcggaag cctgcggctg 60
tcttgtgctg cttctggctt ctccatcaag tactacgtga tcggctggtt tagacaggct 120
cccggcaaag gactggaggg cgtttcttgc atcagctcct ctggcggctc taccaactac 180
gctgattccg tgaagggcag attcaccatc tctcgcgaca acgccaagaa caccgtgtat 240
ctgcagatga attccctgag agccgaggac accgccgtgt actactgcgc cgccgactcc 300
ggcctgtccg actacgcctg ctgggccgat acaagaggcg tcagacgggg ctacctggaa 360
gtgtggggcc agggtaccct ggtgaccgtg tccagcggtg gcggcggttc cggtggcggt 420
ggctctggcg gcggtggttc cagcgacacc ggtagacctt tcgtagagat gtacagtgaa 480
atccccgaaa ttatacacat gactgaagga agggagctcg tcattccctg ccgggttacg 540
tcacctaaca tcactgttac tttaaaaaag tttccacttg acactttgat ccctgatgga 600
aaacgcataa tctgggacag tagaaagggc ttcatcatat caaatgcaac gtacaaagaa 660
atagggcttc tgacctgtga agcaacagtc aatgggcatt tgtataagac aaactatctc 720
acacatcgac aaaccaatac aatcatagat gtggttctga gtccgtctca tggaattgaa 780
ctatctgttg gagaaaagct tgtcttaaat tgtacagcaa gaactgaact aaatgtgggg 840
attgacttca actgggaata cccttcttcg aagcatcagc ataagaaact tgtaaaccga 900
gacctaaaaa cccagtctgg gagtgagatg aagaaatttt tgagcacctt aactatagat 960
ggtgtaaccc ggagtgacca aggattgtac acctgtgcag catccagtgg gctgatgacc 1020
aagaagaaca gcacatttgt cagggtccat gaaaaagaca aaactcacac atgcccaccg 1080
tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 1140
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1200
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1260
acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1320
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1380
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1440
tacaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gacctgcctg 1500
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1560
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctatagc 1620
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1680
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 1737
<210> 32
<211> 579
<212> PRT
<213> 人工序列(artifical sequence)
<400> 32
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Ile Lys Tyr Tyr
20 25 30
Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg
100 105 110
Gly Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val
115 120 125
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu
145 150 155 160
Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro
165 170 175
Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro
180 185 190
Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg
195 200 205
Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu
210 215 220
Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu
225 230 235 240
Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser
245 250 255
His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr
260 265 270
Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro
275 280 285
Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr
290 295 300
Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp
305 310 315 320
Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser
325 330 335
Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
340 345 350
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
355 360 365
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
370 375 380
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
385 390 395 400
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
405 410 415
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
420 425 430
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
435 440 445
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
450 455 460
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
465 470 475 480
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
485 490 495
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
500 505 510
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
515 520 525
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
530 535 540
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
545 550 555 560
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
565 570 575
Pro Gly Lys
<210> 33
<211> 1737
<212> DNA
<213> 人工序列(artifical sequence)
<400> 33
caagtgcaac tagtggaaag tggtggtggt ctggtccggc ctggcggaag cctgagactg 60
tcttgcgccg cttctggctt ttccatcaag tactacgtga tcggctggtt ccggcaggcc 120
cctggaaaag gactcgaggg cgtgtcctgc atctcctctt ctggcggctc caccaactac 180
gctgattccg tgaagggcag attcaccatc tctagagaca acgccaagaa tacagtgtat 240
ctgcagatga actccctgaa gcccgaggac accgccgtgt actactgcgc tgctgactcc 300
ggcctgtccg actacgcctg ttgggccgat accagaggcg tgcggcgcgg ctacctggaa 360
gtgtggggcc agggcaccct ggtgaccgtg tctagcggtg gcggcggttc cggtggcggt 420
ggctctggcg gcggtggttc cagcgacacc ggtagacctt tcgtagagat gtacagtgaa 480
atccccgaaa ttatacacat gactgaagga agggagctcg tcattccctg ccgggttacg 540
tcacctaaca tcactgttac tttaaaaaag tttccacttg acactttgat ccctgatgga 600
aaacgcataa tctgggacag tagaaagggc ttcatcatat caaatgcaac gtacaaagaa 660
atagggcttc tgacctgtga agcaacagtc aatgggcatt tgtataagac aaactatctc 720
acacatcgac aaaccaatac aatcatagat gtggttctga gtccgtctca tggaattgaa 780
ctatctgttg gagaaaagct tgtcttaaat tgtacagcaa gaactgaact aaatgtgggg 840
attgacttca actgggaata cccttcttcg aagcatcagc ataagaaact tgtaaaccga 900
gacctaaaaa cccagtctgg gagtgagatg aagaaatttt tgagcacctt aactatagat 960
ggtgtaaccc ggagtgacca aggattgtac acctgtgcag catccagtgg gctgatgacc 1020
aagaagaaca gcacatttgt cagggtccat gaaaaagaca aaactcacac atgcccaccg 1080
tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 1140
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1200
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1260
acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1320
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1380
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1440
tacaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gacctgcctg 1500
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1560
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctatagc 1620
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1680
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 1737
<210> 34
<211> 579
<212> PRT
<213> 人工序列(artifical sequence)
<400> 34
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
1 5 10 15
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
20 25 30
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
35 40 45
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
50 55 60
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
65 70 75 80
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
85 90 95
Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile
100 105 110
Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr
115 120 125
Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys
130 135 140
His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly
145 150 155 160
Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr
165 170 175
Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met
180 185 190
Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Asp Lys Thr
195 200 205
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
210 215 220
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
225 230 235 240
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
245 250 255
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
260 265 270
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
275 280 285
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
290 295 300
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
305 310 315 320
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
325 330 335
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
340 345 350
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
355 360 365
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
370 375 380
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
385 390 395 400
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
405 410 415
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
420 425 430
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
435 440 445
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly Ser
450 455 460
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Ile Lys Tyr Tyr Val
465 470 475 480
Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ser
485 490 495
Cys Ile Ser Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
500 505 510
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
515 520 525
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
530 535 540
Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg Gly
545 550 555 560
Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val Thr
565 570 575
Val Ser Ser
<210> 35
<211> 1737
<212> DNA
<213> 人工序列(artifical sequence)
<400> 35
agcgacaccg gtagaccttt cgtagagatg tacagtgaaa tccccgaaat tatacacatg 60
actgaaggaa gggagctcgt cattccctgc cgggttacgt cacctaacat cactgttact 120
ttaaaaaagt ttccacttga cactttgatc cctgatggaa aacgcataat ctgggacagt 180
agaaagggct tcatcatatc aaatgcaacg tacaaagaaa tagggcttct gacctgtgaa 240
gcaacagtca atgggcattt gtataagaca aactatctca cacatcgaca aaccaataca 300
atcatagatg tggttctgag tccgtctcat ggaattgaac tatctgttgg agaaaagctt 360
gtcttaaatt gtacagcaag aactgaacta aatgtgggga ttgacttcaa ctgggaatac 420
ccttcttcga agcatcagca taagaaactt gtaaaccgag acctaaaaac ccagtctggg 480
agtgagatga agaaattttt gagcacctta actatagatg gtgtaacccg gagtgaccaa 540
ggattgtaca cctgtgcagc atccagtggg ctgatgacca agaagaacag cacatttgtc 600
agggtccatg aaaaagacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 660
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 720
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 780
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 840
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 900
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 960
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1020
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 1080
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1140
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 1200
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1260
tacacgcaga agagcctctc cctgtctccg ggtaaaggtg gcggcggttc cggtggcggt 1320
ggctctggcg gcggtggttc ccaggtgcag ctggttgaat ctggcggagg actcgttaga 1380
cctggcggct ctctgagact gtcttgtgcc gcctctggct tctccattaa gtactatgtg 1440
atcggctggt tcagacaggc ccctggcaaa gagagagagg gcgtcagctg catctcttcc 1500
tctggcggat ctaccaacta cgccgactcc gtgaagggca gattcaccat ctccagagac 1560
aacgccaaga acaccgtgta cctgcagatg aactccctga agcctgagga caccgccgtg 1620
tactactgtg ccgctgattc tggcctgtcc gactacgcct gttgggctga tacaagaggc 1680
gtgcggagag gctacctgga agtttgggga cagggcaccc tggtcacagt gtcatct 1737
<210> 36
<211> 579
<212> PRT
<213> 人工序列(artifical sequence)
<400> 36
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
1 5 10 15
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
20 25 30
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
35 40 45
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
50 55 60
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
65 70 75 80
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
85 90 95
Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile
100 105 110
Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr
115 120 125
Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys
130 135 140
His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly
145 150 155 160
Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr
165 170 175
Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met
180 185 190
Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Asp Lys Thr
195 200 205
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
210 215 220
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
225 230 235 240
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
245 250 255
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
260 265 270
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
275 280 285
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
290 295 300
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
305 310 315 320
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
325 330 335
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
340 345 350
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
355 360 365
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
370 375 380
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
385 390 395 400
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
405 410 415
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
420 425 430
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
435 440 445
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly Ser
450 455 460
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Val Asp Tyr Tyr Val
465 470 475 480
Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ser
485 490 495
Cys Ile Ser Ser Ser Gly Trp Ile Thr Asn Tyr Ala Asp Ser Val Lys
500 505 510
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
515 520 525
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
530 535 540
Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg Gly
545 550 555 560
Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val Thr
565 570 575
Val Ser Ser
<210> 37
<211> 1737
<212> DNA
<213> 人工序列(artifical sequence)
<400> 37
agcgacaccg gtagaccttt cgtagagatg tacagtgaaa tccccgaaat tatacacatg 60
actgaaggaa gggagctcgt cattccctgc cgggttacgt cacctaacat cactgttact 120
ttaaaaaagt ttccacttga cactttgatc cctgatggaa aacgcataat ctgggacagt 180
agaaagggct tcatcatatc aaatgcaacg tacaaagaaa tagggcttct gacctgtgaa 240
gcaacagtca atgggcattt gtataagaca aactatctca cacatcgaca aaccaataca 300
atcatagatg tggttctgag tccgtctcat ggaattgaac tatctgttgg agaaaagctt 360
gtcttaaatt gtacagcaag aactgaacta aatgtgggga ttgacttcaa ctgggaatac 420
ccttcttcga agcatcagca taagaaactt gtaaaccgag acctaaaaac ccagtctggg 480
agtgagatga agaaattttt gagcacctta actatagatg gtgtaacccg gagtgaccaa 540
ggattgtaca cctgtgcagc atccagtggg ctgatgacca agaagaacag cacatttgtc 600
agggtccatg aaaaagacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 660
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 720
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 780
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 840
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 900
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 960
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1020
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 1080
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1140
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 1200
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1260
tacacgcaga agagcctctc cctgtctccg ggtaaaggtg gcggcggttc cggtggcggt 1320
ggctctggcg gcggtggttc ccaggtgcag ctggttgaat ctggcggagg actcgttaga 1380
cctggcggct ctctgagact gtcttgtgcc gcctctggct tctccgtgga ctactatgtg 1440
atcggctggt tcagacaggc ccctggcaaa gagagagagg gcgtcagctg catctcttcc 1500
tctggctgga ttaccaacta cgccgactcc gtgaagggca gattcaccat ctccagagac 1560
aacgccaaga acaccgtgta cctgcagatg aactccctga agcctgagga caccgccgtg 1620
tactactgtg ccgctgattc tggcctgtcc gactacgcct gttgggctga tacaagaggc 1680
gtgcggagag gctacctgga agtttgggga cagggcaccc tggtcacagt gtcatct 1737
<210> 38
<211> 579
<212> PRT
<213> 人工序列(artifical sequence)
<400> 38
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
1 5 10 15
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
20 25 30
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
35 40 45
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
50 55 60
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
65 70 75 80
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
85 90 95
Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile
100 105 110
Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr
115 120 125
Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys
130 135 140
His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly
145 150 155 160
Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr
165 170 175
Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met
180 185 190
Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Asp Lys Thr
195 200 205
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
210 215 220
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
225 230 235 240
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
245 250 255
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
260 265 270
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
275 280 285
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
290 295 300
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
305 310 315 320
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
325 330 335
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
340 345 350
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
355 360 365
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
370 375 380
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
385 390 395 400
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
405 410 415
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
420 425 430
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
435 440 445
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly Ser
450 455 460
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Ala Asp Tyr Tyr Val
465 470 475 480
Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ser
485 490 495
Cys Ile Ser Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
500 505 510
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
515 520 525
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
530 535 540
Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg Gly
545 550 555 560
Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val Thr
565 570 575
Val Ser Ser
<210> 39
<211> 1737
<212> DNA
<213> 人工序列(artifical sequence)
<400> 39
agcgacaccg gtagaccttt cgtagagatg tacagtgaaa tccccgaaat tatacacatg 60
actgaaggaa gggagctcgt cattccctgc cgggttacgt cacctaacat cactgttact 120
ttaaaaaagt ttccacttga cactttgatc cctgatggaa aacgcataat ctgggacagt 180
agaaagggct tcatcatatc aaatgcaacg tacaaagaaa tagggcttct gacctgtgaa 240
gcaacagtca atgggcattt gtataagaca aactatctca cacatcgaca aaccaataca 300
atcatagatg tggttctgag tccgtctcat ggaattgaac tatctgttgg agaaaagctt 360
gtcttaaatt gtacagcaag aactgaacta aatgtgggga ttgacttcaa ctgggaatac 420
ccttcttcga agcatcagca taagaaactt gtaaaccgag acctaaaaac ccagtctggg 480
agtgagatga agaaattttt gagcacctta actatagatg gtgtaacccg gagtgaccaa 540
ggattgtaca cctgtgcagc atccagtggg ctgatgacca agaagaacag cacatttgtc 600
agggtccatg aaaaagacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 660
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 720
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 780
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 840
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 900
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 960
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1020
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 1080
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1140
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 1200
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1260
tacacgcaga agagcctctc cctgtctccg ggtaaaggtg gcggcggttc cggtggcggt 1320
ggctctggcg gcggtggttc ccaggtgcag ctggttgaat ctggcggagg actcgttaga 1380
cctggcggct ctctgagact gtcttgtgcc gcctctggct tcaaggcgga ctactatgtg 1440
atcggctggt tcagacaggc ccctggcaaa gagagagagg gcgtcagctg catctcttcc 1500
tctggcggat ctaccaacta cgccgactcc gtgaagggca gattcaccat ctccagagac 1560
aacgccaaga acaccgtgta cctgcagatg aactccctga agcctgagga caccgccgtg 1620
tactactgtg ccgctgattc tggcctgtcc gactacgcct gttgggctga tacaagaggc 1680
gtgcggagag gctacctgga agtttgggga cagggcaccc tggtcacagt gtcatct 1737
<210> 40
<211> 579
<212> PRT
<213> 人工序列(artifical sequence)
<400> 40
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
1 5 10 15
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
20 25 30
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
35 40 45
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
50 55 60
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
65 70 75 80
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
85 90 95
Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile
100 105 110
Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr
115 120 125
Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys
130 135 140
His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly
145 150 155 160
Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr
165 170 175
Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met
180 185 190
Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Asp Lys Thr
195 200 205
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
210 215 220
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
225 230 235 240
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
245 250 255
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
260 265 270
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
275 280 285
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
290 295 300
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
305 310 315 320
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
325 330 335
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
340 345 350
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
355 360 365
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
370 375 380
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
385 390 395 400
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
405 410 415
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
420 425 430
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
435 440 445
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser
450 455 460
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Ile Lys Tyr Tyr Val
465 470 475 480
Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val Ser
485 490 495
Cys Ile Ser Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
500 505 510
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
515 520 525
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
530 535 540
Ala Asp Ser Gly Leu Ser Asp Tyr Ala Cys Trp Ala Asp Thr Arg Gly
545 550 555 560
Val Arg Arg Gly Tyr Leu Glu Val Trp Gly Gln Gly Thr Leu Val Thr
565 570 575
Val Ser Ser
<210> 41
<211> 1737
<212> DNA
<213> 人工序列(artifical sequence)
<400> 41
agcgacaccg gtagaccttt cgtagagatg tacagtgaaa tccccgaaat tatacacatg 60
actgaaggaa gggagctcgt cattccctgc cgggttacgt cacctaacat cactgttact 120
ttaaaaaagt ttccacttga cactttgatc cctgatggaa aacgcataat ctgggacagt 180
agaaagggct tcatcatatc aaatgcaacg tacaaagaaa tagggcttct gacctgtgaa 240
gcaacagtca atgggcattt gtataagaca aactatctca cacatcgaca aaccaataca 300
atcatagatg tggttctgag tccgtctcat ggaattgaac tatctgttgg agaaaagctt 360
gtcttaaatt gtacagcaag aactgaacta aatgtgggga ttgacttcaa ctgggaatac 420
ccttcttcga agcatcagca taagaaactt gtaaaccgag acctaaaaac ccagtctggg 480
agtgagatga agaaattttt gagcacctta actatagatg gtgtaacccg gagtgaccaa 540
ggattgtaca cctgtgcagc atccagtggg ctgatgacca agaagaacag cacatttgtc 600
agggtccatg aaaaagacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 660
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 720
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 780
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 840
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 900
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 960
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1020
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 1080
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1140
cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 1200
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1260
tacacgcaga agagcctctc cctgtctccg ggtaaaggtg gcggcggttc cggtggcggt 1320
ggctctggcg gcggtggttc ccaagtgcaa ctagtggaaa gtggtggtgg tctcgtgaag 1380
cccggcggat ctctgcggct gtcttgtgct gcttctggct tctccatcaa gtactacgtg 1440
atcggctggt ttagacaggc ccctggcaag ggcctggagg gcgtcagctg catctcctcc 1500
tctggcggct ctaccaacta cgctgattcc gtgaaaggca gattcaccat ctctcgggac 1560
aatgccaaga acaccctgta cctgcagatg aactccctga gagccgagga cacagccgtg 1620
tactactgcg ccgctgactc cggactgtcc gactacgcct gctgggccga taccagaggc 1680
gtgcggcgcg gatatctgga agtgtggggc cagggcaccc tggtgaccgt gtccagc 1737
<210> 42
<211> 11
<212> PRT
<213> 人工序列(artifical sequence)
<400> 42
Gly Phe Ser Leu Thr Asp Tyr Tyr Tyr Met Thr
1 5 10
<210> 43
<211> 16
<212> PRT
<213> 人工序列(artifical sequence)
<400> 43
Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala Lys Gly
1 5 10 15
<210> 44
<211> 11
<212> PRT
<213> 人工序列(artifical sequence)
<400> 44
Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile
1 5 10
<210> 45
<211> 11
<212> PRT
<213> 人工序列(artifical sequence)
<400> 45
Gln Ala Ser Glu Ile Ile His Ser Trp Leu Ala
1 5 10
<210> 46
<211> 7
<212> PRT
<213> 人工序列(artifical sequence)
<400> 46
Leu Ala Ser Thr Leu Ala Ser
1 5
<210> 47
<211> 12
<212> PRT
<213> 人工序列(artifical sequence)
<400> 47
Gln Asn Val Tyr Leu Ala Ser Thr Asn Gly Ala Asn
1 5 10
<210> 48
<211> 120
<212> PRT
<213> 人工序列(artifical sequence)
<400> 48
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr Ala Thr Trp Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp Ile Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 49
<211> 112
<212> PRT
<213> 人工序列(artifical sequence)
<400> 49
Met Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val
1 5 10 15
Gly Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Ile Ile His Ser
20 25 30
Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Val Tyr Leu Ala Ser
85 90 95
Thr Asn Gly Ala Asn Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 50
<211> 252
<212> PRT
<213> 人工序列(artifical sequence)
<400> 50
Met Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val
1 5 10 15
Gly Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Ile Ile His Ser
20 25 30
Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Val Tyr Leu Ala Ser
85 90 95
Thr Asn Gly Ala Asn Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser
145 150 155 160
Leu Thr Asp Tyr Tyr Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys
165 170 175
Gly Leu Glu Trp Val Gly Phe Ile Asp Pro Asp Asp Asp Pro Tyr Tyr
180 185 190
Ala Thr Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
195 200 205
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Ala Gly Gly Asp His Asn Ser Gly Trp Gly Leu Asp
225 230 235 240
Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 51
<211> 97
<212> PRT
<213> 人工序列(artifical sequence)
<400> 51
Pro Phe Val Ala Phe Gly Ser Gly Met Glu Ser Leu Val Glu Ala Thr
1 5 10 15
Val Gly Glu Arg Val Arg Ile Pro Ala Lys Tyr Leu Gly Tyr Pro Pro
20 25 30
Pro Glu Ile Lys Trp Tyr Lys Asn Gly Ile Pro Leu Glu Ser Asn His
35 40 45
Thr Ile Lys Ala Gly His Val Leu Thr Ile Met Glu Val Ser Glu Arg
50 55 60
Asp Thr Gly Asn Tyr Thr Val Ile Leu Thr Asn Pro Ile Ser Lys Glu
65 70 75 80
Lys Gln Ser His Val Val Ser Leu Val Val Tyr Val Pro Pro Gly Pro
85 90 95
Gly
<210> 52
<211> 227
<212> PRT
<213> 人工序列(artifical sequence)
<400> 52
Asp Lys Thr His Thr Cys Pro Leu Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Ala Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 53
<211> 526
<212> PRT
<213> 人工序列(artifical sequence)
<400> 53
Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His
1 5 10 15
Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro
20 25 30
Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro
35 40 45
Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser
50 55 60
Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val
65 70 75 80
Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn
85 90 95
Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser
100 105 110
Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn
115 120 125
Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His
130 135 140
Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met
145 150 155 160
Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp
165 170 175
Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys
180 185 190
Asn Ser Thr Phe Val Arg Val His Glu Lys Pro Phe Val Ala Phe Gly
195 200 205
Ser Gly Met Glu Ser Leu Val Glu Ala Thr Val Gly Glu Arg Val Arg
210 215 220
Ile Pro Ala Lys Tyr Leu Gly Tyr Pro Pro Pro Glu Ile Lys Trp Tyr
225 230 235 240
Lys Asn Gly Ile Pro Leu Glu Ser Asn His Thr Ile Lys Ala Gly His
245 250 255
Val Leu Thr Ile Met Glu Val Ser Glu Arg Asp Thr Gly Asn Tyr Thr
260 265 270
Val Ile Leu Thr Asn Pro Ile Ser Lys Glu Lys Gln Ser His Val Val
275 280 285
Ser Leu Val Val Tyr Val Pro Pro Gly Pro Gly Asp Lys Thr His Thr
290 295 300
Cys Pro Leu Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
305 310 315 320
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
325 330 335
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
340 345 350
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
355 360 365
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
370 375 380
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
385 390 395 400
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
405 410 415
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
420 425 430
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
435 440 445
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
450 455 460
Gln Pro Glu Asn Asn Tyr Lys Ala Thr Pro Pro Val Leu Asp Ser Asp
465 470 475 480
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
485 490 495
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
500 505 510
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
515 520 525
Claims (10)
1.一种双特异性结合分子,包含特异性结合人VEGF的抗原结合位点和特异性结合人PK的抗原结合位点;
优选地,所述特异性结合人VEGF的抗原结合位点包含VEGFR-1的胞外结构域2和VEGFR-2的胞外结构域3;更优选地,所述特异性结合人VEGF的抗原结合位点进一步包含VEGFR-2的胞外结构域4;更优选地,所述特异性结合人VEGF的抗原结合位点还包含免疫球蛋白Fc片段。
2.根据前述权利要求1所述的结合分子,其特征在于,所述特异性结合人VEGF的抗原结合位点包含VEGFR-1的胞外结构域2、VEGFR-2的胞外结构域3和免疫球蛋白Fc片段;
其中所述VEGFR-1的胞外结构域2包含SEQ ID NO:7所述的氨基酸序列;
所述VEGFR-2的胞外结构域3包含SEQ ID NO:8所述的氨基酸序列;
所述免疫球蛋白Fc片段包含SEQ ID NO:9所述的氨基酸序列;
优选地,所述特异性结合人VEGF的抗原结合位点包含SEQ ID NO:10所述的氨基酸序列。
3.根据前述任一项所述的结合分子,其特征在于,所述特异性结合人PK的抗原结合位点包含PK结合性免疫球蛋白单一可变域,并具有SEQ ID NO:1-3所述的CDR1-3区,或者SEQID NO:1、SEQ ID NO:4和SEQ ID NO:3所述的CDR1-3区;
优选地,所述PK结合性免疫球蛋白单一可变域为VHH域;
更优选地,所述PK结合性的VHH域包含SEQ ID NO:5、SEQ ID NO:12、SEQ ID NO:14、SEQID NO:16、SEQ ID NO:18和SEQ ID NO:20中任一所述的氨基酸序列;
最优选地;所述结合分子具有如SEQ ID NO:22、SEQ ID NO:24、SEQ ID NO:26、SEQ IDNO:28、SEQ ID NO:30、SEQ ID NO:32、SEQ ID NO:34、SEQ ID NO:36、SEQ ID NO:38和SEQID NO:40中任一所述的氨基酸序列。
4.根据前述权利要求所述的结合分子,其特征在于,所述结合分子为二价、三价或者四价结合分子,优选二价结合分子。
5.分离的核酸,其编码权利要求1~4任一项所述的双特异性结合分子。
6.包含权利要求6所述核酸的载体,优选地所述载体是表达载体。
7.包含权利要求5的核酸或权利要求6的载体的宿主细胞,优选地,所述宿主细胞是原核细胞或真核细胞。
8.一种药物组合物,其特征在于包含权利要求1-4中任一项所述的结合分子,和药学上可接受的赋形剂。
9.权利要求1-4中任一项所述的结合分子在制备用于预防或治疗血管疾病的药物中的用途。
10.根据权利要求9所述的用途,所述血管疾病为水肿、类风湿性关节炎、痛风、肠道疾病、口腔粘膜炎、神经性疼痛、炎性疼痛、椎管狭窄-退行性脊柱疾病、糖尿病、动脉或静脉血栓形成、主动脉瘤、骨关节炎、脉管炎、肺栓塞、中风、败血病、系统性红斑狼疮性肾炎和烧伤、眼部疾病;
优选地,所述水肿优选自遗传性血管性水肿、脑水肿或头部外伤;
优选地,所述眼部疾病优选自糖尿病性黄斑水肿,视网膜静脉阻塞,年龄相关性黄斑变性,继发于视网膜静脉阻塞的黄斑水肿,葡萄膜炎、眼内炎或息肉状脉络膜血管病变。
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